ped neurotransmitters disord

8/4/2019 Ped Neurotransmitters Disord

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Journal of Child Neurology

DOI: 10.1177/0883073807302619

2007; 22; 606J Child NeurolPhillip L. Pearl, Jacob L. Taylor, Stacey Trzcinski and Alex Sokohl

The Pediatric Neurotransmitter Disorders

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and serotonin. Figure 1 illustrates the key pathways involvedin their synthesis and degradation. Tryptophan is convertedto 5-hydroxytryptophan by the enzyme tryptophan hydroxy-lase. Likewise, tyrosine is converted to L-dopa by tyrosinehydroxylase. 5-Hydroxytryptophan and L-dopa are then con-

verted to serotonin and dopamine, respectively. Both of these

reactions are catalyzed by the same enzymearomatic L-amino acid decarboxylase. Serotonin and dopamine are bro-ken down through similar pathways, both of which involvemonoamine oxidase-A and -B. In addition, dopamine is con-

verted into norepinephrine by dopamine beta-hydroxylase.Deficiencies in tyrosine hydroxylase, aromatic amino aciddecarboxylase, monoamine oxidase, and dopamine beta-hydroxylase have been identified in human patients.

Tetrahydrobiopterin is a necessary cofactor for bothtryptophan hydroxylase and tyrosine hydroxylase. Therefore,enzymatic deficiencies that lead to reduced levels oftetrahydrobiopterin can interfere with the synthesis of the

monoamine neurotransmitters. Tetrahydrobiopterin is syn-thesized in 3 steps from guanine triphosphate (see Figure 2).Deficiencies have been identified in each of the enzymesin this pathway: guanine triphosphate cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, and sepiapterin reduc-tase. When tetrahydrobiopterin acts as a cofactor for

various hydroxylases (including tryptophan hydroxylase,tyrosine hydroxylase, and phenylalanine hydroxylase), it isconverted to pterin-4a-carbinolamine. This is then recy-cled back into tetrahydrobiopterin in a 2-step processinvolving the enzymes pterin-4a-carbinolamine dehy-dratase and dihydropteridine reductase.

The pediatric neurotransmitter disorders refer to aninherited group of neurometabolic syndromesattributable to a disturbance of neurotransmitter

metabolism. This represents an enlarging group of recog-nized disorders often requiring specialized diagnostic pro-cedures for detection. This review considers clinical

disorders of monoamine (catecholamine and serotonin),glycine, and -amino butyric acid (GABA) metabolism.Many of these disorders involve deficiencies in enzymesdirectly involved in the synthetic or degradative pathwaysof the neurotransmitters themselves. Other disordersinvolve enzymes that are involved in the synthesis ofessential cofactors. For example, tetrahydrobiopterin is anecessary cofactor for several enzymes that are involved inmonoamine synthesis. Chronically low levels of tetrahy-drobiopterin can therefore lead to chronically low levels ofmonoamine neurotransmitters. The specific disorders dis-cussed in this review are listed in Table 1.

Disorders of Monoamine Metabolism

The monoamine neurotransmitters include the cate-cholamines (dopamine, norepinephrine, and epinephrine)

Topical Review Article

The Pediatric Neurotransmitter Disorders

Phillip L. Pearl, MD, Jacob L. Taylor, BA, Stacey Trzcinski, BS, and Alex Sokohl, BA

The pediatric neurotransmitter disorders represent an enlarging

group of neurological syndromes characterized by abnormalities

of neurotransmitter synthesis and breakdown. The disorders of

dopamine and serotonin synthesis are aromatic amino acid

decarboxylase deficiency, tyrosine hydroxylase deficiency, and

disorders of tetrahydrobiopterin synthesis. Amino acid decar-

boxylase, tyrosine hydroxylase, sepiapterin reductase, and

guanosine triphosphate cyclohydrolase (Segawa disease) defi-

ciencies do not feature elevated serum phenylalanine and

require cerebrospinal fluid analysis for diagnosis. Segawa dis-

ease is characterized by dramatic and lifelong responsivenessto levodopa. Glycine encephalopathy is typically manifested

by refractory neonatal seizures secondary to a defect of the

glycine degradative pathway. -amino butyric acid (GABA)

metabolism is associated with several disorders, including glu-

tamic acid decarboxylase deficiency with nonsyndromic cleft lip/

palate, GABA-transaminase deficiency, and succinic semialde-

hyde dehydrogenase deficiency. The latter is characterized

by elevated -hydroxybutyric acid and includes a wide range

of neuropsychiatric symptoms as well as epilepsy. Pyridoxine-

dependent seizures have now been associated with deficiency

of alpha-aminoadipic semialdehyde dehydrogenase, as well

as a new variant requiring therapy with pyridoxal-5-phosphate,

the biologically active form of pyridoxine.

Keywords: neurotransmitters;-aminobutryric acid; dopamine

From the Department of Neurology, Childrens National Medical Center,The George Washington University School of Medicine, Washington, DC.

