Rudolph's Pediatrics, 22nd Ed.

CHAPTER 141. Disorders of Metabolism of Neurotransmitter Amino Acids

Jaak Jaeken

INTRODUCTION

This chapter deals with defects in the catabolism of gamma-aminobutyric acid (GABA), with defects in receptors of neurotransmitters (GABA and glycine) and in monoamine metabolism. (Glutamine synthase deficiency is discussed in Chapter 145, pyridoxine responsive disorders in Chapter 149, and glycine/serine disorders in Chapter 139.)

Two genetic defects are known in GABA catabolism (Fig. 141-1): the extremely rare, severe, and untreatable GABA transaminase deficiency, and the much more frequent and, to some extent, treatable succinic semialdehyde dehydrogenase (SSADH) deficiency.

Hyperekplexia is a dominantly inherited defect in subunits of the glycine receptor (α1 and β) and in the receptor-associated protein gephyrin. This disease is characterized by excessive startle responses, which are treatable with clonazepam. Mutant GABAA receptor γ-2 subunit causes absence epilepsy and febrile seizures.

FIGURE 141-1. Brain metabolism of GABA. B6: pyridoxal phosphate coenzyme; 1: GABA transaminase; 2: succinic semialdehyde dehydrogenase. Enzyme defects are indicated by solid red bars.

Nine defects have been reported in the metabolism of monoamines (Figs. 141-2 and 141-3): five in the synthesis of the cofactor tetrahydrobiopterin, tyrosine-hydroxylase (TH) deficiency, aromatic amino acid decarboxylase (AADC) deficiency, dopamine β-hydroxylase (DBH) deficiency, and monoamine oxidase A (MAO-A) deficiency. All are associated with neurological symptoms except DBH deficiency (orthostatic hypotension). With the exception of MAO-A deficiency, they are more or less efficiently treatable.

GABA CATABOLISM DEFECTS

GABA TRANSAMINASE DEFICIENCY

Clinical Presentation

GABA transaminase deficiency was reported in 1984 in a brother and sister from a Flemish family. No other patients have been reported. The siblings showed feeding difficulties from birth, often necessitating gavage feeding; profound axial hypotonia; and generalized convulsions. Hyperreflexia was present during the first 6 to 8 months. Psychomotor development was nearly absent. Growth acceleration was present from birth, due to growth hormone hypersecretion. Postmortem examination of the brain showed spongiform leukodystrophy.

Metabolic Derangement

The CSF and plasma concentrations of GABA, GABA conjugates, and β-alanine were increased due to a decrease of GABA transaminase activity. β-alanine is an alternative substrate for GABA transaminase, which explains its increase in this disease.

Genetics

GABA transaminase deficiency (OMIM number: 137150) is an autosomal recessive disease. The patients were compound heterozygotes for two missense mutations of GABAT on chromosome 16p13.3.

Diagnostic Tests

The diagnosis requires amino acid analysis of the CSF. Since free GABA CSF levels are low, sensitive techniques must be used, such as ion-exchange chromatography with fluorescence detection or a stable isotope dilution technique. Enzymatic confirmation is obtained using lymphocytes, lymphoblasts, or liver. Prenatal diagnosis is possible by enzymatic analysis of chorionic villus tissue, not of amniocytes.

Treatment

No efficient treatment is available. The siblings died at the ages of 1, 2, and 7 years.1

FIGURE 141-2. Monoamine metabolism. 5-HTRP: 5-hydroxytryptophan; BH4: tetrahydrobiopterin; B6: pyridoxal phosphate coenzyme; VMA: vanillylmandelic acid; MHPG: 3-methoxy-4-hydroxyphenylglycol; HVA: homo-vanillic acid; 5-HIAA: 5-hydroxyindole acetic acid; 1: tyrosine hydroxylase; 2: aromatic L-amino acid decarboxylase; 3: dopamine beta hydroxylase; 4: monoamine oxidase. Enzyme defects are indicated by solid red bars.

FIGURE 141-3. Tetrahydrobiopterin metabolism. GTP: guanosine triphosphate; BH4: tetrahydrobiopterin; qBH2: quinonoid dihydrobiopterin; 1: GTP cyclohydrolase (GTPCH); 2: 6-pyruvoyl tetrahydropterin synthase (PTPS); 3: sepiapterin reductase (SR); 4: pterincarbinolamine reductase (PCBD); 5: dihydropterin reductase (DHPR). Enzyme defects are indicated by solid red bars.

SUCCINIC SEMIALDEHYDE DEHYDROGENASE DEFICIENCY

Clinical Presentation

SSADH deficiency was first reported in 1981 and has been documented in at least 350 patients. The clinical picture ranges from mild to severe and usually comprises psychomotor retardation, delayed speech development, hypotonia, and ataxia. Less frequent features are convulsions, aggressive behavior, oculomotor apraxia, choreoathetosis, and nystagmus. Ataxia may resolve with age. Brain MRI may show basal ganglia abnormalities, delayed myelination, and cerebellar atrophy.

Metabolic Derangement

An increase of β-hydroxybutyrate in body fluids is the hallmark of the disease. This accumulation tends to decrease with age. Other compounds are variably increased such as metabolites of the α- and β-oxidation of β-hydroxybutyrate. The latter is a pharmacologically active compound, which may explain at least part of the symptomatology.

Genetics

The gene for SSADH (OMIM number: 610045) maps to chromosome 6p22. The mode of inheritance is autosomal recessive.

