Functional abilities, respiratory and cardiac function in a large cohort of adults with Duchenne muscular dystrophy treated with glucocorticoids.

BACKGROUND AND PURPOSE: The transition to adult services, and subsequent glucocorticoid management, is critical in adults with Duchenne muscular dystrophy. This study aims (1) to describe treatment, functional abilities, respiratory and cardiac status during transition to adulthood and adult stages; and (2) to explore the association between glucocorticoid treatment after loss of ambulation (LOA) and late-stage clinical outcomes. METHODS: This was a retrospective single-centre study on individuals with Duchenne muscular dystrophy (≥16 years old) between 1986 and 2022. Logistic regression, Cox proportional hazards models and survival analyses were conducted utilizing data from clinical records. RESULTS: In all, 112 individuals were included. Mean age was 23.4 ± 5.2 years and mean follow-up was 18.5 ± 5.5 years. At last assessment, 47.2% were on glucocorticoids; the mean dose of prednisone was 0.38 ± 0.13 mg/kg/day and of deflazacort 0.43 ± 0.16 mg/kg/day. At age 16 years, motor function limitations included using a manual wheelchair (89.7%), standing (87.9%), transferring from a wheelchair (86.2%) and turning in bed (53.4%); 77.5% had a peak cough flow <270 L/min, 53.3% a forced vital capacity percentage of predicted <50% and 40.3% a left ventricular ejection fraction <50%. Glucocorticoids after LOA reduced the risk and delayed the time to difficulties balancing in the wheelchair, loss of hand to mouth function, forced vital capacity percentage of predicted <30% and forced vital capacity <1 L and were associated with lower frequency of left ventricular ejection fraction <50%, without differences between prednisone and deflazacort. Glucocorticoid dose did not differ by functional, respiratory or cardiac status. CONCLUSION: Glucocorticoids after LOA preserve late-stage functional abilities, respiratory and cardiac function. It is suggested using functional abilities, respiratory and cardiac status at transition stages for adult services planning.

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.

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.

Intelligence quotient (IQ) among children with epilepsy: National epidemiological study - Sudan.

BACKGROUND: Many studies of selected groups of children with epilepsy have demonstrated an association between epilepsy and cognitive deficits. The aim of this study was to assess the intellectual skills of children with epilepsy and to investigate the influence of gender, age at seizure onset, type of epilepsy, antiepileptic drug used, and control of epilepsy on their intellectual function. METHODS: This is a descriptive prospective study in which one hundred and eighty-seven patients at school age (6-14 years) were recruited. Epilepsy was classified using the International League Against Epilepsy (ILAE) Commission on Classification and Terminology 2005-2009 report. An intelligence quotient (IQ) test was conducted to all patients using Stanford-Binet Fifth Edition (SB5)/Arabic version. RESULTS: Eighty-eight (47.1%) patients had an average score on Full Scale IQ (FSIQ), 44 (23.5%) had low average, whereas 18 (9.6%) had borderline impaired or delayed score. In the nonverbal IQ (NVIQ) score, the majority 84 (44.9%) had average score. The performance of the patients in the nonverbal score is better than in the verbal score, which was found to be statistically significant (P-value = 0.01). The FSIQ score was negatively affected by younger age at onset of epilepsy, polytherapy, and uncontrolled seizures. CONCLUSIONS: Most of children with epilepsy had an average FSIQ; uncontrolled seizure had worse effect on overall FSIQ and memory. Interventions to support children with epilepsy should focus on epilepsy management and school psychosocial domains.

Classification and management of epilepsy and epileptic syndromes in a cohort of 202 school children- a 2 year follow up study- Sudan.

BACKGROUND: In this paper, seizure types, and epilepsy syndromes are elucidated as per ILAE (2010) classification. A brief outline of the antiepileptic drug regimens used and the outcome of seizure control in a two -year period is presented. The applicability of the ILAE classification in resource limited countries has been revisited. METHODS: This is a descriptive prospective study, in which 202 patients were enrolled. The Cohort group was seen and evaluated by a pediatric neurologist at the Pediatric neurology Outpatients Department (OPD). Epilepsy was classified using the International League Against Epilepsy (ILAE) classification (2005-2009) report. All patients had an Electroencephalogram (EEG) at the start of the study, and this was repeated as deemed appropriate. Brain imaging (MRI) was done to patients when indicated. Treatment decisions were made by pediatric neurologists. Outcomes were categorized into four groups: fully recovered, well controlled, partially controlled and uncontrolled. RESULTS: The mean age is 10.5 + 2.7 years. Male to female ratio was 1.7: 1. Thirty five (17.3%) patients had generalized onset seizures, 46(22.8%) had focal onset seizures, 104(51.5%) had a specific epilepsy syndrome, and 17(8.4%) patients were unclassified. 170 (84.2%) patients were on mono-therapy on their initial visit, 30(14.8%) were on two Antiepileptic Drugs (AEDs) while two (1.0%) patients were on poly-therapy. After 2 years; 155(76.7%) patients were on mono-therapy, 36(17.8%) on two AEDs while ten were (4.0%) on polytherapy. One eighty (88.2%) patients were controlled. Fifteen (7.4%) of them were off medication after being seizure free for 2 years. Twenty (9.8%) have partial control, while two (1.0%) patients were uncontrolled. Patients with focal epilepsy, those on polytherapy and those with abnormal imaging had poor prognosis. CONCLUSIONS: The ILAE classification can be used in resource limited countries. Childhood epilepsies have a good prognosis provided they are well classified and treated.

