evidence table of systematic literature search...evidence table of systematic literature search...

027/018 – Glutarazidurie Typ I aktueller Stand: 06/2016

*Die Evidenztabelle wurde von der Leitliniengruppe gemeinsam erarbeitet und in englischer Sprache erstellt.

Evidence table of systematic literature search* according to SIGN Level

Listed are published data since January 1st, 2011.

For the time period from January 1st 1975 – December 31th 2010, please see the evidence table of systematic literature research generated for the

1st guideline revision in 2011 (page 36).

Level 2++, 1++, 1+, 1-. None

Level 2+. Evidence from well-conducted case-control or cohort studies with a low risk of confounding, bias, or chance and a moderate

probability that the relationship is causal.

First Author

Title Study Design

Patients (n) Clinical End points

Results / Conclusions Bias (according to

GRADE)

Confounding (according to

GRADE)

SIGN Level

Boy et al. (2015) Orphanet J Rare Dis; 10:163

A cross-sectional controlled developmental study of neuropsychological functions in patients with glutaric aciduria type I

Cross sectional study

30 patients diagnosed by newborn screening (n = 13), high-risk screening (n = 3) or targeted metabolic testing (n = 14) n=13 dystonic patients, n=17 asymptomatic patients

Dystonia was categorized using the Barry-Albright-Dystonia Scale (BADS) simple reaction time (SRT), continuous performance (CP), visual working memory (VWM), visual-motor coordination (Tracking) and visual search (VS).

BADS scores correlated with speed tests but not with tests measuring stability or higher cognitive functions Developmental functions of patients differed from controls for SRT and VS but not for VWM. Dystonic patients were slower in SRT and CP but reached their asymptote of performance similar to asymptomatic patients and controls in all tests. Asymptomatic patients

Effect of severe dystonia might be underestimated; False negative findings are possible due to unequal sizes of age groups

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2

did not differ from controls. Data across all age groups of patients and controls fitted well to a model of negative exponential development. Conclusion Dystonia results in motor speed impairment, but not in higher cognitive functions. Asymptomatic patients did not differ from controls. Developmental functions were similar in patients and controls. Performance in tests with higher cognitive demand might be preserved in GA-I, even in patients with striatal degeneration.

Boy et al. (2013) J Inherit Metab Dis: 36:525–533

Low lysine diet in glutaric aciduria type I – effect on anthropometric and biochemical follow-up parameters

Patients identified by newborn screening were followed prospectively during the first six years of life, prospective follow-up cohort study

33 (n=29 asymptomatic, n=4, dystonic) diagnosed via NBS

Dietary parameters: Lysine intake, energy intake, protein intake, Anthropometric parameters: wheight, length, head circumference; Biochemical parameters P

Diet: Lysine intake 101% (asym.) and 103% (dyst.); natural protein (109 vs 121%), AAS protein (108 vs 104%), energy (106 vs 110%), according to recommendations. Lysine intake increases after 6

th year

of life; L-carnitine supplementation was similar in both groups; Anthropometry: asymptomatic patients showed normal wheight gain and tendency for lower length development. Dystonic patients showed poor wheight and length gain. Biochemistry: no group difference, age effect for MC//Hb, age-dependent changes for calcium, CK and ASAT. SD scores for albumin,

Imprecision (low n in dystonic group)

2+

3

ferritin, phosphate and ALAT were normal; Plasma lysine in lower normal range in both groups and not differing, excretor status had no influence on plasma lysine carnitine status was normal in both groups Conclusion: Low lysine diet promotes normal anthropometric development in asymptomatic children up to age 6 year. Individualized recommendations for biochemical monitoring for asymptomatic patients.

Garbade et al. (2014) J Inherit Metab Dis: 37, 763-773.

Unravelling the complex MRI pattern in glutaric aciduria type I using statistical models-a cohort study in 180 patients.

Retrospective cohort study on MRI patterns using questionnaire-based survey

180 (n=130 symptomatic, n=50 asymptomatic or minor neurological signs)

Neuroradiological abnormalities, Movement disorder (MD), Morbidity score

Neonatal diagnosis was made by extended NBS (n=21), high-risk family screening (n=18), high-risk population screening (n=2), or due to macrocephaly (n=9). Mean chronical age 10.2 y. n=158 on low lysine diet and carnitine supplementation. MRI pattern and motor function: Patients with severe symptoms had more abnormalities in 5 regions: putamen, caudate, cortex, ventricles and external CSF spaces and more often demonstrated subdural hematoma or hygroma than patients without or with minor neurological symptoms. Abnormalities in globus pallidus were not clearly associated with a movement disorder. Putaminal changes and strongly dilated ventricles

Selection bias (many different centres)

no internal controls Indirectness (Übertragbarkeit)

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4

predicted movement disorder. Putamen, caudate and pallidal changes remained stable. White matter abnormalities increased with time. Conclusion: complex statistical methods are useful to detect MRI patterns and are helpful to elucidate the clinical relevance

Kölker et al. (2015a) J Inherit Metab Dis. 38:1155-6

The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation.

Prospective cohort study of OAD and UCD patient registered in EIMD database from 2011-2013.

n=150 with GA1. n=77 symptomatic, n=73 asymptomatic

Age at diagnosis, time to diagnosis after symptom onset; problems during pregnancy, postnatal problems, anthropometry, metabolic parameters, clinical parameters at presentation

Majority of UCD/OAD patients diagnosed clinically. Most asymptomatic patients in NBS group (v.a. GA1 and IVA). Diagnosis: Median age at diagnosis for GA1=270 days. Delay from symptoms to diagnosis in 63 LO GA1 patients 1day->1y. Clinical presentation: GA1 patients at birth more macrocephalic than other OAD. Anthropometry at birth normal. n=51 with encephalopathic crisis (none neonatal). Median age at first symptoms=300 days. 12/74 LO patients showed epilepsy as initial clinical presentation; dystonia without preceding EC in 39 % of LO patients high frequency of insidious- onset type dystonia. Conclusion: initial clinical symptoms are variable. Fetal disease manifestation in GA1. Neonatal crisis in GA1 is rare. Asymptomatic patients mostly in NBS group. Majority of symptomatic patients

Patients with severe phenotype might be missed due to lack of NBS programs

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5

presents with EC. Epilepsy is a common clinical presentation. High frequency of insidious-onset type dystonia.

Kölker et al. (2015b) J Inherit Metab Dis. 38: 1059-1074

The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype

Prospective multi-centre cohort study of OAD and UCD patient registered in EIMD database from 2011-2013.

n=150 with GA1. n=77 symptomatic, n=73 asymptomatic

Anthropometry; clinical parameters (neurological: movement disorder, urogenital, haematologic, endocrine, cardiac: heart insufficiency, QTc time, gastrointestinal), mortality

Anthropometry: GA1 often presented with macrocephaly. Patients with a movement disorder showed tendency to decreased SDS for body length and significantly decreased SDS for body weight Neurological signs more movement disorder in OAD patients (especially GA1). Decreased joint mobility due to dystonia in n=32. Arterial hypertension n=5. Decreased strength 28%. Abnormal gross motor development 40% (fine 46%). Movement disorder 46%. Seizures 7%. EEG abnormalities 34%. Urogenital: moderate increase of chronic renal failure with age, similar in high and low excretors. No association with movement disorder. Other: No increased rate of heart problems Conclusions: intrauterine disease manifestation macrocephaly at birth. Neurologic symptoms are common. Unexpected chronic renal failure in GA1 emphasizes importance of a systematic clinical and biochemical follow-up. No differences in HE and LE.

Patients with severe phenotype might be missed due to lack of NBS programs, Only descriptive, no evaluation of therapeutic interventions

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6

Disease might progress after age 6y.

Kölker et al. (2012) Mol Gen Metab 107, 72-80.

Complementary dietary treatment using lysine-free, arginine-fortified amino acid supplements in glutaric aciduria type I - a decade of experience.

Prospective two-armed multi-centre cohort study with comparison of two amino acid supplements (Milupa Metabolics vs Nutricia)

34 patients diagnosed by NBS from 2000-2011 (median age, 7.43 years; cumulative follow-up period, 221.6 patient years). Comparison to Strauss et al 2011 (n=12)

Dietary parameters: arginine intake, LYS/ARG Ratio (Plasma), biochemical, anthropometrical; neurological parameters (gross motor milestones, BADS)

All patients under guideline-recommend therapy. Milupa and SHS arginine contents vary in 1

st year only. SHS is

similar to GlutarAde Junior (Strauss et al 2011). Dietary and anthropometric parameters of patients similar to n=12 reported by Strauss et al. 2011. Group 1 (Milupa; n=8): dystonia 12.5%. Group 2 (Nutricia SHS; n=26): higher arginine intake and lower lysine-to-arginine ratio during 1

st year. Dystonia 8%.

Dietary intake in both groups: Daily arginine intake increased in both groups (137 mg/kg). Similar arginine intake in 2

nd and 3

rd year of

life. Dietary lysine-to arginine ratio was decreased (mean 0.7) compared to infants receiving human milk and other natural foods. Diet/Biochemistry: Plasma lysine-to-arginine ratio did not differ. Dietary arginine intake and plasma lysine-to-arginine ratio did not correlate. Dietary lysine intake and plasma lysine-to-arginine ratio did not correlate. Neurological outcome: No clinical differences between G1 and G2: low frequency of dystonia, similar gross motor development.

General effect of arginine supplementation on clinical outcome and endpoints is unknown

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7

Conclusions: Both arginine fortified AAS are effective and similar. Higher arginine intake in SHS group during 1

st year without clinical

effect. Plasma concentrations did not reveal discrepancy between groups 1 and 2 and did not correlate with dietary parameters. Guideline recommended therapy is benefitial (low rate of dystonia and normal gross motor development)

Strauss et al. (2011) Mol Gen Metab 104: 93-106.

Safety, efficacy and physiological actions of a lysine-free, arginine-rich formula to treat glutaryl-CoA dehydrogenase deficiency: Focus on cerebral amino acid influx.

Prospective cohort study

Amish Community, USA: n=12 (LYSx; 2006-2010) treated with low lysine diet, carnitine supplement and emergency treatment; n=8 from NBS, n=4 diagnosed neonatally by cord blood n=25 (PROx;1995-2005) treated with natural protein restriction and carnitine n=6 (1990-1994, start of NBS) n=17 (pre-1990, no NBS) n=52 controls for amino acid

Clinical parameters, genetic analysis, biochemical parameters, calculation of cerebral amino acid influx, anthropometry

LYSx patients: all diagnosed neonatally, all homozygous for GCDH mutations; normal anthropometric and neurological development after 28 aggregate patient-years of follow up. Biochemistry: No abnormalities detected at biochemical follow-up (Alb, Gluc, Hb, MCV, WBC, Zinc, VitD3, Selenium); During illness, plasma arginine decreased by 50%. Dietary intake 1

st year: 20% lower lysine

intake and two-fold higher arginine intake 50% lower plasma lysine, 3-fold lower plasma lysine/arginine concentration ratio, 42% lower cerebral lysine influx, 54% higher calculated cerebral arginine influx, 50% less 3-OH-glutarate excretion, and a 3-fold lower

Selection Bias (only Amish patients) Indirectness (population difference)

Cerebral transport and metabolism of LYS and ARG not known and difficult to calculate Endogenous arginine production not considered

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8

comparison hospitalization rate Conclusion: Best outcome in patients with early diagnosis (NBS), low lysine diet and emergency treatment (=guideline according); Low lysine diet with better outcome than natural protein restriction which alone is not a reliable way to control plasma lysine but, when combined with arginine fortification, a dietary lysine/arginine ratio of 0.5–0.9mg:mg can entail an approximate 50% decrease of brain lysine uptake; LYSx group with lower cerebral lysine influx and increased arginine influx; Lys-Arg competition exists at both cerebrovascular and gastrointestinal barriers, suggesting their co-administration is key to efficacy

Viau et al. (2012) Mol Gen Metab 106: 430-438.

Glutaric acidemia type 1: Outcomes before and after expanded newborn screening.

Cohort study 19 north american patients (n=10 diagnosed by NBS, n=9 diagnosed symptomatically) Treatment: low lysine diet (relaxed at age 6y), lysine-free AAM, carnitine and emergency treatment. (guideline-according)

Clinical parameters including disability score mutation analysis biochemical parameters anthropometry Neuroradiological abnormalities

NBS group: age range 4m-7y; start of treatment 7-28 days; LE: 4, HE: 6; n=2 enzyme activity low (rest N/A); all typical MRI findings; Disability score 2-5; n=2 insidious onset dystonia, n=1 EC; overall:90% normal feeding function, 90% normal gross motor function, 20% dystonia Selective screening: age range 6-30y; start of treatment 7.5-36m); n=2 no enzyme activity, n=1 LE, rest N/A; LE: 3; HE: 5; disability score 3-9; dystonia

NBS group might be too young to evaluate outcome (1 patient <1y) Outcome parameters (segregation dystonia from other symptoms)

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9

Routine monitoring only AS and carnitine, additional tests only if indicated. Disability score (Kyllermann et al. 2004): speech, motor function, cognition

in 7/9; MRI: 5/8 abnormal basal ganglia; Overall: 78% abnormal feeding function, 78% impaired gross motor function, 78% dystonia Genetics: 15 different mutations (n=6 novel) in 12 patients Diet: Intake for natural protein, protein from AAM and calories according to guideline Anthropometrics: Normal development (all patients) Biochemistry: C5DC correlated with urinary GA, 3-OH-GA; plasma lysine normal except n=2 (above), correlation of plasma lysine and urinary GA (not 3-OH-GA) Conclusion: Early diagnosis and treatment improve neurological outcome. No correlation between biochemical phenotype and neurological outcome. Correlation between plasma lysine and urinary GA concentrations.

10

Level 2-. Evidence from case-control or cohort studies with a high risk of confounding, bias, or chance and a significant risk that the relationship is not causal.

First Author

Title Study Design

Patients (n) Clinical End points

Results / Conclusions Bias Confounding SIGN Level

Couce et al. (2013) J Europ Paediatr Neurology 17: 383-389.

Glutaric aciduria type I: Outcome of patients with early- versus late-diagnosis.

Cohort study of patients diagnosed by NBS (urinary C5DC as 2

nd tier)

and selective screening over 12y mean follow-up time NBS patients = 56 months, unscreened patients = 97 months

9 (n=6 NGS, n=3 selective screening, 2/3 with acute encephalopathic crisis)

Clinical parameters, biochemical parameters anthropometric development, neurological assessment (scoring system by Kyllerman et al.), cognitive function (Psychomotor Development Index (PDI) or (IQ) using the Brunet Lezine Scale in infants, the McCarthy Scales of Psychomotor Skills (MSCA) in preschool children and Wechsler Intelligence Scale for Children Revised (WISC-R) in children older than 6 years; mutation analysis

NGS: 248.415 newborns screened, n=6 with GA1, n=1 false-negative (symptomatic patient); Prevalence 1:35,027. High blood C5DC concentration in 8/9 patients, high urinary C5DC in all patients. Genetics: 8 different mutations were identified, p.R227P the most common, 4 novel. No genotype-phenotype correlation Treatment: NGS patients started on low lysine diet, carnitine supplementation and Riboflavin until age 6y and less restricted after 6 y; emergency treatment during infect episodes; Macrocephalic patients (4/6) needed high energy intake in 1

st

year, 2/4 needed parenteral feeding. NGS patients still remain asymptomatic and have normal cognitive function. Symptomatic patients: n=1 false negative NGS. Treatment efficacy was poor in unscreened patients, two of them showing a severe spastic tetraparesis. PDI/IQ < 60 in 2/3. n=1 patient improved. Monitoring: Plasma levels of

Imprecision (low n) 2-

11

lysine normal mostly plasma carnitine elevated, C5DC elevated in all, GA/3-OH-GA elevated in 4/6 and did not show any correlation with the clinical course. Conclusion: early diagnosis and treatment strategies are essential. Urinary C5DC is a good biomarker. Dietary restriction after 6 years necessary. Riboflavine without effect. High and low excretors with similar clinical course. No genotype/phenotype correlation

Georgiou et al. (2014) Clin Biochem 47: 1300-1305.

