Browsing by Author "Azzouz, H."
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- Mutation spectrum of Gaucher disease in Tunisia: high frequency of N370S/Rec NciI compound heterozygousPublication . Cherif, W.; Ben Turkia, H.; Tebib, N.; Amaral, O.; Ben Rhouma, F.; Abdelmoula MS, M.S.; Azzouz, H.; Caillaud, C.; Sà Miranda, M.C.; Abdelhak, S.; Ben Dridi, M.F.Gaucher disease is the most common lysosomal storage disorder, it results from the inherited deficiency of the enzyme glucocerebrosidase, the accumulation of its substrate causes many clinical manifestations. Since the discovery of GBA gene, more than 200 different mutations have been identified, but only handful mutations are recurrent (N370S, L444P and c.84insG). In order to determine the mutation spectrum in Tunisia, we performed recurrent mutation screening in ten unrelated Tunisian children with Gaucher disease. Screening of recurrent mutation by PCR/RFLP and direct sequencing, has shown that N370S is the most frequent mutation (6/20 mutant alleles, 30%), followed by recombinant allele (RecNciI) which is found in five patients (5/20 mutant alleles, 25%), the L444P mutation represent 20% (4/20 mutant alleles). Our findings revealed that five among ten studied patients, were compound heterozygous N370S/RecNciI (50%). The screening of these mutations provides a simple tool for molecular diagnosis of Gaucher disease in Tunisian patients and allows also genetic counselling for their family members.
- Phenotype and genotype in 101 males with X-linked creatine transporter deficiencyPublication . van de Kamp, J.M.; Betsalel, O.T.; Mercimek-Mahmutoglu, S.; Abulhoul, L.; Grünewald, S.; Anselm, I.; Azzouz, H.; Bratkovic, D.; de Brouwer, A.; Hamel, B.; Kleefstra, T.; Yntema, H.; Campistol, J.; Vilaseca, M.A.; Cheillan, D.; D'Hooghe, M.; Diogo, L.; Garcia, P.; Valongo, C.; Fonseca, M.; Frints, S.; Wilcken, B.; von der Haar, S.; Meijers-Heijboer, H.E.; Hofstede, F.; Johnson, D.; Kant, S.G.; Lion-Francois, L.; Pitelet, G.; Longo, N.; Maat-Kievit, J.A.; Monteiro, J.P.; Munnich, A.; Muntau, A.C.; Nassogne, M.C.; Osaka, H.; Ounap, K.; Pinard, J.M.; Quijano-Roy, S.; Poggenburg, I.; Poplawski, N.; Abdul-Rahman, O.; Ribes, A.; Arias, A.; Yaplito-Lee, J.; Schulze, A.; Schwartz, C.E.; Schwenger, S.; Soares, G.; Sznajer, Y.; Valayannopoulos, V.; Van Esch, H.; Waltz, S.; Wamelink, M.M.; Pouwels, P.J.; Errami, A.; van der Knaap, M.S.; Jakobs, C.; Mancini, G.M.; Salomons, G.S.BACKGROUND: Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype--genotype correlation has been lacking. METHODS: We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8). RESULTS AND CONCLUSIONS: Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 3' end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones