Bi-allelic PRRT2 variants may predispose to Self-limited Familial Infantile Epilepsy.

Heterozygous PRRT2 variants are frequently implicated in Self-limited Infantile Epilepsy, whereas homozygous variants are so far linked to severe presentations including developmental and epileptic encephalopathy, movement disorders, and intellectual disability. In a study aiming to explore the genetics of epilepsy in the Sudanese population, we investigated several families including a consanguineous family with three siblings diagnosed with self-limited infantile epilepsy. We evaluated both dominant and recessive inheritance using whole exome sequencing and genomic arrays. We identified a pathogenic homozygous splice-site variant in the first intron of PRRT2 [NC_000016.10(NM_145239.3):c.-65-1G > A] that segregated with the phenotype in this family. This work taps into the genetics of epilepsy in an underrepresented African population and suggests that the phenotypes of homozygous PRRT2 variants may include milder epilepsy presentations without movement disorders.

Cross-Sectional Content Evaluation of Spinal Cord Injury Medicine Fellowship Websites.

This study evaluated the quality and accessibility of the websites of the Spinal Cord Injury Medicine (SCIM) fellowship programs to identify potential areas for improvement for future applicants. Twenty-four SCIM fellowship program websites were analyzed based on 44 predetermined criteria: website accessibility, education, research, recruitment, and incentives. This study found that many evaluated websites needed more information on didactics, educational resources, evaluation criteria, call requirements, schedules, and expected caseloads, which could lead to an incomplete understanding of the fellowship program. Additionally, more information on education and research can be needed for applicants to adequately compare programs and make informed decisions about which programs to apply to. Information about the selection process, current board pass rates, mentorship opportunities, technology/simulation, and alumni was limited across several evaluated websites. Incentives, fellow wellness, and harassment policies were also found to be insufficient or absent. The study emphasizes that SCIM fellowship programs should provide comprehensive and accurate information on their websites to facilitate applicants in choosing the program that aligns best with their professional goals. Including detailed and accurate information regarding general program qualities, educational and research opportunities, recruitment, and incentive data will provide prospective applicants with a holistic understanding of the program. By providing detailed and transparent information on their websites, SCIM fellowships can attract more qualified applicants and enhance the applicant pool, ultimately improving the quality of their program.

A novel homozygous mutation in TRAPPC9 gene causing autosomal recessive non-syndromic intellectual disability.

BACKGROUND: The etiology of intellectual disabilities is diverse and includes both genetic and environmental factors. The genetic causes of intellectual disabilities range from chromosomal aberrations to single gene disorders. The TRAPPC9 gene has been reported to cause autosomal recessive forms of intellectual disabilities in 56 patients from consanguineous and non-consanguineous families around the world. METHODS: We analyzed two siblings with intellectual disability, microcephaly and delayed motor and speech development from a consanguineous Sudanese family. Genomic DNA was screened for mutations using NGS panel (NextSeq500 Illumina) testing 173 microcephaly associated genes in the Molecular Genetics service in Robert Debre hospital in Paris, France. RESULTS: A novel homozygous mutation (NM_031466.7 (TRAPPC9):c.2288dup, p. (Val764Glyfs*7) in exon 14 of TRAPPC9 gene was found in the two patients. The mutation was predicted to cause nonsense mediated decay (NSMD) using SIFT prediction tool. The variant has not been found in either gnomAD or Exac databases. Both parents were heterozygous (carriers) to the mutation. CONCLUSION: This is the first study to report patients with TRAPPC9-related disorder from Sub-Saharan Africa.

Case Report: A New Family With Pontocerebellar Hypoplasia 10 From Sudan.

Pontocerebellar hypoplasia type 10 (PCH10) is a very rare autosomal recessive neurodegenerative disease characterized by intellectual disability, microcephaly, severe developmental delay, pyramidal signs, mild cerebellar atrophy, and white matter changes in the brain, as shown by magnetic resonance imaging (MRI). The disease has been described in only twenty-one patients from ten Turkish families with a founder missense pathogenic variant in the CLP1 gene involved in tRNA processing and maturation. We analyzed three siblings from a consanguineous Sudanese family who presented with intellectual disability, dysmorphic features, developmental delay, regression of milestones, microcephaly, epilepsy, extrapyramidal signs, mild pontine, and cerebellar atrophy. We identified through whole-exome sequencing the same pathogenic variant (c.419G>A; p(Arg140His) reported before in all Turkish families. Our study extends the phenotypes of PCH10 and reports for the first time cases with PCH10 of non-Turkish origin.