Molecular analysis of cypriot patients with glutaric aciduria type I: Identification of two novel mutations.

Cross-sectional study

10 (symptomatic)

Genetic analysis, enzyme activity, neuroradiological abnormalities

All patients clinically diagnosed at 4.5m-16y. Mutation detection rate 100%. 5 missense mutations identified: n=2 novel, and n=3 previously described; Enzyme activity decreased in 3/10 (rest not determined). No genotype-phenotype correlation. Conclusion: Two novel mutations, account for the majority of disease alleles (76.5%) in Cypriot patients. GA1 should be implemented in NBS.

Indirectness (population difference) (Übertragbarkeit) Imprecision (low n)

2-

Gokmen-Ozel et al. (2012) J Hum Nutr Diet 25: 514-519.

Dietary practices in glutaric aciduria type 1 over 16 years.

retrospective case control study; assessment of dietary treatment in patients over 16y period in UK without NBS

20 (age range 2.2-24 y); n=9 without EC, n=11 with EC

Dietary treatment, nutritional outcome neurological outcome, anthropometry, biochemical markers

9 patients without EC: 3/9 high risk screening, 6/9 symptomatic at diagnosis: [seizures (n=1), hypotonia (n=1), macrocephaly (n=2), hypertonia (n=1), subdural haematoma (n=1), unsteady gait (n=1), delayed speech (n=1), developmental delay (n=3) and learning difficulties (n=2)]. Median age at diagnosis=1.1y; 6/9 diagnosed <2y; 3/9 > 3 y. Treatment varied according to

Selection bias, performance bias, detection bias (retrospective study); Indirectness

Treatment was modified during obervation (AAM supplement) no assessment of low lysine diet (low protein only) No clear information how the neurological

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age of diagnosis: 4/6 diagnosed <2y: protein restriction (median 1.3g/kg/day), carnitine and lysine-free AAM (medium 1.6 g/kg/d), emergency treatment (not guideline-according). Rest of patients (n=5): protein restriction (median 1.5g/kg/d), carnitine. Clinical worsening in n=2 (n=1 with vanishing white matter disease and AAM+protein restriction died, n=1 with protein restriction only). Rest remained clinically well. 11 patients with EC: median age at EC 10m. All with severe movement disorder. n=1 improved under low protein diet (currently age 15y). n=4 died, n=6 severe disablitiy. 7/9 had tube feeding. n=7 with low protein diet and carnitine. Anthropometrics: median weight was higher in subjects on a low protein diet with AAM than in subjects on low protein diet only (not statistically significant) Biochemistry: Patients with AAM had higher concentrations of Vit B12, Alb, Ca, Hb, plasma AA than patients on low protein diet only Conclusion: Best outcome in patients with early diagnosis without EC on low protein diet, AAM and emergency treatment; NBS for GA1 should be introduced in UK. Use of AAM associated with better biochemical and hematological status. Low protein diet can be effective >6y.

outcome was assessed (standardized protocols?)

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Harting et al. (2015) J Inherit Metab 38: 829-838.

(1)H-MRS in glutaric aciduria type 1: Impact of biochemical phenotype and age on the cerebral accumulation of neurotoxic metabolites.

Prospective cohort study, analysis of metabolic patterns using 1H magnetic resonance spectroscopy (1H-MRS) with focus on detecting GA/3-OH-GA and compared with control spectra

12 (age range 7m-22y) patients and n=17 controls (age range 9m-17y)

Intracerebral concentrations of specific metabolites; neuroradiological abnormalities

All patients treated according to guidelines. All patients: GA elevated in white matter (not basal ganglia). In younger patients none of the metabolites differed between controls, low, and high excreting patients. n=3 Low excretors: mildly, elevated GA and mildly subnormal N-acetylaspartate (tNAA). LE not significantly different from controls in metabolites and white matter changes. n=9 high excretors: significantly increased GA. 3-OH-GA was highest and significantly increased in older HE with white matter changes. tNAA was mildly subnormal in younger and decreased in older HE. tCr reduced in HE with white matter changes. <3y: myelination delayed >3y: myelination complete, White matter changes in 5/7 Conclusions: GA and 3-OH-GA are detectable by in vivo 1HMRS, which might finally allow biochemical follow-up monitoring, HE phenotype might be a risk factor for cerebral GA accumulation, white matter changes and neuroaxonal impairment (tNAA decrease)

Imprecision (only 3 LE) High variablility of measurement values

2-

Jamiolkowski et al. (2016) J Inherit Metab Dis 39:231–241

Behavioural and emotional problems, intellectual impairment

Cohort/case control

n=152 with organic aciduria (OAD), n=52 with urea cycle defects (UCD)

Behavioural problems, emotional problems, mental disabality (IQ score)

Behavioural/emotional problems are increased in OADs or UCDs patients. Mental disability (IQ ≤70) was found in 31 % of OAD. Behavioural/emotional problems

Global assessment, no independent GA1 analysis

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and health-related quality of life in patients with organic acidurias and urea cycle disorders

were significantly associated with intellectual functioning Quality of life was decreased in the physical domain, but in the normal range (possibly compensated by coping strategies of their families.

Koeth et al. (2013) Nat Med 19:576-85

Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis.

microbiota-dependent metabolism of L-carnitine to produce TMAO in both rodents and humans (omnivores and vegans)

Prospective cohort study

Biochemical parameters (TMAO, carnitine) Cardiac events

L-carnitine produces trimethylamine-N-oxide (TMAO) and accelerates atherosclerosis in mice. Plasma L-carnitine levels in subjects undergoing cardiac evaluation (n = 2,595) predicted increased risks for both prevalent cardiovascular disease (CVD) and incident major adverse cardiac events (myocardial infarction, stroke or death), but only among subjects with high TMAO levels. Chronic dietary L-carnitine supplementation in mice altered cecal microbial composition, markedly enhanced synthesis of TMA and TMAO, and increased atherosclerosis

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Mohammad et al. (2015) Pediatric radiology 45: 1696-1705.

Glutaric aciduria type 1: Neuroimaging features with clinical correlation.

Retrospective case control study; MRI assessment by 2 radiologists.

49 patients in Egypt (n=20 excluded) 29 included

Neuroradiological abnormalities, clinical parameters, morbidity score

Mean age at MRI 16.9m. n=16 with EC; n=3 were asymptomatic; n=10 had insidious onset type with developmental delay with/without dystonia. Total n=19 had dystonia. MRI: widening of sylvian fissures and subarachnoidal space widening in 100%; subdural collection in 34%; ventricular dilation: 45%; Gray matter abnormalities: n=26; globus pallidus mostly abnormal (93%); Putamen affected in 73% and caudate in 60% of dystonic patients Central tegmental tract

Selection bias n=20 patients excluded due to low quality MRI Indirectness (population differences)

Study population: diagnosis mode not classified Treatment modalities not provided No further differentiation of gray matter abnormalities correlated to morbidity No clear description

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was abnormal in n=21. White matter abnormalities in 11/14 children (79%) including one asymptomatic child. Clinical correlation: correlation between gray matter score and morbidity score, not for white matter. Almost all dystonic patients had basal ganglia abnormalities. Conclusion: Morbidity is related to abnormality of gray matter

of subgroups dystonic-non-dystonic patients (n of non dystonic patients with basal ganglia abnormalties only in discussion)

Moore et al. (2012) J Inherit Metab 35: 431-435.

An improved LC-MS/MS method for the detection of classic and low excretor glutaric acidemia type 1.

Evaluation of new diagnostic LC-MS/MS method: fragment (m/z 115) is unique to C5DC, and (2) underivatized C10-OH has a unique precursor mass (m/z 332) that can be used to distinguish between the two; “classic” MS/MS method uses m/z 388/85; retrospective case control study

10 (n=7 HE; n=3 LE) with confirmed GA1 n=21 with mildly elevated C5DC (“false-positive”; GA1 initially excluded) n=29 controls

Biochemical parameters (acylcarnitine concentrations)

LC-MS/MS method that discriminates C5DC from C10-OH by the use of precursor-product ion pairs specific for butylated C5DC (m/z 388-115) and underivatized C10-OH (m/z 332-85). Excellent precision and accuracy were also observed. By using the m/z 388-115 ion pair, all cases of GA1, including the low excretor variant, were distinguished from controls. Patients with ambiguous elevations of C5DC or C10-OH demonstrated clearly elevated levels of C10-OH (m/z 332-85) but normal C5DC (m/z 388-115), confirming that the apparent elevation of C5DC is due to interference by C10-OH. n=3 of false-positive confirmed with FAOD (n=1 MCAD, n=2 LCHAD) Conclusion: the method results in excellent detection of GA1, including low-excretor variant.

Imprecision (low n of LE)

2-

Mushimoto et al. (2011) Mol Gen Metab 102: 343-348.

Clinical and molecular investigation of 19 japanese cases of

Case control study

19 patients in Japan; n=15 symptomatic, n=3 newborn screening

Genetic analysis enzyme activity biochemical parameters

Therapy: dietary restriction, L-carnitine, emergency treatment Normal: n=3 detected by NBS; n=1 high risk at 2y, n=1 selective

No detailed data on dietary treatment provided

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glutaric acidemia type 1.

pilot study, n=1 high risk screening; 3 groups based on disability score (motor function, cognition, speech); normal development: n=5, mild impairment: n=3 Severe impairment: n=11

clinical parameters: disability score (motor function, cognitive function, speech); macrocephaly, age at onset age at diagnosis

screening (macrocephaly); normal outcome until 5-7y; 3/5 mild changes by neuroimaging Mild: mean age at onset 2.3m; age at diagnosis 4.7m; frontotemporal atrophy and striatum signal abnormalities in all. Severe: mean age at onset 5.7m; age at diagnosis 11.6m; n=3 died (EC), rest diagnosed after neurologic symptoms; n=8 with preceding infection; atrophy and striatum signal abnormalities in all Macrocephaly in all patients. Genetics: 19 mutations in 26 alleles and 8 were novel. No genotype-phenotype correlation. Conclusion: Genetic variability in japan; best outcome associated with NBS and early treatment; Patients with mild impairment diagnosed and treated earlier than severely impaired cases.

Imprecision (low n); Indirectness (population difference)

Pfeil et al. (2013) Orphanet J rare Dis 8: 167.

Newborn screening by tandem mass spectrometry for glutaric aciduria type 1: A cost-effectiveness analysis.

Hypothetic cohort study assess of cost-effectiveness of NBS for GAI compared to a scenario where GA-I is not included in NBS.

Markov model to evaluate clinical outcomes for hypothetical cohort of 100.000 newborns from birth to ages 20 and 70y DALYs: Disability Adjusted Life Years =measurement of overall disease burden, combining expected years of life lost

Cost-effectiveness Hypothetical model: No NBS: diagnosis based on high-risk screening of macrocephaly in 15%, while the other 85% will be diagnosed after clinical presentation (derived from n=279; Kölker et al. 2006) Among these, 23 diagnosed by NBS while of the remaining 256 n=24 diagnosed by high-risk screening, 14 by macrocephaly and 218 individuals were detected after clinical presentation. NBS: 11.5% MD Effectiveness:

No evidence on long-term clinical course of GA1 existing; uncertainty

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with years lived with disability

20 year time horizon: GA-I screening averts approximately 3.7 DALYs and about one life year is gained per 100,000 neonates screened initially. NBS saves a total of around 30,682 Euro per 100,000 screened neonates over 20 year time horizon. 70 years: 4.1 life years and 6.0 DALYs. Conclusion: MS/MS NBS for GA-I is a highly cost-effective

Radha Rama Devi et al. (2016) Brain Dev: 38: 54-60.

Spectrum of mutations in glutaryl-CoA dehydrogenase gene in glutaric aciduria type I - study from south india.


12 symptomatic patients in India, biochemically suggestive for GA1

clinical, neurological, radiological and biochemical evaluation

n=12 consanguineous parents; n=12 symptomatic patients; diagnosis 15d-24m); n=8 severe, n=3 mild phenotype; 1 patient diagnosed neonatally normal phenotype; 8/12 insidious onset type (5 severe, 3 mild). Genetics: 11 mutations; n=9 homozygous, 1 heterozygous and 2 synonymous; 4 novel mutations, 7 reported MRI: n=12 had affected basal ganglia Mild phenotype observed in heterozygous or benign synonymous SNP patients. Multiple sequence alignment (MSA) of GCDH revealed that observed novel mutations are not tolerated by protein structure and function. Conclusion: heterogeneity in GCDH gene mutations among South Indian population. No genotype phenotype correlation. Early treatment associated with best outcome.

Performance bias (only symptomatic patients), Detection bias (no clear endpoints)

Insidious onset number not clear no internal controls imprecision (low n) Indirectness (population difference) Low quality study

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Wang et al. (2014) Brain & development

Clinical and mutational spectra of 23

Case control study

23 Treatment: protein-

Clinical parameters, genetic analysis, biochemical

n=1 diagnosed via NBS, n=22 clinically (range 5m-51y) or high risk screening

Only symptomatic patients (no

Indirectness (population difference)

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36: 813-822. chinese patients with glutaric aciduria type 1.

restriction; riboflavin, carnitine; baclofen, aminobutyric acid Follow up range 8m-10y

parameters, neuroradiologic abnormalities

symptomatic: n=20 (n=17 onset <5y, n=3 onset >5y); n=11 with trigger events; dystonia 16/20; developmental delay 18/20, Seizures 6/20, n=1 died; early onset: late onset: symptoms at 8,9,51y including cerebral infarction asymptomatic: n=3 Biochemics: 17/20 carnitine depletion at diagnosis Genetics: 29 mutations in GCDH were identified (n=11 novel) Neuroradiology: 19/20 abnormal; n=6 leukencephalopathy Conclusion: genetic profiles of Chinese patients are different from those of other populations; no effect of treatment started after symptom onset (except n=1)

internal controls risk for bias)

Imprecision (small n)

Yang et al. (2011) Med Sci Monit 17: PH55-59.

Diagnosis, treatment and outcome of glutaric aciduria type I in zhejiang province, china.

cohort study 129,415 newborns screened 2008-2010 in Zhejiang; 9,640 high risk screenings (neurologic symptoms) Treatment (guideline-orientated): Lys-restricted diet, natural protein 0.5-1.5g/kg/d, lysine-free AAM 2-3g/kg/d; Carnitine, riboflavin; emergency treatment

Clinical parameters, neuropsychological function (Bayley-I, MDI, PDI); neuroradiological parameters

n=2 diagnosed by high risk screening (symptomatic); n=3 via NBS NBS group: normal development: n=2; n=1 mental retardation (refuse of treatment) Symptomatic group: mildly impaired cognitive function n=1, significant delay n=1 Conclusions: poor outcome in symptomatic patients

Risk for Bias Imprecision (low n) No internal controls (low n of NBS patients) Indirectness (population difference)

2-

Zaki et al. (2014) Egypt J

Demographic and clinical features of


26 (all diagnosed clinically 2010-

Age at onset, Clinical parameters,

9 families with multiple affected siblings (n=3 included, n=6

No control group

2-

19

Med Hum Gen 15: 187–192.

glutaric acidemia type 1; a high frequency among isolates in Upper Egypt.

2012) biochemical parameters, social status

deceased); n=14 families consanguineous (mainly muslim), mean age at onset of symptoms 5.8m, mean delay to diagnosis 11.7m; high frequency of Christian families (43%, no increased consanguinity) symptoms at diagnosis: 85% macrocephaly, 69% dystonia, convulsions 50%, acute febrile illness in 68% Conclusions: NBS should be implemented in Egypt

Indirectness (population difference) No data on genetics and treatment No details on biochemistry

20

Level 3. Non-analytical studies, e.g. case reports, case series

First Author

Title Study Design

Patients (n)

Clinical End points


Afroze & Yunus (2014) J Pakist Med Assoc 64: 593-595.

