Mongia Hachicha

Fanconi anemia in Tunisia: high prevalence of group A and identification of new FANCA mutations

AbstractFanconi anemia (FA) is a rare autosomal recessive disease characterized by progressive pancytopenia, congenital malformations, and predisposition to acute myeloid leukemia. Fanconi anemia is genetically heterogeneous, with at least eight distinct complementation groups of FA (A, B, C, D1, D2, E, F, and G) having been defined by somatic cell fusion studies. Six genes (FANCA, FANCC, FANCD2, FANCE, FANCG, and FANCF) have been cloned. Mutations of the seventh Fanconi anemia gene, BRCA2, have been shown to lead to FAD1 and probably FAB groups. In order to characterize the molecular defects underlying FA in Tunisia, 39 families were genotyped with microsatellite markers linked to known FA gene. Haplotype analysis and homozygosity mapping assigned 43 patients belonging to 34 families to the FAA group, whereas one family was probably not linked to the FANCA gene or to any known FA genes. For patients belonging to the FAA group, screening for mutations revealed four novel mutations: two small homozygous deletions 1693delT and 1751–1754del, which occurred in exon 17 and exon 19, respectively, and two transitions, viz., 513G→A in exon 5 and A→G at position 166 (IVS24+166A→G) of intron 24. Two new polymorphisms were also identified in intron 24 (IVS24–5G/A and IVS24–6C/G).

Severe head injury among children: Prognostic factors and outcome

AIM To determine predictive factors of mortality among children after traumatic brain injury. METHODS A retrospective study over 8 years of 222 children with severe head injury (Glasgow Coma Scale score < or = 8) admitted to a university hospital (Sfax, Tunisia). Basic demographic, clinical, biological and radiological data were recorded on admission and during intensive care unit stay. RESULTS The study included 163 boys (73.4%) and 59 girls, with mean age 7.54+/-3.8 years. The main cause of trauma was road traffic accident (75.7%). Mean Glasgow Coma Scale score was 6+/-1.5, mean Injury Severity Score (ISS) was 28.2+/-6.9, mean Paediatric Trauma Score (PTS) was 3.7+/-2.1 and mean Paediatric Risk of Mortality (PRISM) was 14.3+/-8.5; 54 children (24.3%) died. Univariate analysis showed that low PTS on admission, high ISS or PRISM, presence of shock or meningeal haemorrhage or bilateral mydriasis, and serum glucose > 10 mmol l(-1) were associated with mortality rate. Multivariate analysis showed that factors associated with a poor prognosis were PRISM > 20 and bilateral mydriasis on admission. CONCLUSIONS In Tunisia, head injury is a frequent cause of hospital admission and is most often due to road traffic accidents. Short-term prognosis is poor, with a high mortality rate (24.3%), and is influenced by demographic, clinical, radiological and biological factors.

Long-Term Outcome of Patients With Congenital Adrenal Hyperplasia Due to 21-hydroxylase Deficiency

Introduction:Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder affecting adrenal steroid synthesis. In this study, the authors aim to evaluate the impact of CAH due to 21-hydroxylase deficiency on final height (FH), bone health, cardiometabolic risk, fertility, neurocognition and quality of life in a hospital-based sample from Tunisia. Methods:Twenty-six patients (11 males and 15 females; mean age: 27.4 ± 8.2 years) were recruited. Results:Mean FH was 159.5 ± 9.7 cm. Twenty-one patients (80.7%) had a FH below the target height. Ten patients (38.4%) exhibited bone demineralization. Eight patients (30.7%) had obesity. Lipid profile alterations and carbohydrate metabolism disorders were detected in 10 (38.4%) and 5 (19.2%) patients, respectively. Seven patients (27%) had insulin resistance. Ambulatory blood pressure monitoring showed abnormalities in 6 patients (23%). Increased carotid intima-media thickness was found in 14 patients (53.8%). Inhibin B level was decreased in 4 male patients. Semen analysis showed abnormalities in 4 of 10 patients. Testicular tumors were detected in 6 of 11 patients. Anti-Müllerian hormone level was reduced in 4 female patients. Six patients showed poly-cystic ovary syndrome. Brain magnetic resonance imaging showed abnormalities in 11 patients (42.3%). Quality of life was reduced in 14 of 22 patients (63.6%). Many of the suboptimal outcomes appeared to be related to poor adherence to medication schedules, some to overtreatment. Conclusion:CAH patients have a number of issues due to the disease or its treatment. Regular follow-up, early lifestyle interventions, bone health assessment, testicular ultrasound and psychological management are needed.