Genetic diagnosis in Sudanese and Tunisian families with syndromic intellectual disability through exome sequencing.

BACKGROUND: Intellectual disability is a form of neurodevelopmental disorders that begin in childhood and is characterized by substantial intellectual difficulties as well as difficulties in conceptual, social, and practical areas of living. Several genetic and nongenetic factors contribute to its development; however, its most severe forms are generally attributed to single-gene defects. High-throughput technologies and data sharing contributed to the diagnosis of hundreds of single-gene intellectual disability subtypes. METHOD: We applied exome sequencing to identify potential variants causing syndromic intellectual disability in six Sudanese patients from four unrelated families. Data sharing through the Varsome portal corroborated the diagnosis of one of these patients and a Tunisian patient investigated through exome sequencing. Sanger sequencing validated the identified variants and their segregation with the phenotypes in the five studied families. RESULT: We identified three pathogenic/likely pathogenic variants in CCDC82, ADAT3, and HUWE1 and variants of uncertain significance in HERC2 and ATP2B3. The patients with the CCDC82 variants had microcephaly and spasticity, two signs absent in the two previously reported families with CCDC82-related intellectual disability. CONCLUSION: In conclusion, we report new patients with pathogenic mutations in the genes CCDC82, ADAT3, and HUWE1. We also highlight the possibility of extending the CCDC82-linked phenotype to include spastic paraplegia and microcephaly.

Novel variants causing megalencephalic leukodystrophy in Sudanese families.

Mutations in MLC1 cause megalencephalic leukoencephalopathy with subcortical cysts (MLC), a rare form of leukodystrophy characterized by macrocephaly, epilepsy, spasticity, and slow mental deterioration. Genetic studies of MLC are lacking from many parts of the world, especially in Sub-Saharan Africa. Genomic DNA was extracted for 67 leukodystrophic patients from 43 Sudanese families. Mutations were screened using the NGS panel testing 139 leukodystrophies and leukoencephalopathies causing genes (NextSeq500 Illumina). Five homozygous MLC1 variants were discovered in seven patients from five distinct families, including three consanguineous families from the same region of Sudan. Three variants were missense (c.971 T > G, p.Ile324Ser; c.344 T > C, p.Phe115Ser; and c.881 C > T, p.Pro294Leu), one duplication (c.831_838dupATATCTGT, p.Ser280Tyrfs*8), and one synonymous/splicing-site mutation (c.762 C > T, p.Ser254). The segregation pattern was consistent with autosomal recessive inheritance. The clinical presentation and brain MRI of the seven affected patients were consistent with the diagnosis of MLC1. Due to the high frequency of distinct MLC1 mutations found in our leukodystrophic Sudanese families, we analyzed the coding sequence of MLC1 gene in 124 individuals from the Sudanese genome project in comparison with the 1000-genome project. We found that Sudan has the highest proportion of deleterious variants in MLC1 gene compared with other populations from the 1000-genome project.

Pathogenic Variants in ABHD16A Cause a Novel Psychomotor Developmental Disorder With Spastic Paraplegia.

Introduction: Hereditary spastic paraplegia is a clinically and genetically heterogeneous neurological entity that includes more than 80 disorders which share lower limb spasticity as a common feature. Abnormalities in multiple cellular processes are implicated in their pathogenesis, including lipid metabolism; but still 40% of the patients are undiagnosed. Our goal was to identify the disease-causing variants in Sudanese families excluded for known genetic causes and describe a novel clinico-genetic entity. Methods: We studied four patients from two unrelated consanguineous Sudanese families who manifested a neurological phenotype characterized by spasticity, psychomotor developmental delay and/or regression, and intellectual impairment. We applied next-generation sequencing, bioinformatics analysis, and Sanger sequencing to identify the genetic culprit. We then explored the consequences of the identified variants in patients-derived fibroblasts using targeted-lipidomics strategies. Results and Discussion: Two homozygous variants in ABHD16A segregated with the disease in the two studied families. ABHD16A encodes the main brain phosphatidylserine hydrolase. In vitro, we confirmed that ABHD16A loss of function reduces the levels of certain long-chain lysophosphatidylserine species while increases the levels of multiple phosphatidylserine species in patient's fibroblasts. Conclusion: ABHD16A loss of function is implicated in the pathogenesis of a novel form of complex hereditary spastic paraplegia.