Glutaric aciduria type 1 — importance of early diagnosis and treatment

Case Report

2 Dystonia

Two siblings; P1: 12 m old with loss of milestones from age 6 months and severe dystonia, MRI showed typical GA1-pattern; P2: brother of P1, high risk screening led to GA1-diagnosis; asymptomatic under guideline-according therapy (at present 3.6y old) Conclusion: Timely diagnosis before the onset of neurological impairment and the use of maintenance and emergency therapy can effectively prevent an encephalopathic crisis. Value of treatment after the onset of neurological damage is unclear

No clear information how the neurologically affected child has been treated (low protein diet, carnitine supplementation).

3

Air et al. (2011) J Neurosurg Pediatr 8: 566-574.

Deep brain stimulation in children: experience and technical pearls

Prospective single center study for patients receiving deep brain stimulation

31 patients, n=1 with GA1

Neurological parameters before and 12 months after surgery using the BFMDRS and BADS score J

Ad1. Deep brain stimulation results in modest results for children with secondary dystonia unlike patients with primary dystonia. Ad2. Patient with GA-I experienced reduced dystonia and improved functionality in his left arm following unilateral right deep brain stimulation (DBS) placement. The patient subsequently underwent left DBS placement for progressive dystonia of the right arm. Ad3. Lack of sensitive outcome parameters for pediatric

Detection bias (only one measurement)

Ad1. Onset of dystonia-onset and time between dystonia-onset and operation are unknown (age of operation for the GA-I patient: 16.8 years). Ad2. Further disease course is not reported. Standardized evaluation parameters do not necessarily correlate with subjective

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patients suffering from secondary dystonia, reflecting improvement of quality of life. Ad4. Risks of DBS is not sufficiently studied (infections, etc.) Conclusion: Outcome in patients with secondary dystonia were variable and much less marked than in those with primary dystonia.

improvements of the patients (quality of life)

Badve et al. (2015) NZMJ 128: 61-64.

Rare presentation of a treatable disorder: glutaric aciduria type 1

Case report 1 Mood Migraine episodes Genetical analysis

32-year-old female patient with migraine, bipolar disorder and bilateral pyramidal tract signs; MRI: bilateral symmetric white matter signal T2-abnormality and cerebral atrophy, dilatation of Sylvian fissures secondary to fronto-temporal atrophy, Psychologic testing: frontal lobe dysfunction, biochemical GA1 pattern (high excretor); Genetic testing revealed compound heterozygoty (p.Asn215fs, c.636-10_642dup mutation in exon 8 and the p.Glu365Lys, c.1093G>A mutation) in exon 11; start of L-carnitine supplementation. On follow-up 3 months later improved mood with reduced mood swings and migraine episodes. Conclusion: GAI should be included in the differential diagnosis of diffuse white matter disease in adults

3

Baradaran et al. (2014) Arch Iran Med. 17: 629 – 632

Molecular Determination of Glutaric Aciduria Type I in Individuals from Southwest Iran

Case series GCDH gene amplification and sequencing in iranian GA1 patients

18 Mutation analysis

n=10 homozygous/compound heterozygous for E181Q, n=3 for R402Q and n=1 c.h. for S255L, n=4 with normal results.

Indirectness (Population differences)

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Bross et al. (2012) J Inherit Metab Dis 35:787–796

Heterozygosity for an in-frame deletion causes glutaryl-CoA dehydrogenase deficiency in a patient detected by newborn screening: investigation of the effect of the mutant allele

Case-report 1 Mutation analysis, enzyme activity

NBS C5DC 0.28 µmol/L Biochemistry: low excretor phenotype (GA 43 µmol/mol Crea, 3OHGA 19.2 µmol/mol crea) DNA sequencing: heterozygous mutation (c.553_570del18) resulting in deletion of six amino acids (p.Gly185_Ser190del) in one allele. Enzyme activity in leukocytes showed 12% activity. Recombinant expression of mutant variant in E. coli showed that the GCDH (p.Gly185_Ser190del) protein displayed severely decreased assembly into tetramers and enzyme activity. Dominant negative effect of mutant protein in prokaryotic expression system was demonstrated. GCDH activities in father and sister (clinically asymptomatic) with the same genotype were similar to the proband. Patient asymptomatic at age 5 y. Conclusion: heterozygosity for this mutation leads to dominant negative effect resulting in a GCDH enzyme activity < 50%. First report with abnormal metabolites in a GCDH heterozygote

Detection bias

no intern controls Imprecision (low n)

3

Brown et al. (2015) JIMD reports 18: 125-134.

Neurodevelopmental Profiles of Children with Glutaric Aciduria Type I Diagnosed by Newborn Screening: A Follow-Up Case Series

Non-analytic case series with longitudinal design Follow-up case series of patients 3-6y detected by newborn

6 Fine motor skills, IQ scores, executive functioning (attention, memory, language), behavior

Fine motor skills was below average in all patients, gross motor skills were normal in n=5, speech affected in n=4 but improved with therapy, IQ scores remained stable in n=5, executive functioning was

Selection bias Only two time points of investigation (Initially: 3 – 6 years

Only male patients investigated No information if these patients, diagnosed by NBS, were asymptomatic

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screening using a neuropsychological test battery (MABC-2, CELF-4, WASI, WPSSI-III, NEPSY II, BRIEF) patients were 6-12 y at follow-up assessment (2-)

normal/high in n=4, verbal memory regression in n=2, visual memory normal in all, n=2 had behavioral problems Conclusion: GA-I affects fine motor skills and speech, but not intellectual functions. GA-I patients should be referred for assessment and appropriate early intervention where required.

Follow-up: 6 – 12 years)

or symptomatic before or became symptomatic during the observation interval No information on early treatment one patient with low SES, history of neglect and foster care, one patient with family history of autism (environmental deprivation) imprecision (low n) no internal controls

Carman et al. (2012) J Paediatr Child Health 48:712

Glutaric aciduria type 1 presenting as subdural haematoma

Case report 1 Milestones, Neuroradiological abnormalities

17m old Turkish girl with minor head trauma and seizure, CT scan revealed SDH that was operated. Loss of milestones at age 24m, MRI showed temporal hypoplasia, selective screening led to GA1 diagnosis (20-fold increase of GA), begin of low lysine therapy and L-carnitine supplementation

No follow-up details provided

3

Crombez et al. (2008) Mol Gen Met 94:132–134.

Maternal glutaric acidemia, type I identified by newborn screening.

Case report 2 Biochemical parameters, genetic testing

In 2 newborns low carnitine levels were found, mothers had low plasma carnitine. In M1, fibroblast studies showed no signs for carnitine transporter defect, selective screening when child was 6m old showed maternal GA1 HE profile. Symptoms: intermittent fatigue. Genetics: compound-heterozygous (Chain

No enzyme activity tested

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terminating/C228F). M2 had direct selective screening revealed GA1 high excretor type. Symptoms: intermittent fatigue. Genetics: homozygous mutation in exon 6 (E181G/E181G). Plasma C5DC was normal in both mothers. Conclusion: abnormal newborn screening can reveal maternal affection as in PKU

Doraiswamy et al. (2015) Int J Epilepsy 2:44-48.

Batwing appearance - A neuroradiologic clue to glutaric aciduria type 1.

Case report 1 Neurological parameters

16m old girl with acute encephalopathic crisis at 7m during viral illness with dystonic spasms, tonic seizures and loss of milestones. CT showed wide sylvian fissures and temporal lobe atrophy (“bat wing sign”); MRI: bilateral basal ganglia hyperdensity; elevated C5DC, GA and 3OHGA; begin of low lysine diet, carnitine, Riboflavine and antiepileptics (Lorazepam, Phenobarbital).

No follow-up 3

Estrella et al. (2014) J Inherit Metab Dis 37:881-7. see Wilcken et al. 2003

Expanded newborn screening in New South Wales: missed cases.

Retrospective study of missed patients in South Wales, Australia

1/15 with GA1

Biochemical metabolites genetic analysis

15 patients missed by NBS (0.24%). n=1 GA1 patient diagnosed at age 10m at check up with developmental delay, hypotonia. NBS: Day 4 C5DC: 1.2 μmol/L (≥0.8); Day 15 repeat sample : 0.6 μmol/L. Biochemical low excretor. Compound heterozygote R227P (exon 7) c. 1244-2A>C

3

Fradiakis et al. (2015) JIMD reports 18: 85-92.

Rare late-onset presentation of glutaric aciduria type I in a 16-year-old woman with a novel GCDH mutation

Case report 1 Clinical signs, genetic testing, neuroradiologic abnormalities

16-year-old Greek female with syncope after exercise with mild developmental delay, learning difficulties and macrocephaly. Exam: bilateral foot cloni. MRI: periventricular white matter signal changes and typical GA1-

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abnormalities. Biochemical HE and genetically compound heterozygote for a novel mutation (IVS10-2A>G) affecting splicing at GCDH and a common missense mutation c. 1240C>T; p.Arg402Trp, R402W. Low protein diet and carnitine supplementation were started. Clinically stable at 1 y follow-up. novel mutation is the nucleotide position of a common mutation found almost exclusively in patients of Chinese/Taiwanese origin (IVS10-2A>C). Conclusion: importance of including GA-I in the differential diagnosis of leukoencephalopathy discovered in adolescence

Garcia et al. (2008) Eur J Pediatr 167:569–573

Outcome of three cases of untreated maternal glutaric aciduria type I

Case series 3 (2 mothers)

Biochemical parameters, clinical parameters, cognitive function

P1: hyocarnitinemia in NGS (no GA1 screening), start of carnitine supplementation in child; at 4m GA1-typical MRI abnormalities, GA1 diagnosis in 24y old mother; has moderate cognitive deficit and typical MRI P2 (mother of P1): already diagnosed, not treated before and during delivery P3 boy born to a 21y old GA1 patient (diagnosed age 8y), no treatment (but diet??), baby: C5DC increased, low free carnitine

No metabolic details on P1 Why was mother investigated? No information if carnitine transporter deficiency has been ruled out? No information regarding peripartal management in P3 No diet informations in P3 but in discussion stated to be “untreated”

3

Gramer et al. (2014) J Inherit Metab Dis 37: 189-95.

Living with an inborn error of metabolism detected by newborn screening-parents' perspectives on child development and

Non-analytic Parents of 187 patients with metabolic disorders detected by

Parents rated child development, perceived burdens on child and family, and future expectations on a

In 26.2% of patients, parents perceived delays in global development. Mild burden posed on the family (child) by the metabolic disorder was stated by 56.1% of parents,

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impact on family life. newborn screening

questionnaire with standardized answers

severe burden by 19.3%. Disorders rated as potentially very burdensome by experts were not rated accordingly by parents, demonstrating different perspectives of professionals and parents Conclusion: living with a metabolic disorder may cause considerable stress on patients and families. Different perspectives of professionals and parents.

Gupta et al. (2015) JIMD reports 21: 45-55.

Glutaric acidemia type 1-clinico-molecular profile and novel mutations in GCDH gene in indian patients.

Case-series 17 symptomatic patients in India

Clinical parameters, Developmental Assessment Scale for Indian Infants (DASII) for 0–30 months, Developmental Profile 3 (DP 3) for 0–12 years, Malin’s Intelligence Scale for Indian Children (MISIC) for 6–15 years, 3moleculargenetic analysis, neuroradiological abnormalities

Median age at diagnosis 6m., 12/17 had febrile illness. Development: n=6 dystonia+regression, n=2 seizures, n=1 dystonia; The rest (n=8) had developmental delay with or without regression with associated extrapyramidal symptoms in all except one. n=13 had developmental dysfunction in physical / adaptive domain; n=3 mild developmental delay, n=5 severe to profound delay. Clinical: Macrocephaly (12/17), dystonia (11/17), choreoathetosis (1/17) and seizures (9/17). n=2 died. MRI: Both striatal and extrastriatal abnormalities in all patients. Treatment: indigenous lysine- and tryptophan-restricted diet (vegetarian Indian diet) and carnitine supplementation (50–100 mg/kg/day); lysine intake 90-120 mg/kg/d, total protein 1-2g/kg/d. Riboflavin 100-300

No emergency treatment evaluated (only home emergency treatment), no AAM supplements Indirectness (population difference) (Übertragbarkeit) Study limitation (no internal controls, only 1 group studied)

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mg/d. No AAM supplements. Genetics: 15 mutations, 7 novel and 8 reported mutations. Genotype-biochemistry correlation was found, but no genotype-phenotype correlation Conclusion: GA1 should be implemented in NBS in India. No genotype-phenotype correlation. p.Arg402Trp mutation is common mutation in Muslim families

Herskovitz et al. (2013) Neurology 81: 849-850.

Subependymal mass lesions and peripheral polyneuropathy in adult-onset glutaric aciduria type I.

Case report 1 Neurological signs, cognitive function, nerve conduction function, biochemical parameters

56y old Iraqi-Jewish with 30y history of feet pain, weakness in legs, speech disturbance and incontinence; Exam: Mini-Mental-State 25/30, impaired cognitive function (executive function, working memory, learning), bilateral weakness in legs, pes cavus Electrophysiology: axonal polyneuropathy; MRI: communication hydrocephalus, frontotemporal atrophy, bilateral arachnoidal cysts, subependymal cauliflower-like mass lesions, biochemical GA1 pattern, GCDH mutation analysis: homozygous Gly101Arg mutation. Start of carnitine supplementation. Follow up after 3y: cognitive decline, otherwise stable. Conclusion: 2

nd report of mass

lesions in GA1

3

Jamuar et al. (2012) Mol Genet Metab 106: 488-490.

Rhabdomyolysis, acute renal failure, and cardiac arrest secondary to status dystonicus in a child

Case report 1 Genetic analysis, neurologic symptoms, biochemical parameters,

8y old GA 1 patient diagnosed at 4m age after EC. Mutation analysis c.344G>A; p.C115Y and c.1204C>T; p.R402W on low protein diet, carnitine

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with glutaric aciduria type I.

neuroradiologic abnormalities

supplement 50 mg/kg/d, AAM supplement, riboflavin 200 mg/day. At age 4y tube placement (oropharyngeal dysphagia). At age 8.5y acute decompensation with fever, pneumonia, acute kidney failure, hepatopathy, status dystonicus, CP hypotension/hypoxia cardiopulmonary arrest; 10 min resuscitation; Echo: LV dysfunction. Rhabdomyolysis (CK, Myoglobin); hemodialysis 15d. MRI day 5 gyral swelling and restricted diffusion within cortex and corpus callosum, basal ganglia idem. Slow recovery, left hip dislocation and spasticity bilateral hip osteotomy and adductor cord lengthening. Discharge after 4 months. Follow-up: 2 more episodes of mild rhabdomyolysis

Kamate et al. (2012) Ann Indian Acad Neurol 15: 31-34.

Glutaric aciduria type I: A treatable neurometabolic disorder.

Case series 11 (2008-2010) clinically diagnosed Treatment: riboflavin, carnitine, protein-restriction; emergency treatment according to guidelines

Clinical, biochemical, neuroradiologic parameters, genetical parameters

73% consanguinity Age at diagnosis: n=6 <6m; n=4 6m-1y; n=1 >1y Symptoms at diagnosis; macrocephaly (n=8), n=4 encephalitis-like crisis, abnormal movements (dystonia, choreoathetosis) n=10, n=9 developmental delay MRI: typical GA1 features in all patients: Bat wing n=11, frontotemporal atrophy with white matter disease and basal ganglia injury in n=6 Biochemistry: n=9 elevated C5DC, n=5 elevated urinary GA/3-OH-GA

No controls (Selection bias)

No details on diagnostic and treatment parameters Indirectness (population difference)

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Genetics (n=1): novel mutation P217S Follow-up: n=2 died, n=6 dystonia (n=2 progressive), n=1 normal development Conclusion: poor outcome if treatment started after onset of symptoms

Kurtcan et al. (2015) Brain Dev. 37:546-51

MRS features during encephalopathic crisis period in 11 years old case with GA-1.

