Journal of Child Neurology

http://jcn.sagepub.com The Pediatric Neurotransmitter Disorders

Phillip L. Pearl, Jacob L. Taylor, Stacey Trzcinski and Alex Sokohl J Child Neurol 2007; 22; 606 DOI: 10.1177/0883073807302619 The online version of this article can be found at: http://jcn.sagepub.com/cgi/content/abstract/22/5/606

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Topical Review Article

The Pediatric Neurotransmitter Disorders

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

Journal of Child Neurology Volume 22 Number 5 May 2007 606-616 2007 Sage Publications 10.1177/0883073807302619 http://jcn.sagepub.com hosted at http://online.sagepub.com

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 decarboxylase, tyrosine hydroxylase, sepiapterin reductase, and guanosine triphosphate cyclohydrolase (Segawa disease) deficiencies do not feature elevated serum phenylalanine and require cerebrospinal fluid analysis for diagnosis. Segawa disease is characterized by dramatic and lifelong responsiveness to 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 glutamic acid decarboxylase deficiency with nonsyndromic cleft lip/ palate, GABA-transaminase deficiency, and succinic semialdehyde dehydrogenase deficiency. The latter is characterized by elevated -hydroxybutyric acid and includes a wide range of neuropsychiatric symptoms as well as epilepsy. Pyridoxinedependent 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

he pediatric neurotransmitter disorders refer to an inherited group of neurometabolic syndromes attributable to a disturbance of neurotransmitter metabolism. This represents an enlarging group of recognized disorders often requiring specialized diagnostic procedures 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 enzymes directly involved in the synthetic or degradative pathways of the neurotransmitters themselves. Other disorders involve enzymes that are involved in the synthesis of essential cofactors. For example, tetrahydrobiopterin is a necessary cofactor for several enzymes that are involved in monoamine synthesis. Chronically low levels of tetrahydrobiopterin can therefore lead to chronically low levels of monoamine neurotransmitters. The specific disorders discussed in this review are listed in Table 1.

Disorders of Monoamine Metabolism

The monoamine neurotransmitters include the catecholamines (dopamine, norepinephrine, and epinephrine)
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: ppearl@cnmc.org. Pearl PL, Taylor JL, Trzcinski S, Sokohl A. The pediatric neurotransmitter disorders. J Child Neurol. 2007;22:606-616.

and serotonin. Figure 1 illustrates the key pathways involved in their synthesis and degradation. Tryptophan is converted to 5-hydroxytryptophan by the enzyme tryptophan hydroxylase. Likewise, tyrosine is converted to L-dopa by tyrosine hydroxylase. 5-Hydroxytryptophan and L-dopa are then converted to serotonin and dopamine, respectively. Both of these reactions are catalyzed by the same enzymearomatic Lamino acid decarboxylase. Serotonin and dopamine are broken down through similar pathways, both of which involve monoamine oxidase-A and -B. In addition, dopamine is converted into norepinephrine by dopamine beta-hydroxylase. Deficiencies in tyrosine hydroxylase, aromatic amino acid decarboxylase, monoamine oxidase, and dopamine betahydroxylase have been identified in human patients. Tetrahydrobiopterin is a necessary cofactor for both tryptophan hydroxylase and tyrosine hydroxylase. Therefore, enzymatic deficiencies that lead to reduced levels of tetrahydrobiopterin can interfere with the synthesis of the monoamine neurotransmitters. Tetrahydrobiopterin is synthesized in 3 steps from guanine triphosphate (see Figure 2). Deficiencies have been identified in each of the enzymes in this pathway: guanine triphosphate cyclohydrolase I, 6pyruvoyl-tetrahydropterin synthase, and sepiapterin reductase. When tetrahydrobiopterin acts as a cofactor for various hydroxylases (including tryptophan hydroxylase, tyrosine hydroxylase, and phenylalanine hydroxylase), it is converted to pterin-4a-carbinolamine. This is then recycled back into tetrahydrobiopterin in a 2-step process involving the enzymes pterin-4a-carbinolamine dehydratase and dihydropteridine reductase.

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Table 1.

