Faculty of Medicine and Surgery
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Item Case report of a novel homozygous splice site mutation in PLA2G6 gene causing infantile neuroaxonal dystrophy in a Sudanese family(BMC Medical Genetics, 2018) Elsayed,Liena E. O; Mohammed,Inaam N; Hamed,Ahlam A. A; Elseed,Maha A; Salih,Mustafa A. M; Yahia,Ashraf; Siddig,Rayan A; Amin,Mutaz; Koko,Mahmoud; Elbashir,Mustafa I; Ibrahim,Muntaser E; Brice,Alexis; Ahmed,Ammar E; Stevanin,GiovanniBackground: Infantile neuroaxonal dystrophy (INAD) is a rare hereditary neurological disorder caused by mutations in PLA2G6. The disease commonly affects children below 3 years of age and presents with delay in motor skills, optic atrophy and progressive spastic tetraparesis. Studies of INAD in Africa are extremely rare, and genetic studies from Sub Saharan Africa are almost non-existent. Case presentation: Two Sudanese siblings presented, at ages 18 and 24 months, with regression in both motor milestones and speech development and hyper-reflexia. Brain MRI showed bilateral and symmetrical T2/FLAIR hyperintense signal changes in periventricular areas and basal ganglia and mild cerebellar atrophy. Whole exome sequencing with confirmatory Sanger sequencing were performed for the two patients and healthy family members. A novel variant (NM_003560.2 c.1427 + 2 T > C) acting on a splice donor site and predicted to lead to skipping of exon 10 was found in PLA2G6. It was found in a homozygous state in the two patients and homozygous reference or heterozygous in five healthy family members. Conclusion: This variant has one very strong (loss of function mutation) and three supporting evidences for its pathogenicity (segregation with the disease, multiple computational evidence and specific patients’ phenotype). Therefore this variant can be currently annotated as “pathogenic”. This is the first study to report mutations in PLA2G6 gene in patients from Sudan.Item Intra-familial phenotypic heterogeneity in a Sudanese family with DARS2-related leukoencephalopathy, brainstem and spinal cord involvement and lactate elevation: a case report(BMC Neurology, 2018) Yahia,Ashraf; Elsayed,Liena; Babai,Arwa; Salih,Mustafa A; El-Sadig,Sarah Misbah; Amin,Mutaz; Koko,Mahmoud; Abubakr,Rayan; Idris,Razaz; Taha,Shaimaa Omer M.A; Elmalik,Salah A; Brice,Alexis; Ahmed,Ammar Eltahir; Stevanin,GiovanniBackground: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL, OMIM #611105) is a genetic disease of the central nervous system characterized by lower limb spasticity, cerebellar ataxia and involvement of the dorsal column. The disease is caused by mutations in the DARS2 gene but has never been reported in sub-Saharan Africa so far. Case presentation: Two siblings, aged 18 years and 15 years, from a consanguineous family presented with pyramidal signs and symptoms since infancy and developmental delay. Whole exome sequencing of the proband identified two compound heterozygous variants (NM_018122.4:c.1762C > G and c.563G > A) in DARS2. Sanger sequencing confirmed the presence of the mutations and their segregation in trans in both patients and in their elder sister (aged 20 years), who showed only brisk reflexes and mild lower limb spasticity. Surprisingly, in contrast to her subtle clinical presentation, the elder sister had abnormal MRI features and serum lactate levels comparable to her ill sisters. Conclusion: This report illustrates intra-familial phenotypic variation in LBSL and provides an example of a marked dissociation between the clinical and radiological phenotypes of the disease. This may have implications for the detection of mutation carriers in LBSL.Item Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan(European Journal of Human Genetics, 2016) Elsayed,Liena EO; Mohammed,Inaam N; Hamed,Ahlam AA; Elseed,Maha A; Johnson,Adam; Mairey,Mathilde; Mohamed,Hassab Elrasoul SA; Idris,Mohamed N; Salih,Mustafa AM; El-sadig,Sarah M; Koko,Mahmoud E; Mohamed,Ashraf YO; Raymond,Laure; Coutelier,Marie; Darios,Frédéric; Siddig,Rayan A; Ahmed,Ahmed KMA; Babai,Arwa MA; Malik,Hiba MO; Omer,Zulfa MBM; Mohamed,Eman OE; Eltahir,Hanan B; Magboul,Nasr Aldin A; Bushara,Elfatih E; Elnour,Abdelrahman; Rahim,Salah M Abdel; Alattaya,Abdelmoneim; Elbashir,Mustafa I; E Ibrahim,Muntaser; Durr,Alexandra; Audhya,Anjon; Brice,Alexis; Ahmed,Ammar E; Stevanin,GiovanniHereditary spastic paraplegias (HSP) are the second most common type of motor neuron disease recognized worldwide. We investigated a total of 25 consanguineous families from Sudan. We used next-generation sequencing to screen 74 HSP- related genes in 23 families. Linkage analysis and candidate gene sequencing was performed in two other families. We established a genetic diagnosis in six families with autosomal recessive HSP (SPG11 in three families and TFG/SPG57, SACS and ALS2 in one family each). A heterozygous mutation in a gene involved in an autosomal dominant HSP (ATL1/SPG3A) was also identified in one additional family. Six out of seven identified variants were novel. The c.64C4T (p.(Arg22Trp)) TFG/SPG57 variant (PB1 domain) is the second identified that underlies HSP, and we demonstrated its impact on TFG oligomerization in vitro. Patients did not present with visual impairment as observed in a previously reported SPG57 family (c.316C4T (p.(Arg106Cys)) in coiled-coil domain), suggesting unique contributions of the PB1 and coiled-coil domains in TFG complex formation/function and a possible phenotype correlation to variant location. Some families manifested marked phenotypic variations implying the possibility of modifier factors complicated by high inbreeding. Finally, additional genetic heterogeneity is expected in HSP Sudanese families. The remaining families might unravel new genes or uncommon modes of inheritance.