Case report 1 Neurological parameters Neuroradiological parameters

11y old patient, at 5m of age developmental delay and dyskinetic CP, presented with seizure, coordination deficits; elevated 3-OH-GA in urine (high excretor), enzyme acitivity in fibroblasts: 0%. MRI: frontotemporal atrophy, enlarged sylvian fissures, bilateral basal ganglia hyperintensities, periventricular white matter disease; DWI: restricted diffusion; MRS (white matter, basal ganglia): Cho + MI/Cr mildly increased, tNAA/Cr mildly decreased, lactate peak.

encephalopathic crisis most likely already during early childhood as patient was followed due to “CP”.

3

Langendonk et al. (2012) J Inherit Metab Dis 35: 419-424

A series of pregnancies in women with inherited metabolic disease.

Case report 2 Maternal metabolic problems during pregnancy, and fetal and maternal health outcome postpartum

1. No metabolic decompensation or neurological manifestation during pregnancy (even while being complicated by recurrent urinary tract infections and sepsis prior to delivery in one woman; this woman received IV glucose during during the peripartal period) 2. Normal fetal outcome 3. Treatment with vitamin B12, riboflavin, iron supplementation and carnitine Conclusion: There is no evidence for metabolic decompensation or neurological

Dietary treatment was not described in detail. The protocol of the neurological evaluation of newborns was not described (if existing or performed in a standardized way).

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deterioration during pregnancy. No reported evidence for fetopathy induced by maternal GA1

Lee et al. (2013) Metabolic brain disease 28: 61-67.

Promising outcomes in glutaric aciduria type I patients detected by newborn screening.

Case series 6 patients in Taiwan diagnosed via NBS followed every 3 months

Clinical parameters: encephalopathic crisis, cognitive function (WPPSI, Bayley-III), Neuroradiological abnormalities, genetic analysis

Diagnosis: newborn screening DBS C5DC levels 0.21 - 6.33 μM. n=1 low excretor. IVS10-2A>C mutation represented 50 % of mutations. Treatment low lysine diet, carnitine supplement start at 8-35 days. n=1 had EC and n=1 insidious-onset type, n=4 asymptomatic. Monitoring: 4-9y follow-up. Biochemistry: Plasma lysine at lower normal range. Neuroradiology: All patients had white matter hyperintensities. n=1 with developmental delay showed resolving of pallidal hyperintensities (detected at age 1.3y) at age 6y. n=1 with insidious onset-type (dystonia, spasticity) with poor cognition; MRI at 1.1 y revealed lesions over putamen and globus pallidus which resolved gradually age 4y only outer regions of putamen involved. Conclusion: Patients diagnosed by NBS have promising outcomes, risks of disease progression remain. Normal cognitive results in asymptomatic patients

Detection bias (short follow-up period)

No controls (only series of cases) imprecision (low n) indirectness (population differences) No detailed description of maintenance and emergency treatment

3

Ma et al. (2013) Movement disorders 28:1808.

A case of choreoathetosis due to glutaric aciduria type 1

Case report 1 Neurological parameters

20y old patient with mild choreoathetosis and dysarthria starting in childhood leading to GA1 diagnosis. Treatment with L-carnitine and B2 partially

No detailed informations provided.

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improved symptoms.

Ma et al. (2013) Pediatric dermatology 30: 502-504.

Acquired protein energy malnutrition in glutaric acidemia.

Case report 1 Clinical parameters (dermatological) P

18m old GA1 patient with 6-week history of irritability, skin eruption, edema, and nonbloody diarrhea. Treatment: protein-free formula with iron, vitamins, minerals (no details) Status: Kwashiorkor with generalized edema and desquamative plaques. Skin biopsy: spongiotic psoriasiform dermatitis. Biochemistry: Albumin and zinc deficiency. Treatment: kcal 90-95 kcal/kg/d, protein 1.2 g/kg/d, zinc, iron supplements; skin normalization after 6 wk Conclusion: nutritional deficiency should be considered when children on diet present with edema and desquamative dermatitis

No treatment details provided. Sister with atopic dermatitis

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Marigliano et al. (2013) Diabetes care 36: e135-136.

Difficult management of glucose homeostasis in a 21-month-old child with type 1 diabetes and unknown glutaric aciduria type I - A case report.

Case report 1 Neurological status Encephalopathic crisis

21m old patient with diabetes mellitus type I (diagnosis at age 15m) presenting with ketoacidosis and hypotonia. Hypo- and hyperglycemic episodes were associated with acute EC characterized by hypotonia, dyskinetic movements and opisthotonus; Biochemical screening revealed elevated 3-OH-GA, MRI: bilateral striatal lesions. Conclusion: glucose homeostasis crucial in GA1

3

Marti-Masso et al. (2012) Hum Genet 131:435–442

Exome sequencing identifies GCDH (glutaryl-CoA dehydrogenase) mutations as a cause

Case report 2 siblings of one Spanish family

Neurological parameters Genetic analysis Neuroradiological abnormalities

2 affected daughters with progressive and early-onset form of generalized dystonia Sister 1: age 55y, dystonia, dysphagia, no language, at 45y:

Insidious-onset-type dystonia or undiagnosed EC at early childhood?

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of a progressive form of early-onset generalized dystonia.

Biochemical parameters

progressive paraparesis related to myelopathy C5-C6. Cognitive function normal (studies psychology) Sister 2: age 50y with similar clinical course. Treatment with levodopa, anticholinergics and neuroleptics drugs did not affect clinical symptoms. Whole exome sequencing: homozygous disease-segregating mutation (p.Val400Met) in GCDH gene. MRI: bilateral striatal lesions. Biochemical confirmation showed elevated 3-OH-GA (57.1 and 58.3 mmol/mol Creatinine); GA was normal. Conclusion: mutation is associated with Spanish GA1 patients (but high GA concentration, Busquets et al. 2000).

No enzyme activity testing

Pierson et al. (2015) Neurogenetics 16: 325-328.

Adult-onset glutaric aciduria type I presenting with white matter abnormalities and subependymal nodules.

Case report 1 Clinical parameters Biochemical parameters Neuroradiologyical parameters Genetical analysis

55-year-old Mexican female (known M. Crohn) presented with 6-year history of paresthesias, pain, incontinence, spasticity, and gait abnormalities. MRI: white matter abnormalities affecting the periventricular deep and subcortical white matter tracts associated with multiple subependymal nodules; basal ganglia normal Biochemistry: increased serum C5DC and urinary GA and 3-OHGA (HE). Genetics: compound Heterozygosity, novel variant

Immunesuppressive treatment of M. Crohn No follow-up

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(c.1219C>G; p.Leu407Val) and pathogenic mutation (c.848delT; p.L283fs).

Pusti et al. (2014) Case Rep Pediatr 2014: 256356.

A treatable neurometabolic disorder: Glutaric aciduria type 1.

Case report 2 (India) Neurological parameters Neuroradiological findings

Case1: 1.5y old boy with developmental delay, macrocephaly, recurrent seizures; selective screening suggested GA1; MRI: typical GA1 features; Treatment: protein restriction, carnitine, riboflavin supplement, anticonvulsants; improvement under therapy Case2: 3m old boy with macrocephaly, developmental delay, hypotonia. MRI: typical GA1 features with hyperintense basal ganglia. Same therapy as case1, improvement after 3 months

No follow-up 3

Singh et al. (2011) Neurology 77: e6.

Teaching neuroimages: Glutaric aciduria type 1 (glutaryl-CoA dehydrogenase deficiency).

Case report 1 Neurological parameters Neuroradiological abnormalities

14m boy with loss of milestones and tonic spasms following a diarrheal illness. Examination:macrocephaly, axial hypotonia, and dystonia; MRI: Widening of the sylvian fissures, mesencephalic cistern, and enlarged pretemporal subarachnoid spaces

3

Vilarinho et al. (2010) J Inherit Metab Dis 33:S133–S138

Four years of expanded newborn screening in Portugal with tandem mass spectrometry

Case series 3 NBS in 316,243 patients; 132 patients with 24 diseases identified. 8 cases of maternal disease, 3 cases of maternal GA1 (all by low free carnitine), 3 cases in newborns

2/3 already published by Garcia et al. 2008 No detailed information provided

3

Young-Lin et al. (2013) Neurology 81: e182-183.

Teaching neuroimages: Infant with glutaric aciduria type 1 presenting with infantile spasms and hypsarrhythmia

Case report 1 Neurological parameters EEG Neuroradiological abnormalities

7m old patient presented with 1 week of clustered flexor spasms. Status: mild hypotonia, without encephalopathy. EEG: hypsarrhythmia and infantile spasms; MRI: acute basal

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ganglia injury. Treatment: 3 weeks prednisolone, 5-month follow-up showed continued resolution of hypsarrhythmia and spasms

Zielonka et al. (2015) J Child Neurol 30: 1065-1069.

Severe acute subdural hemorrhage in a patient with glutaric aciduria type I after minor head trauma: A case report.

Case report 1 Neurological parameters Neuroradiological abnormalities

GA1 patient diagnosed via NBS and asymptomatic under guideline according treatment until 23m. Admission after minor head trauma, no neurologic abnormalities, vomiting stopped, discharge after 48hrs. Few hours later generalized seizure coma, anisocoria (elevated ICP), CT: SDH with midline shift, start of emergency treatment, surgery (decompressive hemicraniectomy) with implantation of intracranial pressure sensor; post-OP persisting anisocoria, CT: hypodensity of dorsal lobe and basal ganglia region; MRI: hypoxic lesions left hemisphere/basal ganglia; after extubation (d10) spastic tetraparesis, dystonia, severe hypotonia, start of PHB: recurrent SDH; at d29 VP shunt due to posthemorrhagic hydrocephalus, tube feeding. Follow-up: improvement of tetraparesis, no further seizures, PHB terminated Conclusion: SDH is a complication in GA I patients even in the absence of enlargement of subdural spaces and therefore should be considered in any unwell patient

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after minor accidental head injury.

36

Level 4. Expert opinion

First Author

Title Study Design

Patients (n)

Clinical End points


Glasziou et al. (2005) BMJ 330: 644-648.

Monitoring in chronic disease: a rational approach

Review Different diseases Thrombocyste aggregation Epileptic seizures HbA1c concentration

Monitoring aims to establish the response to treatment, detect the need to adjust treatment, and detect adverse effects Monitoring is not always necessary or beneficial and can lead to inappropriate changes Control charts help distinguish natural variability from true change and reduce unnecessary adjustment Monitoring for both benefit and harm is important, preferably with a single measurement

4

Thies et al. (2013) Biochim Biophys Acta 1832: 1463-72

Acute renal proximal tubule alterations during induced metabolic crises in a mouse model of glutaric aciduria type 1.

Animal model Induced metabolic crises in Gcdh(-/-) mice lead to an altered renal expression pattern of NaC3 and OATs and intracellular GA and 3-OHGA accumulation. OAT1 transporters are mislocalized to the apical membrane during metabolic crises accompanied by a pronounced thinning of proximal tubule membranes, mitochondrial swelling and increased excretion of low molecular weight proteins indicate functional tubulopathy.

4

Vester et al. (2015) Forensic Sci Med Pathol 11: 405-415.

Subdural hematomas: Glutaric aciduria type 1 or abusive head trauma? A systematic review.

Review (20 publications, 4 case series and 16 case reports)

20 Clinical parameters, neuroradiologic abnormalities, treatment modalities

n=20 cases; In 8/20 child abuse work up performed (all negative); 8/20 trauma; 17/20 with macrocephaly; 4/20 with known diagnosis prior to SDH; All started medical and dietary treatment once the diagnosis was established; MRI showed typical abnormalities in 19/20; Surgery in 13/20; n=4: VP shunt, n=3 subdural shunt, n=6 drainage system (craniotomy, burr holes) Conclusion: GA1 diagnosis is made by

Publication bias Relevant articles might have been missed

Imprecision: only case reports included

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specific MR abnormalities; with normal MRI GA1 should be removed as differential diagnosis of SDH/AHT

Zeltner et al. (2016) JIMD Rep [Epub ahead of print].

Living with Intoxication-Type Inborn Errors of Metabolism: A Qualitative Analysis of Interviews with Paediatric Patients and Their Parents

Interviews (Cross sectional)

Interviews with 19 paediatric patients and 26 parents

Numeric scales of quality of life measurements

Both patients and parents perceived dietary restrictions and social stigmatisation as major burdens. Dietary restrictions and emotional burdens were more important for young (<8 years) patients whereas cognition, fatigue and social issues were more relevant to older patients (≥8 years)

Global assessment of intixication type metabolic diseases, no independent analysis for GA1

Inconsistancy 4

38

Evidence table of systematic literature search 1975 - 2010 according to SIGN Level,

generated for the 1st guideline revision in 2011.

Level 1++, 1+, 1-. None

Level 2++. High-quality systematic reviews of case control or cohort studies; high quality case control or cohort studies with a very low risk

of confounding or bias and a high probability that the relationship is causal.

Authors Title Study design Results / Conclusions

Heringer et al (2010) Ann Neurol 68: 743-752. see also: Kölker et al (2007)

Use of guidelines improves the neurological outcome in glutaric aciduria type I.

Study design: - Prospective multi-centre follow-up study in Germany (1999-2009) - n=52 patients identified by newborn screening, n=3 patients with a low excretor phenotype missed by newborn screening - Treatment protocol: According to the guideline proposal (Kölker et al. J Inherit Metab Dis 2007; 30: 5-22) - Outcome was assessed by the occurrence of acute encephalopathic crises, the severity of motor disorder (Barry Albright Dystonia Scale and other predefined score), and survival. - Effect of treatment according to guideline, follow-up by a metabolic centre, migrational background and biochemical phenotype on the neurological outcome was evaluated.

- Patients treated in full accordance with treatment recommendations and followed by metabolic centres had the best outcome (5% of patients had movement disorder). Overall, 11% of patients of neonatally diagnosed patients had an acute encephalopathic crisis and, subsequently, develop severe movement disorder; further 11% of patients develop insidious motor delay without preceding crisis and showed a mild to moderate movement disorder. - 13 patients with the low excretor phenotype were identified correctly by newborn screening, whereas three low excreting patients were known to be missed, and two of them presented with acute encephalopathic crisis and severe movement disorder. - Deviations from basic metabolic treatment resulted in an intermediate outcome (44% of movement disorder), whereas disregard of emergency

39

treatment was associated with a poor outcome (100% movement disorder) - Treatment regimens deviating from recommendations significantly increased the risk for movement disorder (Odds ratio=35). Accordance to emergency treatment (Odds ratio=185) had a higher impact on the outcome the accordance to basic treatment (Odds ratio=14). - Barry-Albright Dystonia Scale does not adequately assess the severity of the complex movement disorder in infants and young children if they present not only with dystonia but also with severe axial hypotonia. - Conclusion: This is the first study investigating the beneficial effect of previous treatment recommendations showing that both basic and emergency treatment is required to receive and optimal outcome and that children followed by metabolic centres had the best outcome.

Nasser et al (2009) Cochrane Database Syst Rev 2: CD006659.

Carnitine supplementation for inborn errors of metabolism.

Study design: - Systematic review of randomised controlled trials and quasi-randomized controlled trials comparing carnitine supplementation (in different dose, frequency, and duration) versus placebo in children and adults diagnosed with an inborn error of metabolism, including GA-I

- No RCT trials were found. - Conclusions: There are no published or ongoing randomised controlled clinical trials relevant to this review question. Therefore, in the absence of any high level evidence, clinicians should base their decisions on clinical experience and in conjugation with preferences of the individual where appropriate. This does not mean that carnitine is ineffective or should not be used in any inborn error of metabolism. Methodologically sound trials are required. It should be considered whether placebo-controlled trials in potentially lethal diseases, e.g. GA-I, are ethical.