An identical-by-descent novel splice-donor variant in PRUNE1 causes a neurodevelopmental syndrome with prominent dystonia in two consanguineous Sudanese families.

PRUNE1 is linked to a wide range of neurodevelopmental and neurodegenerative phenotypes. Multiple pathogenic missense and stop-gain PRUNE1 variants were identified in its DHH and DHHA2 phosphodiesterase domains. Conversely, a single splice alteration was previously reported. We investigated five patients from two unrelated consanguineous Sudanese families with an inherited severe neurodevelopmental disorder using whole-exome sequencing coupled with homozygosity mapping, segregation, and haplotype analysis. We identified a founder haplotype transmitting a homozygous canonical splice-donor variant (NM_021222.3:c.132+2T > C) in intron 2 of PRUNE1 segregated with the phenotype in all the patients. This splice variant possibly results in an in-frame deletion in the DHH domain or premature truncation of the protein. The phenotypes of the affected individuals showed phenotypic similarities characterized by remarkable pyramidal dysfunction and prominent extrapyramidal features (severe dystonia and bradykinesia). In conclusion, we identified a novel founder variant in PRUNE1 and corroborated abnormal splicing events as a disease mechanism in PRUNE1-related disorders. Given the phenotypes' consistency coupled with the founder effect, canonical and cryptic PRUNE1 splice-site variants should be carefully evaluated in patients presenting with prominent dystonia and pyramidal dysfunction.

Novel Homozygous Missense Mutation in the ARG1 Gene in a Large Sudanese Family.

Background: Arginases catalyze the last step in the urea cycle. Hyperargininemia, a rare autosomal-recessive disorder of the urea cycle, presents after the first year of age with regression of milestones and evolves gradually into progressive spastic quadriplegia and cognitive dysfunction. Genetic studies reported various mutations in the ARG1 gene that resulted in hyperargininemia due to a complete or partial loss of arginase activity. Case Presentation: Five patients from an extended highly consanguineous Sudanese family presented with regression of the acquired milestones, spastic quadriplegia, and mental retardation. The disease onset ranged from 1 to 3 years of age. Two patients had epileptic seizures and one patient had stereotypic clapping. Genetic testing using whole-exome sequencing, done for the patients and a healthy parent, confirmed the presence of a homozygous novel missense variant in the ARG1 gene [GRCh37 (NM_001244438.1): exon 4: g.131902487T>A, c.458T>A, p.(Val153Glu)]. The variant was predicted pathogenic by five algorithms and affected a highly conserved amino acid located in the protein domain ureohydrolase, arginase subgroup. Sanger sequencing of 13 sampled family members revealed complete co-segregation between the variant and the disease distribution in the family in line with an autosomal-recessive mode of inheritance. Biochemical analysis confirmed hyperargininemia in five patients. Conclusion: This study reports the first Sudanese family with ARG1 mutation. The reported variant is a loss-of-function missense mutation. Its pathogenicity is strongly supported by the clinical phenotype, the computational functional impact prediction, the complete co-segregation with the disease, and the biochemical assessment.

Congenital brain malformations in Sudanese children: an outpatient-based study.

Congenital brain malformations (CBMs) are a heterogeneous group characterised by abnormal structure of the developing brain. Their aetiology includes in-utero infections, teratogenicity and in a considerable group, genetic causes. Due to the high rate of consanguineous marriages and the possible high prevalence of prenatal infections in Sudan, CBMs are likely to be common. The main aim of this study was to review the clinical profile of children with CBMs attending two main tertiary paediatrics neurology outpatient clinics in Khartoum State, Sudan. Children under the age of 18 years who presented with developmental delay, seizures or abnormal head size were evaluated clinically and with neuroimaging for possible CBMs. Out of 2,114 patients seen within 6 months (September 2016-March 2017) at the Outpatient Departments, 105 patients (5%) were diagnosed with CBMs. Sixty patients (57.1%) had a single brain anomaly, 36 patients (34.1%) had two brain anomalies while nine patients (8.6%) had multiple brain anomalies. Collectively, cortical malformations either isolated or in combination with other anomalies were observed in 37 patients (35.1%), thus by representing the commonest CBMs. Community-based epidemiological studies are needed to ascertain CBMs prevalence, common causes and long-term outcomes.