Neurotransmitter Disorders Discussed in This Article

Disorders of Monoamine Metabolism Disorders of Monoamine Synthesis Tyrosine hydroxylase deficiency Aromatic L-amino acid decarboxylase deficiency Disorders of BH4 Synthesis Autosomal 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 Metabolism Glycine encephalopathy Disorders of -Amino Butyric Acid (GABA) Metabolism Disorders of GABA Synthesis Glutamic acid decarboxylase deficiency Pyridoxine and pyridoxal-5-phosphate dependency* Disorders of GABA Degradation GABA-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).

Disorders of Monoamine Synthesis Tyrosine Hydroxylase Deficiency Tyrosine hydroxylase catalyzes the conversion of tyrosine into L-dopa. Tyrosine hydroxylase deficiency leads to impaired synthesis of dopamine as well as epinephrine and norepinephrine. This is an autosomal recessive condition, with gene locus 11p15.5. It is represented by a progressive encephalopathy and poor prognosis. Clinical features include dystonia that is minimally or nonresponsive to Ldopa, extrapyramidal symptoms, ptosis, miosis, and postural hypotension. 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 lowdose L-dopa (3 mg/kg/d divided in 6 doses) with selegiline (5 mg/d in a single dose) was reported as helpful in 1 patient.2 Aromatic Amino Acid Decarboxylase Deficiency Aromatic amino acid decarboxylase deficiency is an autosomal recessive disorder that combines serotonin and catecholamine deficiency. The gene locus is 7p11. Aromatic amino acid decarboxylase catalyzes the decarboxylation of L-dopa and 5-hydroxytryptophan to dopamine and serotonin, respectively. Aromatic amino acid decarboxylase deficiency is characterized by a cerebrospinal fluid profile of low homovanillic acid and 5-hydroxyindoleacetic acid,

high L-dopa, 5-hydroxytryptophan, 3-O-methyldopa (an Ldopa metabolite), and normal pterin levels. The associated clinical features are hypotonia and extrapyramidal movement disorders such as torticollis, dystonia, blepharospasm, athetosis, and myoclonus. Other manifestations are profound developmental delay, irritability, sleep disturbances, and autonomic manifestations such as temperature instability, impaired diaphoresis, hypersalivation, recurrent syncope, or cardiorespiratory arrest. Impaired sympathetic responses, with maintenance of systemic blood pressure following nitroprusside infusion, are demonstrable.3 The syndrome 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, or hyperekplexia. Neuroimaging is generally unremarkable but may reveal progressive cerebral atrophy. Treatment effects appear highly variable. Some authors advocate conservative dosing of levadopa/carbidopa, titrating slowly over weeks or months with L-dopa, while using ample carbidopa to block peripheral aromatic amino acid decarboxylase enzymatic activity.1 This includes giving more frequent and lower doses throughout the day. Various therapies have been tried in a limited number of patients. Pons et al4 review a series of 13 patients (6 cases plus 7 from literature reports) and describe 1 group (5 males) who responded to treatment and made developmental progress, as well as 1 group (1 male, 5 females) who responded poorly to treatment and often developed druginduced dyskinesias. Treatments reported in this condition are anecdotal and include pyridoxine (cofactor for the enzyme), dopamine receptor agonists, trihexyphenidyl, monoamine oxidase inhibitors, antiepileptic agents, serotonergic agents, buspirone, and melatonin.1,4,5 6-Pyruvoyl-Tetrahydropterin Synthase and Other Tetrahydrobiopterin Defects With Peripheral Hyperphenylalaninemia In addition to acting as a cofactor for tryptophan hydroxylase and tyrosine hydroxylase, tetrahydrobiopterin is also a cofactor for phenylalanine hydroxylase, the enzyme responsible for converting phenylalanine to tyrosine. Thus, several of the secondary disorders of monoamine metabolism are associated with high levels of serum phenylalanine. These include autosomal-recessive guanine triphosphate cyclohydrolase deficiency, pterin-carbinolamine dehydratase deficiency, dihydropteridine reductase deficiency, and pyruvoyl-tetrahydropterin synthase deficiency. These disorders with hyperphenyalaninemia can be distinguished by measurement of urine biopterin, which is elevated in dihydropteridine reductase deficiency and decreased in pyruvoyl-tetrahydropterin synthase deficiency (versus normal in phenylketonuria). Pyruvoyl-tetrahydropterin synthase deficiency is the most prevalent and heterogeneous form of hyperphenylalaninemia