Watson et al (2006) Pediatrics 117 : S315-S319.

Newborn screening: toward a uniform screening panel and system – executive summary.

Study design: - ACMG convened a group, the Newborn Screening Expert Group - The expert group used a 2-tiered approach: first, specific evaluation of evaluation criteria by recognized experts; second, quantification data were subjected to an analysis of the evidence base for each specific screening criterion score. - Systematic review on 19 evaluation criteria on three categories: 1) clinical characteristics (e.g incidence, disease burden if not treated), 2) analytical characteristics of the screening test (e.g. availability and features of the platform); and 3) diagnosis, treatment, and management of the condition in acute and chronic forms (this criterion includes the availability of experienced health professionals). - Based on the categorical evaluation a sum score was generated allowing to identify the strengths and limitations for each condition tested and to summarize the results in a ranking list.

- Nearly 300 individuals from the United States and other countries completed the data collection instrument. - Many respondents provided information on multiple conditions, yielding information on nearly 4000 individual disease-specific responses. - MCAD deficiency, congenital hyperthyroidism, and PKU received the highest scoring, GA-I was scored within the upper third of conditions for which efficacious treatment and sufficient natural history information were considered to be appropriate for newborn screening. - The expert group identified 29 conditions (among them, GA-I) for which screening should be mandated. - Conclusion: Based on this GA-I is recommended for inclusion in the newborn screening disease panel.

40

Level 2+. Evidence from well-conducted case-control or cohort studies with a low risk of confounding, bias, or chance and a moderate

probability that the relationship is causal.


Harting et al (2009) Brain 132: 1764-1782.

Dynamic changes of striatal and extrastriatal abnormalities in glutaric aciduria type I

Study design: - Retrospective study on 68 MRI studies of 38 patients (age range 9 days to 66 years) using a systematic and quantitative assessment of region-specific MRI abnormalities. - 18 patients had neurological symptoms and 21 patients had no neurological symptoms at time point of MRI study - First multiple rater MRI study for GA-I - Evaluation of neurological symptoms and developmental stage at time point of MRI using predefined scores to assess motor disability and standardized psychological tests (BSID, Wechsler, SON-R)

- Major changes after acute encephalopathic crises were found in putamen, nucleus caudatus, globus pallidus and ventricles. Motor disabilities was associated with pathologic changes in these regions. - Analysis of empirical cumulative distribution frequencies, however, demonstrated that isolated pallidal abnormalities did not significantly differ over time in patients with and without crises. - A high frequency of extrastriatal abnormalities including immature gyral pattern, myelination delay and abnormal T2 signals in periventricular white matter, substantia nigra, thalamus, tractus tegmentalis centralis and dentate gyri was found in patients with and without crises. The clinical relevance of these findings remains to be elucidated. - Conclusions: The authors hypothesize that neuroradiological and neurological abnormalities in GA-I can be explained by overlaying episodes of cerebral alterations including maturational delay in utero, acute striatal injury during infancy and chronic progressive changes that may continue lifelong.

Kölker et al (2007) Pediatr Res 62: 357-363.

Decline of acute encephalopathic crises in children with glutaryl-CoA dehydrogenase deficiency identified by newborn screening in Germany.

Study design: - Prospective multi-centre follow-up study in Germany - 38 patients identified by newborn screening and 62 patients from a historical cohort diagnosed after the onset of neurological symptoms. - Median age at latest report: a) NBS group: 49 months; b) historical cohort: 133 months. - Standardized treatment protocol for the NBS group. - Outcome parameters: Survival, motor disability (using predefined scores), gross motor milestones, anthropometrical parameters (height, weight, body mass index, head circumference)

- Newborn screening in combination with standardized metabolic treatment using low lysine diet, carnitine supplementation and intermittent emergency treatment during intercurrent illness significantly improves the outcome (11% of patient had encephalopathic crises in the NBS group and 77% of patients in the historical cohort). - Numbers needed to treat to prevent one encephalopathic crises = 1.50 patients - First encephalopathic crisis in the NBS group occurred by a median age of 10 months (range: 1-37 months). - The study does not allow evaluation of the individual impacts of dietary treatment, carnitine supplementation, or emergency treatment on outcome. - The study shows that low lysine diet does not impair growth. - There is no evidence that newborn screening selects patients with a mild disease variants. - No patient was known to be missed during the study period, however, there is no regular tracking system in Germany. - Seven patients with a low-excreting phenotype were identified by newborn screening.

41

- Conclusions: Newborn screening in combination with intensive metabolic management improves the short-term outcome of GA-I patients.

Kölker et al (2006) Pediatr Res; 59: 840-847.

Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency.

Study design: - Questionaire-based evaluation of n=279 patients from Europe, America, Africa and Asia. Data collection on treatment-dependent and –independent variables. - Non-parametric statistical analysis; CART analysis to assess the impact of single variables on outcome parameters.

Mode of diagnosis - n=61 asymptomatic patients (neonatal screening, high-risk screening, siblings, macrocephaly); n=218 symptomatic patients (acute encephalopathic crisis, insidious-onset) Acute encephalopathic crisis - The majority of crises occurred before age 3 years; no crisis was reported after age 6 years; - Most patients (70%) had only one crisis and revealed a moderate to severe movement disorder. Mortality - Approximately 20% of all patients died. - The cause of death often remained unknown, pneumonia was the most frequently considered cause of death; - Deceased patients showed the highest morbidity score and the highest number of acute crises. Variables that influence the outcome Positive effect: - Early diagnosis (< 3 months of age), i.e. before the window for acute striatal damage opens - Oral carnitine supplementation - Lysine-restricted diet No effect: - Riboflavin - Protein-restricted diet Not evaluated: - Emergency treatment could not be evaluated by this approach, since important parameters (hours of delay, exact protocols used) remained unknown in included patients. Genotype phenotype correlation - No correlation between residual GCDH deficiency and neurological outcome. Open questions - Nature of insidious-onset type (distinct disease course or abortive crisis); - Individual risk and protection factors to suffer an acute crisis.

Strauss et al

(2003) Am J

Type I glutaric aciduria, part 1: Natural history of 77 patients

Study design: - Monocentric study

Basal ganglia injury: a) Symptomatic: 85 % (non-Amish) – 94 % (Amish)

42

Med Genet

121C:38-52.

see also: Morton

et al (1991)

- Progressive follow-up study in the U.S.A. (1988-2002; 14 years), a) n=40 Non-Amish (all symptomatic), b) n=37 Amish (n=17 symptomatic, n=20 pre-symptomatic); - n=57 symptomatic, n=20 pre-symptomatic Maintenance treatment: - Natural protein (1-1.25 g/kg/d), - Calories 100-115 kcal/kg/d; - Carnitine 100 mg/kg/d - Riboflavin 10 mg/kg/d - Additional treatment: Creatine (100mg/kg/d), glutamine (100mg/kg/d), alpha-lipoic acid (10 mg/kg/d), coenzyme Q (8.4 mg/kg/d), panthothenic acid (5.6 mg/kg/d), alpha-linolenic acid (150 mg/kg/d), phenobarbital (4-6 mg/kg/d), ibuprofen (10-15 mg/kg q6 h) if fever and inflammation, montekulast (5-10 mg/kg/d) if inflammatory disease, ondansetron (0.15 mg/kg q8 h) if vomiting - No riboflavin (no patient was riboflavin-sensitive) Emergency treatment: - Stop all protein intake, - Carnitine IV 400 mg/kg/d - Identify and treat infections, - Dextrose therapy: 8-10 mg/kg/min IV (plus insulin if necessary), - Alkalize urine, output > 4 ml/kg/h (lasix 0.5-1 mg/kg/dose if necessary), - Sedation and neuroprotection: phenobarbital, fosfenytoin, consider N-acetylcysteine, - Measures to reduced CSF production and ICP: lasix, acetazolamide.

b) Pre-symptomatic: 35 % (Amish) Degree of motor disability: a) Symptomatic (Amish and non-Amish): 12 % asymptomatic, 14% subtle and mild, 74 % moderate and severe, b) Pre-symptomatic (Amish): 65 % asymptomatic, 9% subtle and mild, 26 % moderate and severe. Acute encephalopathic crises : Occurred until age 18 months

Strauss et al

(2007) Brain

130: 1905-

1920.

see also: Strauss

et al (2003)

Multimodal imaging of striatal degeneration in Amish patients with glutaryl-CoA dehydrogenase deficiency.

Study design: - Retrospective, monocentric MRI study including T1, T2 and ADC maps - 25 Amish patients homozygous for c.1296C>T (p. A421V).

- Delineated three stages of striatal injury: 1) acute stage, within 24 h of motor regression, characterized by cytototoxic edema within the basal ganglia, cerebral oligemia, and rapid transit of blood throughout gray matter; 2) subacute stage, 4-5 days after the onset of clinical signs, characterized by reduced striatal perfusion and glucose uptake, and supervening vasogenic edema; and 3) a chronic stage of striatal atrophy. - ADC maps revealed that at least two of the six patients with insidious motor delay suffered striatal injuries before or shortly after birth, followed by latent periods of several months before disability was apparent. - Therapy: Intravenous fluid and dextrose therapy for illnesses during the first 2 years of life was thought to be the only intervention that was clearly neuroprotective in this cohort. The authors, however, only show that newborn screening was neuroprotective. Metabolic maintenance

43

treatment (dietary treatment and carnitine supplementation) had no significant effect (however, the groups tested were quite small). - Conclusions: Acute and insidious presentations may occur by similar mechanisms, and differ only with regard to the timing of injury

44

Level 2-. Evidence from case-control or cohort studies with a high risk of confounding, bias, or chance and a significant risk that the

relationship is not causal.


Bijarnia et al

(2008) J Inherit

Metab Dis 31 :

503-507.

Glutaric aciduria type I: outcome following detection by newborn screening.

Study design: - Retrospective study in New South Wales (Australia) - Follow-up of 10 patients identified during the last decade either clinically (n=3) or by newborn screening (n=7) - Standardized treatment: low lysine diet (supplemented with precursor-free amino acid mixtures), carnitine supplementation and intermittent emergency treatment during intercurrent illness

- Prevalence was 1 in 90,000 newborns - Clinically diagnosed patients were all symptomatic: severity scores 3, 5 and 9 (out of 9) - Six of 7 patients diagnosed neonatally remained asymptomatic, one patient had a severe decompensation at age 7 months (despite full management advice and treatment), and later died. - Conclusion: the study confirms that newborn screening in combination with intensive metabolic management significantly reduces the frequency of severe neurological complications in GA-I.

Bjugstad et al

(2000) J Pediatr

137 : 681-686.

Age at symptom onset predicts severity of motor impairment and clinical onset of glutaric aciduria type I.

Study design: - Meta-analysis of previously published case reports and cohort studies (n=42 articles). - Multiple regression analysis ; n=115 patients

Encephalopathic crises - 87% of encephalopathic crises occur until age 24 months; age at onset predicts severity of neurologic disease. Treatment and Monitoring - Treatment has no benefit in symptomatic patients; - No statement on benefit in asymptomatic patients (not enough available data); - No statement on emergency treatment; - No statement on monitoring.

Boneh et al

(2008) Mol Genet

Metab 94 : 287-

291.

see also: Beauchamp

et al (2009)

Newborn screening for glutaric aciduria type I in Victoria: treatment and outcome.

Study design: - Prospective follow-up study of GA-I patients identified by newborn screening in Victoria, Australia, between October 2001 and September 2007 - Assessment of neurological outcome using standardized neuropsychological tests. - Standardized treatment protocol: protein 2.0-2.5 g/kg per day (no precursor-free amino acid supplements), 100 mg/kg per day carnitine and emergency treatment

- Prevalence: 1 in 65,275 - Neuropsychological examinations revealed normal to high cognitive and gross motor function in all patients; the manifestation of encephalopathic crises and dystonia was prevented in all of them (35 hospital admissions for emergency treatment). - Some deficiencies in fine motor activities and speech abnormalities were identified. This has been published In detail in another article of the same authors Beauchamp et al. (2009). - Conclusions: The study confirms that newborn screening in combination with intensive metabolic management improves the outcome in GA-I. The authors highlight that more in-depth consideration of speech and language function is necessary to document specific deficits in these children and plan proactive interventions.

45

during intercurrent illness. Busquets et al

(2000) Pediatr

Res 48 : 315-322.

Glutaryl-CoA dehydrogenase deficiency in Spain: evidence of two groups of patients, genetically and biochemically distinct.

Study design: - Cohort study of 43 Spanish patients (from 35 unrelated families) - Evaluation of disease course (acute encephalopathy versus insidious onset) and severity of disability - Correlation of genotypes and biochemical and clinical phenotypes - No assessment of follow-up - No evaluation of therapy

Biochemical and clinical presentation - n=26 high excretors (A293T, R402W), n=17 low excretors (V400M, R227P), n=24 with acute encephalopathic crises, n=18 patients with insidious-onset type, 71% of low excretors and 50% of high excretors showed a ‘severe’ clinical phenotype, - 91% of patients with an encephalopathic crisis presented with a ‘severe’ clinical phenotype. Conclusion - Two genetically and biochemically distinct subgroups in Spain, - Severity of clinical phenotype is closely linked to development of encephalopathic crises rather than to residual enzyme activity or genotype.

Gitiaux et al

(2008) Mov

Disord 23 : 2392-

2397.

Spectrum of movement disorders associated with glutaric aciduria type 1 : a study of 16 patients.

Study design: - Prospective study in France - n=16 patients diagnosed symptomatically - Prospective follow-up and standardized neurological evaluation - Retrospective analysis of medical records and MRI studies of the same patients - Movement disorder was video taped and two raters have evaluated it independently - MRI scans were blinded and were reviewed by neuroradiologist, and severity scored as described previously (→ Twomey et al 2003) - No validated dystonia rating scales (e.g. Burke Fahn Marsden Scale or Barry Albright Dystonia Scale) were used to assess the severity of motor dysfunction.

- A complex movement disorder was found which was best described as generalized dystonia superimposed on baseline axial hypotonia. - With aging, the movement disorder tended to evolve from mobile to fixed dystonia and to be associated with akinetic-rigid parkinsonism. Prominent orofacial involvement was a consistent feature in GA-I patients with movement disorders, resulting in speech disorders with features of combined hyperkinetic dysarthria and speech apraxia. - Videos of two patients are included in the online version of the article. - Conclusion: These gradual changes in the motor type should taken into consideration for rehabilitation and for patients’ selection and evaluation in therapeutic trials. The time course of the movement disorder may reflect the response of the developing brain to static damage that occurred early in life, rather than being an ongoing disease process. This natural disease course of movement disorder during aging and disease progression is quite similar to that observed in other neurometabolic diseases with hyperkinetic disorders, such as Lesch-Nyhan disease and GM1 gangliosidosis.

Hennermann et

al (2009) J Inherit

Metab Dis, DOI:

10.1007/s10545-

009-9017-6.

False-positive newborn screening mimicking glutaric aciduria type I in infants with renal insufficiency.

Study design: - Retrospective monocentric study - Newborn screening results on 173,846 newborns from January 2005 to December 2008. - Evaluation of C5DC elevation in 11 patients in whom C5DC has remained elevated after recall. - First systematic study evaluating the

- None of the 11 newborns with elevated C5DC had GA-I. Five of them had congenital and six of them acquired renal insufficiency. - C5DC was shown to be significantly associated with renal dysfunction and was significantly higher in infants with congenital renal insufficiency than in those with acquired renal insufficiency. - Creatinine correlated with C5DC and with various C5DC/acylcarnitine ratio. - Conclusion: Renal insufficiency is an important pitfall of C5DC screening.