Impact of PYROXD1 deficiency on cellular respiration and correlations with genetic analyses of limb-girdle muscular dystrophy in Saudi Arabia and Sudan.

Next-generation sequencing is commonly used to screen for pathogenic mutations in families with Mendelian disorders, but due to the pace of discoveries, gaps have widened for some diseases between genetic and pathophysiological knowledge. We recruited and analyzed 16 families with limb-girdle muscular dystrophy (LGMD) of Arab descent from Saudi Arabia and Sudan who did not have confirmed genetic diagnoses. The analysis included both traditional and next-generation sequencing approaches. Cellular and metabolic studies were performed on Pyroxd1 siRNA C2C12 myoblasts and controls. Pathogenic mutations were identified in eight of the 16 families. One Sudanese family of Arab descent residing in Saudi Arabia harbored a homozygous c.464A>G, p.Asn155Ser mutation in PYROXD1, a gene recently reported in association with myofibrillar myopathy and whose protein product reduces thiol residues. Pyroxd1 deficiency in murine C2C12 myoblasts yielded evidence for impairments of cellular proliferation, migration, and differentiation, while CG10721 (Pyroxd1 fly homolog) knockdown in Drosophila yielded a lethal phenotype. Further investigations indicated that Pyroxd1 does not localize to mitochondria, yet Pyroxd1 deficiency is associated with decreased cellular respiration. This study identified pathogenic mutations in half of the LGMD families from the cohort, including one in PYROXD1. Developmental impairments were demonstrated in vitro for Pyroxd1 deficiency and in vivo for CG10721 deficiency, with reduced metabolic activity in vitro for Pyroxd1 deficiency.

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.

A novel missense variant in the ATPase domain of ATP8A2 and review of phenotypic variability of ATP8A2-related disorders caused by missense changes.

ATPase, class 1, type 8A, member 2 (ATP8A2) is a P4-ATPase with a critical role in phospholipid translocation across the plasma membrane. Pathogenic variants in ATP8A2 are known to cause cerebellar ataxia, mental retardation, and disequilibrium syndrome 4 (CAMRQ4) which is often associated with encephalopathy, global developmental delay, and severe motor deficits. Here, we present a family with two siblings presenting with global developmental delay, intellectual disability, spasticity, ataxia, nystagmus, and thin corpus callosum. Whole exome sequencing revealed a homozygous missense variant in the nucleotide binding domain of ATP8A2 (p.Leu538Pro) that results in near complete loss of protein expression. This is in line with other missense variants in the same domain leading to protein misfolding and loss of ATPase function. In addition, by performing diffusion-weighted imaging, we identified bilateral hyperintensities in the posterior limbs of the internal capsule suggesting possible microstructural changes in axon tracts that had not been appreciated before and could contribute to the sensorimotor deficits in these individuals.

Disease-associated comorbidities, medication records and anthropometric measures in adults with Duchenne muscular dystrophy.

We investigated the comorbidities, associated factors, and the relationship between anthropometric measures and respiratory function and functional abilities in adults with Duchenne muscular dystrophy (DMD). This was a single-centre cross-sectional study in genetically diagnosed adults with DMD (>16 years old). Univariate and multivariate analyses identified factors associated with dysphagia, constipation, Body Mass Index (BMI), and weight. Regression analysis explored associations between BMI, weight, and respiratory/motor abilities. We included 112 individuals (23.4 ± 5.2 years old), glucocorticoid-treated 66.1 %. The comorbidities frequency was 61.6 % scoliosis (61.0 % of them had spinal surgery), 36.6 % dysphagia, 36.6 % constipation, and 27.8 % urinary conditions. The use of glucocorticoids delayed the time to spinal surgery. The univariate analysis revealed associations between dysphagia and constipation with age, lack of glucocorticoid treatment, and lower respiratory and motor function. In the multivariate analysis, impaired cough ability remained as the factor consistently linked to both conditions. Constipation associated with lower BMI and weight. BMI and weight positively correlated with respiratory parameters, but they did not associate with functional abilities. Glucocorticoids reduce the frequency of comorbidities in adults with DMD. The ability to cough can help identifying dysphagia and constipation. Lower BMI and weight in individuals with DMD with compromised respiratory function may suggest a higher calories requirement.

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.

Clinical phenotyping and genetic diagnosis of a large cohort of Sudanese families with hereditary spinocerebellar degenerations.

