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MEDICINE
Psychiatric Symptoms Associated with Inborn Errors of Metabolism
Susan Beckwitt Turkel1 & Derek Wong2& Linda Randolph3
Accepted: 8 July 2020# Springer Nature Switzerland AG 2020
AbstractInborn errors of metabolism (IEM) are individually rare but collectively common disorders, occurring in 1:800 to 1:1000 births.There are more than 1000 known inherited disorders characterized by disruption of metabolic pathways which may present withdiverse symptoms affecting any organ at any age, including with psychiatric symptomsmimicking primary psychiatric disorders.This review is intended to help psychiatrists and other physicians suspect an inborn error of metabolism in a patient presentingwith psychiatric symptoms. A comprehensive literature review was undertaken, using Index Medicus and resources at theUniversity of Southern California Norris Medical Library to identify specific information for each individual disorder described.Those inborn errors of metabolism most likely to present with psychiatric symptoms primarily impact the brain, acting eitherdirectly on biochemical pathways in the central nervous system or indirectly reflecting dysfunction in other organs. Symptomsmay occur episodically under stress when metabolic demands are highest or progressively evolve over time reflecting gradualneuropsychiatric deterioration. Cognitive impairment and psychosis appear to be the most frequently reported psychiatricproblems. Noting age of onset, patterns of psychiatric presentation, and associated symptoms in other organ systems can increasesuspicion and facilitate diagnosis of psychiatric symptoms due to an inborn error of metabolism. Psychiatric problems can be seenwith multiple inborn errors of metabolism with associated systemic dysfunction or as isolated symptoms. It is important forphysicians to be aware of clues that might increase suspicion of an underlying genetic disorder, and to recognize that consultationwith a medical geneticist is recommended for diagnosis and to provide the patient optimal care in either situation.
Keywords Psychiatric symptoms .Metabolic disorders . Genetics . Pediatrics
Introduction
The overall incidence of inborn errors of metabolism is estimatedto range from 1:800 to 1:1000 live births, although the incidenceis probably much higher given difficulties in clinical diagnosis
and limitations in diagnostic testing [1, 2]. Inborn errors of me-tabolism are a heterogeneous group of disorders that may presentwith psychiatric symptoms at any age [3] and their symptomscan be easily confused with primary psychiatric disorders [4, 5].There are more than 1000 known inherited disorders character-ized by disruption of metabolic pathways typically due to defi-cient enzymes, cofactors, or transporters [6]. They may presentwith diverse symptoms affecting any organ at any age, includingwith psychiatric symptoms easily confused with primary psychi-atric disorders [2, 7]. Perhaps as many as 0.5% of patients pre-senting with psychosis may have an underlying metabolic disor-der [8], and a variety of these disorders present first with psycho-sis [9, 10]. Newer methods of genetic analysis and increasedsuspicion make it likely that inborn metabolic errors will berecognized more often in psychiatric patients than previously[11]. A positive family history of early childhood death in sib-lings or other relatives can increase suspicion and be helpful fordiagnosis, but a negative family history does not exclude a ge-netic disorder which may have arisen de novo or may not havebeen recognized before [12]. A patient with a history of parentalconsanguini ty; unexplained episodic symptoms;
Previously presented at the American Neuropsychiatry Associationannual meeting March, 2016 in San Diego, California
This article is part of the Topical Collection onMedicine
* Susan Beckwitt Turkelsbturkel@usc.edu
1 Department of Psychiatry, University of Southern California KeckSchool of Medicine, Los Angeles, CA, USA
2 Department of Pediatrics, Mattel Children’s Hospital, Division ofMedical Genetics, University of California Los Angeles GeffenSchool of Medicine, Los Angeles, CA, USA
3 Department of Pediatrics, Children’s Hospital Los Angeles, Divisionof Medical Genetics, University of Southern California Keck Schoolof Medicine, Los Angeles, CA, USA
https://doi.org/10.1007/s42399-020-00403-z
/ Published online: 13 August 2020
SN Comprehensive Clinical Medicine (2020) 2:1646–1660
decompensation during stress or illness; failure to thrive; symp-toms in high-energy-utilizing organs such as the brain, heart,liver, or muscle; avoidance of certain foods; or atypical responseto psychotropic medication should all increase concern for anunderlying metabolic disorder [1, 13]. These observations mayhelp distinguish patients with an underlying inborn error of me-tabolism, but psychiatric symptomsmay occurwithout historical,familial, or systemic symptoms to assist in diagnosis.Psychiatrists and other physicians need to remain open to thepossibility that metabolic disorders may present with isolatedpsychiatric symptoms alone. This review is intended to increasesuspicionwhen a patient presents with psychiatric symptoms andto encourage consultation with a specialist for definitive diagno-sis and collaborative care.
A comprehensive literature review using Index Medicus andresources at theUniversity of SouthernCaliforniaNorrisMedicalLibrary was employed to identify specific information for eachdisorder described. Patient charts were not evaluated andInstitutional Review Board clearance was not required. This ar-ticle does not contain any studies with human participants per-formed by any of the authors.
Porphyria
The porphyrias are disorders that result from decreased activityof the enzymes in the heme synthetic pathway. The largestamounts of heme are produced in the bone marrow for makinghemoglobin, and in the liver for making cytochrome P450 en-zymes. The porphyrias lead to the accumulation and excess ex-cretion of metabolic intermediates and products of heme synthe-sis. Most porphyrias are autosomal dominant, so males and fe-males are equally affected, although females aremore likely to besymptomatic. Symptoms can be precipitated by factors that de-plete intracellular heme including alcohol or starvation. Affectedpatients have 50% or less of enzyme activity. Given that only10–20% patients with the gene defect may be symptomatic, fam-ily history is often negative [5].
Acute Intermittent Porphyria
Acute intermittent porphyria (AIP) is the most common formof porphyria. There are close to 400 different mutations of theporphobilinogen deaminase gene which result in AIP. It isinherited as an autosomal dominant condition, although mostpeople with AIP never develop symptoms. AIP occurs in 1–2/10000 Europeans, with the highest rate in Scandinavia andFrance, and rates 50–200 times higher in psychiatric inpatientscompared to the general population [5, 8].
AIP is associated with intermittent elevations inporphobilinogen and related prophyrins, and symptoms aretypically episodic. Acute attacks can be triggered by fasting,stress, steroid hormones, and certain drugs. Diagnosis is
usually made by finding increased porphobilinogen, porphy-rin, and δ-aminolevulinic acid in the urine. Porphyrins in urineoxidize on standing, which turns urine red or dark brownish incolor [14].
Patients with AIP classically present with abdominal pain,psychiatric symptoms, and peripheral neuropathies. Abdominalpain may suggest pancreatitis, and is typically accompanied bynausea, vomiting, and constipation. AIPmay also present acutelywith tachycardia, hypertension, renal disease, pain,muscle weak-ness, agitation, confusion, depression, hallucinations, or convul-sions [15]. Patients can present with delirium, psychosis, depres-sion, or anxiety, and psychiatric symptoms may be the onlymanifestation of AIP [5, 16]. Acute attacks are rare before pu-berty, and the onset of symptoms typically occurs after puberty.Most patients present in the second to fourth decade. Whensuspected, AIP is confirmed by finding excess α-aminolevulinic acid (ALA) and porphobilinogen (PBG) in urineat the same time that porphobilinogen deaminase activity(PBGD) is decreased in the patient’s erythrocytes [5].
Psychotropic medications are generally effective in man-aging psychiatric symptoms in patients with AIP, but cautionis needed because some agents can precipitate or exacerbatean acute episode. Sedative-hypnotics (secobarbital, butalbital,phenobarbital, meprobamate, chlordiazepoxide) can exacer-bate AIP. Antipsychotics (trifluoperazine, chlorpromazine,olanzapine, clozapine, risperidone), lithium, and some benzo-diazepines (lorazepam, and clonazepam) have no impact onAIP. The effects of other psychotropic drugs (amitriptyline,nortriptyline, imipramine, clonazepam, diazepam, oxazepam)remain controversial [17].
Specific treatments for AIP are available. Hematin is effec-tive during an acute attack and for the prevention of an attack,while hemin acts faster by suppressing the overproduction ofporphyrin precursors and is currently used more often [18].
Disorders of Copper Metabolism
Copper is essential for cellular metabolism, but excess copper istoxic, and acts as a pro-oxidant for formation of free radicals andoxidation of lipids and proteins. Copper causes hepatocellulardamage and high intracellular levels of copper lead to hepaticcell death. The liver is the main organ that regulates copperhomeostasis, and excretion into bile is the only method of copperelimination. Over 90% of copper in the body is bound to ceru-loplasmin which transports copper in the blood [19].
Wilson’s Disease
Wilson’s disease is an autosomal recessive disorder of coppermetabolism. Its worldwide prevalence is 1/20000 to 1/100000and its carrier rate is about 1:90. Wilson’s disease results fromimpaired excretion of copper from hepatocytes to bile canaliculi
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due to a defective gene for P-type adenosine triphosphatase B(ATP7B). ATP7B is large transmembrane protein expressedmostly in the liver. The gene for ATP7B is found on chromo-some 13q.14.3 and mutations of ATP7B are closely linked toimpaired copper excretion [20].
There is considerable allelic heterogeneity in Wilson’s dis-ease. Almost 500 mutations of ATP7B have been identifiedand more than 300 have been associated with clinical Wilson’sdisease. Different patterns ofmutation are found in different partsof the world and environmental factors can influence clinicalphenotypic expression [19].