46

impact of renal insufficiency on elevated C5DC in newborn screening.

Hoffmann et al

(1996)

Neuropediatrics

27: 115-123.

see also: Hoffmann

et al (1991)

Clinical course, early diagnosis, treatment, and prevention of disease in glutaryl-CoA dehydrogenase deficiency.

Study design: - Retrospective analysis in Europe; - n=21 pre-symptomatic children (mean age at diagnosis: 12 mo, range 0-120 mo); - n=36 symptomatic children (mean age at diagnosis: 27 months, range 3-173 mo); - Treatment: a) Maintenance treatment: - No definite treatment protocol (n=13 of asymptomatic patients received lysine/tryptophan-restricted diet, whereas n=8 received moderate protein restriction or even no diet); - Carnitine supplementation (dosage ?) - No riboflavin (no sensitivity) b) Emergency treatment: - Glucose and electrolyte infusion (no exact protocol published), - Fever control/antipyretics - Carnitine dosagenot specified.

Clinical presentation a) Pre-symptomatic children: - 20/21 remained asymptomatic; 1/21 died (see also Monvari and Naughten 2000) using emergency treatment and carnitine supplementation - “The importance for dietary therapy remains unclear and needs further evaluation”. b) Symptomatic children: - No clear benefit (but further neurologic deteroriation may have been prevented) 1/78 asymptomatic, 13/78 moderate handicap, 64/78 severe handicap, 16/78 died; - Neurological deterioriation: Insidious-onset type 19%, encephalopathic crisis 81%. Monitoring: - Risk of tryptophan depletion using lysine- and tryptophan-reduced diet if not monitored.

Kyllerman et al

(2004) Eur J

Paediatr Neurol.

8 :121-129.

see also: Kyllerman

et (1994)

Long-term follow-up, neurological outcome and survival rate in 28 Nordic patients with glutaric aciduria type 1.

Study design: - Retrospective analysis of 28 Scandinavian patients diagnosed between 1975 – 2001. - n=25 symptomatic patients, - n=3 siblings; - Median follow-up: 14 years - Treatment: Dietary treatment (protein restriction or lysine- and tryptophan-restricted diet), carnitine, and riboflavin: evaluation of the benefit from different therapies for movement disorders.

Morbidity - Six patients died (21%) - At 10 years of age the cumulative survival rate was 89% and at 35 years 44%. Movement disorders - Dystonia (n=20), dyskinesia (n=4), slight spastic signs (n=3) Acute encephalopathic crises - The onset was acute encephalopathic in 24 patients and insidious in 3. Treatment - Neurological deficits did not improve on the offered treatment (diet, carnitine, riboflavine). - Deterioration may have been averted by intense acute metabolic treatment in a few patients.

Monavari and

Naughten (2000)

Arch Dis Child 82:

Prevention of cerebral palsy in glutaric aciduria type I by dietary

Study design: - Prospective follow-up study in Ireland, - n=6 asymptomatic patients, - n=6 symptomatic patients;

Outcome a) Asymptomatic patients: 1/6 crises, 4/6 no neurologic abnormality, 1/6 fluctuating neurologic problems, 1/10 died (pneumonia, no adequate emergency treatment, prematurity, placenta previa); b) Symptomatic patients: 6/6 movement disorders, 5/6 died

47

67-70.

see also: Naughten

et al (2004); Twomey et

al (2003)

management Treatment: See Naughten et al (2004)

Naughten et al

(2004) J Inherit

Metab Dis 27:

917-920.

see also: Monavari

and Naughten (2000);

Twomey et al (2003)

Glutaric Aciduria Type I, Outcome in the Republic of Ireland

Study design: - Prospective follow-up study in Ireland (1988-2004; 16 years), - n=10 asymptomatic patients, - n=11 symptomatic patients; Treatment: Maintenance treatment: - Protein restriction (0.5-2.0 g/kg/d), AA mixture (total protein: 1.5-3.0 g/kg/d); - Carnitine 100 mg/kg/d - No riboflavin (no patient was riboflavin-sensitive) Emergency treatment: - Stop natural protein (24-48 h), continue AA (p.o. or i.v.), - Increase energy intake (120%), - Double carnitine (200 mg/kg/d) Monitoring: - Regular (no definite time schedule given); - Anthropometrics; - OA (urine), FC (serum), AA (plasma); - MRI/CCT: 1 scan / year.

Outcome a) Asymptomatic patients: 1/10 crises, 6/10 no neurologic abnormality, 4/10 fluctuating neurologic problems (e.g. ataxia, delayed speech development), 1/10 died (pneumonia, no adequate emergency treatment, prematurity, placenta previa); b) Symptomatic patients: 10/11 movement disorders, 7/11 died Conclusions - Symptomatic patients had a poor outcome despite aggressive treatment (treatment may prevent a more rapid deterioration); - Asymptomatic patients had a good outcome with aggressive treatment (see also comment of Leonard and Collins: aggressive emergency treatment might be helpful whereas the benefit of diet is not proven); - No helpful biochemical marker for monitoring is known.

48

Level 3. Non-analytical studies, e.g. case reports, case series


Beauchamp et al (2009)

J Inherit Metab Dis, DOI:

10.1007/s10545-009-

1167-z.

see also : Boneh et al (2008)

Cognitive, behavioural and adaptive profiles of children with glutaric aciduria type I detected by newborn screening.

Study design: - Case series (n=4) of children with GA-I diagnosed by newborn screening (n=3) or through cascade screening (n=1) - A comprehensive battery of standardized tests was administered including measures of intellectual function, attention/memory, as well as behavioural and adaptive skills. - For further details are published in Boneh et al. 2008

- The results reveal overall average cognitive outcomes. - Subtle, but significant fine motor and articulation deficits were observed. - Conclusion: These findings highlight the importance of in-depth assessments of all aspects of neuropsychological function in patients with GA-I and provide a basis for future neuropsychological assessment in similar groups of children. This allows for planning of early and adequate therapeutic interventions.

Bennett et al (1986) Eur

J Peditatr 145: 403-405.

see also : Bjugstad et al

(2000)

Glutaric aciduria type 1: Biochemical investigations and post mortem findings.

Study design: - Case report (n=1) and post mortem examination of a fatal course of the disease.

Clinical presentation and therapy - Confirmation of diagnosis after acute encephalopathy crisis at age 6 months - Successful biochemical control was achieved using a lysine- and tryptophan-restricted diet. - Death occurred at 10.5 months with a bronchopneumonia. Post mortem examination - CNS: mild gyral atrophy with atrophy of caudate nucleus; fatty infiltration of liver, kidneys, and heart. - Glutaric acid (frontal cortex): 40 µmol/L (i.e. more than 10-fold lower than in untreated post mortem cases)

Bodamer et al (2004) J

Inherit Metab Dis 27 :

877-883.

Nuclear magnetic resonance spectroscopy in glutaryl-CoA dehydrogenase deficiency.

Study design: - Magnetic resonance imaging and spectroscopy in n=1 patient (adult-onset type GA-I) presenting with a leukoencephalopathy

Neuroradiological findings - Elevated levels of intracerebral lactate and elevated choline/N –acetylaspartate ratios in areas with severe white matter abnormalities; - normal spectra in basal ganglia Conclusion - Increased myelin turnover and reduced neuronal integrity in periventricular white matter

Brandt et al (1979) J

Pediatr 94: 669-673.

see also: Bjugstad et al (2000)

Treatment of glutaryl-CoA dehydrogenase deficiency (glutaric aciduria).

Study design: - Intervention study (each 1 week: lysine/tryptophan-reduced diet, low-protein diet, riboflavin - n=3 symptomatic patients - Determination of biochemical response (GA, 3-OH-GA, glycine, 2-amino-adipic acid) - Clinical response: no standardized measurements, subjective scale

Response to treatment - Biochemical response to lysine/tryptophan-reduced, low-protein diet, and riboflavine; - “difficulties to accept lysine/tryptophan-reduced diet” - Clinical improvement during low-protein and lysine/tryptophan-reduced diet (1 week!), no long-term follow-up data; - No carnitine, no emergency treatment; Conclusion - Low-protein diet and riboflavin is recommended for diet

49

Brismar and Ozand

(1995) Am J

Neuroradiol; 16: 675-

683.

CT and MR of the brain in glutaric aciemia type I: a review of 59 published cases and a report of 5 new patients.

Study design: - Clinical and neuroradiological investigations in glutaric aciduria type I - Report on n=5 prospectively followed patients - Review on n=59 patients

Clinical findings - In half the patients macrocephaly was present, and in half the onset was acute, often following infection and mimicking encephalitis. Neuroradiological findings - Brain atrophy or hypoplasia: 61% - White matter changes: 51% - Open opercula (usually very widely open) and often also wide cerebrospinal fluid spaces anterior to the temporal lobes: 93%. - Basal ganglia lesions (presenting as volume loss and high T2 signal in the caudate head and often also the lentiform nucleus bilaterally): 44% - Extracerebral fluid collections: 10% Conclusion - The finding of very widely open opercula suggests glutaric aciduria type I, and if combined with basal ganglia lesions is almost pathognomonic, especially in a child with macrocephaly.

Burlina et al (2004) J


911-915.

Management of movement disorders in glutaryl-CoA dehydrogenase deficiency : Anticholinergic drugs and botulinum toxin as additional therapeutic options.

Study design: Follow-up study on 4 Italian patients - Evaluation of movement disorders after symptomatic treatment with different drugs

Response to treatment - Anticholinergic drugs and botulinum toxin A were well tolerated and had a positive influence on the treatment on generalized and focal dystonia of affected children.

Cerisola et al (2009)

Pediatr Neurol 40 : 426-

431.

Seizures versus dystonia in encephalopathic crisis of glutaric aciduria type I.

Study design: - Retrospective monocentric study based on clinical history of GA-I patients with encephalopathy seen at the Sant Joan de Déu Hospital in Barcelona - n=13 patients confirmed biochemically and genetically - Evaluation of biochemical and clinical parameters as well as EEG.

- 12/13 patients had paroxysmal episodes at onset. Other clinical features included irritability (12/13), neurologic depression (11/13) and hypotonia (7/13). All patients evolved to dystonic tetraparesis. - Thirty-five EEGs were recorded in the acute stage and during the first year of follow-up. Spike discharges were only seen in 2 of the 13 patients, and 8 had slow background activity. No patient developed seizures during follow-up. - Conclusions: Most paroxysmal movements seen in symptomatic GA-I patients appear to be dystonic episodes but not epileptic seizures.

Chow et al (1988) Acta

Neuropathol 76 : 590-

594.


Neuropathology in glutaric acidaemia type I.

Study design: - Case reports and post mortem examinations in three children (2.5- 9 years of age) with fatal disease course.

Clinical presentation and therapy - Acute encephalopathic crises occurred at 5-17 months of age, resulting in dystonia. - Treatment was inconsistent: lysine-restricted diet (case 1), no treatment (case 2), baclofen and riboflavin (case 3). No neurological improvement was found in any of these children. - Cause of death: epileptic state (case 1), bronchopneumonia (case 3), unknown (case 3) Post mortem examination - Brain weights were normal - Putamina and globi pallidi were shrunken. Histology showed marked loss

50

of neurons in the striatum associated with gliosis; scattered neurons were usually of the large type. - Marked spongiform changes in the white matter at many sites.

Desai et al (2003) Invest

Radiol 38 : 489-496.

Magnetic resonance imaging of the brain in glutaric aciduria type I.

Study design: - MRI study in n=4 childen - Review of the literature

Neuroradiological findings - Abnormal increased signal intensity putamen and globus pallidus in all cases. - Involvement of caudate nucleus was minimal or absent - 15 months and older, FLAIR improved recognition of basal ganglia and white matter abnormalities. Conclusion - Abnormalities of the caudate nucleus may be not as prominent as previously suggested; FLAIR scans should be used at age > 15 months.

Elster (2004) J Comput

Assist Tomogr 28: 98-

100.

Value of diffusion-weighted resonance imaging for diagnosing acute striatal necrosis.

Study design: - Comparative study on CCT and MRI (T1, T2, DWI, MRS) - n=1 child

Neuroradiological findings - CCT: only subtle basal ganglia abnormalities; - T2: lesions in putamina; DWI: lesions in putamina, caudate nuclei and pallida; - MRS: no abnormality Conclusion - DWI is most sensitive to detect acute striatal injury in glutaric aciduria type I.

Fernandez-Alvarez et

(2003) Mov Disord 18:

1076-1079.

Hand tremor and orofacial dyskinesia : clinical manifestation of glutaric aciduria type I in a young girl.

Study design: - Case report (n=1)

- Late-onset neurologic disease (tremor, orofacial dyskinesia) in a 16-year old female adolescent - MRI: Small lesion of dorsolateral aspects of putamen, leukoencephalopathy (preferentially of frontal areas)

Forstner et al (1999)

Pediatr Radiol 29 : 138-

143.

Glutaric aciduria type I: ultrasonographic demonstration of early signs.

Study design: - Comparative study on US, CCT and MRI - n=6 children

Neuroradiological findings - Macrocephaly was found in all patients, being present in three children at birth or developing rapidly within the first weeks of life. - US showed, in all patients, bilateral symmetrical cyst-like dilatation of the sylvian fissures. Progressive fronto-temporal atrophy developed within the first months. - CT and MRI demonstrated fronto-temporal atrophy with lack of opercularisation in all cases and basal ganglia or periventricular hypodensities in three patients. Conclusions - US should be performed as the primary imaging modality. - Cyst-like bilateral widening of the sylvian fissures is the first sign of GA-I, followed by progressive fronto-temporal and ventricular enlargement.

Funk et al (2005) Brain

128 : 711-722.

Neuropathological, biochemical, and molecular findings in a glutaric aciduria type 1 cohort.

Study design: - Case reports (n=6) and post mortem examinations in a cohort of Oji-Cree patients (8 months to 40 years of age)

Clinical presentation and therapy - Acute encephalopathic crises occurred from 4 to 10.5 months of age, resulting in movement disorders.

51

with fatal disease course. All patients were homozygous for the Oji-Cree mutation (IVS-1

+5g>t).

- Treatment was performed inconsistently. - Dietary treatment was not used. Post mortem examination - CNS: Increased brain weight at different degree. - All patients had striatal atrophy with severe loss of medium-spiny neurons and mild loss of large striatal neurons. - Spongiform white matter changes were restricted to the brainstem. - Glutaric acid (all regions): approx. 600-3,200 µmol/L; 3-hydroxyglutaric acid (all regions): approx. 40-110 µmol/L.

Goodman et al (1975)

Biochem Med 12 : 12-

21.


Glutaric aciduria: a ‘new’ inborn error of amino acid metabolism.

Study design: - Presentation of the two index cases (brother and sister) with this disease.

Clinical presentation - Description of a novel neurodegenerative disease starting at about 6 months of age and characterized by opisthotonus, dystonia, and athetoid posturing. Biochemical presentation - Urinary excretion of glutaric acid, which was increased by oral administration of L-lysine. Inherited deficiency of glutaryl-CoA dehydrogenase deficiency was suggested as underlying reason.

Goodman et al (1977) J

Pediatr 90 : 746-750.


Glutaric aciduria: Biochemical and morphologic considerations.

Study design: - Case report and first published post mortem examination in one child (age 10 years) with fatal disease course.

Clinical presentation and therapy - Acute encephalopathic crisis at age 7.5 months, resulting in dystonia and mental retardation. - Diagnosis was not made before age 7.5 years. No specific therapy (e.g. diet, carnitine, riboflavine) was performed. - Numerous hospitalizatons due to episodes of high fever, vomiting, and diarrhea. - The patient died during an episode of recurrent vomiting, increasing lethargy, hepatomegaly, resembling Reye-like syndrome. Post mortem examination - CNS: Increased brain weight, cerebral edema. 75% of the putamen (and lateral margins of caudate) showed severe neuronal loss and fibrous gliosis. Glutarate concentration (frontal cortex): approx. 1,000 µmol/L. - Fatty changes in liver, kidney, and myocardium.