A case of Kearns-Sayre syndrome with two novel deletions (9.768 and 7.253 kb) of the mtDNA associated with the common deletion in blood leukocytes, buccal mucosa and hair follicles

Kearns-Sayre syndrome is a mitochondrial disorder characterized by the emergence before the age of 20 years of progressive external ophthalmoplegia, pigmentary retinopathy, with other heterogeneous clinical manifestations. Generally, mitochondrial DNA deletions were associated with KSS but the size and position of these deletions differ among patients. This study reported a Tunisian patient with typical features of KSS. Long-range PCR amplification of the mtDNA in different tissues from this patient showed multiple mitochondrial deletions: two novel 9.768 and 7.253 kb deletions spanning respectively nucleotides 6124-15,893 and 8572-15,826 associated with the common 4.977 kb deletion.

Two new mutations in the MT-TW gene leading to the disruption of the secondary structure of the tRNATrp in patients with Leigh syndrome.

Leigh syndrome is a progressive neurodegenerative disorder occurring in infancy and childhood characterized in most cases by a psychomotor retardation, optic atrophy, ataxia, dystonia, failure to thrive, seizures and respiratory failure. In this study, we performed a systematic sequence analysis of mitochondrial genes associated with LS in Tunisian patients. We sequenced the encoded complex I units: ND2, ND3, ND4, ND5 and ND6 genes and the mitochondrial ATPase 6, tRNA(Val), tRNA(Leu(UUR)), tRNA(Trp) and tRNA(Lys) genes in 10 unrelated patients with Leigh syndrome. We revealed the presence of 34 reported polymorphisms, nine novel nucleotide variants and two new mutations (T5523G and A5559G) in the tested patients. These two mutations were localized in two conserved regions of the tRNA(Trp) and affect, respectively, the D-stem and the T-stem of the mitochondrial tRNA leading to a disruption of the secondary structure of this tRNA. SSP-PCR analysis showed that the T5523G and A5559G mutations were present with respective heteroplasmic rates of 66% and 43 %. We report here the first mutational screening of mitochondrial mutations in Tunisian patients with Leigh syndrome which described two novel mutations associated with this disorder.

Congenital heart disease in 37,294 births in Tunisia: birth prevalence and mortality rate.

AIM To investigate the previously unknown birth incidence, treatment, and mortality of children with congenital heart disease in Tunisia. METHODS We undertook a retrospective review of medical records of all patients who were born in 2010 and 2011, and were diagnosed in Sfax (Tunisia) with congenital heart defect. RESULTS Among 37,294 births, 255 children were detected to have congenital heart disease, yielding a birth incidence of 6.8 per 1000. The most frequently occurring conditions were ventricular septal defects (31%), ostium secundum atrial septal defects (12.9%), and pulmonary valve abnormalities (12%). Coarctation of the aorta, tetralogy of Fallot, univentricular physiology, pulmonary atresia with ventricular septal defect, and transposition of the great arteries were found in 4.3%, 6.2%, 3.4%, 2.7%, and 2.7%, respectively. During the follow-up of 1 year, 23% of the children died. About three-quarters of those deaths happened before surgery. CONCLUSION The present study is in line with the general estimates in the world. It has revealed a high case of mortality among the patients awaiting corrective surgery. These children need more facilities.