Address correspondence to: Phillip L. Pearl, MD, Department of Neurology,Childrens National Medical Center, 111 Michigan Ave, NW, Washington,DC 20010; e-mail: [email protected].

Pearl PL, Taylor JL, Trzcinski S, Sokohl A. The pediatric neurotransmitterdisorders.J Child Neurol. 2007;22:606-616.

Journal of Child Neurology

Volume 22 Number 5

May 2007 606-616

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Pediatric Neurotransmitter Disorders /Pearl et al 607

Disorders of Monoamine Synthesis

Tyrosine Hydroxylase Deficiency

Tyrosine hydroxylase catalyzes the conversion of tyrosineinto L-dopa. Tyrosine hydroxylase deficiency leads toimpaired synthesis of dopamine as well as epinephrine andnorepinephrine. This is an autosomal recessive condition,with gene locus 11p15.5. It is represented by a progressiveencephalopathy and poor prognosis. Clinical featuresinclude dystonia that is minimally or nonresponsive to L-dopa, extrapyramidal symptoms, ptosis, miosis, and posturalhypotension. This is a progressive and often lethal disorder,which can be improved but not cured by L-dopa.Conservative dosing is advocated.1 A combination of low-dose L-dopa (3 mg/kg/d divided in 6 doses) with selegiline

(5 mg/d in a single dose) was reported as helpful in 1patient.2

Aromatic Amino Acid Decarboxylase Deficiency

Aromatic amino acid decarboxylase deficiency is an auto-somal recessive disorder that combines serotonin and cat-echolamine deficiency. The gene locus is 7p11. Aromaticamino acid decarboxylase catalyzes the decarboxylation ofL-dopa and 5-hydroxytryptophan to dopamine and sero-tonin, respectively. Aromatic amino acid decarboxylasedeficiency is characterized by a cerebrospinal fluid profileof low homovanillic acid and 5-hydroxyindoleacetic acid,

high L-dopa, 5-hydroxytryptophan, 3-O-methyldopa (an L-dopa metabolite), and normal pterin levels. The associatedclinical features are hypotonia and extrapyramidal move-ment disorders such as torticollis, dystonia, blepharospasm,athetosis, and myoclonus. Other manifestations are pro-found developmental delay, irritability, sleep disturbances,and autonomic manifestations such as temperature insta-

bility, impaired diaphoresis, hypersalivation, recurrent syn-cope, or cardiorespiratory arrest. Impaired sympatheticresponses, with maintenance of systemic blood pressure fol-lowing nitroprusside infusion, are demonstrable.3 The syn-drome may present in the neonate with hypothermia,lethargy, poor sucking, ptosis, and hypotension.4 Typically,patients are initially diagnosed with cerebral palsy, epilepsy,suspected mitochondrial encephalopathies, myasthenia, orhyperekplexia. Neuroimaging is generally unremarkable butmay reveal progressive cerebral atrophy.

Treatment effects appear highly variable. Some authorsadvocate conservative dosing of levadopa/carbidopa, titrat-

ing slowly over weeks or months with L-dopa, while usingample carbidopa to block peripheral aromatic amino aciddecarboxylase enzymatic activity.1 This includes givingmore frequent and lower doses throughout the day. Varioustherapies have been tried in a limited number of patients.Pons et al4 review a series of 13 patients (6 cases plus 7from literature reports) and describe 1 group (5 males)who responded to treatment and made developmentalprogress, as well as 1 group (1 male, 5 females) whoresponded poorly to treatment and often developed drug-induced dyskinesias. Treatments reported in this condition areanecdotal and include pyridoxine (cofactor for the enzyme),

dopamine receptor agonists, trihexyphenidyl, monoamine oxi-dase inhibitors, antiepileptic agents, serotonergic agents, bus-pirone, and melatonin.1,4,5

6-Pyruvoyl-Tetrahydropterin Synthase and OtherTetrahydrobiopterin Defects With PeripheralHyperphenylalaninemia

In addition to acting as a cofactor for tryptophan hydroxy-lase and tyrosine hydroxylase, tetrahydrobiopterin is also acofactor for phenylalanine hydroxylase, the enzyme respon-sible for converting phenylalanine to tyrosine. Thus, several

of the secondary disorders of monoamine metabolism areassociated with high levels of serum phenylalanine. Theseinclude autosomal-recessive guanine triphosphate cyclo-hydrolase deficiency, pterin-carbinolamine dehydratasedeficiency, dihydropteridine reductase deficiency, andpyruvoyl-tetrahydropterin synthase deficiency. These dis-orders with hyperphenyalaninemia can be distinguishedby measurement of urine biopterin, which is elevated indihydropteridine reductase deficiency and decreased inpyruvoyl-tetrahydropterin synthase deficiency (versus nor-mal in phenylketonuria).

