Leukodystrophies : genetic and molecular aspects in Morocco

Les leucodystrophies (LD) sont des troubles héréditaires affectant la substance blanche (SB) du système nerveux central (SNC) avec ou sans atteinte du système nerveux périphérique (SNP). Ces troubles ont en commun des anomalies de la cellule gliale ou de la gaine de la myéline. L’imagerie par résonance magnétique (IRM) représente l’outil majeur pour la détection des anomalies de la SB, ainsi l’IRM accompagnée d’un examen clinique permettent d’orienter le diagnostic étiologique. La confirmation de ce diagnostic est principalement basée sur la biologie moléculaire qui permet la détermination du gène muté. Sachant qu’au Maroc aucune étude sur les leucodystrophies n’avait été réalisée auparavant, nous avons mené une étude prospective afin de déterminer le profil des patients marocains atteints de ces troubles et de mettre en place un diagnostic moléculaire des formes les plus fréquentes. Pour cela nous avons rassemblé des échantillons de familles dont un ou plusieurs membres avaient une suspicion de leucodystrophie. Par la suite nous avons réalisé un séquençage des gènes connu pour leur implication dans les leucodystrophies. Le séquençage s’est déroulé en deux phases. La première, par séquençage Sanger, a concerné les patients présentant un marqueur biochimique positif. La deuxième phase, par séquençage nouvelle génération ou Next-Generation Sequencing (NGS) a concerné les patients sans marqueurs biochimiques apparent. Cette approche nous a permis d’identifier les types de leucodystrophies présentes au sein de la population marocaine, mais aussi de mettre en évidence de nouvelles mutations.Leukodystrophies are hereditary disorders affecting central nervous system white matter (WM) with or without damages in peripheral nervous system. These disorders have in common abnormalities of the glial cell and the sheath of the myelin. Magnetic resonance imaging (MRI) is the major tool to detect WM abnormalities, so MRI in association with a good clinical examination can help to provide an accurate medical diagnosis. Moreover, the confirmation of this or that leukodystrophy remains in the field of molecular biology by the detection of mutated gene translating the phenotype of the patient. Knowing that in Morocco no previous study on leukodystrophies had been carried out, we sought to know the characteristics of Moroccan patients carrying these disorders so as to be able to establish a molecular diagnosis of the most frequent forms. We collected samples from families with one or more members had a suspicion of leukodystrophy. Thus, we carried out a sequencing with an approach that consists in analyzing directly by Sanger method the leukodystrophies having a positive biochemical marker and by next generation sequencing or Next-Generation Sequencing (NGS) leukodystrophies without known biochemical markers. This approach allowed us, to identify leukodystrophies in a sample of the Moroccan population but also to identify new mutations

The polymorphism G894 T of endothelial nitric oxide synthase (eNOS) gene is associated with susceptibility to essential hypertension (EH) in Morocco

Abstract Background Hypertension is a multifactorial disease involving both environmental and genetic Factros. G894 T eNOS polymorphism has been suggested to be responsible for reduced NO synthesis, and EH development. The objective of our case-control study is to evaluate the potential association of G894 T eNOS polymorphism with Essential Hypertension (EH) susceptibility, among a sample of Moroccan patients. Methods One hundred forty five hypertensive patients were recruited from the department of Cardiology, University Hospital Center Ibn Rochd, Casablanca, Morocco, and compared to 184 apparently healthy subjects. DNA samples were genotype by PCR-RFLP method using MboI restriction enzyme. Results Our results showed a positive correlation between G894 T eNOS distribution and Alcohol and Obesity rik factors (P = 0.009 and 0.02 respectively). Patients with elevated Cardio Vascular Risk (CVR) carried out the higher frequency of homozygous mutant genotype TT (62.2%) and T mutant allele (77.8%), compared to median and low CVR groups. G894 T eNOS distribution was significantly associated to a high risk of EH occurrence under the GT and TT genotypes (OR [95% CI] = 20.2 [7.7–52.4], P <  0.0001; OR [95% CI] = 332.5 [98.2–1125.4], P <  0.0001 respectively), and the 3 genotypic transmission models (Dominant: OR [95% CI] = 43.2 [17.9–104.09], P <  0.0001; Recessive: OR [95% CI] = 47.7 [18.6–122.3]; P <  0.0001; Additive: OR [95% CI] = 14.02 [9.6–20.45], P <  0.0001). Conclusion Our study suggests a strong association of G894 T eNOS polymorphism with susceptibility to EH in Morocco. Studies trying to identify contributing genes may be very useful and allow recognizing the vulnerable individuals and classifying patients in subgroups with definite genetic and pathogenic mechanisms to achieve better prevention and therapeutics

A novel mutation in the ABCD1 gene of a Moroccan patient with X-linked adrenoleukodystrophy: case report

International audienceAbstractBackgroundX-linked adrenoleukodystrophy (X-ALD; OMIM: 300100) is the most common peroxisomal disease caused by mutations in the ATP-binding cassette, sub-family D member 1 gene or ABCD1 (geneID: 215), the coding gene for the adrenoleukodystrophy protein (ALDP), which is an ATP-binding transport protein associated to an active transport of very long chain fatty acids (VLCFAs). Dysfunction of ALDP induces an accumulation of VLCFAs in all tissues leading to a neurodegenerative disorder that involves the nervous system white matter.Case presentationIn our case report, magnetic resonance imaging (MRI) as well as the high levels of VLCFAs prompted the diagnosis the X-ALD. Molecular analysis of ABCD1 gene have shown a pathogenic homozygous nonsense mutation (c.1677C > G; p.(Tyr559*)) in exon 7.ConclusionThus, we identified here a novel mutation in the ABCD1 gene in a Moroccan patient causing X-linked adrenoleukodystrophy