Report of two never treated adult sisters with aromatic L-amino Acid decarboxylase deficiency: a portrait of the natural history of the disease or an expanding phenotype?

Abstract

Two sisters were diagnosed in their adulthood with aromatic L-amino acid decarboxylase (AADC) deficiency (OMIM#608643). They experienced early myasthenia-like manifestations, myoclonic jerks, oculogyric crises, tremors, and developmental delay during childhood; clinical stabilization afterwards; and spontaneous improvement during adolescence and young adulthood. Two novel pathogenic mutations on DDC gene [p.Tyr37Thrfs*5 (c.105delC) and p.F237S (c.710 T>C)] were associated with undetectable enzyme activity in plasma and only a mild reduction of biogenic amines in cerebrospinal fluid (CSF). The increase of both 3-O-methyldopa and 5-hydroxytryptophan on CSF was the most relevant biochemical alteration denoting AADC defect in these subjects. Transdermal rotigotine remarkably improved their gross motor functions and the asthenic status they complained. The present cases broaden the phenotypic spectrum of AADC deficiency and suggest that (1) AADC defect is not a progressive neurological disease and behaves rather as a neurodevelopmental disorder that improves during the second decade of life; (2) treatment-naïve adults can still respond well to neurotransmitter therapy; and (3) the possibility of a mild presentation of AADC deficiency should be considered when examining young adults with asthenic and parkinsonian symptoms.

Fig. 1

Pedigree of the family

Fig. 2

The figure shows the consequences of the two mutations on the protein encoded by the gene DDC, as assessed by the software SwissPdbViewer version 4.1.0. The mutation c.105delC generates a premature stop codon after the change of 4 amino acids (Tyr>Thr in yellow, Leu>Cys in red, Arg>Gly in green, and Pro>Arg in pink): p.Tyr37Thrfs*5. Nevertheless, it is very likely that the stop mutation causes an early degradation of RNA by NMD (Nonsense Mediated Decay). Project HOPE (retrieved from http://www.cmbi.ru.nl/hope/home) (Venselaar et al. 2010) analysis of the mutation p.F237S suggested that : i) while the wild-type residue secondary structure, according to Uniprot, is a β-strand, the mutant residue forms a different secondary structure, which potentially destabilizes the local conformation; ii) the residue is hidden in the core of a domain that may be altered by the mutant residue; iii) the mutant residue is smaller than the wild-type residue; therefore, the mutation causes an empty space in the core of the protein; iv) the mutation would cause loss of hydrophobic interactions in the protein core