Pyruvoyl-tetrahydropterin synthase deficiency is the mostprevalent and heterogeneous form of hyperphenylalaninemia

Table 1. Neurotransmitter Disorders Discussedin This Article

Disorders of Monoamine MetabolismDisorders of Monoamine Synthesis

Tyrosine hydroxylase deficiency

Aromatic L-amino acid decarboxylase deficiency

Disorders of BH4 SynthesisAutosomal dominant guanine triphosphate cyclohydrolase

deficiency (Segawa disease)

Autosomal recessive guanine triphosphate cyclohydrolase

deficiency

Pyruvoyl-tetrahydropterin synthase deficiency

Sepiapterin reductase deficiency

Dihydropteridine reductase deficiency

Pterin-4a-carbinolamine dehydratase deficiency

Disorders of Monoamine Degradation

Monoamine oxidase deficiency

Dopamine beta-hydroxylase deficiency

Disorders of Glycine MetabolismGlycine encephalopathy

Disorders of-Amino Butyric Acid (GABA) MetabolismDisorders of GABA Synthesis

Glutamic acid decarboxylase deficiencyPyridoxine and pyridoxal-5-phosphate dependency*

Disorders of GABA DegradationGABA-transaminase deficiency

Succinic semialdehyde dehydrogenase deficiency

Homocarnosinosis

*Traditionally classified as a disorder of GABA synthesis, although new findings

indicate these are deficiencies of amino-adipic dehydrogenase and pyridox(am)ine

phosphate oxidase, respectively (see text).



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608 Journal of Child Neurology/ Vol. 22, No. 5, May 2007

Figure 1. Monoamine metabolism pathway. BH4 = tetrahydrobiopterin; q-BH2 = q-dihydrobiopterin; Trp OHase = tryptophan hydroxylase; TH =tyrosine hydroxylase; 5-HTP = 5-hydroxytryptophan; OMD = 3-O-methyldopa; AADC = aromatic L-amino acid decarboxylase; DA= dopamine; NA=norepinephrine; EPI = epinephrine; DBH = dopamine beta-hydroxylase; MAO = monoamine oxidase; 5-HIAA= 5-hydroxyindole acetic acid; HVA =

homovanillic acid; MHPG = 3-methoxy-4-hydroxyphenylglycol; VMA=vanillylmandelic acid.

Figure 2. Tetrahydrobiopterin (BH4) metabolism pathway. GTP = guanine triphosphate; GTPCH = GTP cyclohydrolase I; PTPS = 6-pyruvoyl-tetrahydropterin synthase; SR = sepipterin reductase; BH4 = tetrahydrobiopterin; DHPR = dihydropterin reductase; Trp OHase = tryptophan

hydroxylase; TH = tyrosine hydroxylase; PAH = phenylalanine hydroxylase; 5-HTP = 5-hydroxytryptophan; HVA= homovanillic acid; PCD = pterin-

carbinolamine reductase; q-BH2 = q-dihydrobiopterin.



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not attributed to phenylalanine hydroxylase deficiency.Three hundred cases of 6-pyruvoyl-tetrahydropterin syn-thase deficiency are listed in the international BIODEFdatabase6; most have the typical severe form. Commonlyreported symptoms are initial truncal hypotonia, subse-quent appendicular hypertonia, bradykinesia, cogwheelrigidity, generalized dystonia, and marked diurnal fluctu-

ation. Other reported clinical features include difficultyin swallowing, oculogyric crises, somnolence, irritability,hyperthermia, and seizures. Chorea, athetosis, hypersali-

vation, rash with eczema, and sudden death have alsobeen reported. Patients with mild phenotypes may deteri-orate if given folate antagonists such as methotrexate,which can interfere with a salvage pathway throughwhich dihydrobiopterin is converted into tetrahydro-biopterin via dihydrofolate reductase. Treatment optionsinclude substitution with neurotransmitter precursors(dopa, 5-hydroxytryptophan), monoamine oxidase andcatechol-O-methyl transferase inhibitors, and tetrahydro-

biopterin. In dihydropteridine reductase deficiency, thereare basal ganglia calcifications that are reversible withfolinic acid supplementation.7

Tetrahydrobiopterin Defects WithoutPeripheral Hyperphenylalaninemia

Segawa disease. Guanine triphosphate cyclohydrolase 1deficiency was first described by Dr M. Segawa in 1971as a hereditary basal ganglia disease with marked diurnalfluctuation.8 Typically, patients have dystonia that wors-ens during the latter part of the day. The syndrome wasultimately recognized as an autosomally dominant inher-ited partial deficiency of guanine triphosphate cyclohy-drolase activity. This enzyme represents the rate-limitingstep in tetrahydrobiopterin synthesis. Tetrahydrobiopterinis a cofactor required for synthesizing the catecholamineneurotransmitters as well as serotonin. The responsiblegene has been mapped to chromosome region 14q22.1-q22.2, spanning a 30-kb region and containing 6 exons. Adisparate collection of mutations with variable pene-trance has been reported.9

The cardinal clinical features of guanine triphosphatecyclohydrolase deficiency, or Segawa dopa-responsive dysto-nia, are fluctuating dystonia and tremor in the presence of

normal cognition. Both the dystonia and tremor may have aprominent postural component. Isolated toe gait, a femalepredominance, and presentation with only prominentpostural tremor in adulthood have all been described.10

Eventually, the phenotype involves progressive postural dys-tonia and worsening tremor. The response to L-dopa in thissyndrome may be overwhelming and profoundly life alteringat any age. Although this is not the only form of dystonia thatmay respond to dopamine, it has the most prominent andrewarding response. Patients often benefit significantly withlow-dose L-dopa/carbidopa. Indeed, a trial of L-dopa can bediagnostic. Tetrahydrobiopterin may be helpful but is rarely

used. The dopamine synthesis line appears far moreinvolved than the serotonergic line; hence, serotonin reup-take inhibitors are not standard therapy.

