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
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.
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-hydroxyphenylethyleneglycol
(MHPG), the catabolites of dopamine and norepinephrine, respectively. In
addition, 5-hydroxyindoleacetic acid (5-HIAA) levels are normal,
and serotonin metabolism is unaffected.
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.
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.
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