Ahlam A. Hamed

A novel nonsense mutation in DNAJC6 expands the phenotype of autosomal recessive juvenile‐onset Parkinson disease

We appreciate Dr. Jiang’s and Liu’s interest in our recent study, where we reported that the minor allele of a missense variant (rs3796529) in the REST gene may be protective for rate of hippocampal volume loss in individuals with mild cognitive impairment (MCI) with APOE E3/E3 genotype. In their letter, the authors reported that rs3796529 was not significantly associated with the volumes of 7 subcortical regions of human brain determined by magnetic resonance imaging using data from the large-scale genome-wide association study (GWAS) summary statistics from the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) consortium. The authors’ negative findings in contrast to the association we reported may be due to numerous differences, including the following factors. First, the ENIGMA consortium included patients diagnosed with anxiety, Alzheimer disease (AD), epilepsy, major depressive disorder, or schizophrenia (>20% of the discovery participants). Although the presence of any diagnosis was used as a covariate in ENIGMA, various neurologic and psychiatric disorders may have differential effects on brain structure volumes, and this may have averaged out any influence of the REST variant. In contrast, the discovery samples in our study included only individuals with MCI, often representing a prodromal stage of AD. Second, the participants of the ENIGMA consortium were aged 9 to 97 years, covering most of the human lifespan, whereas the participants in our study were older adults (mean age 5 74.4 years, range 5 57.8–85.7 years). Finally, it should be noted that our sample included only participants with APOE E3/E3 genotype, as it was designed to identify variants independent of the well-established APOE E4 AD risk factor. In contrast, Dr. Jiang and Liu examined GWAS summary statistics obtained using all ENIGMA samples regardless of APOE E4 genotype. We believe Dr. Jiang’s and Liu’s negative findings are interesting yet should be interpreted with caution given the marked differences in sample characteristics and study design from the Alzheimer’s Disease Neuroimaging Initiative report that addressed a very specific older adult population. The large sample size in ENIGMA should not dissuade further studies, which we believe are warranted to more precisely characterize the association of this and other REST variants with subcortical brain structure volumes in cognitively normal older adults as well as those with neurodegenerative disorders.

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.

Apert Syndrome: Late presentation and treatment challenges.

Apert syndrome is a rare autosomal dominant disorder characterized by craniosynostosis, craniofacial anomalies, and severe symmetrical syndactyly of the hands and feet. Anomalies of the viscera, skeleton and cardiovascular system have also been reported… Untreated craniosynostosis leads to inhibition of brain growth and an increase in intracranial and intraorbital pressure. Most cases are sporadic, resulting from new mutations with a paternal age effect. The prognosis of Apert Syndrome depends on the severity of brain malformation and early surgical interventions. We describe a Sudanese infant with Apert syndrome who presented for the first time at the age of three months and had limited options for intervention.

Prevalence of epilepsy in 74,949 school children in Khartoum State, Sudan

Abstract Background: Data on childhood epilepsy in Sudan are scarce and the only published study on its prevalence was published in 1983. This study aimed to determine the current prevalence of epilepsy in school children in Khartoum State. Methods: This is an analytical population-based, cross-sectional study conducted in Khartoum State, Sudan. The study included students in the basic (primary) schools aged 6–14 years. Simple random sampling was used to draw a cluster of four of the seven localities comprising Khartoum State. The sample frame consisted of 1609 public schools (808,624 pupils) and 787 private schools (194,613 pupils), a total of 2396 schools (1,003,237 pupils). A sample size of 75 940 pupils was estimated and 250 schools were drawn from a sample frame of 2396 schools using a stratified random sampling technique. Consent was obtained from the headmaster/head teacher of the selected schools who arranged a meeting with the tutor/teacher responsible for each class. The study team asked whether any of the pupils was ever noticed or known to have had any kind of seizures, and a confidential letter was sent to the parents of each identified pupil. The letter included an explanation of the aims of the study, information on the research group and the kind of help the research group could offer; contact numbers and email addresses were made available if they wished to participate in this study. Those who consented to participate were then given an appointment at the Epilepsy Outpatient Department, Gaafar Ibnauf Children’s Hospital, Khartoum where they were evaluated by the paediatric neurologist. Results: Altogether, 74,949 pupils were enrolled for the study, 398 of whom were identified initially as having seizures and 332 of whom (83.4%) were identified by a paediatric neurologist. Of the 332, 303 (91.3%) proved to have epileptic seizures, 250 (82.5%) were known to have epilepsy, and 53 (17.5%) were newly diagnosed during the survey. The male to female ratio was 1.5:1. The total prevalence of epilepsy in Khartoum State was estimated to be 4/1000. The highest prevalence was in Jabal Awliya Locality (4.87/1000) and the lowest was in Khartoum Locality (3.35/1000). Twenty-nine (8.7%) patients proved to have non-epileptic seizures. The majority (15, 51.6%) had psychogenic non-epileptic seizures, and four (13.6%) had syncope. The majority (171, 56.43%) of patients had generalised epilepsy, 109 (35.97%) had focal epilepsy, and 23 (7.6%) had unclassified epilepsy. Conclusion: The prevalence of epilepsy in school children in Khartoum State (4/1000) is higher than that reported previously from Khartoum Province in 1983 (0.9/1000).

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 8 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. Similar results were obtained with overexpression of p.Asn155Ser mutant human PYROXD1 in C2C12 myoblasts. Knockdown of CG10721 (Pyroxd1 fly homologue) 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.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.

Brain tuberculoma, an unusual cause of stroke in a child with trisomy 21: a case report

BackgroundTuberculosis remains a public health problem in developing countries and is associated with lethal central nervous system complications. Intracranial tuberculomas occur in 13% of children with neurotuberculosis. Patients with trisomy 21 have an increased risk for stroke, which usually stems from cardiovascular defects.Case presentationWe report a case of a 12-year-old Sudanese boy with trisomy 21 who was presented to our hospital with focal convulsions and right-sided weakness. The results of neuroimaging and histopathological examinations were consistent with cerebral tuberculoma. The patient had a good initial response to antituberculosis drugs and steroids. To the best of our knowledge, this is the first case report of multiple brain tuberculomas described in a child with trisomy 21.ConclusionsPatients with trisomy 21 have an increased risk for stroke. Our patient had an exceptional case of stroke caused by tuberculoma. The present case emphasizes the need to consider tuberculomas in the differential diagnosis of children with neurological symptoms living in areas of high tuberculosis incidence.