Segawa disease is not associated with high serumlevels of phenylalanine; there is adequate intrahepaticconversion of phenylalanine to tyrosine. Therefore, thediagnosis is typically made by the clinical presentation

and assay of cerebrospinal fluid neurotransmitters. Thereis selective impairment of dopaminergic transmission,and cerebrospinal fluid neurotransmitters reveal lowhomovanillic acid, neopterin, and tetrahydrobiopterin.Genetic analysis of patients with autosomal dominantdopa-responsive dystonia reveals mutations in guaninetriphosphate cyclohydrolase about half of the time, as notall mutations are known.11 Clinicians should be aware ofatypical presentations, such as spastic diplegia, asymmet-ric limb dystonia, or even writers cramp. The geneticpenetrance is incomplete, so there may be highly variablephenotypes within the same family.

Sepiapterin Reductase Deficiency

Sepiapterin reductase catalyzes the final step in tetrahy-drobiopterin synthesis. As with Segawa disease, it toorequires analysis of cerebrospinal fluid for diagnosis. Theclinical phenotype of recessive sepiapterin reductase defi-ciency includes progressive psychomotor retardation,altered tone, seizures, choreoathetosis, tempera-ture instability, hypersalivation, microcephaly, andirri tabi lity. Patients with sepiapterin reductase deficiencyalso manifest dystonic posturing with diurnal variation,oculogyric crises, tremor, hypersomnolence, oculomotor

apraxia, and weakness.12,13A murine model of sepiapterinreductase deficiency confirms that in the absence of thisenzyme, there are greatly reduced levels of the cate-cholamines and serotonin, the neurotransmitters thatdepend on tetrahydrobiopterin for their synthesis.14

Disorders of Monoamine Degradation

Monoamine Oxidase Deficiency

Monoamine oxidase-A and oxidase-B catalyze the oxida-tive deamination of the biogenic amines, including sero-tonin, epinephrine, and norepinephrine, and minor

amines, including tyramine. Both have been mapped tothe Xp11.23-11.4 region. Monoamine oxidase-A defi-ciency has been documented in a single family of affectedmales with mild mental retardation and violent aggressivebehavior.15 Measurement of urine neurotransmitters andmetabolites can detect the disease; subjects should noteat tyramine-rich foods prior to laboratory testing. Theenzyme deficiency can be confirmed by measurement infibroblasts. Monoamine oxidase-B deficiency has beenassociated with Norrie disease,16 a syndrome of congeni-tal blindness, deafness, and mental retardation mappedto X11.4.




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Dopamine Beta-Hydroxylase Deficiency

Dopamine beta-hydroxylase catalyzes the synthesis of nor-epinephrine from dopamine. Patients with this disorderhave low levels of norepinephrine, epinephrine, and theirmetabolites in plasma, cerebrospinal fluid, and urine. Inaddition, norepinephrine normally acts as an inhibitor oftyrosine hydroxylase. Thus, in this disorder, tyrosinehydroxylase is overactive, resulting in an even higher con-centration of dopamine.

Dopamine beta-hydroxylase deficiency is typicallydiagnosed in adults presenting with orthostatic hypoten-sion and noradrenergic failure. There is no other evidenceof neurological problems. Retrospective case histories,however, have indicated ptosis, hypotension, hypother-mia, and hypoglycemia in the perinatal period.17 It is sus-pected that adults living with this disorder have themildest end of the phenotypic spectrum. Mothers ofaffected patients have a notable history of a high rate ofspontaneous abortions.17,18 Embryo mortality is very highin dopamine beta-hydroxylase knockout mice.19 Survivingmice have increased susceptibility to seizures and alteredcellular immunity.20,21 Some studies have suggested thatlow maternal serum dopamine beta-hydroxylase levels areassociated with a heightened risk for familial autism22 andthat the dopamine beta-hydroxylase gene is a candidategene for autism spectrum disorder.23

Disorders of Glycine Metabolism

Glycine, a simple amino acid structurally but ubiquitous

and vital, functions as a neurotransmitter with dual excita-tory (cortical) and inhibitory (spinal cord and brainstem)effects. Glycine has multiple properties, as it is gluconeo-geneic via pyruvate; constitutes over 15% of amino acids ofessential structural proteins such as collagen, elastin, andgelatin; is incorporated into purines, glutathione, and theheme protein; and is involved in important detoxifying con-

jugation reactions. Nonketotic hyperglycinemia was origi-nally named to distinguish it from ketotic hyperglycinemia,which is now known to be propionic acidemia. Because thedistinction is no longer required and clinical confusionbetween hyperglycinemia and hyperglycemia occurs, thepreferred term isglycine encephalopathy.