The storage capacity for copper in the liver is limited.Excessive copper deposition is found mostly in the liver andbrain. Copper is deposited in the cornea as Kayser-Fleischerrings, in the kidneys disrupting renal function, in joints, and incardiacmuscle resulting in cardiomyopathy [19]. The commonlyobserved increase in serum ceruloplasmin in Wilson’s disease isan epiphenomenon. Ceruloplasmin levels increase to accommo-date increased amounts of copper in the blood, but as liver dam-age increases and hepatocellular production of ceruloplasmin iscompromised, ceruloplasmin levels decline. Hepatic symptomsare usually recognized first as copper accumulates in the liver,typically at 10 to 13 years. Deposition in the central nervoussystem follows and leads to neuropsychiatric symptoms usually5 to 10 years later [21].
It takes longer for the diagnosis of Wilson’s disease if psychi-atric symptoms present first, which occurs in 20–30%of patients,and 30–40%of patients have psychiatric symptoms at the time ofdiagnosis [22]. Abnormal behavior and mood symptoms aremost common when Wilson’s disease presents psychiatrically,but psychosis, anxiety, obsessive-compulsive disorder, anorexia,cognitive impairment, and isolated irritability have all been re-ported. Neuroimaging typically shows T2 hyperintensity signalsin the basal ganglia, thalamus, brainstem, and cerebellum; andSPECT shows hypoperfusion in the cerebral cortex, putamen,and caudate [23].
Treatment for Wilson’s disease begins with chelating agents(D-penicillamine or trientine) to decrease copper levels, and thenmaintenance with penicillamine or zinc [24, 25]. With progres-sive disease, liver transplant is recommended. Hepatic and usu-ally neurologic symptoms improve significantly after transplant,but improvement in psychiatric symptoms is usually modest[26]. Anxiety ismore persistent than other psychiatric symptoms.Antipsychotics, mood stabilizers, and anxiolytics may be neededin addition to chelating agents to control psychiatric symptoms[27, 28]. Screening first degree relatives of patientswithWilson’sdisease is recommended to identify those affected early, as zinctherapy appears effective in preventing significant copper accu-mulation and end-organ damage in asymptomatic relatives [24].
Aminoacidopathies
Phenylketonuria
Phenylketonuria (PKU) is the most common and probably thebest-known disorder of amino acid metabolism. It was the firstinborn error of metabolism to be screened in newborns. PKUwas initially recognized in 1934 in intellectually disabled chil-dren with decreased activity of phenylalanine hydroxylase lead-ing to increased levels of phenylalanine in the blood and excre-tion of urinary phenylpyruvic acid. There are more than 550mutations resulting in PKU. The overall global prevalence is1:12000, and the carrier rate is 1:55 [29].
Untreated, PKU presents with severe mental retardation,hyperactivity, seizures, light complexion, eczema, and a“mousy odor.” Excessive phenylalanine is thought to interferewith brain growth, myelination, and neurotransmitter synthe-sis, which results in intellectual impairment, epilepsy, motordeficits, microcephaly, and behavioral disturbances. Childrenand adolescents frequently have psychiatric symptoms andsignificant problems with attention, achievement, motivation,social competence, autonomy, and self-esteem despite earlytreatment. Generalized anxiety, depression, social isolation,and behavioral immaturity are common in early-treated adults,and psychosocial factors and the burden of living with achronic illness may contribute to psychological difficulties atany age [29].
A phenylalanine restricted diet is the main treatment forPKU, but strict adherence to it is onerous and compliancedecreases as patients get older. High phenylalanine levels areassociated with mood, anxiety, and attention problems [30],and with dopamine and serotonin deficits which may explainbrain damage and progressive neuropsychiatric impairment inadult PKU patients [31]. Psychotherapy can improve compli-ance with treatment, which is important in limiting cognitiveimpairment and psychiatric symptoms [32].
Even when well treated early, there may be subtle deficits inexecutive functioning, mild reduction in mental processingspeed, social difficulties, and emotional problems, which in turnare related to problems in relationships, maintaining compliance,and job performance [33]. Psychiatric disorders are noted in25.7%patients even after early treatment, withmore internalizingdisorders and more women affected. Lack of adherence is direct-ly related to associated cognitive and executive functional declineand psychiatric problems [34].
Sapropterin is a synthetic form of tetrahydrobiopterin, thecofactor for phenylalanine hydroxylase. It can stabilize andincrease residual enzyme activity and about one-third ofPKU patients respond to oral sapropterin. Additional noveltherapies to reduce phenylalanine levels are under investiga-tion [34].
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Sulfur Amino Acids: Methionine, Cysteine,Homocysteine
Methionine, homocysteine, and cysteine are sulfur-containingamino acids connected by a methylation cycle. Methionine isan essential amino acid from diet, and it is converted to ho-mocysteine in the methylation cycle. The metabolism of ho-mocysteine is linked to folate, cobalamin (vitamin B12), andpyridoxine (vitamin B6) [35, 36].
Homocysteine is required for the synthesis of neurotrans-mitters and DNA, and in excess can be directly toxic to neu-rons and blood vessels. Elevated levels of homocysteine occurwith homocystinuria, MTHRF deficiency, and cobalamin dis-orders, and are associated with megaloblastic anemia, com-bined degeneration of the spinal cord, dementia, and psycho-sis [37]. Elevated homocysteine alters the release of mono-amines, affects neurotoxicity via N-methyl-D-aspartate(NMDA) receptors, causes leukodystrophy due to disruptedmyelination, and can present as a psychiatric disorder, includ-ing personality disorders, behavioral disturbances, depression,mood disorders, obsessive-compulsive disorder, and psycho-sis resembling schizophrenia [10, 38].
Homocystinuria
Homocystinuria is commonly attributed to cystathionine β-synthetase (CBS) deficiency, which leads to accumulation ofmethionine and homocysteine in blood, CSF, and urine. It isan autosomal recessive trait found in 1:150000 in the USA.About half the patients will respond to dietary therapy withpyridoxine and have a milder course. Psychiatric symptomscan be recognized in about two-thirds of adult patients [39]and may be the presenting symptom in 3%; adolescents mayrarely present with acute psychosis [40].
Methylene Tetrahydrofolate Reductase
Methylene tetrahydrofolate reductase (MTHFR) is a key en-zyme in folate/homocysteine metabolism, and its dysfunctionmimics folate deficiency. The MTHFR gene is polymorphicand associated with a spectrum of disorders [41]. Deficiencyof the enzyme 5,10-methylene tetrahydrofolate reductase(MTHFR) leads to impaired production of 5-methylenetetra-hydrofolate, resulting in decreased methionine synthetase.Deficiency of MTHFR has been reported with psychiatricdisorders, schizophrenia-like symptoms [10], malignancies,paraplegia, developmental delay, decreased levels of mono-amine neurotransmitters, seizures, atherosclerotic cerebrovas-cular disease, infantile apnea, and neonatal death [42]. Betainetreatment improves outcome and can prevent symptoms ifgiven early, while parenteral cobalamin has no proven benefit,and folic acid should be avoided [43].
Psychiatric symptoms are common in patients withMTHFR deficiency, but they do not fit a consistent pattern.The role of MTHFR in psychiatric disorders has been contro-versial. A recent meta-analysis of available case studies sug-gestedMTHFRC677T polymorphismmay be a risk factor forschizophrenia, but a definitive relationship between MTHFRand specific psychiatric disorders has not been established andmeta-analyses have been inconsistent [44].
Cobalamin
Cobalamin, or vitamin B12, is an organometallic compoundcontaining cobalt found in food of animal origin and synthe-sized by bacteria. Dietary deficiency of cobalamin is rare inWestern diets with the exception of strictly vegan diets orbreast-fed babies. The absorption of cobalamin involvescobalamin-binding proteins and receptors, so disorders relatedto the absorption and transport of B12 are considered inbornerrors of metabolism.
Methylmalonic acid and homocysteine accumulate inblood and urine with dietary B12 deficiency, impaired B12absorption, or impaired conversion of dietary B12 into meta-bolically active forms. Errors in the cobalamin pathway canresult in methylmalonic aciduria, homocystinuria, or both[45].
Cobalamin C
Cobalamin C disease is an inborn metabolic error with im-paired intracellular synthesis of the 2 active forms of cobala-min, adenosylcobalamin and methylcobalamin. It is related tomutations in the methylmalonic aciduria and homocystinuriatype C protein (MMACHC) gene [46]. Cobalamin C defect isthe most common inborn error involving B12 metabolismwith at least 40 mutations reported, and it results in increasedlevels of methylmalonic acid and homocysteine in blood andurine [45].
Presenting symptoms vary by age, with severe multi-systemic symptoms in the first year; hemolytic uremic syn-drome and pulmonary hypertension in preschool children;psychiatric symptoms, cognitive impairment, ataxia, and my-elopathy in older children and adolescents; and thromboem-bolic events and glomerulopathy almost exclusively in adults[47]. Later onset is less common and is associated with amilder phenotype, longer survival, and psychiatric symptomsof psychosis, confusion, dementia, and delirium are reported[45].
Urea Cycle Defects
The urea cycle is the primary nitrogen-disposal pathway andrequires the coordinated function of enzymes in the cytosol
1649SN Compr. Clin. Med. (2020) 2:1646–1660
and mitochondrial matrix. The liver is the only organ in whichall the urea cycle enzymes are found. Urea cycle defects areautosomal recessive, with the exception of ornithinetranscarbamyl transferase deficiency, which is X-linked. Thephenotypic spectrum of urea cycle defects varies consider-ably, and their overall prevalence is between 1:8000 and1:35000 [48, 49]. Two-thirds of patients will have their initialsymptoms after the newborn period, and postnatalhyperammonemic episodes are typically precipitated by anintercurrent infection. Mortality varies from 11% with lateonset, to 24% with neonatal onset, to 42% with carbamoylphosphate synthetase 1 (CPS1) deficiency [49] (Table 1).