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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-pyruvoyltetrahydropterin 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 = pterincarbinolamine reductase; q-BH2 = q-dihydrobiopterin.
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not attributed to phenylalanine hydroxylase deficiency. Three hundred cases of 6-pyruvoyl-tetrahydropterin synthase deficiency are listed in the international BIODEF database6; most have the typical severe form. Commonly reported symptoms are initial truncal hypotonia, subsequent appendicular hypertonia, bradykinesia, cogwheel rigidity, generalized dystonia, and marked diurnal fluctuation. Other reported clinical features include difficulty in swallowing, oculogyric crises, somnolence, irritability, hyperthermia, and seizures. Chorea, athetosis, hypersalivation, rash with eczema, and sudden death have also been reported. Patients with mild phenotypes may deteriorate if given folate antagonists such as methotrexate, which can interfere with a salvage pathway through which dihydrobiopterin is converted into tetrahydrobiopterin via dihydrofolate reductase. Treatment options include substitution with neurotransmitter precursors (dopa, 5-hydroxytryptophan), monoamine oxidase and catechol-O-methyl transferase inhibitors, and tetrahydrobiopterin. In dihydropteridine reductase deficiency, there are basal ganglia calcifications that are reversible with folinic acid supplementation.7 Tetrahydrobiopterin Defects Without Peripheral Hyperphenylalaninemia Segawa disease. Guanine triphosphate cyclohydrolase 1 deficiency was first described by Dr M. Segawa in 1971 as a hereditary basal ganglia disease with marked diurnal fluctuation.8 Typically, patients have dystonia that worsens during the latter part of the day. The syndrome was ultimately recognized as an autosomally dominant inherited partial deficiency of guanine triphosphate cyclohydrolase activity. This enzyme represents the rate-limiting step in tetrahydrobiopterin synthesis. Tetrahydrobiopterin is a cofactor required for synthesizing the catecholamine neurotransmitters as well as serotonin. The responsible gene has been mapped to chromosome region 14q22.1q22.2, spanning a 30-kb region and containing 6 exons. A disparate collection of mutations with variable penetrance has been reported.9 The cardinal clinical features of guanine triphosphate cyclohydrolase deficiency, or Segawa dopa-responsive dystonia, are fluctuating dystonia and tremor in the presence of normal cognition. Both the dystonia and tremor may have a prominent postural component. Isolated toe gait, a female predominance, and presentation with only prominent postural tremor in adulthood have all been described.10 Eventually, the phenotype involves progressive postural dystonia and worsening tremor. The response to L-dopa in this syndrome may be overwhelming and profoundly life altering at any age. Although this is not the only form of dystonia that may respond to dopamine, it has the most prominent and rewarding response. Patients often benefit significantly with low-dose L-dopa/carbidopa. Indeed, a trial of L-dopa can be diagnostic. Tetrahydrobiopterin may be helpful but is rarely

