(a) MRI abnormalities in phenylketonuria are the result of a distinctive alteration of white matter suggesting the intracellular accumulation of a hydrophilic metabolite, which leaves unaffected white matter architecture and structure. (b) White matter abnormalities do not seem to reflect the mechanisms involved in the derangement of mental development in PKU. (c) Our data do not support the usefulness of conventional brain MRI examination in the clinical monitoring of phenylketonuria patients.

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.

The authors report a kindred in which GTP-CH deficiency resulted in a myoclonus-dystonia syndrome. The proband, a 17-year-old boy, presented with early-onset myoclonus and later, dystonia and bradykinesia. Blood prolactin was increased and CSF homovanillic acid, 5-hydroxyindoleacetic acid, and biopterin were all reduced. L-Dopa/carbidopa administration resulted in clinical improvement. In the paternal branch, the grandfather and three relatives had myoclonus-dystonia and resting or postural tremor of limbs. The authors found a missense mutation in the exon 6 of GCH-1 gene (K224R).

No abstract

A fall in blood phenylalanine (Phe) after tetrahydrobiopterin (BH(4)) administration is a common trait in phenylalanine hydroxylase (PAH, EC 1.14.16.1) deficiency (McKusick 261600). To explore the extent and biological correlates of this phenomenon we studied: (a) the spectrum of BH(4) response in patients with PAH deficiency; (b) the variability of BH(4) response according to the severity of the biochemical phenotype; and (c) the variability of the response to BH(4) in subjects with the same genotype. Fifty PAH-deficient subjects (age 1 month-35 years) were enrolled for the study (5 with mild hyperphenylalaninaemia (MHPHE), 15 with mild phenylketonuria (MPKU) and 30 with classic phenylketonuria (CPKU) and underwent an identical schedule of blood samplings 24 h before and after oral BH(4) challenge (6(R)-BH4, 20 mg/kg per day), leaving Phe intake unchanged. The effect of BH(4) on blood Phe concentration was evaluated according to the percent decrease of Phe during the 24 h following the challenge (criterion a), and as variation exceeding the individual variability of blood Phe (criterion b). The number of BH(4)-responders according to criterion b was 31 (including all the 14 detected by criterion a): 17 out of 30 CPKU (57%), 9 out of 15 MPKU (60%), and all the MHPHE subjects (chi(2) = 3.45, df = 2, p = 0.178). The effect of BH(4) showed a large interindividual variability unrelated to diagnostic classification, basal value of blood Phe, maximum percentage of Phe reduction, Phe intake, and genotype. Some inconsistencies were found in patients with identical genotype. The first responsive case homozygous for the severe R408W mutation was found. Two new mutations, Y387X and G352C, were identified (the former was BH(4)-responsive), and the responsiveness of three already reported mutations (R261Q, D338Y, T92I) was substantiated.