Glycine encephalopathy is a group of autosomal reces-sive conditions related to varying defects of the complextetrameric protein that constitutes the glycine cleavagesystem. This tetramer consists of a P protein containing apyridoxal phosphate-dependent glycine decarboxylase; anH protein with a lipoic acid containing hydrogen carrier;a T protein, which is tetrahydrofolate dependent; and anL protein, which is a lipoamide dehydrogenase moiety.Defects of the glycine cleavage system are detected by aratio of cerebrospinal fluid to plasma glycine > 0.08.

There have been 150+ patients identified with the clas-sic neonatal phenotype, often presenting with in utero

seizures. Associated clinical findings include neonatalencephalopathy with lethargy, hypotonia, myoclonus, andapnea. Electroencephalographic tracings reveal a burst-suppression pattern. Neuroimaging studies have demon-strated agenesis of the corpus callosum, and neuropathologicfindings are those of spongiform white matter degeneration.Magnetic resonance spectroscopy may reveal a peak corre-

sponding to glycine.24Variations on this theme include aninfantile pattern with presentation after 6 months of partialseizures or hypsarrhythmia; a childhood later variant withmild mental retardation, delirium, chorea, and vertical gazepalsies; and a late-onset pattern in adults with progressivespastic diplegia and optic atrophy. The P protein defect isassociated with the neonatal onset forms. Although H andT protein defects are associated with later onset forms,there are also milder phenotypes of the neonatal onset formshowing mutations in the glycine decarboxylase gene.25

Measurements of glycine cleavage activity in liver or cul-tured lymphoblasts, or genetic identification, are available

for accurate diagnosis.26

Secondary causes of hyperglycine-mia include valproic acid and D-glyceric acidemia.

Sodium benzoate has been used to reduce glycine con-centrations in plasma and cerebrospinal fluid, and dex-tromethorphan has been used as an N-methyl-D-aspartatereceptor blocker. The outcome is generally poor,27 althoughbenefit was described in 3 affected siblings with a mild phe-notype and considerable residual enzymatic activity.28 Inaddition, 2 cases of deterioration with vigabatrin therapyhave been described.29

Disorders of-AminoButyric Acid Metabolism

-amino butyric acid, the major inhibitory neurotrans-mitter of the brain, is used in up to one third ofbrain synapses. It is found in nonneural tissues as well,including the pancreatic islet cells and kidney. It is syn-thesized primarily from glutamate via glutamic aciddecarboxylase. The first enzymatic degradative step ofGABA involves the enzyme GABA-transaminase, whichuses alpha-ketoglutarate from the Krebs cycle to regener-ate a molecule of glutamate for every molecule of GABAthat is catabolized. Hence, the vital neurotransmitterpools of GABA and glutamate are constantly replenishedand tightly regulated. The product of the GABA-transam-inase reaction is succinic semialdehyde, which is nor-mally converted to succinic acid via the enzyme succinicsemialdehyde dehydrogenase. Succinic acid therebyenters the Krebs cycle, where alpha-ketoglutarate is formed.The ongoing conversion of glutamate to GABA and thenback to glutamate is known as the GABA shunt. Disorders ofglutamic acid decarboxylase, GABA-transaminase, and suc-cinic semialdehyde dehydrogenase have all been identi-fied. Succinic semialdehyde dehydrogenase deficiency isthe most common neurotransmitter disease discussed in



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this article. -amino butyric acid also exists in the form of adipeptide with histidine, known as homocarnosine.

Disorders of-Amino Butyric Acid Synthesis

Glutamic Acid Decarboxylase Deficiency

Glutamic acid decarboxylase is a pyridoxal-5-phosphaterequiring enzyme that converts glutamate to GABA. It existsin 2 isoforms, GAD65 and GAD67. -amino butyric acidhas an important role in embryonic development, as sub-stantiated by the association of cleft palate in transgenicmice deficient in GAD67. Mice null for GAD67 were bornat the expected frequency but died of severe cleft palate dur-ing the first morning after birth. Glutamic acid decarboxy-lase activities and GABA contents in the cerebral cortexwere reduced to 20% and 7%, respectively.30 A recent

Japanese population study reported linkage in patients withnonsyndromic cleft lip with and without cleft palate andspecific GAD67 haplotypes.31 This supports a role for the

GABA-synthesizing GAD67 gene in normal human facialdevelopment and represents a newly recognized disorder ofGABA synthesis.