used. The dopamine synthesis line appears far more involved than the serotonergic line; hence, serotonin reuptake inhibitors are not standard therapy. Segawa disease is not associated with high serum levels of phenylalanine; there is adequate intrahepatic conversion of phenylalanine to tyrosine. Therefore, the diagnosis is typically made by the clinical presentation and assay of cerebrospinal fluid neurotransmitters. There is selective impairment of dopaminergic transmission, and cerebrospinal fluid neurotransmitters reveal low homovanillic acid, neopterin, and tetrahydrobiopterin. Genetic analysis of patients with autosomal dominant dopa-responsive dystonia reveals mutations in guanine triphosphate cyclohydrolase about half of the time, as not all mutations are known.11 Clinicians should be aware of atypical presentations, such as spastic diplegia, asymmetric limb dystonia, or even writers cramp. The genetic penetrance is incomplete, so there may be highly variable phenotypes within the same family. Sepiapterin Reductase Deficiency Sepiapterin reductase catalyzes the final step in tetrahydrobiopterin synthesis. As with Segawa disease, it too requires analysis of cerebrospinal fluid for diagnosis. The clinical phenotype of recessive sepiapterin reductase deficiency includes progressive psychomotor retardation, altered tone, seizures, choreoathetosis, temperature instability, hypersalivation, microcephaly, and irritability. Patients with sepiapterin reductase deficiency also manifest dystonic posturing with diurnal variation, oculogyric crises, tremor, hypersomnolence, oculomotor apraxia, and weakness.12,13 A murine model of sepiapterin reductase deficiency confirms that in the absence of this enzyme, there are greatly reduced levels of the catecholamines and serotonin, the neurotransmitters that depend on tetrahydrobiopterin for their synthesis.14 Disorders of Monoamine Degradation Monoamine Oxidase Deficiency Monoamine oxidase-A and oxidase-B catalyze the oxidative deamination of the biogenic amines, including serotonin, epinephrine, and norepinephrine, and minor amines, including tyramine. Both have been mapped to the Xp11.23-11.4 region. Monoamine oxidase-A deficiency has been documented in a single family of affected males with mild mental retardation and violent aggressive behavior.15 Measurement of urine neurotransmitters and metabolites can detect the disease; subjects should not eat tyramine-rich foods prior to laboratory testing. The enzyme deficiency can be confirmed by measurement in fibroblasts. Monoamine oxidase-B deficiency has been associated with Norrie disease,16 a syndrome of congenital blindness, deafness, and mental retardation mapped to X11.4.

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Dopamine Beta-Hydroxylase Deficiency Dopamine beta-hydroxylase catalyzes the synthesis of norepinephrine from dopamine. Patients with this disorder have low levels of norepinephrine, epinephrine, and their metabolites in plasma, cerebrospinal fluid, and urine. In addition, norepinephrine normally acts as an inhibitor of tyrosine hydroxylase. Thus, in this disorder, tyrosine hydroxylase is overactive, resulting in an even higher concentration of dopamine. Dopamine beta-hydroxylase deficiency is typically diagnosed in adults presenting with orthostatic hypotension and noradrenergic failure. There is no other evidence of neurological problems. Retrospective case histories, however, have indicated ptosis, hypotension, hypothermia, and hypoglycemia in the perinatal period.17 It is suspected that adults living with this disorder have the mildest end of the phenotypic spectrum. Mothers of affected patients have a notable history of a high rate of spontaneous abortions.17,18 Embryo mortality is very high in dopamine beta-hydroxylase knockout mice.19 Surviving mice have increased susceptibility to seizures and altered cellular immunity.20,21 Some studies have suggested that low maternal serum dopamine beta-hydroxylase levels are associated with a heightened risk for familial autism22 and that the dopamine beta-hydroxylase gene is a candidate gene 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 excitatory (cortical) and inhibitory (spinal cord and brainstem) effects. Glycine has multiple properties, as it is gluconeogeneic via pyruvate; constitutes over 15% of amino acids of essential structural proteins such as collagen, elastin, and gelatin; is incorporated into purines, glutathione, and the heme protein; and is involved in important detoxifying conjugation reactions. Nonketotic hyperglycinemia was originally named to distinguish it from ketotic hyperglycinemia, which is now known to be propionic acidemia. Because the distinction is no longer required and clinical confusion between hyperglycinemia and hyperglycemia occurs, the preferred term is glycine encephalopathy. Glycine encephalopathy is a group of autosomal recessive conditions related to varying defects of the complex tetrameric protein that constitutes the glycine cleavage system. This tetramer consists of a P protein containing a pyridoxal phosphate-dependent glycine decarboxylase; an H protein with a lipoic acid containing hydrogen carrier; a T protein, which is tetrahydrofolate dependent; and an L protein, which is a lipoamide dehydrogenase moiety. Defects of the glycine cleavage system are detected by a ratio of cerebrospinal fluid to plasma glycine > 0.08. There have been 150+ patients identified with the classic neonatal phenotype, often presenting with in utero

