Unusually mild phenotype of AADC deficiency in 2 siblings

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Abstract

Aromatic l-amino acid decarboxylase deficiency is a rare neurotransmitter defect leading to serotonin, dopamine and norepinephrine deficiency. Affected individuals usually present in infancy with severe developmental delay, oculogyric crises and extrapyramidal movements. We present the clinical, molecular and biochemical features of a pair of siblings who presented with fatigability, hypersomnolence and dystonia and who showed excellent response to treatment. Analysis of CSF biogenic amines, plasma AADC levels and direct sequencing of the DDC gene was performed. CSF catecholamine metabolites were reduced, with elevation of 3-O-methyldopa. Plasma AADC activity was undetectable in both siblings, and decreased in their carrier parents. One missense mutation (853C > T) was found in exon 8, and a donor splice site mutation was found in the intron after exon 6 (IVS6+4A > T). Both siblings showed excellent response to MAO inhibitor and dopamine agonist treatment. This report expands the clinical spectrum of AADC deficiency and contributes to the knowledge of the genotype and phenotype correlation for the DDC gene. It is important to recognize the milder phenotypes of the disease as these patients might respond well to therapy.

Section snippets

Biochemical analysis

Aromatic amino acids and metabolites in CSF and AADC activity in plasma were analyzed as previously described by Hyland et al. [9].

Molecular analysis

Genomic DNA was extracted according to standard protocols. For exon 6, a 418 bp product was obtained from 100 ng genomic DNA using specific oligonucleotides (Forward primer 5′-AGTTCTGCCTCCTGTGCCGTT and reverse primer 5′-GTTCACGCCATTCTCCTGCCT), 0.5 U Taq DNA polymerase (Qiagen Inc, Valencia, CA, USA). PCR amplification cycle was as follows: denaturation at 95 °C for 3 min

CSF biogenic amines

CSF neurotransmitter profile for Patient 1 showed very low 5-hydroxyindoleacetic acid (5HIAA) (13 nmol/L; normal 67–189 nmol/L) and homovanillic acid (HVA) levels (64 nmol/L; normal 167–563 nmol/L), and raised 3-O-methyldopa (3-OMD) levels (310 nmol/L; normal <100 nmol/L).

Plasma AADC levels

The AADC levels were undetectable in both sisters (<1 pmol/min/ml; normal 36–129 pmol/min/ml), and lower than normal in their heterozygote father (11.9 pmol/min/ml; normal 24-43 pmol/min/ml) and mother (5.3 pmol/min/ml; normal 24-43

Discussion

AADC is an enzyme that decarboxylates l-dopa and 5-hydroxytryptophan (5-HT), resulting in impaired synthesis of dopamine and serotonin. Since Hyland et al. described the first 2 cases in 1990 [8], more than 10 cases have been reported [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [13] in the literature and additional cases have been found (K Hyland, unpublished data). Both these affected siblings had undetectable plasma AADC levels, and typical CSF biogenic amine profile

Conclusion

This report highlights the potential for good treatment response for AADC deficiency, a condition with dismal outcome to date. The underlying mutation is the most likely factor in determining disease severity and response to treatment.

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