Disorders of-Amino Butyric

Acid Degradation

GABA-Transaminase Deficiency

GABA-transaminase deficiency is an autosomal recessivedisorder characterized by abnormal development, seizures,and high levels of GABA in serum and cerebrospinal fluid.32

The disorder appears to be extremely rare and has been con-firmed in a single Flemish family.33

Succinic Semialdehyde Dehydrogenase Deficiency

Jakobs and coworkers34 described the index case of succinicsemialdehyde dehydrogenase deficiency (-hydroxybutyricaciduria) in 1981. Since then, more than 350 cases havebeen identified and more than 60 of them reported.35

Succinic semialdehyde dehydrogenase activity is deficient,impairing the predominant oxidative conversion of succinicsemialdehyde to succinic acid, in response to which succinic

semialdehyde is reduced to 4-hydroxybutyric acid in a reac-tion catalyzed by 4-hydroxybutyrate dehydrogenase.The phenotype of succinic semialdehyde dehydrogenase

deficiency encompasses a wide spectrum of neurologicalmanifestations, although it universally leads to a significantneurodevelopmental disorder, including severe expressivelanguage deficits with a high incidence of psychiatric dys-function.36We currently have a database of 95 patients andhave collected detailed clinical data using a systematic ques-tionnaire on 60 patients. The most common clinical find-ings are developmental delay, mental retardation, andhypotonia. Neuropsychiatric problems are manifest in 70%of patients and are most commonly characterized by sleep

disturbances, inattention, hyperactivity, and anxiety.37 Othercommon neurological features are hyporeflexia and nonpro-gressive cerebellar ataxia. The disorder typically has a staticcourse and not the progressive or intermittent pattern clas-sically associated with a metabolic encephalopathy. There isa minority of patients, involving 10%, with a degenerativecourse featuring regression and prominent extrapyramidal

manifestations.38Sleep disturbances are reported in 42% of patients,

including excessive daytime somnolence (80%), parasom-nias (30%), disorders of initiating or maintaining sleep(20%), and nocturnal seizures (10%). Approximately halfof patients with succinic semialdehyde dehydrogenasedeficiency have epilepsy, usually with generalized tonic-clonic seizures and also atypical absence and myoclonicseizures. Occasional patients have refractory seizures,including bouts of generalized convulsive status epilepti-cus. Electroencephalography recordings reveal back-ground slowing and disorganization in one third and

epileptiform abnormalities in one third. The latter are bothgeneralized and multifocal, and photosensitivity and elec-trographic status epilepticus during slow-wave sleep havebeen described. Peripheral neuromuscular studies have notbeen consistent, showing mild demyelinating neuropathy,borderline axonal changes, or normal findings.39 The long-term outlook for affected patients is characterized by vari-able degrees of mental retardation with persistence ofsevere expressive language deficit, neuropsychiatric mor-bidity with prominent anxiety and hallucinations, and con-tinuing dependence for activities of daily living.40

The biochemical hallmark of succinic semialdehyde

dehydrogenase deficiency is the accumulation of -hydroxybutyric acid (4-hydroxybutyric acid) in physiologi-cal fluids without an accompanying metabolic acidosis.41

Concentrations of-hydroxybutyric acid in patients rangefrom 2-fold to 800-fold normal in urine, 4-fold to 200-fold in plasma, and a 100-fold to 1200-fold in cere-brospinal fluid in comparison with control ranges.42 Inaddition to 4-hydroxybutyric acid, other compounds aredetected at elevated levels in affected patients including4, 5-dihydroxyhexanoic acid. Urinary metabolites indica-tive of-oxidation of excess 4-hydroxybutyric acid include3,4-dihydroxybutyric, 3-oxo-4-hydroxybutyric, and gly-

colic acids.

43

Increased urinary 2,4-dihydroxybutyric (andits lactone) and 3-hydroxypropionic acid levels indicatemetabolism of 4-hydroxybutyric acid by-oxidation.

Availability of purified mammalian succinic semialde-hyde dehydrogenase protein has permitted cloning of therelevant cDNAs encoding rat and human succinic semi-aldehyde dehydrogenase. The human gene, ALDH5A1,maps to chromosome 6p22 and consists of 10 exonsencompassing 38 kb of DNA.44 More than 35 mutationshave been identified, including missense, nonsense, andsplicing errors, without hotspots.45 Thus far, there is noclear phenotype/genotype correlation. Heterozygotes (car-riers) are typically asymptomatic. One report suggests




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absence epilepsy with myoclonias and photosensitivitymay be related to the heterozygous state.46

Neuroimaging has typically revealed the presence ofan increased T2-weighted magnetic resonance imaging(MRI) signal most commonly involving the globus pallidibilaterally and symmetrically, as well as the subcorticalwhite matter, cerebellar dentate nucleus, and brain-

stem.47 A dentatopallidal pattern has been described toemphasize the combined involvement of the pallidi anddentate nuclei.48 Occasional patients have had asymmet-ric pallidal signal, and progression of signal abnormalitieshas been noted in patients over time. Specialized 3H MRIspectroscopy edited for small amino acids have revealedelevations in GABA, -hydroxybutyric acid, and homo-carnosine in brain parenchyma.49