seizures. Associated clinical findings include neonatal encephalopathy with lethargy, hypotonia, myoclonus, and apnea. Electroencephalographic tracings reveal a burstsuppression pattern. Neuroimaging studies have demonstrated agenesis of the corpus callosum, and neuropathologic findings are those of spongiform white matter degeneration. Magnetic resonance spectroscopy may reveal a peak corresponding to glycine.24 Variations on this theme include an infantile pattern with presentation after 6 months of partial seizures or hypsarrhythmia; a childhood later variant with mild mental retardation, delirium, chorea, and vertical gaze palsies; and a late-onset pattern in adults with progressive spastic diplegia and optic atrophy. The P protein defect is associated with the neonatal onset forms. Although H and T protein defects are associated with later onset forms, there are also milder phenotypes of the neonatal onset form showing mutations in the glycine decarboxylase gene.25 Measurements of glycine cleavage activity in liver or cultured lymphoblasts, or genetic identification, are available for accurate diagnosis.26 Secondary causes of hyperglycinemia include valproic acid and D-glyceric acidemia. Sodium benzoate has been used to reduce glycine concentrations in plasma and cerebrospinal fluid, and dextromethorphan has been used as an N-methyl-D-aspartate receptor blocker. The outcome is generally poor,27 although benefit was described in 3 affected siblings with a mild phenotype and considerable residual enzymatic activity.28 In addition, 2 cases of deterioration with vigabatrin therapy have been described.29

Disorders of -Amino Butyric Acid Metabolism

-amino butyric acid, the major inhibitory neurotransmitter of the brain, is used in up to one third of brain synapses. It is found in nonneural tissues as well, including the pancreatic islet cells and kidney. It is synthesized primarily from glutamate via glutamic acid decarboxylase. The first enzymatic degradative step of GABA involves the enzyme GABA-transaminase, which uses alpha-ketoglutarate from the Krebs cycle to regenerate a molecule of glutamate for every molecule of GABA that is catabolized. Hence, the vital neurotransmitter pools of GABA and glutamate are constantly replenished and tightly regulated. The product of the GABA-transaminase reaction is succinic semialdehyde, which is normally converted to succinic acid via the enzyme succinic semialdehyde dehydrogenase. Succinic acid thereby enters the Krebs cycle, where alpha-ketoglutarate is formed. The ongoing conversion of glutamate to GABA and then back to glutamate is known as the GABA shunt. Disorders of glutamic acid decarboxylase, GABA-transaminase, and succinic semialdehyde dehydrogenase have all been identified. Succinic semialdehyde dehydrogenase deficiency is the most common neurotransmitter disease discussed in

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this article. -amino butyric acid also exists in the form of a dipeptide with histidine, known as homocarnosine. Disorders of -Amino Butyric Acid Synthesis Glutamic Acid Decarboxylase Deficiency Glutamic acid decarboxylase is a pyridoxal-5-phosphate requiring enzyme that converts glutamate to GABA. It exists in 2 isoforms, GAD65 and GAD67. -amino butyric acid has an important role in embryonic development, as substantiated by the association of cleft palate in transgenic mice deficient in GAD67. Mice null for GAD67 were born at the expected frequency but died of severe cleft palate during the first morning after birth. Glutamic acid decarboxylase activities and GABA contents in the cerebral cortex were reduced to 20% and 7%, respectively.30 A recent Japanese population study reported linkage in patients with nonsyndromic cleft lip with and without cleft palate and specific GAD67 haplotypes.31 This supports a role for the GABA-synthesizing GAD67 gene in normal human facial development and represents a newly recognized disorder of GABA synthesis. Disorders of -Amino Butyric Acid Degradation GABA-Transaminase Deficiency GABA-transaminase deficiency is an autosomal recessive disorder 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 confirmed in a single Flemish family.33 Succinic Semialdehyde Dehydrogenase Deficiency Jakobs and coworkers34 described the index case of succinic semialdehyde dehydrogenase deficiency (-hydroxybutyric aciduria) in 1981. Since then, more than 350 cases have been identified and more than 60 of them reported.35 Succinic semialdehyde dehydrogenase activity is deficient, impairing the predominant oxidative conversion of succinic semialdehyde to succinic acid, in response to which succinic semialdehyde is reduced to 4-hydroxybutyric acid in a reaction catalyzed by 4-hydroxybutyrate dehydrogenase. The phenotype of succinic semialdehyde dehydrogenase deficiency encompasses a wide spectrum of neurological manifestations, although it universally leads to a significant neurodevelopmental disorder, including severe expressive language deficits with a high incidence of psychiatric dysfunction.36 We currently have a database of 95 patients and have collected detailed clinical data using a systematic questionnaire on 60 patients. The most common clinical findings are developmental delay, mental retardation, and hypotonia. Neuropsychiatric problems are manifest in 70% of patients and are most commonly characterized by sleep