When the diagnosis of a urea cycle defect is suspected,confirmation is necessary by documenting elevated blood am-monia levels. Ammonia is present in serum as NH4+ and istoxic. Hyperammonemia will alter neurotransmission and canresult in irreversible cerebral edema, causing neurologic dam-age, intracranial hypertension, herniation, and death. Milderforms of urea cycle defects may be difficult to differentiateclinically from drug abuse, psychosis and psychiatric disor-ders, or hepatic encephalopathy [50]. Adult onset urea cycledisorders may present with psychiatric symptoms, which oc-casionally can be the initial presentation [51]. Agitation andhallucinations can occur, and associated neurologic symptomsmay provide the clue to an underlyingmetabolic disorder [51].
Ornithine Carbamoyl Transferase Deficiency
Ornithine carbamoyl transferase deficiency (ornithinetranscarbamylase deficiency, OCT) is X-linked and is themost common urea cycle defect. It is found in more than halfthe cases and is associated with a 57% risk for liver dysfunc-tion. It results from deficiency of the mitochondrial enzyme,ornithine transcarbamylase, which catalyzes the conversion ofornithine and carbamoyl phosphate to citrulline [52].
OCT usually presents in males in the newborn period withacute hyperammonemia, feeding problems, vomiting, respira-tory distress, convulsions, coma, and death. Male patientswith later onset, from 15 months to 5 years, present withheadache, vomiting, lethargy, hyperventilation, episodes ofabnormal behavior, disorientation, confusion, ataxia, hypoto-nia, and rarely focal neurologic signs. Associated CNS dam-age is probably related to accumulation of glutamine, andcystic changes with degenerated neurons and eosinophilicgranular material may be seen in the CNS at autopsy. Olderpatients often voluntarily avoid high protein foods and adopt avegetarian diet. Adults may occasionally present with psychi-atric symptoms initially, with hallucinations, agitation, anddelirium [51]. Females heterogeneous for the defect havemilder symptoms, and usually only become symptomatic inassociation with a very high protein intake, intercurrent infec-tion, trauma, anesthesia, surgery, childbirth, and post-partumpsychosis [48, 49, 53]. A chronic low protein diet can result in
normal weight and linear growth. Nitrogen-scavenger therapywith phenylbutyrate can result in low levels of branched-chainamino acids, requiring patients to be monitored for amino aciddeficiencies [54].
Citrullinemia
Deficiency of argininosuccinate synthetase results incitrullinemia, an autosomal recessive disorder. Psychosismay be the first manifestation of citrullinemia, leading to di-agnostic confusion with schizophrenia for many years [55].Additional symptoms of memory loss, drowsiness, liver dys-function, and hyperactivity increase suspicion of a metabolicdisorder, and elevated ammonia and citrulline levels indicatethe high likelihood of a urea cycle defect. Nocturnal delirium,aggression, irritability, hyperactivity, restlessness, delusionalthinking, disorientation, memory loss, drowsiness, seizures,and coma are also consistent with citrul l inemia.Citrullinemia can be treated with sodium pyruvate and argi-nine, or by liver transplant [55].
Lysosomal Storage Diseases
Lysosomes are membrane-bound intracytoplasmic bodieswhich contain hydrolytic enzymes, store material to be metab-olized, and sequester material that cannot be adequatelydigested [56]. There are at least 50 known lysosomal storagedisorders, with an overall frequency of 1:5000 live births.Genes associated with lysosomal storage disorders code forlysosomal enzymes and lysosomal membrane proteins [57].Most lysosomal storage disorders are autosomal recessive anda few are X-linked. Those with severe systemic features typ-ically present in the first years of life, and less severe present inlater childhood, adolescence, or adulthood. Psychiatric symp-toms are usually associated with later presentation, and caninclude depression or mania, psychosis with hallucinations orparanoia, or aggressive behavior [58]. Dementia is common inthe late stages of lysosomal disorders [].
Metachromatic Leukodystrophy
Metachromatic leukodystrophy (MLD) is an autosomal reces-sive disorder related to deficiency of arylsulfatase A. It occursrarely in the general population (1/40000–1/130000 livebirths), but more frequently in Western Navaho Nation(1/2520 live births) [57, 59]. Deficiency of arylsulfatase Aresults in sulfatide accumulation in lysosomes in the centraland peripheral nervous system, which can be seen microscop-ically as metachromatic staining in myelin sheaths. The term“metachromatic” refers to variable staining of the sulfatidecontaining lysosomes. Sulfatide accumulation leads to demy-elination of axons and peripheral nerves, leaving cell bodies
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Table1
Sum
maryof
pattern
ofinheritance,frequency,chromosom
allocatio
nof
genetic
defect,disorderedmetabolism,typicalageof
onset,psychiatricandsystem
icsymptom
s,andavailabletreatm
ent
ofinborn
errorsdescribed
Disorder
Genetics
Frequency
Chrom
osom
eMetabolicdefect
Age
onset
Symptom
sTreatment
Acuteinterm
ittent
porphyria
AD
1–2/10000
11q23
Porphobilinogendeam
inase
defectleadsto
porphobilin
ogen
and
α-aminolevulinicacid
inurine
Lateadolescence
Abdom
inalpain,
anxiety,neuropathy
Hem
in,hem
atin;
psychotropic
medications
may
precipitatesymptom
s
Wilson’sdisease
AR
1/20000–1/100000
13q14.3
P-typeATP7
Bdefectleadsto
accumulationof
copper
intissue,
firstliver,thenCNS;later
liver
failu
re,psychosis,coagulopathy
8–20
years
Psychosis,liver
failu
reChelatin
gagentsfirst,
then
liver
transplant
Ureacycledefects
AR
1/8000–1/35000
Abnormallevelsof
differentamino
acids:glutam
ine,alanine,citrullin
e,arginine,argininosuccinate,
ornithine,homocitrullin
e
Mostafternewborn
period
Phenotypicspectrum
;may
resemble
prim
arypsychotic
disorder
ordrug
abuse
Low
-protein
diet
Ornith
ine
transcarbamylase
deficiency
(OCT)
XR
Xp21.1
Deficiencyof
ornithine
transcarbamylase
New
born
males
but
laterin
females
oroldermales
HighNH3,seizures,
vomiting
Low
-protein
diet,
phenylbutyrateand
monito
rforam
inoacid
deficiencies
Citrullin
emia
AR
Infant
9q34
Adult7q2
Deficiencyof
argininosuccinate
synthetase
Deficiencyof
citrin
Infant:T
ype1
Adult:
Type2
Presentswith
psychosis
inadultslik
eschizophrenia
Sodium
pyruvateand
arginine;liver
transplant
Phenylketonuria(PKU)
AR
1/12000carrier1:55
12q22
Increasedphenylalaninedueto
defect
inphenylalaninehydroxylase
New
born
Severemental
retardationseizures
eczemabehavior
problems
Phenylalanine
free
diet,
sapropterin,vitamin
supplements
Hom
ocystin
uria
AR
21q22.3
Cystathionine
β-synthetase
Adolescent
Psychosis
Increaseddietary
pyridoxine
Cobalam
in(B12):
cobalamin
Cdefect
(MMACHC)
AR
1p23.2
Accum
ulatemethylm
alonicacid
and
homocysteinein
urineandblood
Varies
Psychiatricsymptom
sin
olderchild
including
psychosis
Methylene
tetrahydrofolate
reductasedeficiency
(MTHFR
)
AR
1p36.22and
14q23.3
Failu
reof
remethylatio
nfrom
absence
ofmethylg
roup
providingenzyme
substrate
Varies
Mim
icsfolate
deficiency,large
varietyof
disorders
with
nospecific
psychiatricsymptom
s
Betaine
avoidfolate
cobalamin
ineffective
Tay-Sachs
disease
AR
1/200000,1:250
carrierin
general,
1:27
inAskenazi
Jews
15q23
β-G
alactosidase
deficiency
leadsto
storageof
GM2ganglio
side
inneuronsasmem
branouscytoplasmic
bodies
Infant (4–6
months)
Lateonset
(adolescento
radult)
Infants:rapiddecline,
hypotonia,weakness,
loss
ofmilestones,
cherry
redspot
inmacula
Lateonset:psychosis
Supportiv
eSo
mebenefitfrom
bone
marrowtransplant
and
enzymereplacem
ent
Gaucher’sdisease
AR
Carrier
1/100
1q22
Deficiencyin
glucocerebrosidase
and
storageof
glycolipid
Psychiatricsymptom
sin
type
3
1651SN Compr. Clin. Med. (2020) 2:1646–1660
Tab
le1
(contin
ued)
Disorder
Genetics
Frequency
Chrom
osom
eMetabolicdefect
Age
onset
Symptom
sTreatment
Neuronalceroid
lipofuscinosis
Usually
AR,few
adulto
nsetAD
1/25000inUSA
and
Scandinavia
1/100000
worldwide
1p34 15
q23;
160
mutations
in8genes
Accum
ulationof
ceroid
lipopigments,
notspecificbutm
arkerof
abnorm
alcellmetabolism
Classifiedby
ageof
onset
Blin
dnessinfants,
psychiatricsymptom
sin
75%
olderpatients
Intraventricular
cerliponasealfa
for
CLN2
Fabry’sdisease
XR
1/40000–1/60000
males
About
600
mutations
reported
Deficiencyof
α-galactosidase
AMultip
leorgans,pain,
risk
ofsuicide,
psychosis;symptom
sin
carriers
Enzym
ereplacem
entw
ithagalsidase
alfa;o
rMigalastat
“chaperone”forsome
variants
Metachrom
atic
Leukodystrophy
AR
1/40000–1/130000;
1/2520
inwestern
Navajo
22q13
Arylsulfatase
deficiency,accum
ulation
ofsulfatideinlysosomes
inCNSand
PNS
Onsetrelatedto
degree
ofdeficiency
Behaviorandcognitive
problemsearlier;
psychosis,catatonia
inolder
Earlycord
bloodstem
cell
transplant
Hurler
MPS
IAR
1/100000
4p16.3
Deficiencyα-L-iduronidase;
accumulationderm
atan
andheparan
sulfate
Abnormalfacial,
skeletalstructure;
anxiety,learning
problems
Laronidaseenzyme
replacem
ent
HunterMPSII
XR
1/111000
males
Xq27
Deficiencyof
iduronate-2-sulfatase
Languagedelay,
ADHD,seizures
Idursulfaseenzyme
replacem
ent
SanfilippoMPS
III
AR
0.28–4.1/100,000
12q14
4typeswith
defectin
catabolism
ofheparinsulfate
Disruptivebehavior,
disordered
sleep,
psychiatricproblems
after10
yearsold
Niemann-Pick
disease
AR
1/100000
TypeC1:
18q11;
TypeC2:
14q24
TypeC1:largemem
braneglycoprotein
TypeC2:
smallm
embrane
glycoprotein
Errorsin
cellu
lartraffickingof
cholesterol
Progressivefatal
neonataltype
toadulto
nset
neurodegenera-
tion
Cognitiv
edeclineto
dementia,psychosis,
ADHD,depression,
aggressive
and
disorganized
behavior
Adrenoleukodystrophy
(ALD)
XR
1/8000–1/20000
males
Xq21
Peroxisomaldisorder
with
defective
VLCFA
synthetase,decreased
beta
oxidation,andincreasedVLCFA
2–10
yearsmost
common
ADHD,abnormal
behavior,neurologic
symptom
s;psychiatricsymptom
swith
adolescent
onset;may
present
with
psychosisor
mania
“Lorenzo’soil”and
decreaseddietaryfat
may
slow
deterioration
ifgivenearly;
neurolepticsmay
cause
severe
dystonicside
effects;bone
marrow
transplant;g
ene
therapypossible
MELAS:
mito
chondrial
encephalopathy,
lacticacidosis,and
stroke-likeepisodes
Polygenicmutations
inmaternal
mito
chondriaDNA
Childhood
tolate
adolescence
Seizures,diabetes,
depression,psychosis
1652 SN Compr. Clin. Med. (2020) 2:1646–1660
unaffected. Age of presentation is related to the degree ofenzyme deficiency. The infantile form presents by 30 months,and the juvenile form presents with behavioral and cognitiveproblems between 3 and 16 years and occasionally in patientsolder than 16 years [60].