Case report of a novel homozygous splice site mutation in PLA2G6 gene causing infantile neuroaxonal dystrophy in a Sudanese family.

BACKGROUND: 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.

Research: Prevalence of neural tube defects Khartoum, Sudan August 2014-July 2015.

BACKGROUND: Neural tube defects (NTDs) are birth defects that results from failure of the neural tube to develop properly during early pregnancy. METHODS: We studied the prevalence of neural tube defects in newborns admitted to the NICU in Soba University and Omdurman Maternity hospitals, during the period 1st August 2014 to 31st July 2015. A cross-sectional hospital based study, involved all newborns with any type of neural tube defect admitted to the NICU in the study area during the study period. Data was collected using a questionnaire reviewing the medical, social history and clinical examination. RESULTS: Out of the 36,785 delivered newborns during the study period, the prevalence of NTDs was 2.8:1000. Females were 56 (54.4%) predominated males 47 (45.6%). History of neural tube defects was found in 11 (10.7%) of the affected newborns siblings. Sixty-eight (66%) of the studied mothers received folic acid during pregnancy with the current child, of those who received folic acid 66 (97.1%) started folic acid after conception, 36 (54.5%) in the first trimester and 39 (57.4%) had no regular intake of the folic acid. The types of NTDs include myelomeningocele 49 (47.6%), anencephaly 18 (17.5%), encephalocele 14 (13.6%), myelomeningocele and hydrocephalus 11 (10.7%) and meningocele 8 (7.8%). CONCLUSION: The prevalence of neural tube defects is 2.8:1000. Myelomeningocele is the commonest encountered NTD. The use of preconception folic acid needs to be advocated.

Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan.

Hereditary 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.64C>T (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.316C>T (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.

A randomised placebo-controlled trial of oral and topical antibiotics for children with clinically infected eczema in the community: the ChildRen with Eczema, Antibiotic Management (CREAM) study.

BACKGROUND: Secondary skin infection is common during eczema exacerbations and many children are treated with antibiotics when this is suspected, although there is little high-quality evidence to justify this practice. OBJECTIVE: To determine the clinical effectiveness of oral and topical antibiotics, in addition to standard treatment with emollients and topical corticosteroids, in children with clinically infected eczema. DESIGN: Multicentre randomised, double-blind, placebo-controlled trial. SETTING: General practices and dermatology clinics in England, Wales and Scotland. PARTICIPANTS: Children (aged 3 months to < 8 years) with a diagnosis of eczema (according to U.K. Working Party definition) and clinical suspicion of infection. INTERVENTIONS: (1) Oral flucloxacillin and topical placebo; (2) topical fusidic acid (Fucidin(®), Leo Laboratories Limited) and oral placebo; and (3) oral and topical placebos, all for 1 week. MAIN OUTCOME MEASURES: Patient-Orientated Eczema Measure (POEM) at 2 weeks (assessing subjective severity in the week following treatment). RESULTS: We randomised 113 children (36 to oral antibiotic, 37 to topical antibiotic and 40 to placebo), which was fewer than our revised target sample size of 282. A total of 103 (92.0%) children had one or more clinical features suggestive of infection and 78 (69.6%) children had Staphylococcus aureus cultured from a skin swab. Oral and topical antibiotics resulted in a 1.52 [95% confidence interval (CI) -1.35 to 4.40] and 1.49 (95% CI -1.55 to 4.53) increase (worse subjective severity) in POEM score at 2 weeks, relative to placebo and controlling for baseline POEM score. Eczema Area and Severity Index (objective severity) scores were also higher (worse) in the intervention groups, at 0.20 (95% CI -0.12 to 0.52) and 0.42 (95% CI 0.09 to 0.75) for oral and topical antibiotics, respectively, at 2 weeks. Analyses of impact on the family, quality of life, daily symptom scores, and longer-term outcomes were all consistent with the finding of no or limited difference and a trend towards worse outcomes in the intervention groups. Sensitivity analyses, including adjusting for compliance and imputation for missing data, were consistent with the main findings. CONCLUSIONS: Our data suggest that oral and topical antibiotics have no effect, or a harmful effect, on subjective eczema severity in children with clinically infected eczema in the community. The CIs around our estimates exclude a meaningful beneficial effect (published minimal clinically important difference for POEM is 3.4). Although most patients in this trial had features suggestive of infection and S. aureus on their skin, participants primarily had mild-moderate eczema and those with signs of more severe infection were often excluded. Clinicians should consider avoiding oral and topical antibiotic use in children with suspected infected eczema in the community who do not have signs of 'severe infection'. Further research should seek to understand how best to encourage the use of topical steroids and limit use of antibiotics in those with eczema flares without signs of severe infection, as well as developing tools to better phenotype eczema flares, in order to better define a population that may benefit from antibiotic treatment. TRIAL REGISTRATION: European Union Drug Regulating Authorities Clinical Trials (EudraCT) number 2011-003591-37 and Current Controlled Trials ISRCTN96705420. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The quality of life among Sudanese children with epilepsy and their care givers.