disturbances, inattention, hyperactivity, and anxiety.37 Other common neurological features are hyporeflexia and nonprogressive cerebellar ataxia. The disorder typically has a static course and not the progressive or intermittent pattern classically associated with a metabolic encephalopathy. There is a minority of patients, involving 10%, with a degenerative course featuring regression and prominent extrapyramidal manifestations.38 Sleep disturbances are reported in 42% of patients, including excessive daytime somnolence (80%), parasomnias (30%), disorders of initiating or maintaining sleep (20%), and nocturnal seizures (10%). Approximately half of patients with succinic semialdehyde dehydrogenase deficiency have epilepsy, usually with generalized tonicclonic seizures and also atypical absence and myoclonic seizures. Occasional patients have refractory seizures, including bouts of generalized convulsive status epilepticus. Electroencephalography recordings reveal background slowing and disorganization in one third and epileptiform abnormalities in one third. The latter are both generalized and multifocal, and photosensitivity and electrographic status epilepticus during slow-wave sleep have been described. Peripheral neuromuscular studies have not been consistent, showing mild demyelinating neuropathy, borderline axonal changes, or normal findings.39 The longterm outlook for affected patients is characterized by variable degrees of mental retardation with persistence of severe expressive language deficit, neuropsychiatric morbidity with prominent anxiety and hallucinations, and continuing 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 physiological fluids without an accompanying metabolic acidosis.41 Concentrations of -hydroxybutyric acid in patients range from 2-fold to 800-fold normal in urine, 4-fold to 200fold in plasma, and a 100-fold to 1200-fold in cerebrospinal fluid in comparison with control ranges.42 In addition to 4-hydroxybutyric acid, other compounds are detected at elevated levels in affected patients including 4, 5-dihydroxyhexanoic acid. Urinary metabolites indicative of -oxidation of excess 4-hydroxybutyric acid include 3,4-dihydroxybutyric, 3-oxo-4-hydroxybutyric, and glycolic acids.43 Increased urinary 2,4-dihydroxybutyric (and its lactone) and 3-hydroxypropionic acid levels indicate metabolism of 4-hydroxybutyric acid by -oxidation. Availability of purified mammalian succinic semialdehyde dehydrogenase protein has permitted cloning of the relevant cDNAs encoding rat and human succinic semialdehyde dehydrogenase. The human gene, ALDH5A1, maps to chromosome 6p22 and consists of 10 exons encompassing 38 kb of DNA.44 More than 35 mutations have been identified, including missense, nonsense, and splicing errors, without hotspots.45 Thus far, there is no clear phenotype/genotype correlation. Heterozygotes (carriers) are typically asymptomatic. One report suggests

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absence epilepsy with myoclonias and photosensitivity may be related to the heterozygous state.46 Neuroimaging has typically revealed the presence of an increased T2-weighted magnetic resonance imaging (MRI) signal most commonly involving the globus pallidi bilaterally and symmetrically, as well as the subcortical white matter, cerebellar dentate nucleus, and brainstem.47 A dentatopallidal pattern has been described to emphasize the combined involvement of the pallidi and dentate nuclei.48 Occasional patients have had asymmetric pallidal signal, and progression of signal abnormalities has been noted in patients over time. Specialized 3H MRI spectroscopy edited for small amino acids have revealed elevations in GABA, -hydroxybutyric acid, and homocarnosine in brain parenchyma.49 Pharmacologic strategies and enhanced understanding of the pathophysiology of succinic semialdehyde dehydrogenase deficiency are expected to follow from studies in a transgenic animal model. A murine model was developed with deletion of exon 7, leading to complete absence of enzymatic activity in neural and peripheral tissues.50 The mice are born with the expected autosomal recessive inheritance pattern and a phenotype having commonalities with the human disease, including neurological impairment, ataxia, and seizures. At postnatal days 16 to 22, the mice develop repetitive tonic-clonic seizures and subsequent mortality.51 In addition, the mice demonstrate a transition from early absence seizures to generalized seizures and eventually convulsive status epilepticus.52 Pharmacologic intervention studies showed some 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 and vigabatrin.53 Taurine was used due to its high content in murine breast milk because the weaning period was associated with seizure onset in suckling animals. Vigabatrin was associated with the expected elevation in GABA concentrations but not lowering of -hydroxybutyric acid. Studies of the expression and function of the GABA(A) receptor in succinic semialdehyde dehydrogenase-deficient mice revealed downregulation of the beta(2) subunit, reduced GABA(A)-mediated postsynaptic potentials, and augmented postsynaptic population spikes recorded from hippocampal slices.54 These findings suggest that progressive dysfunction of the GABA(A) receptor due to chronic overuse and subsequent downregulation could serve as the mechanism of the transition from absence to convulsive seizures seen in this mouse model as well as patient populations that include succinic semialdehyde dehydrogenase deficiency and primary generalized epilepsies such as juvenile myoclonic epilepsy. Similarly, a use-dependent decrease in GABA(B) receptor-mediated function is suggested by a significant decrease in the binding of a specific GABA(B) receptor antagonist at postnatal day 14 compared to day 7, decreased GABA(B) receptor-mediated synaptic potentials, and region-specific and time-dependent decreases