Psychiatric symptoms can be the first signs of the diseaseand are a prominent feature of the disorder, often leadingpatients to be initially diagnosed with schizophrenia. Morethan half of patients diagnosed from late childhood to earlyadulthood present with psychosis, complex auditory halluci-nations, bizarre delusions, catatonic posturing, personalitychanges, disinhibition, and behavioral disorganization [61].
MRI in metachromatic leukodystrophy shows characteris-tic white matter demyelination extending from periventricularareas in the cerebrum and white matter loss in the cerebellum.Psychotic symptoms are related to demyelination ofsubfrontal white matter and disruption of corticocortical andcorticosubcortical connections [61]. The degree of demyelin-ation correlates with motor and cognitive symptoms, and thecentral demyelination at onset of symptoms can predict dis-ease progression [62].
Newborn screening is not yet available for MLD. Cordblood stem cell transplant may improve the course and slowthe progression of MLD, and transplant would have the mostbenefit if done before symptoms occur [63]. It is still better totransplant before symptoms are advanced since it takes 6 to12 months after transplant for the donor cells to be effective[60]. Although children with MLD have a significantly betteroutcome after transplant, they will still need support servicesin school and long-term follow-up [64].
Tay-Sachs Disease
Tay-Sachs disease is one of the disorders characterized asamaurotic familial idiocy when first described over a centuryago. Tay-Sachs disease is seen in 1/200000 live births. Thecarrier rate is markedly increased to 1/27 in a few groupsincluding Ashkenazi Jews of eastern European descent, non-Jewish French-Canadians from eastern Quebec, and Cajunfamilies in southwest Louisiana [65]. The carrier rate is1/250 for the general population, including Sephardic Jewsof North African or Middle Eastern origin. Tay-Sachs diseaseis an autosomal recessive disorder caused by a deficiency ofβ-hexosaminidase A which leads to ganglioside GM2 accu-mulation in neurons [66]. GM2 forms characteristic membra-nous cytoplasmic bodies when seen by electron microscopy,which can be observed first in fetal spinal cord, then cerebel-lum, and then cerebrum [67].
There are three clinical variants of Tay-Sachs disease dif-ferentiated by age of onset. The infantile variant is the mostcommon, and presents before 6 months with developmentalarrest, hypotonia, startling, and a typical cherry red spot in themacula. It is associated with rapid neurologic deterioration
and death before 5 years. The subacute variant typically pre-sents at about 5 years and is associated with a more protractedcourse, leading to a chronic vegetative state and death by thesecond decade. The late onset variant is characterized by awide spectrum of symptoms and a protracted course with pro-gressive neurologic deterioration, psychosis, catatonia, andmood symptoms in adolescence and thereafter [68].
Management of Tay-Sachs disease is essentially support-ive, although bone marrow transplant and enzyme replace-ment therapy have been done with some benefit. Gene therapyusing viral vectors is under investigation [66].
Niemann-Pick Disease
Niemann-Pick disease type C is an autosomal recessivelipidosis that results from an error in cellular trafficking ofexogenous cholesterol, which leads to the lysosomal accumu-lation of unesterified cholesterol. It occurs in 1/100000 livebirths and presents with significant phenotypic heterogeneity,even in twins. There is a broad spectrum of presentation ofNiemann-Pick disease from rapidly progressive, fatal neonataltype, to adult onset type with a chronic, neurodegenerativecourse [69].
Niemann-Pick disease type C1 is found in 95% of patients.Its gene has been mapped to chromosome 18q11 and codesfor a large membrane glycoprotein. The defect in Niemann-Pick type C2 has been mapped to 14q24.3 and instead codesfor a small soluble lysosomal protein [70].
Progressive cognitive decline appears to be inevitable inpatients with Niemann-Pick type C disease and ranges fromsubtle impairment in executive function to profound dementiawith apathy and mutism. Younger patients have school andbehavior problems, agitation, hyperactivity, sleep disorders,and depression. Almost half of all patients present with psy-chiatric problems including acute psychosis, paranoid delu-sions, hallucinations, disorganized behavior, aggressiveness,self-mutilation, major depressive episodes, bipolar disorder,and obsessive-compulsive disorder. Neurologic symptomsmay be absent when the patient is psychotic [71].
Gaucher Disease
Gaucher disease is a lysosomal glycolipid storage disorderdue to glucocerebrosidase deficiency. Glucocerebroside is abreakdown product of membrane glycosphingolipids, and itaccumulates in the reticuloendothelial system, whileglucosylceramide accumulates in the spleen, liver, and bonemarrow [72].
Gaucher disease is relatively common, and carriers arefound in 1:100 in the general population, and in 1:15Ashkenazi Jews. Type I is the most common form ofGaucher disease, and it is not associated with CNS involve-ment. Type 2 is the acute neuronopathic form which has an
1653SN Compr. Clin. Med. (2020) 2:1646–1660
early onset in infancy with severe CNS involvement, andleads to death by 2 years. Type 3 is primarily associated withvisceral involvement and has a later onset of cognitive prob-lems, mood, anxiety, and psychotic symptoms. Neurologicsymptoms including myoclonus, ataxia, seizures, and demen-tia have also been reported [72].
Neuronal Ceroid Lipofuscinoses
Neuronal ceroid lipofuscinoses (CLN) were previously char-acterized as Batten disease. The name neuronal ceroidlipofuscinoses refers to lysosomal autofluorescentlipopigments which can be seen microscopically in the brainand other tissue. This is a heterogeneous group of more than160 mutations in one of 14 genes that can result in this neu-rodegenerative disorder [73]. Most are autosomal recessive,but autosomal dominant forms also occur. They differ in theage of onset and appearance of the stored material on electronmicroscopy [74].
These are progressive neurodegenerative disorders whichmay initially present with psychiatric symptoms. CLN occur1:25000 in the USA and Scandinavia, and 1:100000 livebirths worldwide [73]. Patients are clinically classified intofour major groups by age. The juvenile form is the most com-mon, with onset between 4 and 10 years, and patients areusually diagnosed in childhood when prominent neurodegen-erative symptoms become apparent. Course is variable andloss of vision is characteristic. Visual loss is associated withseizures, motor and cognitive deterioration, behavioral disor-ganization, and psychiatric symptoms. Patients are usuallyinitially calm, but then become increasingly irritable; developsleeping problems, aggressiveness, restlessness, anxiety, rapidmood changes, and psychosis with visual hallucinations anddelusions; progressing to dementia and death usually in thethird or fourth decade. Adult onset patients lack visual prob-lems but have psychiatric symptoms, seizures, and motor ab-normalities [74].
The enzyme abnormality has been identified in some casesof CLN. Disease-specific treatment with enzyme replacementtherapy is only available for CLN2 with cerliponase alfa. Ithas been approved in the USA, and it is administered via animplanted intraventricular device. Long-term efficacy has yetto be determined [56].