Pharmacologic strategies and enhanced understand-ing of the pathophysiology of succinic semialdehydedehydrogenase deficiency are expected to follow fromstudies in a transgenic animal model. A murine model

was developed with deletion of exon 7, leading to com-plete absence of enzymatic activity in neural and periph-eral tissues.50 The mice are born with the expectedautosomal recessive inheritance pattern and a phenotypehaving commonalities with the human disease, includingneurological impairment, ataxia, and seizures. At postna-tal days 16 to 22, the mice develop repetitive tonic-clonicseizures and subsequent mortality.51 In addition, the micedemonstrate a transition from early absence seizures togeneralized seizures and eventually convulsive statusepilepticus.52 Pharmacologic intervention studies showedsome increased survival following the use of both a

-hydroxybutyric acid antagonist and, to a lesser extent,a GABA(B)-receptor antagonist, as well as taurine andvigabatrin.53 Taurine was used due to its high content inmurine breast milk because the weaning period was asso-ciated with seizure onset in suckling animals. Vigabatrinwas associated with the expected elevation in GABA con-centrations but not lowering of-hydroxybutyric acid.

Studies of the expression and function of the GABA(A)receptor in succinic semialdehyde dehydrogenase-deficientmice revealed downregulation of the beta(2) subunit,reduced GABA(A)-mediated postsynaptic potentials, andaugmented postsynaptic population spikes recorded fromhippocampal slices.54 These findings suggest that progres-sive dysfunction of the GABA(A) receptor due to chronicoveruse and subsequent downregulation could serve as themechanism of the transition from absence to convulsiveseizures seen in this mouse model as well as patient popula-tions that include succinic semialdehyde dehydrogenasedeficiency and primary generalized epilepsies such as juve-nile myoclonic epilepsy. Similarly, a use-dependent decreasein GABA(B) receptor-mediated function is suggested by asignificant decrease in the binding of a specific GABA(B)receptor antagonist at postnatal day 14 compared to day7, decreased GABA(B) receptor-mediated synaptic poten-tials, and region-specific and time-dependent decreases

in GABA(B) receptor subunit protein expression.55

Because GABA(B) receptor dysfunction has been impli-cated as important in cognitive impairment in absenceseizure models, independent of seizure activity,56 the pos-sibility is raised that GABA-induced perturbation ofGABA(B) receptor function could be important in thepathophysiology of mental retardation in succinic semi-

aldehyde dehydrogenase deficiency.Currently, there is no standard treatment for individu-

als with succinic semialdehyde dehydrogenase deficiency. Vigabatrin, an irreversible inhibitor of GABA transami-nase, has been associated with decreases in cerebrospinalfluid -hydroxybutyric acid. Although there has been aninterest in following cerebrospinal fluid -hydroxybutyricacid levels during therapy with vigabatrin in patients withsuccinic semialdehyde dehydrogenase deficiency,57 neitherlaboratory or clinical effects have been consistent with

vigabatrin therapy.58 Benzodiazepines, risperidal, fluoxe-tine, and methylphenidate have been helpful for anxiety

and behavioral problems.59

Symptomatic treatment forseizures using carbamazepine and lamotrigine have alsoshown some success. Valproate is avoided, as it inhibitsactivity of residual succinic semialdehyde dehydrogenase,and its use is associated with increased concentration of-hydroxybutyric acid and other succinic semialdehydedehydrogenase deficiency metabolites.60 Liver-mediatedgene therapy in the murine model demonstrated a reduc-tion in -hydroxybutyric acid levels in liver, kidney, serum,and brain extracts, setting the stage for future clinical tri-als of gene therapy.6

Homocarnosinosis

Homocarnosine is a brain-specific dipeptide of GABA andhistidine. Homocarnosine concentrations are highest inthe dentate and inferior olivary nuclei, intermediate in sub-stantia nigra and globus pallidus, and lowest in the frontalcortex, caudate nucleus, and nucleus accumbens. Oneaffected family has been reported with homocarnosinosis,affecting a healthy 72-year-old Norwegian woman and 3 ofher 4 children with neurological disease. Their phenotypewas onset of progressive spastic paraplegia between 6 and29 years of age with progressive mental deterioration andretinal pigmentation.62 The patients had elevated cere-brospinal fluid homocarnosine and normal carnosine. Anunrelated patient has recently been described,63 with hypo-tonia and developmental delay noted by 6 months andataxia and tremor in adolescence. The disorder may repre-sent a form of carnosinase deficiency.

Pyridoxine-Dependent Seizures

The biologically active form of pyridoxine, pyridoxal 5-phosphate, is a cofactor for many enzymatic reactions.

Although pyridoxine-dependent epilepsy was formerly




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considered a disorder of GABA synthesis due to the roleof pyridoxal 5-phosphate as a cofactor for glutamic aciddecarboxylase, recent findings have suggested that other

biochemical pathways are involved. In addition to GABA,pyridoxine is a cofactor for enzymes involved in themetabolism of several other neurotransmitters, includingthe monoamines, D-serine, and taurine.64 Postmortemquantification of brain GABA and glutamate levels andgenotype analyses have failed to demonstrate consistentunderproduction of GABA or a genetic linkage to eitherisomer of glutamic acid decarboxylase.65 However, therehas been much recent progress in elucidating the patho-physiology of pyridoxine-dependent seizures, and a new

variant of this disorder, pyridoxal 5-phosphate depend-ency, has been described.

