Aromatic L-amino acid decarboxylase deficiency in Taiwan.

BACKGROUND: Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disorder of neurotransmitter synthesis. It has unique clinical presentations. AIMS: The purpose of this study is to delineate the clinical features and molecular spectrum of AADC deficiency in Taiwanese infants and children. METHODS: We report eight patients with characteristic clinical manifestations of AADC deficiency. Clinical presentations, treatment response, outcome and mutations of DOPA decarboxylase (DDC) gene were analyzed. RESULTS: The clinical manifestations were similar to those previously reported, including symptoms onset before age 1 year with features of severe floppiness, oculogyric crises, athetoid movement, prominent startle response, tongue thrusting, ptosis, paroxysmal diaphoresis, nasal congestion, diarrhea, irritability and sleep disorders. In addition, we observed that all patients (100.0%) had small hands and feet. During the period of follow-up, all of them (100.0%) presented severe floppiness in spite of therapeutic trials with vitamin B6, dopamine agonist, MAO inhibitor and/or anticholinergics. Three different mutations were identified in the DDC gene, including two novel mutations 1303 C>T and 1367ins A and one IVS 6+4 A>T mutation. The IVS 6+4 A>T was a splicing mutation, which inserted an additional 37nt of intron 6 into the DDC mRNA. Thirteen out of 16 alleles (81.3%) carried IVS 6+4 A>T mutation and the IVS 6+4 A>T alleles shared a conserved haplotype. CONCLUSIONS: Patients with AADC deficiency in Taiwan have particular clinical manifestations of small hands and feet, which have rarely been mentioned in the literature. The prevalence of IVS 6+4 A>T splicing mutation is high in our study group and the IVS 6+4 A>T mutation might have a founder effect.

[Radiological innovations in the screening and diagnosis of the inborn errors of metabolism]. / Nouveautés radiologiques dans le dépistage et le diagnostic des erreurs innées du métabolisme.

New metabolic diseases are regularly identified by a genetic or biochemical approach. Indeed, the metabolic diseases result from an enzymatic block with accumulation of a metabolite upstream to the block and deficit of a metabolite downstream. The characterization of these abnormal metabolites by MRI spectroscopy permitted to identify the deficient enzyme in two new groups of diseases, creatine deficiencies and polyol anomalies. Creatine deficiency is implicated in unspecific mental retardation. A low peak of creatine at MRI spectroscopy is evocating of creatine deficiency which is treatable by creatine administration. Deficiency of synthesis of polyols, metabolites on the pentose pathway, represent new described metabolic diseases with variable symptoms including a neurological distress, liver disease, splenomegaly, cutis laxa and renal insufficiency. The deficit of ribose-5-phosphate isomerase, one of the enzymes whose diagnosis is evoked in front of the accumulation of ribitol, arabitol and xylitol leads to a leucodystrophy in adults. This new deficit was highlighted by the identification of an abnormal peak in cerebral MRI-spectroscopy corresponding to the abnormal accumulation of polyols in brain. Congenital hyperinsulinism (HI) is characterized by profound hypoglycaemia related to inappropriate insulin secretion. Focal and diffuse forms of hyperinsulinism share a similar clinical presentation but their treatment is dramatically different. Until recently, preoperative differential diagnosis was based on pancreatic venous sampling, an invasive and technically demanding technique. Positron emission tomography (PET) after injection of [18F]Fluoro-L-DOPA has been evaluated for the preoperative differentiation between focal and diffuse HI, by imaging uptake of radiotracer and the conversion of [18F]Fluoro-L-DOPA into dopamine by DOPA decarboxylase. PET with [18F]Fluoro-L-DOPA has been validated as a reliable test to differentiate diffuse and focal HI and is now a major differential diagnosis tool in infantile hyperinsulinemic hypoglycaemia.

3,4-dihydroxyphenylalanine (DOPA) metabolism in screening-detected and non-screening-detected neuroblastoma.