Fabry Disease
Fabry disease is an X-linked recessive disorder ofglycosphingolipid catabolism which results from the deficien-cy of the lysosomal hydrolase, α-galactosidase A. It occurs in1:3100 to 1:117000 live male births. Female carriers are alsousually symptomatic [56]. Fabry’s disease is associated withsevere pain and paresthesias in the extremities, which increasethe risk for major depression, addiction, and suicide. Severe
ocular and skin problems, episodic abdominal pain and diar-rhea, and progressive renal and cardiac failure occur. Fabrydisease may also present with acute psychotic symptoms, de-lusions, and auditory hallucinations, and resemble a formalthought disorder [75]. Enzyme replacement therapy is avail-able with agalsidase alfa which has been shown to be effectiveand safe [76]. It is recommended to start enzyme replacementtherapy once a patient becomes symptomatic, regardless ofage [56]. Migalastat is a pharmacological chaperone that sta-bilizes and facilitates trafficking of α-galactosidase A enzymefrom endoplasmic reticulum to lysosomes and increases lyso-somal activity. It is given orally in adults with Fabry disease[77].
Mucopolysaccharidoses
Mucopolysaccharidoses (MPS) are genetic disorders causedby a deficient activity of one of the lysosomal enzymes neededto break down glycosaminoglycans, which are long un-branched polysaccharides consisting of repeating disaccha-rides [78]. Glycosaminoglycans (GAGs) then accumulate invarious tissues and result in a multisystem clinical presenta-tion and a cascade of interrelated metabolic, inflammatory,and immunologic responses [79]. Mucopolysaccharidosesare mostly autosomal recessive and a few are X-linked reces-sive disorders. There are 11 known enzyme deficienciesresulting in 7 distinct forms of MPS, with a collective inci-dence of 1:25000 live births [78].
Infants are usually normal at birth, and the diagnosis of amucopolysaccharidosis is suspected as the phenotype evolvesover time. The classic presentation occurs in the preschool-aged child with developmental delay, short stature, recurrentear and respiratory infections, hepatosplenomegaly, andcoarsening facial features, then multiorgan involvement withadditional clinical features evolves over time [56]. Themucopolysaccharidoses are chronic disorders which presentafter infancy as either severe bone dysplasia or dysmorphicfeatures with learning difficulties, behavior problems, andeventual cognitive decline. They are occasionally associatedwith other psychiatric symptoms, including sleep and behav-ior problems, autistic symptoms, and hyperactivity [78, 80].Psychosis occurs with adult onset forms in a variety ofmucopolysaccharidoses [].
Early diagnosis and intervention improve outcome, whichhas led to newborn screening, so far only for MPS I.Combined multiple assay of GAGs for screening is underdevelopment []. Enzyme replacement therapy is available forMPS I, MPS II, MPS IV, MPS VI, and MPS VII. Diagnosisprenatally or in the perinatal period allows for treatment beforethe onset of clinical symptoms. The beneficial effects of en-zyme replacement are soon lost if treatment is discontinued,
1654 SN Compr. Clin. Med. (2020) 2:1646–1660
and stopping replacement leads to significant worsening of thepatient’s clinical status and increased risk of death [81].
Hurler (MPS I)
Mucopolysaccharidosis I (Hurler disease, MPS I) is related toa deficiency of α-1-iduronidase which leads to accumulationof dermatan sulfate and heparan sulfate. MPS I typically pre-sents with dysmorphic facial features and skeletal deformities,and anxiety, learning problems, and restlessness are noted at ayoung age. Treatment with laronidase before 5 years can leadto symptomatic improvement. Untreated, patients with severeMPS I usually die before 10 years old from cardiac and respi-ratory disease [81].
Hunter (MPS II)
Mucopolysaccharidosis II (Hunter disease, MPS II) is themost common of the mucopolysaccharidoses. It is related toa deficiency of iduronate sulfatase, and results in the decreasedbreakdown of dermatan sulfate and heparan sulfate. Hunterdisease is the only mucopolysaccharidosis that is X-linked,with an incidence 1:111000 male births. Symptomatic femalecarriers are very rare. MPS II is associated with dysmorphicfeatures, hyperactivity, delayed language, seizures, fearful-ness, and neurodegeneration. Treatment with idursulfase be-fore age 5 years is effective in improving clinical status [81].
Sanfilippo (MPS III)
Mucopolysaccharidosis III (Sanfilippo syndrome, MPS III)is found in 0.28 to 4.1 per 100,000 births. It results from adeficiency in one of the four enzymes needed to breakdown heparan sulfate, which is found in the extracellularmatrix and cell surface glycoproteins. Heparan sulfate thenaccumulates and can be found in urine. This disorder pri-marily affects the nervous system, and presents early withdevelopmental and speech delay, progressing to severe dis-ruptive behavior, hyperactivity, and profound sleep prob-lems by 3 to 4 years. After age 10, neurologic and psychi-atric problems develop, with hyperactivity, chaotic behav-ior, aggression, restlessness, biting/mouthing, autistic be-haviors, and hypersensitivity [80]. Loss of skills continueswith slow deterioration into a vegetative state, usuallyleading to death in the third decade [82].
Peroxisomal Disorders
Adrenoleukodystrophy
Peroxisomes are small intracytoplasmic membrane-boundorganelles which contain catalase and oxidases. X-linked
adrenoleukodystrophy (ALD) is a peroxisomal disorderthat is found in all ethnicities with an overall incidenceof 1:18000 to 1:20000 male births in the USA [83, 84].ALD is caused by mutations in the ABCD1 gene whichleads to the accumulation of very-long-chain fatty acids(VLCFAs) in plasma and tissue [85]. The defect in X-linked ALD codes for a peroxisomal membrane protein[86].
VLCFAs are a major component of CNS membranesand can be toxic when not effectively metabolized. Theaccumulation of VLCFA leads to degenerative changesand cerebral demyelination, loss of axons, and myelin inlong tracts of the spinal cord, and an inflammatory reac-tion in white matter. “Lorenzo’s oil,” a 4:1 mixture ofglyceryl trioleate and glyceryl trierucate, may have someeffect in delaying symptoms of the disease when given inasymptomatic patients. When combined with at leastmoderate reduction of dietary fat, it may normalize orsignificantly lower plasma VLCFA within 4 weeks, butbenefits do not last and the clinical efficacy for Lorenzo’soil remains controversial [87].
The most common age of onset of cerebral ALD is 2 to10 years with rapidly progressive neurodegeneration andcerebral and spinal cord demyelination. One-third of boyswith ALD will develop small inflammatory brain lesionsthat insidiously grow before symptoms manifest [88].Attention-deficit hyperactivity symptoms and other be-havior changes occur early, and are followed by progres-sive cognitive and neurologic deficits, clumsiness, visualdisturbances, seizures, and adrenal dysfunction, then neu-rologic deterioration leads to a vegetative state and deathsoon after [89].
There can be extreme variability in presentation ofALD, and onset and symptoms may differ in membersof the same family, even between twins. ALD may beless severe when it first presents in adolescence (10%patients) with adrenal insufficiency, neurologic dysfunc-tion, and psychiatric symptoms. The adult form of ALDmay present with adrenomyeloneuropathy and slowly pro-gressive spinal disease (25%), at a slightly older age in anolivo-ponto-cerebellar form (8%), or in still older maleswho had unrecognized symptoms earlier and then presentin an adult cerebral form (21%) with gonadal insufficien-cy, cognitive decline, and neurologic and psychiatricsymptoms. ALD may rarely present with adrenal symp-toms alone [89], and the lifetime prevalence of adrenalsymptoms in ALD is about 80%, which warrants regularadrenal assessment in ALD patients [90].
Female carriers of ALD are typically asymptomatic un-til over 30 years of age, and half have symptoms after age40 years, usually with mild myelopathy, increased deeptendon reflexes, and sensory changes in their legs [5, 91].Many symptomatic females are initially diagnosed with
1655SN Compr. Clin. Med. (2020) 2:1646–1660
multiple sclerosis until diagnosis is made in a male in thefamily [92]. A milder and later onset adrenomyeloneuropathyis described in a minority of carriers. Cerebral involvementcan rarely occur in carriers in middle age or later, and clinicaladrenal insufficiency and psychosis are very rare in carriers ofany age [5, 83].
Approximately 40% patients present with psychiatricsymptoms and 20% present with a psychiatric problemexclusively, resembling bipolar disorder or schizophrenia[93].
Psychiatric symptoms with psychosis resemblingschizophrenia may be found in up to 25% of adolescentsand adults with ALD. The diagnosis of ALD becomesmore likely when psychosis is associated with cognitiveimpairment, visual hallucinations, and resistance to anti-psychotic treatment. Catatonia, depression, mania, andobsessive-compulsive disorder are also reported, and cat-aplexy triggered by emotions may rarely occur [91].
Patients with ALD may not respond to antipsychoticsin expected ways, and they may be particularly vulnerableto adverse side effects which may worsen the disease pro-cess. Dystonic side effects from neuroleptics may worsenfunctional impairment by adding rigidity and bradykinesiato spasticity seen with ALD. Akathisia is especially
troublesome if the ALD patient cannot move. Atypicalantipsychotics are generally preferred, but anticholinergicside effects may exacerbate cognitive impairment, dys-phagia from dryness, and hypotension. Manic symptomsare frequent with ALD, and mood stabilizers can be help-ful, although lithium may be a problem because of ALDcan potentially be associated with electrolyte abnormali-ties from adrenal involvement. Benzodiazepines may helpspasticity and agitation with mania but may worsen ataxia[94].
