Molecular and computational characterization of ABCB11 and ABCG5 variants in Tunisian patients with neonatal/infantile low-GGT intrahepatic cholestasis: Genetic diagnosis and genotype-phenotype correlation assessment.

Many inherited conditions cause hepatocellular cholestasis in infancy, including progressive familial intrahepatic cholestasis (PFIC), a heterogeneous group of diseases with highly overlapping symptoms. In our study, six unrelated Tunisian infants with PFIC suspicion were the subject of a panel-target sequencing followed by an exhaustive bioinformatic and modeling investigations. Results revealed five disease-causative variants including known ones: (the p.Asp482Gly and p.Tyr354 * in the ABCB11 gene and the p.Arg446 * in the ABCC2 gene), a novel p.Ala98Cys variant in the ATP-binding cassette subfamily G member 5 (ABCG5) gene and a first homozygous description of the p.Gln312His in the ABCB11 gene. The p.Gln312His disrupts the interaction pattern of the bile salt export pump as well as the flexibility of the second intracellular loop domain harboring this residue. As for the p.Ala98Cys, it modulates both the interactions within the first nucleotide-binding domain of the bile transporter and its accessibility. Two additional potentially modifier variants in cholestasis-associated genes were retained based on their pathogenicity (p.Gly758Val in the ABCC2 gene) and functionality (p.Asp19His in the ABCG8 gene). Molecular findings allowed a PFIC2 diagnosis in five patients and an unexpected diagnosis of sisterolemia in one case. The absence of genotype/phenotype correlation suggests the implication of environmental and epigenetic factors as well as modifier variants involved directly or indirectly in the bile composition, which could explain the cholestasis phenotypic variability.

Clinical and therapeutic characteristics of childhood uveitis in a tertiary center in Tunisia.

INTRODUCTION: Childhood uveitis is a rare condition with various associated diagnostic and therapeutic challenges. AIM: We proposed to describe the distribution, clinical findings, treatment, complications, and visual outcomes of uveitis in children at a tertiary referral center in Sfax, Tunisia. METHODS: A retrospective study of 33 children (54 eyes) with uveitis collected over the period from January 2009 to December 2018 was carried out at the Ophthalmology Department of Habib Bourguiba University Hospital, Sfax, Tunisia. The data from the clinical examination, the etiological assessment, and the used treatments were collected. Standard diagnostic criteria were used for all uveitic syndromes or entities. RESULTS: The mean age of the patients was 11.42 years with a male-to-female ratio of 0.74. Uveitis was bilateral in 63% of the patients. The most common anatomical form was intermediate uveitis (39%). Idiopathic cases accounted for 52%. The major complications were posterior synechiae, optic disc edema, cataract, and cystoid macular edema. Anti-infective treatment was prescribed in 24% of the patients. Oral corticosteroid therapy was used in 67% of the patients. 18% of the patients received immunosuppressive therapy and 6% received a biological agent. The mean final visual acuity was 4.6/10. CONCLUSION: Childhood uveitis is a serious pathology with frequent and vision-threatening complications. The etiologies are variable and the assessment can remain negative. A rigorous diagnostic approach, an oriented etiological assessment in collaboration with the pediatrician, and an appropriate therapy are necessary for management.