To investigate the possible clinical application of the hypothesis that insufficient induction of 3,4-dihydroxyphenylalanine decarboxylase (DDC) causes accumulation and secretion of 3,4-dihydroxyphenylalanine (DOPA) in unfavorable neuroblastomas, we measured plasma DOPA in 28 neuroblastoma patients. Abnormally high levels were demonstrated in patients with neuroblastoma, and the levels in patients with clinical manifestations (median, 44,800 pg/ml; range, 17,700 to 220,000 pg/ml; n = 6) were significantly higher than those in patients detected by screening (median, 5825 pg/ml; range 2890 to 33,300 pg/ml; n = 22) (P = 0.0004). The catecholamine secretion profiles of the two groups were different, and it was suggested that the relative deficiency of DDC caused DOPA secretion in patients in the former group, whose prognosis was unfavorable, except in one case. In both groups, serial determination of plasma DOPA was a good monitor of the disease course. The higher plasma DOPA level (>9400 pg/ml) was significantly correlated with the patients' age (>1 year old) (P = 0.019), tumor stage (III, IV) (P = 0.029), and DNA diploidy (P = 0.018). These results are consistent with previous studies that demonstrated plasma DOPA was a useful marker in the diagnosis and follow-up of neuroblastoma. The results also indicate that higher plasma DOPA levels are associated with the unfavorable characteristics of neuroblastoma, which seem to support the hypothesis on DDC deficiency in unfavorable neuroblastoma.

3,4-dihydroxyphenylalanine (DOPA) decarboxylase deficiency and resultant high levels of plasma DOPA and dopamine in unfavorable neuroblastoma.

Neuroblastoma (NB) is a tumor which arises from neural crest cells. In the developing neural crest cells, the induction of 3,4-dihydroxyphenylalanine (DOPA) decarboxylase is more delayed than that of tyrosine hydroxylase and dopamine-beta-hydroxylase. If NB cells are arrested in an early stage of neural crest development, the induction of DOPA decarboxylase is insufficient and the accumulation and secretion of DOPA can be caused. The biochemically immature phenotype is thought to represent the undifferentiated characteristics of the cells and might correlate with the grade of malignancy. To investigate whether the hypothesis is clinically applicable or not, we have measured plasma DOPA, dopamine and urinary catecholamine metabolites in NB patients. The levels of plasma DOPA, dopamine, urinary homovanillic acid (HVA) and vanillactic acid (VLA) were significantly higher in patients with unfavorable NBs and the higher plasma DOPA level was significantly associated with the patients' age (> 1 year old), tumor stage (III, IV) and DNA diploidy. Serial determination of plasma DOPA was a good monitor of the disease course. These results are compatible with the hypothesis on DOPA decarboxylase deficiency and DOPA secretion in undifferentiated, unfavorable NBs. In conclusion, the plasma DOPA can be used to predict patients' prognosis as well as to follow up patients with NB.

Perturbed pattern of catecholamine-containing neurons in mutant Drosophila deficient in the enzyme dopa decarboxylase.

We have initiated a study of catecholamine-containing neurons in Drosophila melanogaster because of the potential, with this organism, to perturb catecholamine metabolism using genetic tools. The major objectives of this study were (1) to define the pattern of catecholamine-containing neurons and (2) to determine the effect of the absence of dopa decarboxylase (DDC) enzyme activity on the catecholamine-containing neurons. We chose to analyze the catecholamine-containing neurons in the ventral ganglion of the larval CNS. To define the catecholamine-containing neurons, CNSs were dissected and reacted with glyoxylic acid. The catecholamine histofluorescence (CF) neuronal pattern (normal-CF neurons) in the wild-type ventral ganglion is stereotypic. In the mutant ventral ganglia, in the absence of DDC enzyme activity, most normal-CF neurons still exhibit CF, probably indicating the presence of accumulated L-dopa. Interestingly, in the mutant CNSs, additional novel neuronal subsets also exhibit CF. Analysis of CNSs from early developmental stages revealed that the novel-CF neurons become fluorogenic earlier than the normal-CF neurons in the mutant CNS. To determine whether neuronal subsets, in addition to the normal-CF, neurons are able to sequester catecholamines, CNSs from wild-type larvae were incubated in exogenous catecholamine (L-dopa or dopamine). Incubations in L-dopa or dopamine revealed normally nonfluorogenic neurons that are able to take up the amine and become fluorogenic. Among the neurons able to sequester L-dopa or dopamine are subsets that are similar to the novel-CF neurons in the mutant CNS. This similarity is best characterized by a major novel-CF neuronal cluster in the subesophageal-thoracic region. These results suggest that in the absence of DDC activity, subsets of normally nonfluorogenic neurons capable of sequestering L-dopa or dopamine accumulate the fluorogenic catecholamine. Hypotheses that might explain the mode of accumulation of the catecholamine within the novel-CF neurons are considered.