Hereditary spinocerebellar degenerations (SCDs) is an umbrella term that covers a group of monogenic conditions that share common pathogenic mechanisms and include hereditary spastic paraplegia (HSP), cerebellar ataxia, and spinocerebellar ataxia. They are often complicated with axonal neuropathy and/or intellectual impairment and overlap with many neurological conditions, including neurodevelopmental disorders. More than 200 genes and loci inherited through all modes of Mendelian inheritance are known. Autosomal recessive inheritance predominates in consanguineous communities; however, autosomal dominant and X-linked inheritance can also occur. Sudan is inhabited by genetically diverse populations, yet it has high consanguinity rates. We used next-generation sequencing, genotyping, bioinformatics analysis, and candidate gene approaches to study 90 affected patients from 38 unrelated Sudanese families segregating multiple forms of SCDs. The age-at-onset in our cohort ranged from birth to 35 years; however, most patients manifested childhood-onset diseases (the mean and median ages at onset were 7.5 and 3 years, respectively). We reached the genetic diagnosis in 63% and possibly up to 73% of the studied families when considering variants of unknown significance. Combining the present data with our previous analysis of 25 Sudanese HSP families, the success rate reached 52-59% (31-35/59 families). In this article we report candidate variants in genes previously known to be associated with SCDs or other phenotypically related monogenic disorders. We also highlight the genetic and clinical heterogeneity of SCDs in Sudan, as we did not identify a major causative gene in our cohort, and the potential for discovering novel SCD genes in this population.

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.

Methylation of alpha-synuclein in a Sudanese cohort.

BACKGROUND: Several studies suggested a significant role of epigenetic changes, including alterations in miRNA, histone modifications, and DNA methylation of α-synuclein (SNCA) in Parkinson's disease (PD) pathogenicity. As of yet, only very few studies have been carried out in this field in Africa and none in Sudan. MATERIALS AND METHODS: We collected DNA from 172 Sudanese individuals (90 cases, 82 controls) who donated saliva for DNA extraction (mean age of onset: 40.6 ± 22.4 years). A family history of PD was evident in 64 patients. DNA preparation and bisulfite sequencing of SNCAintron1 was performed as described earlier. RESULTS: Of the fourteen analyzed CpGs of SNCAintron1, CpGs 16-23 were hypomethylated in PD (P-value ranged from 0.023 to 0.003). P-values improved, when sporadic cases were excluded from the analysis. CONCLUSION: We identified the presence of a specific pattern of DNA methylation in a young Sudanese cohort of familial PD, which confirms the importance of the methylation of SNCAintron1 for PD. This phenomenon appears to be independent of ethnicity, the impact of environmental factors, drug history, or familial clustering.

West syndrome, can topiramate be on top?

OBJECTIVE: To determine Topiramate efficacy on treatment of infantile spasms and ancillary seizures, and whether there were any improvements on EEG. METHODS: A retrospective study of 18 patients with infantile spasms recruited from the Pediatric Unit at King Fahd Hospital of the University, Dammam University, Saudi Arabia was carried out between January 2004 and December 2008. Topiramate was used as treatment in 7 males and 11 females aged 2-14 months. The maximum dose was 12 mg/kg/day. RESULTS: The etiology in 9 (50%) patients was cryptogenic, 6 (33%) symptomatic, and 3 (17%) idiopathic. After Topiramate treatment 6 (33%) were spasm free, 8 (44%) had ≥50% reduction, 2 (11%) had no change, and one (6%) had worsening of their spasms. Eight patients had ancillary seizures, 2 (25%) were seizure free, 2 (25%) had ≥50% seizure reduction, and 4 (50%) had no change in the ancillary seizure. The EEG showed hypsarrhythmia in 14 (78%). Post Topiramate, the EEG was normal in one (5%), improved in 3 (17%), showed persistent hypsarrhythmia in 8 (44%), and evolved to other features in 3 (17%). Three patients developed side effects such as weight loss and irritability, for which 2 patients stopped the medication. CONCLUSION: Topiramate has a good effect on the clinical features of West syndrome, but not on the EEG. It was tolerated with minimal side effects.

Utility of WhatsApp in healthcare provision and sharing of medical information with caregivers of children with neurodisabilties: experience from Sudan.

The authors used smart phones and its WhatsApp application, as a means of communication among the team members and caregivers for children with neurodisabilities, for patient consultations and medical information sharing as they are faced by an increasing number of patients coming from all over Sudan. The group included 256 mothers (caregivers) of children with neurodisabilities. The caregivers (mostly mothers) were asked to fill in a simple survey to get a feedback regarding the service offered in the WhatsApp group after taking their permission. The main aim of this study is to determine the usefulness of WhatsApp application as a means of communication between neurology team members and caregivers for children with neurodisabilities. Two hundred and forty-two caregivers responded (94.5%). All caregivers think that there is a great benefit from the group in locating the whereabouts of some unattainable/out of stock drugs. Two hundred and forty (99.1%) caregivers think that questions posed in the group are promptly and timely answered; the consultation offered is beneficial and minimises the need to go to hospital or seek a doctor's appointment. In addition, they think that they benefit from the new acquaintance and communication with mothers whose children suffer from similar conditions, which positively impacted their spirits and had a favourable effect psychologically. Using WhatsApp can solve the problems of shortage in neurology service in remote areas in resource limited countries.

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.

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.