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.
Brain metabolism of GABA. B6:pyridoxal
phosphate coenzyme; 1: GABA transaminase; 2: succinic semialdehyde
dehydrogenase. Enzyme defects are indicated by solid red bars.
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.
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.
Monoamine metabolism. 5-HTRP: 5-hydroxytryptophan; BH4: tetrahydrobiopterin; B6: pyridoxal phosphate coenzyme;
VMA: vanillylmandelic acid; MHPG: 3-methoxy-4-hydroxyphenylglycol;
HVA: homovanillic 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.
Tetrahydrobiopterin metabolism. GTP: guanosine triphosphate;
BH4: tetrahydrobiopterin; q-BH2: 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.
GABA Transaminase Deficiency
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.
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 ...