Differential impact of consanguineous marriages on autosomal recessive diseases in Tunisia.

OBJECTIVES: Consanguinity is common in Tunisia. However, little information exists on its impact on recessive disorders. In this study, we evaluate the impact of consanguineous marriages on the occurrence of some specific autosomal recessive disorders and consider how other factors, such as population substructure and mutation frequency, may be of equal importance in disease prevalence. METHODS: Consanguinity profiles were retrospectively studied among 425 Tunisian patients suffering from autosomal recessive xeroderma pigmentosum, dystrophic epidermolysis bullosa, nonsyndromic retinitis pigmentosa, Gaucher disease, Fanconi anemia, glycogenosis type I, and ichthyosis, and compared to those of a healthy control sample. RESULTS: Consanguinity was observed in 341 cases (64.94%). Consanguinity rates per disease were 75.63, 63.64, 60.64, 61.29, 57.89, 73.33, and 51.28%, respectively. First-cousin marriages were the most common form of consanguinity (48.94%) with the percentages of 55.46, 45.46, 47.87, 48.39, 45.61, 56.66, and 35.90%, respectively. A very high level of geographic endogamy was also observed (93.92%), with the values by disease ranging between 75.86 and 96.64%. We observed an overall excess risk associated to consanguinity of nearly sevenfold which was proportional to the number of affected siblings and the frequency of disease allele in the family. Consanguinity was significantly associated with the first five cited diseases (odds ratio = 24.41, 15.17, 7.5, 5.53, and 5.07, respectively). However, no meaningful effects were reported among the remaining diseases. CONCLUSIONS: This study reveals a variation in the excess risk linked to consanguinity according to the type of disorder, suggesting the potential of cryptic population substructure to contribute to disease incidence in populations with complex social structure like Tunisia. It also emphasizes the role of other health and demographic aspects such as mutation frequency and reproductive replacement in diseases etiology.

[Phenotype and mutational spectrum in Tunisian pediatric gaucher disease]. / Phénotype clinique et spectre mutationnel de la maladie de Gaucher pédiatrique en Tunisie.

BACKGROUND: Gaucher disease (GD) is a sphingolipidosis with heterogeneous phenotypic expression. The vital and / or functional prognosis may be threatened by an early visceral severe involvement in type 1 or a neurological degeneration in the more rarest neuroneupathic forms. The phenotypic and genotypic data regarding Gaucher disease are poorly known in Maghrebian countries; they are even less for pediatric forms. THE AIM of the study is to highlight the specific phenotypic and genotypic changing among the widest Gaucher pediatric cohort in the Tunisian population. METHODS: a restrospective study of a sample oh children in voluved by gaucher disease. RESULTS: Twenty one cases of GD were identified, divided into 13 cases with type 1, 5 with type 3 and 3 children with acute neurological form. The first symptoms occurred before 1 year age in one third of patients with type IGD. The clinical phenotype was severe according to the high severity score index and proportion of growth retardation. Portal hypertension was found in 8 patients. Three type 3 GD patients died before occurrence of the neurological signs. The phenotype was intermediate between the classic type 2 GD and its perinatal lethal variant. Three patients were treated with enzyme replacement therapy and 4 others had allogenic bone marrow transplantation with a favorable outcome. Three mutations dominate the genotypic spectrum of GD in this cohort. Additionally to the N370 mutation, L444P and RecNciI mutations seem to occur more frequently compared to the GD forms presenting in adulthood. CONCLUSION: This data confirm the particular severity of Gaucher disease manifesting in childhood. This was enhanced through the high frequency of severe mutations. Further studies on largest cohort are needed to more clarify the phenotypic and genotypic features of Gaucher disease in Tunisia.

[Enzyme replacement therapy for Gaucher paediatric disease: the only Tunisian experience]. / Traitement enzymatique substitutif de la maladie de Gaucher chez l'enfant: premiere experience Tunisienne.

AIM: We report through the first Tunisian experience with enzyme replacement therapy, the goals and consensus recommendations for treatment and monitoring of paediatric non neuronopathic Gaucher disease. METHODS: Three children with Gaucher disease undergone enzyme replacement therapy with Cerezyme for severe visceral and/or bone involvement. Visceral, hematologic, bone, and growth parameters were assessed initially and under treatment. RESULTS: Two children presented with severe visceral or hematologic picture. One patient had myocardiopathy and primitive portal hypertension and another was diagnosed with cirrhosis related to Gaucher disease. Recurrent avascular necrosis and osteoporosis have justified treatment in another child. All patients received an initial dose of 60U/Kg/2 weeks. We have seen a gradual disappearance of hepatosplenomegaly and a rapid normalisation of hematological parameters in two patients. A resistance to treatment indicated splenectomy in one patient. The improvement in bone mineral density was slower. A significant growth gain was observed in patients with growth retardation. No patient had developed Cerezyme antibodies. CONCLUSION: Despite its effectiveness and safety demonstrated in these children, enzyme replacement therapy remains inaccessible because of its cost for emerging countries. The allogeneic bone marrow is an alternative therapy to encourage and to propose precociously for severe paediatric forms of Gaucher disease.

Incidence of mucopolysaccharidoses in Tunisia.

BACKGROUND: The mucopolysaccharidoses (MPS) are a devastating heterogenous group of lysosomal storage disorders. AIM: To evaluate the epidemiological profile of MPS in Tunisia. METHODS: we conducted a retrospective epidemiological survey covering the period 1970-2005. Multiple sources were used to identify affected patients. RESULTS: Ninety six confirmed MPS cases were collected from 132 suspected cases found in the surveyed data. Of the ninety six confirmed cases, 20% were from multiplex families. Consanguinity was found in 83% of the families. The crude rate for all types of mucopolysaccharidoses was 2.3 cases in 100,000 live births. The prevalence of MPS type I, III and IV, those most frequently occurring in the collected data, were estimated at 0.63, 0.7 and 0.45 per 100,000 live births, respectively. The cumulative incidence of MPS type VI (0.3 per 105 live births) was higher than reported in European countries; but, it is likely that... CONCLUSION: The reported frequency of all types of MPS in Tunisia is underestimated.