Diagnostic Tests

The diagnosis is made by organic acid analysis of body fluids. One must consider that β-hydroxybutyrate is unstable in urine and that in some patients the excretion of this compound is only slightly increased. The enzyme deficiency can be demonstrated in lymphocytes and lymphoblasts. Prenatal diagnosis is performed by isotope-dilution mass spectrometry to measure β-hydroxybutyric acid levels in amniotic fluid and determination of SSADH activity in amniocytes or chorionic villus tissue.

Treatment

The GABA transaminase inhibitor vigabatrin was shown to be associated with variable improvement, particularly of ataxia and behavior. However, this drug potentially causes irreversible visual field defects. It was recently shown that a mouse model of this disease can be rescued by a ketogenic diet. Clinical studies in humans are under way.2,3

NEUROTRANSMITTER RECEPTOR DEFECTS

HYPEREKPLEXIA

Clinical Presentation

Hyperekplexia (startle disease) was probably first reported in 1958. Its three main symptoms are (1) generalized stiffness immediately after birth, which normalizes during the first years of life; (2) an excessive startle reflex to unexpected, particularly auditory, stimuli; and (3) a short generalized stiffness following the startle response. There may be associated features such as hernias and epilepsy.

Metabolic Derangement

Most patients show a defect in the α1 subunit of the glycine receptor. Others have a defect in the beta subunit or in the receptor-associated protein gephyrin.

Genetics

Hyperekplexia shows autosomal dominant and autosomal recessive inheritance. The genes for the α1 subunit and the β subunit of the glycine receptor and the genes for gephyrin are on chromosome 5q33, chromosome 4q31.3, and chromosome 14q24 resp. OMIM numbers 138491, 138492, and 603930, respectively.

Diagnostic Tests

The diagnosis is based on the response to treatment: clonazepam reduces the frequency and magnitude of startle responses. It binds to the benzodiazepine site of the GABAA receptor. The diagnosis is confirmed by mutation analysis of the previously mentioned genes and of other genes.

Treatment

The stiffness decreases during the first years of life, but the excessive startle responses remain. The favorable effect of clonazepam is mentioned under “Diagnostic Tests.” However, this drug has less effect on the stiffness.4,5

Table 141-1. Monoamine Metabolism Defects

GABA RECEPTOR DEFECT

Clinical Presentation

Mutations in a GABA receptor have been first reported in 2001 in two large families, one with febrile seizures and generalized tonic-clonic seizures, the other with febrile seizures, childhood absence epilepsy, and other forms of epilepsy. It is a rare form of dominantly inherited epilepsy.

Metabolic Derangement

Mutations of the GABA receptor disturb the inhibitory neurotransmitter function of GABA, predominantly in the gray matter of the central nervous system.

Genetics

Inheritance of GABA receptor defect (OMIM number: 137164) is autosomal dominant. Mutations were found in the γ2 subunit of the GABAA receptor. The gene for this subunit has been mapped to chromosome 5q31.1-33.1.

Diagnostic Tests

The diagnosis is based on mutation analysis of the γ2-subunit of the GABAA receptor.

Treatment

Patients mostly respond to benzodiazepines. Prognosis is largely determined by the type of epilepsy6,7 and febrile seizures.

MONOAMINE METABOLISM DEFECTS

Among the some nine defects in monoamine metabolism, only tyrosine hydroxylase deficiency will be described in extenso; the others are summarized in Table 141-1.

TYROSINE HYDROXYLASE DEFICIENCY

Clinical Presentation

Most patients present in their first year of life with truncal or generalized hypotonia. Another feature is delayed motor development that, in combination with the hypotonia, may mimic a primary neuromuscular disorder. Classical extrapyramidal signs and symptoms generally appear at a later age. A hypokinetic-rigid parkinsonian syndrome can develop. Some patients exhibit a diurnal fluctuation of symptoms.

Metabolic Derangement

Tyrosine hydroxylase (TH) converts tyrosine into L-dopa, the direct precursor of catecholamine biosynthesis (Fig. 141-2). It is a rate-limiting step in this biosynthesis. BH4 is a cofactor of this enzyme and is expressed in the brain and in the adrenals. The biochemical hallmarks of the disease are low CSF levels of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphe-nylethyleneglycol (MHPG), the catabolites of dopamine and norepinephrine, respectively. In addition, 5-hydroxyindoleacetic acid (5-HIAA) levels are normal, and serotonin metabolism is unaffected.

Genetics

Inheritance of tyrosine hydroxylase (OMIM number: 191290) is autosomal recessive, and the gene is located on chromosome 11p15.5. One of the reported mutations is common in the Dutch population.

Diagnostic Tests

The most important diagnostic test is the measurement of HVA, MHPG, and 5-HIAA in the CSF. Urinary measurements are not reliable in the diagnosis of this defect. Tyrosine and phenylalanine levels are usually normal in body fluids of these patients. Enzyme measurement is not a diagnostic option, as there is no enzyme activity detectable in body fluids, blood cells, and fibroblasts.

Treatment

In most cases, TH deficiency can be treated with low-dose L-dopa in combination with an L-dopa decarboxylase inhibitor. However, the response is variable and ranges from complete remission to no improvement. Therapy should be started with low-dose L-dopa (initial dose 2 to 3 mg/kg per day in three divided doses), since these patients are very prone to major side effects even on low doses (mainly irritability, dyskinesia, and ballism).8-13