Pyridoxine-dependent seizures are typically suspectedin a neonate with refractory seizures, potentially ofprenatal onset, and an electroencephalogram showingcontinuous epileptiform activity or a burst-suppressionpattern that then responds dramatically to a trial intra-

venous dose of 50 to 100 mg pyridoxine. The typical clin-ical presentation is characterized by perinatal onset, rapidresponse to therapy, refractoriness to other antiepilepticdrugs, and a lifelong dependence on continued therapy.

Additional clinical features include jitteriness, hypother-mia, neonatal dystonia, and a prodrome of restlessness,irritability, and emesis preceding seizures. There is an

atypical phenotype, with onset described as late as 2 years, prolonged seizure-free intervals up to 5 monthswithout pyridoxine, and clinical response only after

repeated trials.66

The atypical form may have much higherincidence than what is generally suspected with thissyndrome.

A gene locus was mapped to chromosome 5q31 in 4consanguineous families and 1 multiply affected family.67

Further studies established genetic heterogeneity forpyridoxine dependency, yet linkage in some affected fam-ilies to 5q31.68 Elevation of pipecolic acid was reported inplasma and cerebrospinal fluid in pyridoxine-dependentepilepsy.69 Subsequently, mutations in the ALDH7A1gene, which encodes alpha-aminoadipic semialdehydedehydrogenase (also called antiquitin), were demonstrated

with children with pyridoxine-dependent seizures.

70

Whenalpha-aminoadipic semialdehyde dehydrogenase activity isreduced, pipecolic acid and delta-piperideine-5-carboxylateaccumulate (Figure 4). The accumulating carboxylate formsa condensation product with pyridoxal 5-phosphate,which presumably sequesters the latter from the brain.

Dietary intake of pyridoxine comes from vegetables (aspyridoxine) and meat (originally as pyridoxamine). Theseare both oxidized to pyridoxal 5-phosphate via an enzymeknown as pyridox(am)ine oxidase. A newly recognized dis-order, pyridoxine oxidase deficiency, has been associatedwith fetal distress and intractable seizures.71 Cerebrospinal

Figure 3. -amino butyric acid metabolism pathway. GAD = glutamic acid decarboxylase; P5P = pyridoxine-5-phosphate (cofactor for GAD); GABA-T = -amino butyric acid transaminase; GHB = -hydroxybutyric acid; SSADH = succinic semialdehyde dehydrogenase.



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fluid neurotransmitters are very helpful for diagnosis, as aro-matic amino acid decarboxylase is dependent on pyridoxal5-phosphate, and thus a profile consistent with aromatic

amino acid decarboxylase deficiency emerges (vide supra)and leads to consideration of this syndrome. This meta-bolic error is correctable by administration of pyridoxal5-phosphate but not pyridoxine. Although alpha-aminoadipicsemialdehyde dehydrogenase and pyridoxine oxidasedeficiency lead to a presumed brain deficit of pyridoxal5-phosphate, the mechanism for the seizures remainsunknown.

Conclusion

Inherited disorders of neurotransmitters include a groupof metabolic syndromes having important neurologicalmanifestations and particular therapeutic implications.Currently, disorders of the metabolism of monoamines(dopamine, serotonin, norepinephrine, epinephrine), glycine,and GABA have been defined. Disorders of biopterinmetabolism are treated with tetrahydrobiopterin andagents augmenting dopaminergic and serotoninergictransmission. The impressive responsiveness of Segawafluctuating dystonia to L-dopa is a hallmark feature ofpreviously unrecognized neurological morbidity becoming

treatable at any age. The neonatal entities of glycineencephalopathy and pyridoxine-dependent seizures havewidening clinical phenotypes and new variants, including a

form of the latter requiring specific pyridoxal-5-phosphatetherapy. Succinic semialdehyde dehydrogenase deficiencyis relatively common in comparison to the remainder ofthis group of disorders. Other disorders of GABA metab-olism, as well as heretofore unrecognized neurotransmit-ter disorders, will require increasing use of cerebrospinalfluid analysis for diagnosis and treatment. Emerging tech-nologies such as magnetic resonance spectroscopy may helpto identify disorders of other neurotransmitters, such as glu-tamate or melatonin. Disorders of neurotransmitter trans-port, storage, release, and reuptake may be added to thebody of disorders of synthesis and catabolism. The implica-

tions for furthering our understanding of the mechanismsof prevalent neurologically handicapping conditions, rang-ing from epilepsy to mental retardation, autism, and addic-tion, are enormous when one considers the range ofpathology associated with these disorders.

Acknowledgment

The authors acknowledge the Delman Family Fund forPediatric Neurology Research.

Figure 4. Metabolic pathways implicated in pyridoxine and pyridoxal-5-phosphate dependent epilepsy. AASDH = alpha-aminodipic-semialdehyde

dehydrogenase (antiquitin); P6C = delta-piperideine-6-carboxylate; PNPO = pyridox(am)ine oxidase; P5P = pyridoxal-5-phosphate.



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