Dopa-Responsive Dystonia, Tyrosine Hydroxylase Deficiency and Aromatic L-Amino Acid Decarboxylase Deficiency: Multifaceted Diseases That Can Masquerade as Cerebral Palsy • 1874

Abstract

Diagnosis of dopa-responsive dystonia (DRD) due to GTP cyclohydrolase I(GTPCH) deficiency (autosomal dominant), tyrosine hydroxylase (TH) deficiency(autosomal recessive) or aromatic L-amino acid decarboxylase (AADC) deficiency(autosomal recessive) is difficult as symptoms are often non-specific. We have established a series of tests which, either in isolation, or in combination allow identification of these disorders. Measurement of biogenic amine neurotransmitter metabolites in cerebrospinal fluid (CSF) shows low levels of homovanillic acid (HVA - dopamine metabolite) in all three conditions. GTPCH deficiency is distinguished by decreased levels of tetrahydrobiopterin and its precursor, neopterin, and AADC deficiency by high levels of 3-O-methyldopa(3OMD). Low levels of HVA, with normal pterins and 3OMD in the absence of brain lesions is highly suggestive of TH deficiency. Diagnosis is also possible in the absence of CSF. 3OMD concentrations are highly elevated in plasma and urine in AADC deficiency. Confirmation of the diagnosis is accomplished by assay of AADC activity in plasma. Evidence for TH deficiency can be obtained by a finding of reduced concentrations of plasma catecholamines, but final confirmation requires DNA mutation analysis as tissues are not readily available for TH enzyme assay. Due to a secondary inhibition of phenylalanine metabolism, DRD can be diagnosed by measurement of phenylalanine and tyrosine in plasma after an oral phenylalanine load. This battery of tests has to date identified 6 cases of AADC deficiency, 4 cases of TH deficiency, and 4 cases of DRD. Of these, 8 had been described as having cerebral palsy (CP) prior to our diagnosis. As CP is normally considered an untreatable disorder, it is important that patients with CP of unknown etiology be tested, as symptoms in DRD and the TH and AADC deficiencies often respond dramatically to treatment with either levodopa, or a mixture of dopamine agonists and monoamine oxidase inhibitors.