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.

Construction and validation of an algorithm to separate focal and generalised epilepsy using clinical variables: A comparison of machine learning approaches.

PURPOSE: Epilepsy type, whether focal or generalised, is important in deciding anti-seizure medication (ASM). In resource-limited settings, investigations are usually not available, so a clinical separation is required. We used a naïve Bayes approach to devise an algorithm to do this, and compared its accuracy with algorithms devised by five other machine learning methods. METHODS: We used data on 28 clinical variables from 503 patients attending an epilepsy clinic in India with defined epilepsy type, as determined by an epileptologist with access to clinical, imaging, and EEG data. We adopted a machine learning approach to select the most relevant variables based on mutual information, to train the model on part of the data, and then to evaluate it on the remaining data (testing set). We used a naïve Bayes approach and compared the results in the testing set with those obtained by several other machine learning algorithms by measuring sensitivity, specificity, accuracy, area under the curve, and Cohen's kappa. RESULTS: The six machine learning methods produced broadly similar results. The best naïve Bayes algorithm contained eleven variables, and its accuracy was 92.2% in determining epilepsy type (sensitivity 92.0%, specificity 92.7%). An algorithm incorporating the best eight of these variables was only slightly less accurate - 91.0% (sensitivity 89.6%, and specificity 95.1%) - and easier for clinicians to use. CONCLUSION: A clinical algorithm with eight variables is effective and accurate at separating focal from generalised epilepsy. It should be useful in resource-limited settings, by epilepsy-inexperienced doctors, to help determine epilepsy type and therefore optimal ASMs for individual patients, without the need for EEG or neuroimaging.

An epilepsy type algorithm developed in India is accurate in Sudan: A prospective validation study.

PURPOSE: The effects of epilepsy are worse in lower- and middle-income countries (LMICs) where most people with epilepsy live, and where most are untreated. Correct treatment depends on determining whether focal or generalised epilepsy is present. EEG and MRI are usually not available to help so an entirely clinical method is required. We applied an eight-variable algorithm, which had been derived from 503 patients from India using naïve-Bayesian methods, to an adult Sudanese cohort with epilepsy. METHODS: There were 150 consecutive adult patients with known epilepsy type as defined by two neurologists who had access to clinical information, EEG and neuroimaging ("the gold standard"). We used seven of the eight variables, together with their likelihood ratios, to calculate the probability of focal as opposed to generalised epilepsy in each patient and compared that to the "gold standard". Sensitivity, specificity, accuracy, and Cohen's kappa statistic were calculated. RESULTS: Mean age was 28 years (range 17-49) and 53% were female. The accuracy of an algorithm comprising seven of the eight variables was 92%, with sensitivity of 99% and specificity of 72% for focal epilepsy. Cohen's kappa was 0.773, indicating substantial agreement. Ninety-four percent of patients had probability scores either less than 0.1 (generalised) or greater than 0.9 (focal). CONCLUSION: The results confirm the high accuracy of this algorithm in determining epilepsy type in Sudan. They suggest that, in a clinical condition like epilepsy, where a history is crucial, results in one continent can be applied to another. This is especially important as untreated epilepsy and the epilepsy treatment gap are so widespread. The algorithm can be applied to patients giving an individual probability score which can help determine the appropriate anti-seizure medication. It should give epilepsy-inexperienced doctors confidence in managing patients with epilepsy.

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.

Epilepsy classification (ILAE Classification 2017) in resource-limited countries: A cross-sectional study on epilepsy in pediatric patients from Sudan

Background: The objective of this study is to utilize the ILAE 2017 to classify epilepsy patients and determine its applicability in Sudan. Methods: This study is a prospective, descriptive, cross-sectional research conducted in two pediatric epilepsy clinics in Khartoum State, Sudan. Results: In this cross-sectional study, 350 pediatric patients with epilepsy were included, with a mean age of 8.4 ± 4.7 years and a mean illness duration of 4.71 ± 3.91 years. The ILAE classification was applied, showing that 71.11% of patients had generalized onset seizures, 27.7% had focal onset seizures, and only 1.1% had unknown onset seizures. Among patients with focal onset seizures, 56.4% had intact awareness, while 43.6% had impaired levels of awareness. The majority of patients who had generalized onset seizures experienced motor onset seizures, with tonicclonic seizures being the most common (44.2%). Nearly all patients with unknown onset seizures experienced tonic-clonic convulsions. These findings provide insights into the prevalence and types of seizures among pediatric epilepsy patients in Sudan and can guide clinicians in developing appropriate treatment plans. Conclusion: This study highlights the importance of utilizing the latest ILAE classification 2017 in epilepsy classification and its potential utilization in resource limited areas like Sudan.

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.

Knowledge, attitudes, and practices of caregivers of children with epilepsy in Sudan.