Greenberg et al (2002)

Mol Gen Metab 75:70-

78.

see also: Haworth et al

(1991); Funk et al (2005)

Outcome of the three years of a DNA-based neonatal screening program for glutaric aciduria type I in Manitoba and Northwestern Ontaria, Canada.

Study design: Prospective follow-up study in Canada, n=4 asymptomatic patients Treatment: Maintenance treatment: Protein restriction (1.5 g/kg/d), Carnitine (50-100 mg/kg/d), Riboflavin 100 mg/d; b) Emergency treatment; c) Additional treatment: in one child: vitamin E,

- Description of DNA-based high-risk screening in a low excretor cohort (Oji-Cree) - 3 of 4 patients (one infant died) suffered acute encephalopathic crises despite treatment (personal communication 5 / 5 patients suffered crises, C. R. Greenberg); - No statement on monitoring

52

topiramate Monitoring: “1.5 times maintenance fluid, adequate calories…high dose intravenous carnitine, and pharmacological doses of riboflavin” (no exact protocol specified).

Hald et al (1991) Am J

Neuroradiol 12: 407-

409.

Bilateral arachnoid cysts of the temporal fossa in four children with glutaric aciduria type I.

Study design: Comparative study on CCT and MRI - n=5 children

Neuroradiological findings - Four of the patients had findings consistent with bilateral arachnoid cysts of the temporal fossa. Conclusion - The observed association between temporal fluid collections and glutaric aciduria type I suggests that patients with bilateral arachnoid cysts should be investigated for this metabolic disorder.

Hartley et al (2001)

Pediatrics 107: 174-175.

Glutaric aciduria type 1 and nonaccidental head injury.


- Subdural hemorrhages in a child with GA-I; discussion on the differential diagnosis of non-accidential head injury.

Haworth et al (1991) J

Pediatr 118: 52-58.

see also: Bjugstad et al

(2000); Funk et al (2005);

Greenberg et al (2002)

Phenotypic variability in glutaric aciduria type I: report of fourteen cases in five Canadian Indian kindreds

Study design: - n=14 symptomatic patients dietary treatment (short-term, not continued, not specified, no specification of carnitine and riboflavin) - biochemical and clinical response (both not specified)

Treatment - No biochemical or clinical response to dietary treatment; diet was discontinued - High frequency of early deaths: 4/14 pts (9-17 mo), high variability of the other children, no long-term follow-up Conclusion Dietary treatment is not recommended; no statement on carnitine, riboflavin or emergency treatment

Hoffmann et al (1991)

Pediatr 88: 1194-1203


(2000); Hoffmann et al (1996)

Glutaryl-coenzyme A dehydrogenase deficiency: a distinct encephalopathy.

Study design: - n=11 patients (9 symptomatic, 2 presymptomatic), - No standard treatment: low-protein diet and/or lysine/tryptophan-reduced diet, supplementation of carnitine (30-200 mg/kg/d) and riboflavin; no emergency treatment; - Biochemical response determined by GA concentrations (urine, plasma, CSF); - Clinical response: no standardized evaluation, appearance of encephalopathic crises.

Biochemistry - Biochemical response to lysine restriction (40-50 mg/kg/d) decrease of GA excretion, slighty reduction or no reduction in plasma and CSF - Carnitine supplementation: normalization of carnitine depletion - Side effects of tryptophan discussed Outcome - Symptomatic children: 1 slight improvement, no further crises, no further deterioration in the rest of this group; no encephalopathic crises and normal development in pre-symptomatic children Conclusion - Recommendations for treatment: lysine-restricted diet, carnitine supplementation, no tryptophan restriction due to side effects; no statement on emergency treatment

Iafolla et al (1989) J

Pediatr 114: 1004-1006.

Megalencephaly in the neonatal period as the initial manifestation of glutaric aciduria type I.

Study design: - Case report (n=1 pre-symptomatic patient); lysine/tryptophan-restricted diet, supplementation of carnitine and riboflavin; no emergency treatment; 14

- No encephalopathic crisis during the follow-up interval; - Conclusion: early diagnosis and treatment as chance for preventing neurologic deterioration

53

see also: Bjugstad et al (2000) mo follow-up

Jamjoom et al (1995) J

Neurosurg 82 : 1078-

1081.

Bilateral arachnoid cysts of the sylvian region in female siblings with glutaric aciduria type I. Report of two cases.


- Two sisters with macrocephaly, delayed motor development, bilateral arachnoid cysts of the sylvian region (CCT). - Surgery: Cystoperitoneal shunting of the larger cysts resulted in considerable neurological improvement in both children (no long-term follow-up). - Diagnosis was just made afterwards - Conclusions: Association of bilateral arachnoid cysts with GA-I.

Köhler and Hoffmann

(1998) Pediatr Radiol

28: 582

Subdural haematoma in a child with glutaric aciduria type I.


- Subdural hemorrhage and retinal bleeding in a boy with previously diagnosis of GA-I most likely due to minor head trauma. - Discussion on shaken-baby syndrome as relevant differential diagnosis

Kölker et al (2001) J

Pediatr 138: 277-279.

Acute encephalopathy despite early therapy in a patient with homozygosity for E365K in the glutaryl-CoA dehydrogenase gene.

Study design: - Case report (n=1), - Turkish boy, diagnosed and treated early (diagnosed due to macrocephaly); - lysine-restricted diet, carnitine and emergency treatment

- Acute encephalopathic crisis despite early treatment with lysine-restricted diet and carnitine (it has been found out later that this family showed a poor compliance, unpublished observation).

Kölker et al (2003)

Neuropediatrics ; 34 :

253-260.

Glutaryl-CoA dehydrogenase deficiency: Regional-specific analysis of organic acids and acylcarnitines in post mortem brain predicts vulnerability of the putamen.

Study design: - Case report and post mortem examination in one adolescent (age 14 years) with fatal disease course.

Clinical presentation and therapy - Acute encephalopathic crisis occurred at age 6 months, resulting in severe dystonia. Treatment - Lysine- and tryptophan restricted diet was performed and revealed a strong biochemical response (determined by urinary excretion of glutaric acid), whereas vigabatrin and riboflavin revealed no positive biochemical response. Post mortem examination - Increased brain weight, necrosis and severe neuronal loss with reactive astrogliosis in the striatum; spongiform changes in the white matter were moderate. - Glutaric acid and 3-hydroxyglutaric acids were up to 10 µmol/L in the CNS with highest 3-hydroxyglutaric acid concentration in putamen.

Külkens et al (2005)

Neurology; 64: 2142-

2144.

Late-onset neurologic disease in glutaryl-CoA dehydrogenase deficiency.

Study design: Report on n=2 cases (age 15 and 66 years) with late-onset neurologic disease, presenting with leukoencephalopathy and an atypical neurologic-psychiatric symptomatology. - Review on 5 cases with suggested adult-onset type glutaric aciduria type I.

Clinical presentation - Severe headaches, gait disturbances (ataxia), tremor, vertigo, halluzinations, focal epilepsy, dementia. - Partial improvement (older patient) or complete recovery (younger patient) after implementation of mild protein restriction and oral carnitine supplementation. MRI / MRS - Leukoencephalopathy (frontal > occipital), periventricular but not

54

sparing U fibres; older patient also revealed general atrophy. - Basal ganglia appeared normal. MRS (younger patient) revealed elevated lactate in areas with severe white matter changes. Diagnostic work-up - Mutation analysis demonstrated homozygosity for two previously known disease-causing mutations (R88C, R383C) resulting in residual GCDH activity of < 1% and massive excretion of organic acids (high excretors) - Ultima ratio brain biopsy (older patient) demonstrated no leukodystrophy but edematic swelling of tissue. - Concentrations of glutaric acid (approx. 5,000 µmol/L) and 3-hydroxyglutaric acid (appr. 200 µmol/L) were massively elevated.

Kurul et al (2004) Pedatr

Neurol 31: 228-231.

Glutaric aciduria type 1: proton resonance spectroscopy findings.

Study design: - Case report (n=1), magnetic resonance spectroscopy

- MRS of frontal white matter and lentiform nuclei revealed decreased N-acetylaspartate/creatine ratio, slightly increased choline/creatine ratio, and increased myoinositol/creatine ratio - Conclusion: indicates neuroaxonal damage, demyelination, and astrocytosis in these areas.

Kyllerman and Steen

(1980) Arch Pediatr 37;

279.

A “common” metabolic disorder? Study design: Estimation of prevalence in Sweden

- Prevalence of glutaric aciduria type I in Sweden was estimated to 1 in 30,000 newborns.

Kyllerman et al (1994)

Mov Disord 9: 22-30


(2000); Kyllerman et al (2004)

Dystonia and dyskinesia in glutaric aciduria type I: Clinical heterogeneity and therapeutic considerations

Study design: - Retrospective analysis of 12 patients (age 9 months to 16 years) from Sweden and Norway. Evaluation of neurological outcome. Review on 57 pooled cases. See also Kyllerman et (2004).

Movement disorders a) Sweden/Norway: - 10/12 dystonic-dyskinetic disorder, 1/12 mild motor dysfunction, 1/12 asymptomatic. b) Review on 57 pooled cases: - 77% severe dystonia, 10% mild extrapyramidal syndrome, 12% asymptomatic (the authors suggested that this disorder may go undetected in the cerebral palsy and mentally retarded child and adult populations) Deaths - Two children in state of hyperthermia Feeding problems - Carnitine and malnutrition developed in patients with severe dystonia and dysphagia which necessitated replacement therapy and gastrostomy. Neuroradiology - CCT/MRI: 7/10 deep bitemporal spaces Neuropsychological testing - 8/12 receptive language function superior to expressive language and motor function

Lindner et al (2004) J Neonatal screening for glutaryl-CoA Study design: - C5DC, C5DC/C8 and C5DC/16 were clearly elevated initially and during

55

Inherit Metab Dis 27:

851-859.

dehydrogenase deficiency. - MS/MS screening results in GA-I (n=6) and short-term follow-up of C5DC and C5DC/C8 and C5DC/C16 ratios - Review of the literature on prevalence of GA-I and diagnostic pitfalls

short-term follow-up (up to 100 days) in all six children using MS/MS - Report on DNA-based neonatal screening in the Oji-Cree, a Canadian low excretor cohort with a single intron mutation

Lipkin et al (1988) J

Pediatr 112 : 62-65.


A case of glutaric aciduria type I: effect of riboflavin and carnitine.

Study design: - Case report (n=1), - 5-year-old boy (USA), diagnosed at age 45 months after progressive neurological deterioration following two acute encephalopathic crises; treatment with moderate protein restriction (1.5 g/kg/day), riboflavin (100 mg/day), and L-carnitine (100 mg/kg/day); determination of biochemical and clinical response.

Biochemical response - Riboflavin: increase in GABA but no decrease of glutaric acid levels in CSF - Carnitine: Increase in total carnitine (plasma), increase in short-chain acylcarnitines (urine, <1% of oral carnitine) Clinical response - Modest clinical improvement with long-term treatment with carnitine and riboflavin (no standardized examination, no specific tests).

Liu et al (2002) Prenat

Diagn 22 : 725-729.

Novel mutations and prenatal sonographic findings of glutaric aciduria (type I) in two Taiwanese families.


- Report on glutaric aciduria type I in three Taiwanese children, two of them showing dystonia - Prenatal ultrasound in one child (starting at age 30 weeks of gestation): progressive dilatation of the quadrigeminal cistern, macrocephaly, frontotemporal atrophy and enlarged Sylvian fissure. - Hypothesis that macrocephaly and frontotemporal atrophy developed following cytotoxic edema, cell damage and reduced CSF reabsorption (as previously suggested by Naidu and Moser 1991; Am J Neuroradiol 12: 413-416).

Lütcherath et al (2000)

Acta Neurochir (Wien)

142 : 1025-1030

Children with bilateral temporal arachnoid cysts may have glutaric aciduria type 1 (GAT1); operation without knowing that may be harmful.


- Macrocephaly, bitemporal arachnoid cysts, subdural bleeding (one patient), delayed motor development - Neurosurgical interventions: fenestration, subduro-peritoneal and ventriculo-peritoneal shunts - Diagnosis of GA-I was made after the neurosurgical intervention both patients had a very poor outcome after neurosurgery (one patient died at 3 years of age, one had a severe motor handicap) - Conclusions: Children with bitemporal arachnoid cysts may have GA-I; all children with bitemporal cysts should be screened for GA-I before neurosurgical intervention

Martinez-Lage et al

(1994) Childs Nerv Syst

10 : 198-203.

Macrocephaly, dystonia, and bilateral temporal arachnoid cysts : glutaric aciduria type 1.


- Macrocephaly, psychomotor delay, and progressive dystonia in two siblings - The initial diagnosis was of hydrocephalus and bilateral temporal cerebrospinal fluid collections. - VP shunting showed only modest neurological improvement. - Metabolic investigations confirmed GA-I - Conclusion: Macrocephaly, dystonia and bilateral temporal arachnoid cysts seems to be diagnostic of GA-I

McClelland et al (2009) Glutaric aciduria type 1 presenting Study design: - 6-year-old girl with recurrent epileptic seizures. She had no history of

56

Dev Med Child Neurol

51 : 235-239.

with epilepsy. - Case report (n=1) of a 6-year-old girl with recurrent epileptic seizures. - First report of a GA-I patient with epileptic seizures as the sole presenting feature of this disease.

encephalopathy and showed no developmental abnormalities. - The EEG was profoundly abnormal with slow background and mixed multifocal and generalized spike-and-wave discharges. - Seizures deteriorated on valproic acid. - The girl has improved on low protein diet, carnitine, levetiracetam, and lamotrigine. - Conclusions: The case report adds to the clinical spectrum of this disorder. Furthermore, it emphasizes the role of metabolic investigation when first- or second-line treatment of epilepsy is unsuccessful.

Mellerio et al (2008)

Ultrasound Obstet

Gynecol 31 : 712-715.

Prenatal cerebral ultrasound and MRI findings in glutaric aciduria type 1: a de novo case.

Study design: - Case report (n=1) - Fetal and postnatal MRI and ultrasound studies. –

- Fetal MRI study in at gestational age 33 weeks showing enlarged Sylvian fissures, multiple bilateral subependymal cysts, diffuse hyperintensity in the periventricular white matter and severe increase of the the supratentorial subarachnoid spaces. Basal ganglia were normal.

Möller et al (2003).

Neuropediatrics 34 : 57-

60.

Investigation of the cerebral energy status in patients with glutaric aciduria type I by 31P magnetic resonance spectroscopy.

Study design: - Case report (n=2), phosphorus magnetic resonance spectroscopy

- No cerebral depletion of phosphocreatine (PCr) was observed. - Conclusion: a severe global and permanent depletion of cerebral energy supplies was ruled out. Creatine supplementation seems doubtful benefit.

Morton et al (1991) Am

J Med Genet 41:89-95.


(2000); Strauss et al (2003)

A common cause of episodic encephalopathy an spastic paralysis in the Amish of Lancaster County, Pennsylvania

Study design: - Cohort study in 14 children from the Old Order Amish community in Lancaster County, Pennsylvania. See Strauss et al 2003

Clinical course of the disease - Description of a remarkable clinical variation from acute infantile encephalopathy and sudden death to static extrapyramidal cerebral palsy. - 10/14 patients: Manifestation between age 3 to 18 months. Little progression of neurologic disorder after age 5 years in surviving children with sparing of intellect. - Deaths: 4 children in early childhood died during acute illnesses. Treatment options - Restriction of dietary protein, limitation of protein catabolism, dehydration, and acidosis during illnesses may prevent the onset of progression of neurologic disease. Pedigree - A pedigree chart tracing both parents of all except one case to John Lapp and his wife, who immigrated to the United States in 1730s, was presented.

