Vitamin E deficiency ataxia with (744 del A) mutation on alpha-TTP gene: genetic and clinical peculiarities in Moroccan patients.

Ataxia with vitamin E deficiency (AVED) is an autosomal recessive disease characterized clinically by neurological symptoms with often striking resemblance to those of Friedreich's ataxia (FA). Molecular analysis is needed for an early differential diagnosis, in order to initiate therapeutic vitamin E supplementation before damage develops. We studied 16 patients from seven Moroccan families presenting an autosomal recessive Friedreich-like ataxia with vitamin E deficiency. Our patients were homozygous for 744 del A mutation of alpha-TTP gene. Compilation of clinical records revealed a great phenotypic variability and some features indicating a new possible role of vitamin E in hypothalamo-hypophysial system regulation and cardiomyopathy prevention. Early vitamin E supplementation may provide considerable improvement of neurological signs and other associated abnormalities. Clinical heterogeneity is for involvement of other non-genetic defect and indicated another role of vitamin E, which should be better studied.

Exome sequencing can improve diagnosis and alter patient management.

The translation of "next-generation" sequencing directly to the clinic is still being assessed but has the potential for genetic diseases to reduce costs, advance accuracy, and point to unsuspected yet treatable conditions. To study its capability in the clinic, we performed whole-exome sequencing in 118 probands with a diagnosis of a pediatric-onset neurodevelopmental disease in which most known causes had been excluded. Twenty-two genes not previously identified as disease-causing were identified in this study (19% of cohort), further establishing exome sequencing as a useful tool for gene discovery. New genes identified included EXOC8 in Joubert syndrome and GFM2 in a patient with microcephaly, simplified gyral pattern, and insulin-dependent diabetes. Exome sequencing uncovered 10 probands (8% of cohort) with mutations in genes known to cause a disease different from the initial diagnosis. Upon further medical evaluation, these mutations were found to account for each proband's disease, leading to a change in diagnosis, some of which led to changes in patient management. Our data provide proof of principle that genomic strategies are useful in clarifying diagnosis in a proportion of patients with neurodevelopmental disorders.