In the past few years, there has been a progressive increase in appreciation of the importance of quality of life (QOL) especially among patients with epilepsy. This issue had not been addressed in Sudanese children with epilepsy. We here aim to assess the quality of life in Sudanese children with epilepsy and their family care giver. This study was conducted in 2011 at the Epilepsy and Neurodisablity Out-patient Clinic at Saad Abualila University Hospital, Sudan. The study included 100 Children with epilepsy, and their care givers, whose age was between 6-18 years and had seizure for more than one year. The questionnaire used contains 27 questions; it was divided into four sections: impact of epilepsy and treatment, impact on the child development, impact on parents and impact on the family. For each question there were two dimensions: the frequency of the problem and the concerns that it causes. The total score ranges from 0 to 54. A combined total scale scores were calculated. The commonest concern regarding epilepsy was that the child may injure oneself, followed by that the child may stop breathing or develop brain damage or even die. The commonest concern regarding treatment was that medication may cause reduced alertness. The relevant mean scores in frequency and concern were 5.77 and 5.83 out of 10 respectively. In the child development domain, the commonest concern was that the child may become more moody and the related mean scores in frequency and concern were 9.36 and 9.32 out of 18. The commonest concern to parent was decreased ability for self care with relevant mean scores in frequency and concern of 3.14 and 3.16 out of 10. The commonest concern to the family was that the child needs to be more closely watched than other children. The mean scores here in frequency and concern were 5.37 and 5.44 out of 14. The group with epilepsy and associated co morbidities, longer seizure and treatment duration had consistently higher mean scores which were proved to significantly lower their QOL. There is a significant decline in the quality of life among Sudanese children with epilepsy and their family care giver. Psychosocial consultation, family support programs and health education for parent, teachers and publics about different aspects of epilepsy need to be addressed through mass media.

Traditional and spiritual medicine among Sudanese children with epilepsy.

This cross sectional hospital based study, carried out simultaneously in Khartoum and in Wad Madani, Al Gezira State, aimed to study the impact of spiritual beliefs on explanation of the epilepsy etiology and the choices and methods of spiritual and traditional medicine used in the management of epilepsy in Sudan. The study included 180 care givers of whom 165 (91.7%) were mothers. Their ages ranged between 30-40 years. The majority (88.8%) were educated and 60 (33.3%) of them live in rural areas. Fifty eight (32.2%) attributed epilepsy to supernatural causes while 41 (22.8%) and 90 (50%) thought that epilepsy is an untreatable and contagious disorder, respectively. Traditional and spiritual medicine for the treatment of epilepsy was used by 70.5%. The common spiritual technique used was incantations (45.6%), spitting cure (37.2%) and ritual incensing (36.7%). Herbs, black cumin (Nigella sativa), honey and olive oil were mentioned among others as a traditional treatment for epilepsy. About two fifth (42.5%) started traditional or spiritual treatment before seeking any medical advice. Nevertheless, only 2.4% stopped the medical treatment as advised by the traditional healer. Fifty five (43.3%) thought that spiritual and/ or traditional treatment were effective in the management of epilepsy, 60(47.2%) found no difference while 12(9.45) got worse. The majority of patients with epilepsy, although on medical treatment, used traditional and spiritual methods as well. Traditional and spiritual healers may be involved positively in the management of epilepsy and extensive public educational programs are needed.