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Publications (4)27.2 Total impact

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    ABSTRACT: Recently, alpha-aminoadipic semialdehyde (alpha-AASA) dehydrogenase deficiency was shown to cause pyridoxine-dependent epilepsy in a considerable number of patients. alpha-AASA dehydrogenase deficiency is an autosomal recessive disorder characterized by a neonatal-onset epileptic encephalopathy in which seizures are resistant to antiepileptic drugs but respond immediately to the administration of pyridoxine (OMIM 266100). Increased plasma and urinary levels of alpha-AASA are associated with pathogenic mutations in the alpha-AASA dehydrogenase (ALDH7A1/antiquitin) gene. Here, we report an intriguing "silent" mutation in ALDH7A1, a novel missense mutation and a founder mutation in a Dutch cohort (10 patients) with alpha-AASA dehydrogenase deficiency.
    Annals of Neurology 11/2007; 62(4):414-8. · 11.19 Impact Factor
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    ABSTRACT: Guanidinoacetate methyltransferase (GAMT) deficiency (MIM 601240), an autosomal recessive disorder of creatine biosynthesis, presents with mental retardation, extrapyramidal symptoms, autistic-like behavior and epilepsy. Other hallmarks are cerebral creatine deficiency, increased levels of guanidinoacetate in body fluids and mutations in the GAMT gene. Creatine supplementation partially restores cerebral creatine content. Worldwide, 29 patients have been identified and 15 different mutations have been reported in the GAMT gene. Ten out of these 29 patients are of Portuguese origin. Likely, a founder effect and a high carrier rate in Portugal exist, since in 17 out of the 20 Portuguese alleles the c.59G>C; p.Trp20Ser mutation was found. We investigated the carrier rate of the c.59G>C; p.Trp20Ser mutation in different regions of Portugal and confirmed the pathogenic nature of this missense mutation by transient transfections. Anonymous bloodspots (1002) were screened for the presence of the c.59G>C; p.Trp20Ser mutation by SNaPshot (Single Nucleotide Polymorphism Multiplex Kit). Eight carriers of c.59G>C; p.Trp20Ser were detected of which four are derived from the Archipelagos. This suggests that the carrier rate of the c.59G>C; p.Trp20Ser mutation is relatively high in these islands, as well as in other parts of Portugal. It also implies that newborn screening in these regions is warranted for this treatable disorder.
    Molecular Genetics and Metabolism 05/2007; 91(1):1-6. · 2.83 Impact Factor
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    ABSTRACT: Glutaric aciduria type 1 (GA1) is a rare cerebral organic aciduria which typically manifests as an acute encephalopathic crisis followed by profound long-term neurological handicap. We report the diagnosis of 12 new patients from a single laboratory in Israel during a 5-year period. Eleven of the 12 were of Palestinian origin, and only two were related. One patient was asymptomatic whilst one was mildly, one moderately and nine severely affected, two of whom had unusual MRI findings. Two patients had normal glutaric acid excretion and normal blood glutarylcarnitine levels yet glutarylcarnitine excretion was increased, indicating its utility as a diagnostic marker. Four novel GCDH mutations (Thr193_Arg194insHis, Asn329Ser, Thr341Pro, Met405Val) and five previously reported mutations (Ser119Leu, Leu283Pro, Ala293Thr, Gly390Arg and Thr416Ile) were identified. Severely and mildly affected or even asymptomatic patients shared the same genotypes (Thr416Ile/Thre416Ile and Aal293Thr/Thr193_Arg194insHis). Knowledge of the responsible mutation enabled successful prenatal diagnosis on chorionic villous DNA in three families. In conclusion, GA1 is genetically heterogeneous and has a relatively high incidence in the Palestinian population, reflecting the historical tradition of marriages within extended kindreds, particularly in isolated villages. Additional genetic and/or environmental factors must account for the phenotypic heterogeneity in patients with the same genotype. The diagnosis was not suspected in the majority of cases despite typical clinical and/or neuroimaging features, suggesting that glutaric aciduria may be under-diagnosed. Greater awareness of glutaric aciduria amongst pediatricians, neonatologists and radiologists is the key to identifying the disorder in the presymptomatic phase and preventing its catastrophic consequences.
    European Journal of Paediatric Neurology 04/2007; 11(2):81-9. · 1.98 Impact Factor
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    ABSTRACT: D-2-hydroxyglutaric aciduria is a neurometabolic disorder with mild and severe phenotypes. Recently, we reported pathogenic mutations in the D-2-hydroxyglutarate dehydrogenase gene as the cause of the severe phenotype of D-2-hydroxyglutaric aciduria in two patients. Here, we report two novel pathogenic mutations in this gene in one patient with a mild presentation and two asymptomatic siblings with D-2-hydroxyglutaric aciduria from two unrelated consanguineous Palestinian families: a splice error (IVS4-2A-->G) and a missense mutation (c.1315A-->G;p.Asn439Asp). Overexpression of this mutant protein showed marked reduction of the enzyme activity.
    Annals of Neurology 10/2005; 58(4):626-30. · 11.19 Impact Factor