Bone marrow or cord blood stem cell transplant can haltthe progression of ADL and currently offer the best out-come for patients with ALD [88]. Patients younger than4 years with no or only mild gross motor defects and min-imal if any MRI changes when transplanted are likely tohave the most benefit and the mildest course [95]. Patientswith larger cerebral lesions at the time of transplant haveworse clinical outcomes [96], and nontransplanted patientsare most likely to die of disease progression [95]. Genetherapy for ADL using elivaldogene tavalentivec viral vec-tor may provide an alternative to bone marrow transplant[97]. Ultimately, newborn screening for ADL will allowfor early diagnosis and intervention and yield the bestprognosis [98] (Table 2).
Table 2 Checklist of psychiatric symptoms associated with inborn errors
Psychosis Depression Agitation Mania Anxiety Obsessive-compulsivebehavior
Inattention Hyperactivity Disorganizedbehavior,confusion
Autisticbehavior
Porphyria X X X X X X
Wilson’s X X X X X
Phenylketonuria X X X
Homocysteinemia X X X X
MTHFR X
Cobalamin C X X
Urea cycle defects X X X
OCT deficiency X X X
Citrullinemia X X X
Tay-Sachs disease,adult
X X
Niemann-Pick C X X X X X
Gaucher’s disease X X
Neuronal ceroidlipofuscinosis
X X X X
Fabry’s disease X
Metachromaticleukodystrophy
X X
MPS I X
MPS II X
MPS III X X X
Adrenoleukodystrophy X X X X X X X
MELAS X X X X
1656 SN Compr. Clin. Med. (2020) 2:1646–1660
Mitochondrial Disorders
Mitochondrial Encephalopathy, Lactic Acidosis, andStroke-Like Episodes
Mitochondrial encephalopathy, lactic acidosis, and stroke-likeepisodes (MELAS) is a progressive neurodegenerative disor-der associated with polygenetic, maternally inherited mito-chondrial DNA mutations [99]. MELAS usually presents inchildhood and late adolescence, between 2 and 20 years in70% of patients. MELAS is characterized by seizures, enceph-alopathy, stroke, short stature, cognitive impairment, mi-graines, depression, cardiomyopathy, cardiac conduction de-fects, and diabetes mellitus [100]. The stroke-like lesions aretypically in the posterior of the brain, and focal cerebellarinfarction can be the initial sign of MELAS [101].Psychiatric features may predate the diagnosis of MELASand include depressed mood, anxiety, psychosis, cognitivedecline, behavioral disturbance, and aggression [105].Course and prognosis are variable, but progressive cognitive
decline typically leads to dementia, increasing disability, andpremature death [99].
Conclusion
While cognitive problems are probably the most commonneuropsychiatric symptoms overall, symptoms of psychosis,attention problems, anxiety, mood disturbance, confusion, anddisorganized behavior can be seen with multiple IEMs, espe-cially those affecting the central nervous system. It is impor-tant for physicians to be aware that genetic disorders maypresent with only psychiatric symptoms or with systemicsymptoms in addition. The definitive diagnosis of an IEMcan only be made when the physician’s suspicions lead tofurther investigation [3].
Consultation with a specialist is recommended when a pa-tient presents with psychiatric symptoms and an inborn errorof metabolism is suspected.
Psychosis
Neuronal Ceroid Lipofuscinosis (AR, AD)
Metachroma�c leukodystrophy (AR, few AD)
Fabry’s Disease (XR)
Homocysteinemia Cobalamin disorders
MTHFR
Homocys�nuria (AR)
Lysosomaldisorders
Niemann-Pick Type C (AR)
Adrenoleuko-dystrophy (XR)
Citrullinemia (AR)
Porphyria (AD)
Wilson’s Disease (AR)
Late onsetTay-Sachs (AR)
Late onset Gaucher’s (AR)
OCT deficiency (XR)
Urea Cycle Defects:Increased serum ammonia
Variable presenta�on within same family
Liver dysfunc�on,abnormal MRI
Abdominal pain, Red-brown urine
2 forms
Stored material in mul�ple �ssues
Severe extremity pain
Megaloblas�c anemia
Decision tree to facilitate differential diagnosis of psychosis occurring in association with inborn errors of metabolism
1657SN Compr. Clin. Med. (2020) 2:1646–1660
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflicts ofinterest.
Ethical Statement This manuscript is based on literature review.
Ethical Approval Patient charts were not reviewed. This article does notcontain any data from a new study with human participants performed byany of the authors. Institutional ReviewBoard clearance was not required.
References
1. Ahrens-Nicklas RC, Slop G, Ficiciolu C. Adolescent presenta-tions of inborn errors of metabolism. J Adolesc Health. 2015;56:477–82. https://doi.org/10.1016/j.jadohealth.2015.01.008.
2. Saudubray J-M, Garcia-Cazorla A. Inborn errors of metabolismoverview: pathophysiology, manifestations, evaluation, and man-agement. Pediatr Clin N Am. 2018;65:179–208.
3. Mak CM, Lee H-CH, Chan AY-W, Lam C-W. Inborn errors ofmetabolism and expanded newborn screening: review and update.Crit Rev Clin Lab Sci. 2013;50:142–62.
4. Estrov Y, Scaglia F, Bodamer OAF. Psychiatric symptoms ofinherited metabolic disease. J Inherit Metab Dis. 2000;23:2–6.
5. Walterfang M, Bonnot O, Mocellin R, Velakoulis D. The neuro-psychiatry of inborn errors of metabolism. J Inherit Metab Dis.2013;36:687–702. https://doi.org/10.1007/s10545-013-9618-yEpub 2013 May 23.
6. Gambello MJ, Li H. Current strategies for the treatment of inbornerrors of metabolism. J Genet Genomics. 2018;45:61–70.
7. Horvath GA, Stowe RM, Ferreira CR, Blau D. Clinical and bio-chemical footprints of inherited metabolic diseases. III Psychiatricpresentations. Mol Genet Metab. 2020;130:1–6.
8. Demily C, Sedel F. Psychiatric manifestations of treatable hered-itary metabolic disorders in adults. Ann General Psychiatry.2014;13:27–35.
9. Trakadis YJ, Fulginiti V, Walterfang M. Inborn errors of metabo-lism associated with psychosis: literature review and case-controlstudy using exome data from 5090 adult individuals. J InheritMetab Dis. 2018;41:613–21. https://doi.org/10.1007/s10545-017-0023-9.
10. Bonnot O, Herrera PM, Tordjman S, Walterfang M. Secondarypsychosis induced by metabolic disorders. Front Neurosci.2015;9:177. https://doi.org/10.3389/fnins.2015.00177.
11. Sriretnakumar V, Harripaul R, Vincent JB, Kennedy JL, So J.Enrichment of pathogenic variants in genes associated with inbornerrors of metabolism in psychiatric populations. Am JMed Genet.2019;180B:46–54.
12. Nia S. Psychiatric signs and symptoms in treatable inborn errors ofmetabolism. J Neurol. 2014;261(Suppl 2):S559–68.
13. El-Hattab AW. Inborn errors of metabolism. Clin Perinatol.2015;42:413–39.
14. Simon NG, Herkes GK. The neurologic manifestations of theacute porphyrias. J Clin Neurosci. 2011;18:1147–53.
15. Bonkovsky HL, Maddukuri VC, Yazici C, Anderson KE, BissellDM, Bloomer JR, et al. Acute prophyrias in the USA: features of108 subjects from porphyrias consortium. Am J Med. 2014;127:1233–41. https://doi.org/10.1016/j.amjmed.2014.06.036 Epub2014 Jul 10.
16. Manceau H, Gouya L, Puy H. Acute hepatic and erythropoieticporphyrias: from ALA syntheses 1 and 2 to new molecular basesand treatments. Curr Opin Hematol. 2017;24:198–207.
17. Ellencweig N, Schoenfeld N, Zemishlany Z. Acute intermittentporphyria: psychosis as the only clinical manifestation. Israel JPsychiatry Relat Sci. 2006;43:52–6.
18. Holroyd S, Seward RL. Psychotropic drugs in acute intermittentporphyria. Clin Pharmacol Ther. 1999;66:323–5.
19. Wu F, Wang J, Pu C, Qiao L, Jiang C. Wilson’s disease: a com-prehensive review of the molecular mechanisms. Int J Mol Sci.2015;16:6419–31. https://doi.org/10.3390/ijms16036419.
20. Lutsenko S. Modifying factors and phenotypic diversity inWilson’s disease. Ann N Y Acad Sci. 2014;1315:56–63. https://doi.org/10.1111/nyas.12420 Epub 2014 Apr 4.
21. Rosencrantz R, Schilsky M. Wilson disease: pathogenesis andclinical considerations in diagnosis and treatment. Semin LiverDis. 2011;31:245–59.
22. Zimbrean PC, Schilsky ML. Psychiatric aspects of Wilson dis-ease: a review. Gen Hosp Psychiatry. 2014;36:53–62. https://doi.org/10.1016/j.genhosppsych.2013.08.007 Epub 2013 Oct 9.
23. Dening TR, Berrios GE. Wilson’s disease: a longitudinal study ofpsychiatric symptoms. Biol Psychiatry. 1990;28:255–65.
24. Valentino PL, Roberts EA, Beer S, Miloh T, Arnon R, VittorioJM, Schilsky ML. Management of Wilson disease diagnosed ininfancy: an appraisal of available experience to generate discus-sion. J Pediatr Gastroenterol Nut 2020; 70:547–54. https://doi.org/10.1097/MPG0000000000002608.
25. Poujois A, Devedjian JC, Moreau C, Devos D, Chaine P,Woimant F, et al. Bioavailable trace metals in neurological dis-eases. Curr Treat Options Neurol. 2016;18:46. ISSN 1092-8480.https://doi.org/10.1007/s11940-016-0426-1.