in GABA(B) receptor subunit protein expression.55 Because GABA(B) receptor dysfunction has been implicated as important in cognitive impairment in absence seizure models, independent of seizure activity,56 the possibility is raised that GABA-induced perturbation of GABA(B) receptor function could be important in the pathophysiology of mental retardation in succinic semialdehyde dehydrogenase deficiency. Currently, there is no standard treatment for individuals with succinic semialdehyde dehydrogenase deficiency. Vigabatrin, an irreversible inhibitor of GABA transaminase, has been associated with decreases in cerebrospinal fluid -hydroxybutyric acid. Although there has been an interest in following cerebrospinal fluid -hydroxybutyric acid levels during therapy with vigabatrin in patients with succinic semialdehyde dehydrogenase deficiency,57 neither laboratory or clinical effects have been consistent with vigabatrin therapy.58 Benzodiazepines, risperidal, fluoxetine, and methylphenidate have been helpful for anxiety and behavioral problems.59 Symptomatic treatment for seizures using carbamazepine and lamotrigine have also shown some success. Valproate is avoided, as it inhibits activity of residual succinic semialdehyde dehydrogenase, and its use is associated with increased concentration of hydroxybutyric acid and other succinic semialdehyde dehydrogenase deficiency metabolites.60 Liver-mediated gene therapy in the murine model demonstrated a reduction in -hydroxybutyric acid levels in liver, kidney, serum, and brain extracts, setting the stage for future clinical trials of gene therapy.6 Homocarnosinosis Homocarnosine is a brain-specific dipeptide of GABA and histidine. Homocarnosine concentrations are highest in the dentate and inferior olivary nuclei, intermediate in substantia nigra and globus pallidus, and lowest in the frontal cortex, caudate nucleus, and nucleus accumbens. One affected family has been reported with homocarnosinosis, affecting a healthy 72-year-old Norwegian woman and 3 of her 4 children with neurological disease. Their phenotype was onset of progressive spastic paraplegia between 6 and 29 years of age with progressive mental deterioration and retinal pigmentation.62 The patients had elevated cerebrospinal fluid homocarnosine and normal carnosine. An unrelated patient has recently been described,63 with hypotonia and developmental delay noted by 6 months and ataxia and tremor in adolescence. The disorder may represent a form of carnosinase deficiency.

Pyridoxine-Dependent Seizures
The biologically active form of pyridoxine, pyridoxal 5phosphate, is a cofactor for many enzymatic reactions. Although pyridoxine-dependent epilepsy was formerly

