Rare Specific Disorders
Tryptophan hydroxylase deficiency
Tryptophan hydroxylase (TPH) catalyzes the BH4-dependent hydroxylation of tryptophan to 5-HTP, which is then decarboxylated to form serotonin. TPH expression is limited to certain cells in the CNS and periphery, including raphe neurons, pinealocytes, mast cells, mononuclear leukocytes, beta cells of the islets of Langerhans, and enterochromaffin cells of the gut.
Patients with presumed TPH deficiency have recently been reported, although it is not yet certain that their symptoms result from TPH deficiency.31 Clinical features, consisting of ataxia, speech delay, mild psychomotor retardation, and hypotonia, are nonspecific. CSF neurotransmitter metabolite and pterin studies demonstrate the expected low 5-HIAA with normal HVA, neopterin, and biopterin levels. Mutations in the TPH gene have not yet been identified.
Dopamine beta-hydroxylase deficiency
Dopamine beta-hydroxylase (DBH) is the enzyme that converts dopamine to norepinephrine. Presenting symptoms of this disorder have been largely attributed to the importance of this enzyme in postganglionic sympathetic neurons. Patients with severe deficiency of this enzyme, however, cannot synthesize norepinephrine, epinephrine, and octopamine in either the CNS or the peripheral autonomic neurons. Dopamine acts as a false neurotransmitter for noradrenergic neurons. Neonates with DBH deficiency can have episodic hypothermia, hypoglycemia, and hypotension, but survivors then do fairly well until late childhood when overwhelming orthostatic hypotension profoundly limits their activities. The hypotension can be so severe as to lead to convulsive syncope with recurrent clonic seizures.
Most patients reported to date have been identified as young adults. Observation of severe orthostatic hypotension in a patient whose plasma norepinephrine/dopamine ratio is much less than one supports the diagnosis. Orthostatic hypotension, particularly after exercise, and ptosis are constant features. General lethargy and lassitude improve dramatically and blood pressure normalizes with treatment with d-l-threo-dihydroxyphenylserine, a synthetic amino acid that is converted to norepinephrine by aromatic L-amino acid decarboxylase. Whether or not these patients suffer from attention problems or other subtle cognitive deficits has not been adequately studied. Patients may undergo personality change, becoming more aggressive with treatment.
Monoamine oxidase deficiency
Monoamine oxidase is a mitochondrial enzyme involved in the catabolism of biogenic amines. Monoamine oxidase A (MAO-A), the primary type in fibroblasts, preferentially degrades serotonin and norepinephrine. Monoamine oxidase B (MAO-B), the primary type in platelets and in the brain, preferentially degrades phenylethylamine and benzylamine. These enzymes are critical in the neuronal metabolism of catecholamine and indoleamine neurotransmitters.
The genes are closely linked on the X-chromosome, near the Norrie disease locus, and only affected boys have been identified to date. Comparisons of the neurochemical characteristics of previously described patients with combined MAO-A and MAO-B deficiency and selective MAO-A deficiency have led to an improved understanding of the roles of MAO-A and MAO-B in the metabolic degradation of catecholamines and other biogenic amines, including serotonin and the trace amines.
Monoamine oxidase A deficiency
Brunner reported a family with an X-linked nondysmorphic mild mental retardation and a tendency to aggressive or violent behavior including arson, attempted rape, exhibitionism, and attempted suicide. Urine studies revealed marked disturbance of monoamine metabolism. Normal platelet MAO-B activity suggested that the unusual behavior pattern in this family might be caused by isolated MAO-A deficiency, which was later confirmed by identification in all affected males of a point mutation leading to premature termination of the protein.
Measurement of MHPG (3-methoxy, 4-hydroxyphenolglycol, a metabolite of norepinephrine) in plasma is the most sensitive index of MAO-A activity in humans, and can be used to screen potential cases. MAO-A enzyme activity can be measured directly from fibroblasts, however. The inability to identify additional patients despite screening in at-risk males with a mental retardation or behavioral phenotype makes it likely this disorder is rare.10 Interestingly, a high activity MAO-A promoter allele has been found with increased frequency in women with panic disorder. A possible association of decreased enzyme activity in women with bipolar disorder has also been reported.
Monoamine oxidase B deficiency
Isolated MAO-B deficiency has not yet been reported in a patient. Two brothers with a microdeletion including the Norrie locus and MAO-B, however, had features consistent with Norrie disease alone, with congenital blindness and progressive hearing loss caused by cochlear degeneration in adolescence. These patients had neither abnormal behavior nor mental retardation, leading the authors to conclude that MAO-A plays a more significant role than MAO-B in the metabolism of biogenic amines, and MAO-B deficiency alone may have a primarily neurochemical phenotype: that of increased phenylethylamine in urine.
Monoamine oxidase A and B deficiency
Conclusions regarding the phenotype of individuals with combined deficiency of MAO-A and MAO-B come primarily from a study of a single boy with a microdeletion at Xp14 involving the Norrie locus and documented severe deficiency of MAO-A and MAO-B activity. He was severely mentally retarded, blind, and had other neurologic features including myoclonus and tendency for motor stereotypies. Because Norrie disease is an X-linked recessive disorder, obligate carriers would not be expected to have symptoms. In this family, two obligate carriers had normal IQ testing. The proband's mother had psychiatric symptoms characterized by “chronic hypomania and schizotypal features,” however, and both carriers had low MAO activity.
Succinic semialdehyde dehydrogenase deficiency
Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive inborn error of metabolism associated with a defect in the metabolism of 4-gamma-aminobutyric acid or GABA. Phenotypic features range from nonspecific global developmental delay and hypotonia to ataxia, severe mental retardation, visual impairment, and seizures. Urine organic acid screening to detect elevated 4-hydroxybutyric acid is the most easily available screening strategy, but GABA levels in CSF and urine are also elevated. Recently, improvement of seizures in a mouse model of the disorder was demonstrated with treatment with vigabatrin or a GABA B receptor antagonist. The relevance of these findings to treatment of patients, if any, is not yet known.