Descriptive analyses of Turner syndrome: 49 cases in Tunisia

Turner syndrome is linked to the absence or abnormality of one of the X chromosome leading to haplo-insufficiency of genes involved in the development and maintenance of the ovarian stock in women. We report the results of a 21-year retrospective study, conducted in 49 patients with Turner syndrome. The purpose of this study was to establish the clinical, hormonal, cytogenetic and evolutive pattern of a Tunisian population with Turner syndrome and to search for correlations between genotype and phenotype. The average age of our patients at diagnosis was 14 years (1 day-42 years). Twenty-four percent of them were diagnosed in adulthood (greater than or equal to 20 years). Turner syndrome was diagnosed later in the case of mosaicism (P=0.001). Short stature was present in 85% of cases; it was more frequent among the youngest and monosomics. The dysmorphic syndrome was observed in 85% of cases; it was significantly more frequent in monosomics (P=0.003). Delayed puberty was present in 62.4% of cases, it was almost constant in monosomics (P=0.05). The loss of ovarian function was more severe in case of monosomia compared to other forms (P=0.04). Our results report a high frequency of autoimmune diseases (18/46 cases) including dysthyroidism (eight cases). Hepato biliary affections were more frequent in mosaicism compared to monosomy. The average final height was greater even in mosaicism estimated at 150.5 cm compared to 141 cm in monosomics and 138.8 cm in mosaics with abnormal structures.

Molecular investigation of distal renal tubular acidosis in Tunisia, evidence for founder mutations.

BACKGROUND Distal renal tubular acidosis (dRTA) is a rare genetic disease caused by mutations in different genes involved in the secretion of H+ ions in the intercalated cells of the collecting duct. Both autosomal dominant and recessive forms have been described; the latter is also associated with sensorineural hearing loss. METHODS Twenty-two Tunisian families were analyzed for mutations in the ATP6V1B1 and ATP6V0A4 genes by direct sequencing. Dating of the founder mutations was performed. RESULTS Two founder mutations in the ATP6V1B1 gene were found in 16/27 dRTA cases. The p.Ile386Hisfs*56 founder mutation was estimated to be older than 2400 years and no correlations were found with deafness. For the remaining patients, two mutations in the ATP6V0A4 gene, one of them being novel, were found in three Tunisian cases. The presence of a heterozygous missense mutation p.T30I, of the ATP6V1B1 gene, was identified in six patients, while no mutations of the second gene were detected. No deleterious mutations of either ATP6V1B1 or ATP6V0A were found for the two probands. CONCLUSION Our study gives evidence of phenotypic and genotypic heterogeneity of dRTA in the Tunisian population. Five different mutations were found, two of them were due to a founder effect, and screening of these mutations could provide a rapid and valuable tool for diagnosis of dRTA.

A Novel Nonsense Mutation in HSD17B3 Gene in a Tunisian Patient with Sexual Ambiguity

INTRODUCTION 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) isoenzyme is present almost exclusively in the testes and converts delta 4 androstenedione to testosterone. Mutations in the HSD17B3 gene cause HSD17B3 deficiency and result in 46,XY Disorders of Sex Development (46,XY DSD). AIM This study aimed to present the clinical and biochemical features of a Tunisian patient who presented a sexual ambiguity orienting to HSD17B3 deficiency and to search for a mutation in the HSD17B3 gene by DNA sequencing. METHODS Polymerase chain reaction (PCR) amplification and subsequent sequencing of all the coding exons of HSD17B3 gene were performed on genomic DNA from the patient, her family, and 50 controls. RESULTS Genetic mutation analysis of the HSD17B3 gene revealed the presence of a novel homozygous nonsense mutation in the exon 9 (c.618 C>A) leading to the substitution p.C206X. The mutation p.C206X in the coding exons supports the hypothesis of HSD17B3 deficiency in our patient. CONCLUSION The patient described in this study represented a new case of a rare form of 46,XY DSD, associated to a novel gene mutation of HSD17B3 gene. The screening of this mutation is useful for confirming the diagnosis of HSD17B3 deficiency and for prenatal diagnosis.

A novel m.3395A>G missense mutation in the mitochondrial ND1 gene associated with the new tRNA(Ile) m.4316A>G mutation in a patient with hypertrophic cardiomyopathy and profound hearing loss

Mitochondria are essential for early cardiac development and impaired regulation of mitochondrial function was implicated in congenital heart diseases. We described a newborn girl with hypertrophic cardiomyopathy and profound hearing loss. The mtDNA mutational analysis revealed the presence of known polymorphisms associated to cardiomyopathy and/or hearing loss, and 2 novel heteroplasmic mutations: m.3395A>G (Y30C) occurring in a highly conserved aminoacid of the ND1 gene and the m.4316A>G located in the residue A54 of the tRNA(Ile) gene. These 2 novel variations were absent in 150 controls. All these variants may act synergistically and exert a cumulative negative effect on heart function to generate the cardiomyopathy.