26. Weiss KH, Schäfer M, Gotthardt DN, Angerer A, Mogler C,Schirmacher P, et al. Outcome and development of symptomsafter orthotopic liver transplantation for Wilson disease. ClinTranspl. 2013;27:914–22. https://doi.org/10.1111/ctr.12259Epub 2013 Oct 9.
27. Srinivas K, Sinha S, Taly AB, Prashanth LK, Arunodaya GR,Janardhana Reddy YC, et al. Dominant psychiatric manifestationsin Wilson’s disease: a diagnostic and therapeutic challenge. JNeurol Sci. 2008;266:104–8 Epub 2007 Sep 27.
28. Svetel M, Potrebić A, Pekmezović T, Tomić A, Kresojević N,Jesić R, et al. Neuropsychiatric aspects of treated Wilson’s dis-ease. Parkinsonism Relat Disord. 2009;15:772–5.
29. Bone A, Kuehl AK, Angelino AF. A neuropsychiatric perspectiveof phenylketonuria. I: overview of phenylketonuria and its neuro-psychiatric sequelae. Psychosomatics. 2012;53:517–23. https://doi.org/10.1016/j.psym.2012.04.010.
30. Erlich KJ. Case report: neuropsychiatric symptoms in PKU dis-ease. J Pediatr Health Care. 2020;33:718–21.
31. Pilotto A, Blau N, Leks E, Schulte C, Deuschl C, Zipser C, et al.Cerebrospinal fluid biogenic amines depletion and brain atrophyin adult patients with phenylketonuria. J Inherit Metab Dis.2019;42:398–406.
32. Feillet F, Agostoni C. Nutritional issues in treating phenylketon-uria. J Inherit Metab Dis. 2010;33:659–64. https://doi.org/10.1007/s10545-010-9043-4 Epub 2010 Feb 12.
33. Ris MD, Weber AM, Hunt MM, Berry HK, Williams SE, LeslieN. Adult psychosocial outcome in early-treated phenylketonuria. JInherit Metab Dis. 1997;20:499–508.
34. Blau N, Longo N. Alternative therapies to address the unmetneeds of patients with phenylketonuria. Expert OpinPharmacother. 2015;16:791–800.
35. Fowler B. Disorders of homocysteine metabolism. J Inherit MetabDis. 1997;20:270–85.
36. Ramakrishnan S, Sulochana KN, Lakshmi S, Selvi R,Angayarkanni N. Biochemistry of homocysteine in health anddisease. Indian J Biochem Biophys. 2006;43:275–83.
1658 SN Compr. Clin. Med. (2020) 2:1646–1660
37. Watkins D, Rosenblatt DS. Inborn errors of cobalamin absorptionand metabolism. Am J Med Genet. 2011;157:33–44. https://doi.org/10.1002/ajmg.c.30288 Epub 2011 Feb 10.
38. Reif A, Pfuhlmann B, Lesch KP. Homocysteinemia as well asmethylenetetrahydrofolate reductase polymorphism are associatedwith affective psychoses. Prog Neuro-Psychopharmacol BiolPsychiatry. 2005;29:1162–8.
39. RyanMM, Sidhu RK, Alexander J, Megerian JT. Homocystinuriapresenting as psychosis in an adolescent. J Child Neurol. 2002;17:859–60.
40. Almuqbil MA, Waisbren SE, Levy HL, Picker JD. Revising thepsychiatric phenotype of homocystinuria. Genet Med. 8:1827–31.
41. Regland B, Germgård T, Gottfries CG, Grenfeldt B, Koch-Schmidt AC. Homozygous thermolabile methylenetetrahydrofo-late reductase in schizophrenia-like psychosis. J Neural Transm(Vienna). 1997;104:931–41.
42. Nazki FH, Sameer AS, Ganaie BA. Folate: metabolism, genes,polymorphisms and associated diseases. Gene. 2014;533:11–20.
43. Huemer M, Diodato D, Schwahn B, Schiff M, Bandeira A,Benoist J-F, et al. Guidelines for the diagnosis and managementof cobalamin-related remethylation disorders cblC, cblD, cblE,cblF, cblG, cblJ and MTHFR deficiency. J Inherit Metab Dis.2017;40:21–48. https://doi.org/10.1007/ss10545-016-9991-4.
44. Yadav U, Kumar P, Gupta S, Rai V. Role ofMTHFRC677T genepolymorphism in the susceptibility of schizophrenia: an updatedmeta-analysis. Asian J Psychiatr. 2016;20:41–51. https://doi.org/10.1016/j.ajp.2016.02.002 Epub 2016 Feb 15.
45. Martinelli D, Deodato F, Dionisi-Vici C. Cobalamin C defect:natural history, pathophysiology, and treatment. J Inherit MetabDis. 2011;34:127–35. https://doi.org/10.1007/s10545-010-9161-zEpub 2010 Jul 15. Review.
46. Wang S, Chuan C, Wen B, Zhao Y. Clinical feature and outcomeof late-onset cobalamin C disease patients with neuropsychiatricpresentations: a Chinese case series. Neuropsychiatr Dis Treat.2019;15:549–55.
47. Huemer M, Scholl-Burgi S, Hadaya K, Kern I, Beer R, Seppi K,et al. Three new cases of late-onset cblC defect and review of theliterature illustrating when to consider inborn errors of metabolismbeyond infancy. Orphanet J Rare Dis. 2014;9:161. https://doi.org/10.1186/s13023-014-0161-1.
48. Tonini MC, Bignamini V, Mattioli M. Headache and neuropsy-chiatric disorders in the puerperium: a case report with suspecteddeficiency of urea cycle enzymes. Neurol Sci. 2011;32(Suppl 1):S157–9. https://doi.org/10.1007/s10072-011-0518-3.
49. Batshaw ML, Tuchman M, Summar M, Seminara J, Members ofthe Urea Cycle Disorders Consortium. A longitudinal study ofurea cycle disorders. Mol Genet Metab. 2014;113:127–30.https://doi.org/10.1016/j.ymgme.2014.08.001 Epub 2014Aug 10. Review.
50. Thurlow VR, Asafu-Adjaye M, Agalou S, Rahman Y. Fatal am-monia toxicity in an adult due to an undiagnosed urea cycle defect:under-recognition of ornithine transcarbamylase deficiency. AnnClin Biochem. 2010;47:279–81. https://doi.org/10.1258/acb.2010.009250 Epub 2010 Apr 20.
51. Bigot A, Brunault P, Lavigne C, Feillet F, Odent S, Kaphan E,et al. Psychiatric adult-onset of urea cycle disorders: a case series.Mol Genet Metab Rep. 2017;12:103–9.
52. Gallagher RC, Lam C, Wong D, Cederbaum S, Sokol RJ.Significant hepatic involvement in patients with ornithinetranscarbamylase deficiency. J Pediatr. 2014;164:720–5.
53. Fassier T, Guffon N, Acquaviva C, D'Amato T, Durand DV,Domenech P. Misdiagnosed post-partum psychosis revealing alate onset urea cycle disorder. Am J Psychiatry. 2010;168:576–80. https://doi.org/10.1176/appi.ajp.2010.10071032.
54. Gordon N. Ornithine transcarbamylase deficiency: a urea cycledefect. Eur J Paediatr Neurol. 2003;7:115–21.
55. Kyo M, Mii H, Takekita Y, Tokuhara D, Yazaki M, Nakamori Y,et al. Case of adult-onset type II citrullinemia treated as schizo-phrenia for a long time. Psychiatry Clin Neurosci. 2015;69:306–7.https://doi.org/10.1111/pcn.12253 Epub 2014 Dec 29.
56. Sun A. Lysosomal storage disease overview. Ann Transl Med.2018;6:476. https://doi.org/10.21037/atm.2018.11.39.
57. Platt FM, d’Azzo A, Davidson BL, Neufeld EF, Tifft CJ.Lysosomal storage diseases. Nat Rev Dis Primers. 2018;4:27.https://doi.org/10.1038/s41572-01809925-4.
58. Staretz-Chacham O, Choi JH, Wakabayashi K, Lopez G,Sidransky E. Psychiatric and behavioral manifestation of lyso-somal storage disorders. Am J Med Genetics Part B.2010;153B:1253–65.
59. Holve S, Hu D, McCandless SE. Metachromatic leukodystrophyin the Navajo: fallout of the American-Indian wars of the nine-teenth century. Am J Med Genet. 2001;101:203–8.
60. Van Rappard DF, de Vries ALC, Oostrom KJ, Boelens JJ, HollakCEM, van der Knapp MJ, et al. Slowly progressive psychiatricsymptoms: think metachromatic leukodystrophy. J Am AcadChild Adolesc Psychiatry. 2018;57:74–6.
61. Hyde TM, Ziegler JC,Weinberger DR. Psychiatric disturbances inmetachromatic leukodystrophy: insights into the neurobiology ofpsychosis. Arch Neurol. 1992;49:401–6.
62. Strölin M, Krägeloh-Mann I, Kehrer C, Wilke M. Demyelinationload as predictor for disease progression in juvenile metachromat-ic leukodystrophy. Ann Clin Transl Neurol. 2017;4:403–10.
63. Krägeloh-Mann I, Groeschel S, Kehrer C, Opherk K, Nägele T,Handgretinger R, et al. Juvenilemetachromatic leukodystrophy 10years post-transplant compared with a non-transplanted cohort.Bone Marrow Transplant. 2013;48:369–75.
64. Van den Broek BTA, Page K, Paviglianiti A, Hol J, Allewelt H,Volt F, et al. Early and late outcomes after cord blood transplan-tation for pediatric patients with inherited leukodystrophies. BloodAdv. 2018;2:49–60.
65. McDowell GA, Mules EH, Fabacher P, Shapira E, Blitzer MG.The presence of two different infantile Tay-Sachs disease muta-tions in a Cajun population. Am J Hum Genet. 1992;S1:1071–7.
