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INTRODUCTION

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This chapter describes inherited disorders affecting the catabolism of γ-aminobutyric acid (GABA), those affecting receptors for neurotransmitters (GABA and glycine), and those affecting the metabolism of monoamines. Other disorders that impinge on metabolism of neurotransmitter amino acids are described elsewhere in the textbook. (Glutamine synthase deficiency is discussed in Chapter 140, pyridoxine responsive disorders in Chapter 144, and glycine/serine disorders in Chapter 134).

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Two genetic defects are known in GABA catabolism (Fig. 137-1): GABA transaminase deficiency and succinic semialdehyde dehydrogenase (SSADH) deficiency.

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Figure 137-1

Brain metabolism of γ-aminobutyric acid (GABA). 1 = GABA transaminase; 2 = succinic semialdehyde dehydrogenase. Enzyme defects are indicated by solid red bars. B6, pyridoxal phosphate coenzyme.

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Hyperekplexia, characterized by neonatal hypertonia and excessive startle responses, is caused by defects in glycerinergic neurotransmission and is genetically heterogeneous. Mutations in genes encoding various GABAA receptor subunits cause various types of epilepsy.

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Nine defects have been reported in the metabolism of monoamines (Figs. 137-2 and 137-3): 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. In addition, 2 disorders affecting monoamine transport have been described: dopamine transporter deficiency syndrome (DTDS) and vesicular monoamine transporter disease (VMAT2). All are associated with neurologic symptoms except DBH deficiency (orthostatic hypotension). With the exception of MAO-A deficiency, most disorders can be at least partially ameliorated with pharmacotherapeutic approaches.

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Figure 137-2

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

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Figure 137-3

Tetrahydrobiopterin metabolism. 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. BH4, tetrahydrobiopterin; GTP, guanosine triphosphate; q-BH2, quinonoid dihydrobiopterin.

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DEFECTS OF GABA CATABOLISM

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GABA TRANSAMINASE DEFICIENCY

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CLINICAL PRESENTATION

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GABA transaminase deficiency was first reported in 1984 in a Flemish family in association with severe neonatal/early infantile epileptic encephalopathy and growth acceleration. The extremely rare disease has been confirmed in 3 unrelated patients and an older sibling of 1 of these patients who died at the age of 1 year. The siblings also showed feeding difficulties from birth, often necessitating ...

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