Niiyama et al (2001) Eur

J Dermatol 11: 244-246.

Acrodermatitis acidemica secondary to malnutrition in glutaric aciduria type I.


- First report on acrodermatitis acidemica in a child with GA-I - Severe deficiency of amino acids (in particular isoleucine), zinc, selenium, and variety of vitamins were found - Conclusion: Skin lesions were the result of severe malnutrition (like in methylmalonic and propionic acidurias).

Oguz et al (2005)

Neuroradiology 47:229-

Diffusion-weighted MR imaging and MR spectroscopy in glutaric aciduria type I.

Study design: - Case report (n=1), magnetic resonance spectroscopy (MRS) and diffusion-weighted MRI (DWI) was performed

- DWI: Widespread restricted diffusion in the white matter and increased diffusion in bilateral putamen. - MRS: decreased N-acetyl-aspartate (NAA)/creatine (Cr) ratio; no

57

234 after neurological deterioration (most likely during the chronic stage)

significant change in choline (Cho)/Cr ratio. Increased lactate peak reflecting disturbed mitochondrial functions.

Prevett et al (1996) J

Neurol Neurosurg

Psychiatry 60 : 252-253.


Glutaric aciduria type I in adulthood.


- Suspected late-onset glutaric aciduria type I; diagnosis at age 50 years during reassessment of chronic neurological disability - Manifestation of gait disturbance and orofacial dyskinesia (first symptoms starting at age 7 years during an episode of “paralytic illness”) without previous acute encephalopathic crisis - MRI: Basal ganglia with abnormalities, focal areas of white matter changes.

Rakocevic et al (2004)

Stereotact Funct

Neurosurg 82: 80-83.

Bilateral pallidotomy for severe dystonia in an 18-month-old child with glutaric aciduria.

Study design: - Case report (n=1) - 18-months-old male (Cherokee Indian) with severe generalized dystonia who underwent pallidotomy after pharmacological therapy (pharmacotherapy for movement disorders is not given in full detail, botulinum toxin A has been applied only with transient benefit).

- Partial improvement of dystonia and reduction of pain (only subjective estimation is given), “more alert and interactive”, no purposeful use of hands and arms. - Side effect: Pathological eye findings (right gaze preference, limitation of left horizontal gaze).

Seccombe et al (1986)

Neurology 36: 264-267.


L-Carnitine treatment in glutaric aciduria type I.

Study design: - Case report (n=1) - 5-year-old girl (child of non-consangineous Yugoslavian parents), diagnosed at age 23 months after delayed motor development; treatment with protein restriction (1.1 g/kg/day), riboflavin (100 mg/day), and L-carnitine (3x500 mg/day)

Biochemical response: - Carnitine: Strong increase in free carnitine (normalization) and moderate increase in acylcarnitines in plasma. Clinical response: - Protein restriction and carnitine supplementation: no clinical improvement.

Smith et al (2001)

Pediatrics 107: 1184-

1187.

Glutaric academia, type I, missed by newborn screening in an infant with dystonia following promethazine administration.


- Case report on unsuccessful neonatal screening (cut-off problem; negative result at recall) - Child was diagnosed by diagnostic work-up of dystonia

Soffer et al (1992) J

Neurol Sci 107:199-204.


Striatal degeneration and spongy myelinopathy in glutaric acidemia

Study design: - Case report and post mortem examination in one child (age 6.5 years) with fatal disease course. Review on 8 published post mortem cases.

Clinical presentation and therapy - Acute encephalopathic crisis at age 4 months, resulting in severe dystonia. Diagnosis was not made at age 15 months. Death occurred at age 6.5 months due to respiratory failure. - Treatment with lysine-restricted diet, riboflavin, carnitine, and baclofen without improvement of the neurological status. Post mortem examination - CNS: Increased brain weight, cerebral edema. Putamina were shrunken and pale, caudate nuclei were greatly attenuated. Histopathology revealed marked neuronal loss (surviving neurons were mainly of the large type) and prominent astrogliosis in striatum. Spongiform changes of the white matter were demonstrated throughout the brain.

Twomey et al (2003) Neuroimaging findings in glutaric Study design: Neuroradiological findings

58


830.

see also: Monavari and

Naughten (2000); Naughten

(2004)

aciduria type I. - Retrospective evaluation of US, CCT and MRI scans in n=20 Irish patients

- Widening of Sylvian fissures and of the fluid spaces anterior to the temporal lobes: 93% - Widening of mesencephalic cistern: 86% - Abormal high signal intensity in basal ganglia and periventricular white matter (T2): 64% - 9/14 patients with MRI scans had lesions in globus pallidum (in 4 cases isolated), putamen was abnormal in three patients but never isolated) - Abnormal high T2 signal were also found in the dentate nucleus (79%), substantia nigra (43%) and the pontine medial lemniscus (64%). - Four neonates followed with US showed bilateral multiple caudothalamic cysts. Conclusion Widening of Sylvian fissure, mesencephalic cistern and expansion of CSF spaces anterior to the temporal lobes are cardinal signs of GA-I. If combined with abnormalities of the basal ganglia and white matter abnormalities, GA-I should be strongly suspected.

Walter (2003) J Inherit

Metab Dis 26: 181-188.

L-Carnitine in inborn errors of metabolism: What is the evidence?

Study design: - Questionnaire-based evaluation (via Metab-l) of current practice of oral L-carnitine supplementation in MCAD deficiency, propionic (PA) and methylmalonic acidurias (MMA); glutaric aciduria type I was only included into the discussion. - Literature review (PubMed): evaluation of evidence levels according to SIGN

- Questionnaire: Replies from 31 clinics in Europe, North America, Asia, and Australia: 94% of PA and MMA but only 39% of MCAD patients received L-carnitine (25-300 mg/kg/d orally) - Literature review: Most papers supported use of L-carnitine in PA and MMA, documenting biochemical or clinical improvement; only 5 relevant papers were identified for MCAD deficiency. At best, studies could be ranked as 2+ (evidence from well-conducted case-cohort studies with a low risk of confounding, bias, or chance and a moderate probability that the relationship is causal); majority are level 3 (evidence from non-analytical studies, e.g. case reports, case series). - Conclusions: Using SIGN criteria, recommendations for oral L-carnitine supplementation in these diseases would only be graded as D (lowest grade).

Walter et al (2009) J


95-101.

Bloodspot acylcarnitine and amino acid analysis in cord blood samples: efficacy and reference data from a large cohort study.

Study design: - Diagnostic study on cord blood samples collected at birth and analysed for acylcarnitine and amino acid profiles by tandem mass spectrometry in two laboratories - One laboratory used butylated derivates, the other used underivatized samples. The same laboratories performed routine blood spot newborn screening at 5-7 days of age on these babies.

- 24,983 newborns were examined. - No patient with glutaric aciduria type I was identified. - Cord blood testing missed some patients with PKU, MSUD, argininosuccinic aciduria, MMA, GA-II, MCAD deficiency, HMG-CoA lyase deficiency. - Conclusions: cord blood testing is of limited value in detecting inherited metabolic disease. The metabolites associated with most disorders examined were not elevated in cord blood. Some maternal disorders (3-MCC deficiency, carnitine transporter defect) are detected. It can only be extrapolated that for GA-I cord blood might not be advantageous compared to regular newborn screening using dried blood spots.

Woelfle et al (1996) Subdural hematoma and glutaric Study design: - Bilateral subdural hemorrhages and frontotemporal atrophy;

59


781.


aciduria type I. - Case report (n=1) neurosurgical intervention; regression of subdural effusions but deterioration of neurologic disease - Diagnosis was just made after the neurosurgical intervention - Conclusion: GA I should be included into the differential diagnosis of unexplained subdural hematoma and neurological deficits.

60

Level 4. Expert opinion

Authors Title Description Contents

Baric et al (1998) J

Inherit Metab Dis

21 : 326-340.

Diagnosis and management of glutaric aciduria type I.

Review On diagnostic work-up and treatment in glutaric aciduria type I. Based on the presentations and discussions of the 2

nd International

Workshop on Glutaryl-CoA Dehydrogenase Deficiency (Rauischholzhausen, Germany, 1996).

Maintenance treatment: - Carnitine supplementation (30-100 mg/kg/d) ; - Co-factor responsiveness should be investigated but has found in only one patient (Chalmers, unpublished observation); - Benefit of long-term dietary treatment is unclear (lysine restriction until 6 y using AA mixtures and moderate protein restriction [1.5 g/kg/d] at age > 6 y) - Tryptophan-free AA mixtures should be avoided due to severe side effects (sleepliness, ill temper, irritability, loss of appetite, death) - Dystonia may worsen on high-protein meals et vice versa (anecdotal reports) Emergency treatment: a) Management at home: - Stop natural protein (not longer than 24 h) - Increase energy: 1.5 x basal requirements using carbohydrate drinks - Double carnitine dosage (200 mg/kg/d) b) Management at hospital: - See a) - IV Infusion of high-calorie glucose (if necessary with insulin) and lipids; - Sedation: Diazepam 0.25 mg/kg every 6 h; - IV carnitine (100-200 mg/kg/d); - Antipyretics; - Additional medication: riboflavin (100 mg/d), dextrometrophan (initial: 25 mg p.o., maintenance: 2.5 mg/kg every 12 h)

Hoffmann and

Zschocke (1999) J

Inherit Metab Dis

22: 381-391.

Glutaric aciduria type I: From clinical biochemical and molecular diversity to successful therapy.

Review: Based on the presentation at the 37

th SSIEM meeting in York, UK

(1998)

Maintenance treatment: - Restriction of natural protein plus lysine-free AA mixtures - Carnitine supplementation Emergency treatment: - High-dose glucose and carnitine therapy Monitoring: - No statement

61

Kölker et al (2004)

J Inherit Metab Dis

27: 893-902.

Emergency treatment in glutaryl-CoA dehydrogenase deficiency.

Review: Based on a presentation and the discussion at the 3

rd International

Workshop on Glutaryl-CoA Dehydrogenase Deficiency (Heidelberg, Germany, 2003).

Outpatient/home emergency treatment: - Recommendations for maltodextran/dextrose, protein intake, and pharmacotherapy Inpatient emergency treatment - Recommendations for energy requirements, protein intake and pharmacotherapy

Mühlhausen et al

(2004) J Inherit

Metab Dis: 885-

892.

Maintenance treatment of glutaryl-CoA dehydrogenase deficiency.


rd International

Workshop on Glutaryl-CoA Dehydrogenase Deficiency (Heidelberg, Germany, 2003).

Critical review on the state of art on dietary treatment, carnitine supplementation, riboflavin administration, and other treatment strategies (creatine, antioxidations) as well as on surgical interventions (pallidotomy) and monitoring.

Müller and Kölker

(2004) J Inherit

Metab Dis 27: 903-

910.

Reduction of lysine intake while avoiding malnutrition – major goals and major problems in dietary treatment of glutaryl-CoA dehydrogenase deficiency


rd International

Workshop on Glutaryl-CoA Dehydrogenase Deficiency (Heidelberg, Germany, 2003). Including: Calculations on essential amino acids, minerals and micronutrients as a basis for a well-balanced diet of this disease; discussion on age-dependent demands and pitfalls and a reasonable way to use international dietary recommendations.

Major goals and major problems: - To maintain normal growth and development by reducing production of (toxic) organic acids via reduction of lysine while avoiding malnutrition two opposing goals; - Dietary recommendations for natural protein intake has many open questions: No recommendation for handicapped children; mixed vs standard protein; no exact data on intestinal uptake of AA mixtures; - Lysine content in natural protein is highly variable; - In general, dietary treatment can be performed either by protein-restricted or lysine-restricted diet; - Protein restriction has two major disadvantages: a) risk of malnutrition (AA and micronutrients), b) lysine intake cannot be controlled if protein sources are not standardized AA mixtures decrease the risk for malnutrition, in particular during the vulnerable period for encephalopathic crises (risk for malnutrition is highest during the vulnerable period!). - A well-balanced dietary treatment cannot be adequately performed if intake of natural protein is the only parameter under control. - Dietary treatment is not possible without regular monitoring of amino acids, free carnitine, and micronutrients in plasma/serum

Prietsch et al

(2002) J Inherit

Metab Dis 25: 531-

546.

Emergency management of inherited metabolic diseases.

Review: Emergency management in different inborn errors of metabolism, also including “disorders of intoxication type” (this is not specific for GA-I but includes all organic acidurias, hyperammonemias etc).

Principles of emergency treatment for “intoxication type”: - stop oral intake of toxic precursors (protein; not longer than 24-48 h, then introduce step-wise) - reversion of catabolism (glucose 10 mg/kg/min; ie approx. 60 kcal/kg/d) - specific detoxification measures (L-carnitine 100-300 mg/kg/d i.v.)

62

Superti-Furga and

Hoffmann (1997)

Eur J Pediatr 156:

821-828.

Glutaric aciduria type 1 (glutaryl-CoA dehydrogenase deficiency): advances and unanswered questions.

Review: Report from the 2

nd International Workshop on Glutaryl-CoA

Dehydrogenase Deficiency (Rauischholzhausen, Germany, 1996)

Carnitine supplementation: - Lethal outcome in patients without carnitine supplementation; prevention of encephalopathic crises (see Hoffmann et al 1996); - Secondary carnitine depletion in nearly all patients before carnitine supplementation Carnitine supplementation is recommended. Initial dosage: 100 mg/kg/d Dietary treatment: - No significant beneficial effect in lysine- and tryptophan-restricted patient (see Hoffmann et al 1996) - One patient died due to severe tryptophan depletion Lysine- and tryptophan-restricted diet is not recommended, moderate protein restriction is recommended.

Yannicelli et al

(1994) J Am Diet

Assoc 94: 183-191.

Nutrition support for glutaric acidemia type I

Review: Case reports on lysine- and protein (n=14)-restricted patients (n=19); Reference to dietary recommendations for protein and micronutrients

Pharmacological treatment: a) Riboflavin: most studies failed to show a positive effect; b) Valproate: inconsistent results; secondary carnitine depletion as severe side effect; c) Carnitine: 100-300 mg/kg/d to normalize plasma levels of free carnitine. Dietary treatment: - Biochemical response if lysine intake is 70 mg/kg/d and tryptophan intake is 30 mg/kg/d; correlation between plasma lysine and plasma GA concentrations; - Poor growth and low plasma lysine and tryptophan concentration if intake further decreases (lysine < 50 mg/kg/d, tryptophan < 10 mg/kg/d); - Dietary treatment should not be discontinued, since the natural history of the disease is not yet known in the long run. Guidelines for nutrition support: a) Maintenance treatment - Major goal: Promote normal growth and development (or prevent further neurologic deterioration) by lowering GA in plasma, CSF, and urine while maintaing normal plasma levels of lysine and tryptophan. - Intake of essential AA and micronutrients should meet or exceed 100% of RDAs (1989); - lysine content in food is highly variable: protein foods in biologic value (meat, poultry, fish, eggs) is not recommended; - Energy supply may be higher in handicapped children; - Gastrostomy should be considered if feeding difficulties limit oral feeding;

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b) Emergency treatment - Major goal: Inhibit protein catabolism during acute illness; - lysine and tryptophan sources should be temporarily eliminated; - Low protein intake is necessary to avoid catabolism of muscle protein; - Energy: at least 120 % of recommended intake for age; - If oral feeding is not possible, glucose, lipids, and lysine/tryptophan-free solutions should be administered IV c) Monitoring - Anthropometrics - Iron status - Nutrient intake (3-day diet records) - Plasma carnitine status - GA: urine, plasma, (CSF) – initially: weekly, then: every 2 to 4 weeks - Lysine, tryptophan (plasma) – initially: weekly, then: every 2 to 4 weeks - Protein status - Trace minerals

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