66. Solovyeva VV, Shaimardanova AA, Chulpanova DS, KitaevaKV, Chakrabarti L, Rizvanov AA. New approaches to Tay-Sachs disease therapy. Front Physiol. 2018;9:1663. https://doi.org/10.3389/fphys.2018.01663 eCollection 2018.
67. Turkel SB, Levine M. Ultrastructural study of fetal Tay-Sachsdisease. Ultrastruct Res. 1976;55:302.
68. Hurowitz GI, Silver JM, Brin MF, Williams DT, Johnson WG.Neuropsychiatric aspects of adult-onset Tay-Sachs disease: twocase reports with several new findings. J Neuropsychiatr ClinNeurosci. 1993;5:30–6.
69. Benussi A, Alberici A, Premi E, Castiglioni I, Padovani A,Borroni B. Phenotypic heterogeneity of Niemann-Pick diseasetype C in monozygotic twins. J Neurol. 2015;262:642–7. https://doi.org/10.1007/s00415-014-7619-x Epub 2014 Dec 24.
70. Vanier MT, Millat G. Niemann-Pick disease type C. Clin Genet.2003;64:269–81.
71. Sandu S, Jacüowski-Dohrmann S, Ladner A, Haberhausen M,Bachmann C.Niemann-Pick disease type C1 presenting psychosisin an adolescent male. Eur Child Adolesc Psychiatry. 2009;18:583–5. https://doi.org/10.1007/s00787-009-0010-2 Epub 2009Mar 7.
72. Raja M, Azzoni A, Giona F, Regis S, Grossi S, Filocamo M, et al.Movement and mood disorder in two brothers with Gaucher dis-ease. Clin Genet. 2007;72:357–61.
73. Geraets RD, Koh SY, Hastings ML, Kielian T, Pearce DA,Weimer JM. Moving towards effective therapeutic strategies forneuronal ceroid lipofuscinosis. Orphanet J Rare Dis. 2016;11:40–52.
1659SN Compr. Clin. Med. (2020) 2:1646–1660
74. Cotman SL, Karaa A, Staropoli JF, Sims KB. Neuronal ceroidlipofuscinosis: impact of recent genetic advances and expansionof the clinicopathologic spectrum. Curr Neurol Neurosci Rep.2012;13:366. https://doi.org/10.1007/s11910-013-366-z.
75. Gairing S, Wiest R, Metzler S, Theodoridou A, Hoff P. Fabry’sdisease and psychosis: causality or coincidence? Psychopathol.2011;44:201–4. https://doi.org/10.1159/000322794 Epub 2011Mar 17.
76. Tsuboi K, Yamamoto H. Efficacy and safety of enzyme-replacement therapy with agalsidase alfa in 36 treatment-naïveFabry disease patients. BMC Pharmacol Toxicol. 2017;18:43.https://doi.org/10.1186/s40360-017-0152-7.
77. McCafferty EH, Scott LJ. Migalastat: a review in Fabry disease.Drugs. 2019;79:543–54. https://doi.org/10.1007/s40265-019-01090-4.
78. Tomatsu S, Fujii T, Fuüshi M, Oguma T, Shimada T, Maeda M,et al. Newborn screening and diagnosis of mucopolysaccharidoses.Mol Genet Metab. 2013;110:42–53.
79. Opoka-Winiarska V, Jurecka A, Emeryk A, Tylki-Szymańska A.Osteoimmunology in mucopolysaccharidosis type I, II, VI, andVII: immunologic regulation of the osteoarticular system in thecourse of metabolic inflammation. Osteoarthr Cartil. 2013;21:1813–23. https://doi.org/10.1016/j.joca.2013.08.001 Epub 2013Aug 13.
80. Zelei T, Csetneki K, Vokó Z, Siffel C. Epidemiology of Sanfilipposyndrome: results of a systematic literature review. Orphanet JRare Dis. 2018;13:53. https://doi.org/10.1186/s13023-018-0796-4.
81. Muenzer J. Early initiation of enzyme replacement therapy for themucopolysaccharidoses. Mol Genet Metab. 2014;111:63–72.
82. Andrade F, Aldámiz-Echevarría L, Llarena M, Couce ML.Sanfilippo syndrome: overall review. Pediatr Int. 2015;57:331–8. https://doi.org/10.1111/ped.12636.
83. Moser HW, Mahmood A, Raymond GV. X-linked adrenoleuko-dystrophy. Nature Clin Prac Neurol. 2007;3:140–51.
84. Kassmann CM. Myelin peroxisomes – essential organelles for themaintenance of white matter in the nervous system. Biochimie.2014;98:111–8. https://doi.org/10.1016/j.biochi.2013.09.020Epub 2013 Oct 9. Review.
85. Kemp S, Huffnagel IC, Linthorst G, Wanders RJ, Engelen M.Adrenoleukodystrophy – neuroendocrine pathogenesis and redef-inition of natural history. Nat Rev Endocrinol. 2016;12:606–15.
86. Ferrer I, Aubourg P, Pujol A. General aspects and neuropathologyof X-linked adrenoleukodystrophy. Brain Pathol. 2010;20:817–30. https://doi.org/10.1111/j.1750-3639.2010.00390.x Review.
87. Berger J, Pujol A, Aubourg P, Forss-Petter S. Current and futurepharmacological treatment strategies in X-linked adrenoleukodys-trophy. Brain Pathol. 2010;20:845–56. https://doi.org/10.1111/j.1750-3639.2010.00393.x.
88. Haren KV, Engelen M. Decision making adrenoleukodystrophy:when is a good outcome really a good outcome? JAMA Neurol.2017;74:641–2. https://doi.org/10.1001/jamaneurol.2017.0095.
89. Takemoto Y, Suzuki Y, Tamakoshi A, Onodera O, Tsuji S,Hashimoto T, et al. Epidemiology of X-linked adrenoleukodys-trophy in Japan. J Hum Genet. 2002;47:590–3. https://doi.org/10.1007/s100380200090.
90. Huffnagel IC, Laheji FK, Aziz-Bose R, Tritos NA, Marino R,Linthorst GE, et al. The natural history of adrenal insufficiencyin X-linked adrenoleukodystrophy: an international collaboration.J Clin Endocrinol Metab. 2019;104:118–26. https://doi.org/10.1210/jc.2018-81307.
91. Patterson MC. Inborn errors of metabolism for neurology resi-dents. Semin Pediatr Neurol. 2011;18:95–7. https://doi.org/10.1016/j.spen.2011.06.016.
92. Tran C, Patel J, Stacy H, Mamak EG, Faghfoury H, Raiman J,et al. Long-term outcome of patients with X-linked adrenoleuko-dystrophy: a retrospective cohort study. Eur J Paediatr Neurol.2017;21:600–9.
93. Kitchin W, Cohen-Cole SA, Mickel SF. Adrenoleukodystrophy:frequency of presentation as a psychiatric disorder. BiolPsychiatry. 1987;22:1375–87.
94. Garside S, Rosebush PI, Levinson AJ, Mazurek MF. Late-onsetadrenoleukodystrophy associated with long-standing psychiatricsymptoms. J Clin Psychiatry. 1999;60:460–8.
95. Groeschel S, Kühl JS, Bley AE, Kehrer C,Weschke B, Döring M,et al. Long-term outcome of allogeneic hematopoietic stem celltransplantation in patients with juvenile metachromatic leukodys-trophy compared with nontransplanted control patients. JAMANeurol. 2016;73:1133–40.
96. Kühl J-S, Kupper J, Baqué H, Ebell W, Gärtner J, Korenke C,et al. Potential risks to stable long-term outcome of allogenic he-matopoietic stem cell transplantation for children with cerebral x-linked adrenoleukodystrophy. JAMA Netw Open. 2018;1:e180769. https://doi.org/10.1001/jamanetworkopen.2018.0769.
97. Eichler F, Duncan D, Musolino PL, Orchard PJ, De Olieveira S,Thrasher AJ, et al. Hematopoietic stem-cell gene therapy for ce-rebral adrenoleukodystrophy. N Engl J Med. 2017;377:1630–8.
98. Bessey A, Chilcott JB, Leaviss J, Sutton A. Economic impact ofscreening for X-linked adrenoleukodystrophy within a newbornblood spot screening programme. Orphanet J Rare Dis. 2018;13:179. https://doi.org/10.1186/s13021-018-0921-4.
99. Kaufman KR, Zuber N, Rueda-Lara MA, Tobia A. MELAS withrecurrent complex partial seizures, nonconvulsive status epilepti-cus, psychosis, and behavioral disturbances: case analysis withliterature review. Epilepsy Behav. 2010;18:494–7. https://doi.org/10.1016/j.yebeh.2010.05.020 Epub 2010 Jun 26.
100. Sproule DM, Kaufmann P. Mitochondrial encephalopathy, lacticacidosis, and stroke like episodes: basic concepts, clinical pheno-type, and therapeutic management of MELAS syndrome. Ann NY Acad Sci. 2008;1142:133–58. https://doi.org/10.1196/annals.1444.011.
101. Ko A, Lee S-J, Lee Y-M. Focal cerebellar infarction as an initialsign of mitochondrial myopathy, encephalopathy, lactic acidosis,and stroke-like episodes. J Inherit Metab Dis. 2019;42:575–6.
102. Anglin RE, Garside SL, Tarnopolsky MA, Mazurek MF,Rosebush PI. The psychiatric manifestations of mitochondrialdisorders: a case and review of the literature. J Clin Psychiatry2012; 73:506–512. https://doi.org/10.4088/JCP.11r07237.
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1660 SN Compr. Clin. Med. (2020) 2:1646–1660
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