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

considered a disorder of GABA synthesis due to the role of pyridoxal 5-phosphate as a cofactor for glutamic acid decarboxylase, recent findings have suggested that other biochemical pathways are involved. In addition to GABA, pyridoxine is a cofactor for enzymes involved in the metabolism of several other neurotransmitters, including the monoamines, D-serine, and taurine.64 Postmortem quantification of brain GABA and glutamate levels and genotype analyses have failed to demonstrate consistent underproduction of GABA or a genetic linkage to either isomer of glutamic acid decarboxylase.65 However, there has been much recent progress in elucidating the pathophysiology of pyridoxine-dependent seizures, and a new variant of this disorder, pyridoxal 5-phosphate dependency, has been described. Pyridoxine-dependent seizures are typically suspected in a neonate with refractory seizures, potentially of prenatal onset, and an electroencephalogram showing continuous epileptiform activity or a burst-suppression pattern that then responds dramatically to a trial intravenous dose of 50 to 100 mg pyridoxine. The typical clinical presentation is characterized by perinatal onset, rapid response to therapy, refractoriness to other antiepileptic drugs, and a lifelong dependence on continued therapy. Additional clinical features include jitteriness, hypothermia, 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 months without pyridoxine, and clinical response only after repeated trials.66 The atypical form may have much higher incidence than what is generally suspected with this syndrome. A gene locus was mapped to chromosome 5q31 in 4 consanguineous families and 1 multiply affected family.67 Further studies established genetic heterogeneity for pyridoxine dependency, yet linkage in some affected families to 5q31.68 Elevation of pipecolic acid was reported in plasma and cerebrospinal fluid in pyridoxine-dependent epilepsy.69 Subsequently, mutations in the ALDH7A1 gene, which encodes alpha-aminoadipic semialdehyde dehydrogenase (also called antiquitin), were demonstrated with children with pyridoxine-dependent seizures.70 When alpha-aminoadipic semialdehyde dehydrogenase activity is reduced, pipecolic acid and delta-piperideine-5-carboxylate accumulate (Figure 4). The accumulating carboxylate forms a condensation product with pyridoxal 5-phosphate, which presumably sequesters the latter from the brain. Dietary intake of pyridoxine comes from vegetables (as pyridoxine) and meat (originally as pyridoxamine). These are both oxidized to pyridoxal 5-phosphate via an enzyme known as pyridox(am)ine oxidase. A newly recognized disorder, pyridoxine oxidase deficiency, has been associated with fetal distress and intractable seizures.71 Cerebrospinal

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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.

fluid neurotransmitters are very helpful for diagnosis, as aromatic amino acid decarboxylase is dependent on pyridoxal 5-phosphate, and thus a profile consistent with aromatic amino acid decarboxylase deficiency emerges (vide supra) and leads to consideration of this syndrome. This metabolic error is correctable by administration of pyridoxal 5-phosphate but not pyridoxine. Although alpha-aminoadipic semialdehyde dehydrogenase and pyridoxine oxidase deficiency lead to a presumed brain deficit of pyridoxal 5-phosphate, the mechanism for the seizures remains unknown.

Conclusion
Inherited disorders of neurotransmitters include a group of metabolic syndromes having important neurological manifestations and particular therapeutic implications. Currently, disorders of the metabolism of monoamines (dopamine, serotonin, norepinephrine, epinephrine), glycine, and GABA have been defined. Disorders of biopterin metabolism are treated with tetrahydrobiopterin and agents augmenting dopaminergic and serotoninergic transmission. The impressive responsiveness of Segawa fluctuating dystonia to L-dopa is a hallmark feature of previously unrecognized neurological morbidity becoming

treatable at any age. The neonatal entities of glycine encephalopathy and pyridoxine-dependent seizures have widening clinical phenotypes and new variants, including a form of the latter requiring specific pyridoxal-5-phosphate therapy. Succinic semialdehyde dehydrogenase deficiency is relatively common in comparison to the remainder of this group of disorders. Other disorders of GABA metabolism, as well as heretofore unrecognized neurotransmitter disorders, will require increasing use of cerebrospinal fluid analysis for diagnosis and treatment. Emerging technologies such as magnetic resonance spectroscopy may help to identify disorders of other neurotransmitters, such as glutamate or melatonin. Disorders of neurotransmitter transport, storage, release, and reuptake may be added to the body of disorders of synthesis and catabolism. The implications for furthering our understanding of the mechanisms of prevalent neurologically handicapping conditions, ranging from epilepsy to mental retardation, autism, and addiction, are enormous when one considers the range of pathology associated with these disorders.

Acknowledgment
The authors acknowledge the Delman Family Fund for Pediatric Neurology Research.

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