OBJECTIVE: To explore the knowledge, attitudes, and practices of caregivers of children with epilepsy. METHODS: This cross-sectional study included 107 consecutive caregivers of children diagnosed with epilepsy, attending the neurology outpatient clinic in a Pediatric tertiary university hospital, in Khartoum, Sudan for regular check-up. Data were obtained by an interviewer through a structured questionnaire, while clinical parameters of children with epilepsy were taken from medical records. RESULTS: Most respondents knew that epilepsy is not an infectious disease (92.5%), while the least proportion of caregivers (41.1%) knew that epilepsy did not emanate from a supernatural origin. The majority of caregivers were with the idea that epilepsy caused lost opportunities for study (66.4%) and that epilepsy was looked upon negatively by others (64.5%). Less than half (39.7%) of these caregivers rolled their child on to the side during a seizure, and more than a third (37.2%) admitted to sprinkling water over the child during his/her seizure. Caregivers' of children with Generalized Tonic-Clonic (GTC) convulsions, reported significantly lower knowledge scores than caregivers whose children did not experience GTC seizures (p = 0.016). Caregivers of children with GTC seizures were more likely to believe epilepsy was for the most part hereditary (p = 0.006), and that children with epilepsy lost consciousness during a seizure (p < 0.001). CONCLUSION: Our findings suggest that caregivers require periodic epilepsy-related educational programs. This study is an invaluable tool for tailoring the delivery of information and support resources for caregivers in our region.

A children's epilepsy diagnosis aid: Development and early validation using a Bayesian approach.

INTRODUCTION: The diagnosis of epilepsy in children is difficult and misdiagnosis rates can be as much as 36%. Diagnosis in all countries is essentially clinical, based on asking a series of questions and interpreting the answers. Doctors experienced enough to do this are either scarce or absent in very many parts of the world so there is a need to develop a diagnostic aid to help less-experienced doctors or non-physician health workers (NPHWs) do this. We used a Bayesian approach to determine the most useful questions to ask based on their likelihood ratios (LR), and incorporated these into a Children's Epilepsy Diagnosis Aid (CEDA). METHODS: Ninety-six consecutive new referrals with possible epilepsy aged under 10 years attending a pediatric neurology clinic in Khartoum were included. Initially, their caregivers were asked 65 yes/no questions by a medical officer, then seen by pediatric neurologist and the diagnosis of epilepsy (E), not epilepsy (N), or uncertain (U) was made. The LR was calculated and then we selected the variables with the highest and lowest LRs which are the most informative at differentiating epilepsy from non-epilepsy. An algorithm, (CEDA), based on the most informative questions was constructed and tested on a new sample of 47 consecutive patients with a first attendance of possible epilepsy. We calculated the sensitivity and specificity for CEDA in the diagnosis of epilepsy. RESULTS: Sixty-nine (79%) had epilepsy and 18 (21%) non-epilepsy giving pre-test odds of having epilepsy of 3.83. Eleven variables with the most informative LRs formed the diagnostic aid (CEDA). The pre-test odds and algorithm were used to determine the probability of epilepsy diagnosis in a subsequent sample of 47 patients. There were 36 patients with epilepsy and 11 with nonepileptic conditions. The sensitivity of CEDA was 100% with specificity of 97% and misdiagnosis 8.3%. CONCLUSION: Children's Epilepsy Diagnosis Aid has the potential to improve pediatric epilepsy diagnosis and therefore management and is particularly likely to be useful in the many situations where access to epilepsy specialists is limited. The algorithm can be presented as a smartphone application or used as a spreadsheet on a computer.

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.

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.

Overlap of polymicrogyria, hydrocephalus, and Joubert syndrome in a family with novel truncating mutations in ADGRG1/GPR56 and KIAA0556.

Genetic mutations associated with brain malformations can lead to a spectrum of severity and it is often difficult to determine whether there are additional pathogenic variants contributing to the phenotype. Here, we present a family affected by a severe brain malformation including bilateral polymicrogyria, hydrocephalus, patchy white matter signal changes, and cerebellar and pontine hypoplasia with elongated cerebellar peduncles leading to the molar tooth sign. While the malformation is reminiscent of bilateral frontoparietal polymicrogyria (BFPP), the phenotype is more severe than previously reported and also includes features of Joubert syndrome (JBTS). Via exome sequencing, we identified homozygous truncating mutations in both ADGRG1/GPR56 and KIAA0556, which are known to cause BFPP and mild brain-specific JBTS, respectively. This study shows how two independent mutations can interact leading to complex brain malformations.

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

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).

Clinical Profile of Pediatric Neurological Disorders: Outpatient Department, Khartoum, Sudan.

BACKGROUND: There is no available data from Sudan reflecting the magnitude of the neurological disorders and disabilities in the pediatric age-group. This study aims to evaluate the pattern of neurological disorders among Sudanese children. PATIENTS AND METHODS: This is a retrospective survey of children with epilepsy and other neurodisability disorders seen at pediatric neurology outpatient clinic, during the period from January 2007 to August 2013. The data of 9600 patients were analyzed. RESULTS: A total of 6019 patients were included in the study. The majority of the patients had epilepsy that amounted to 52.8%, followed by cerebral palsy (19.1%), congenital anomalies of the central nervous system (6.2%), neuromuscular disorders (3.2%), stroke (2.4%), ataxia and movement disorders (1.9%), assumed genetic syndromes (1.2%), and others. CONCLUSION: Neurological disorders constitute a major cause of chronic morbidity in pediatric age-group.

Spectrum of attention deficit hyperactivity disorders (ADHD) among Sudanese children with epilepsy.

Epilepsy is commonly encountered in children with attention deficit hyperactivity disorder (ADHD). This study aims to determine the spectrum of ADHD among Sudanese children with epilepsy. The study was conducted at the Epilepsy and Neurodisabilities Outpatient Clinic for Children at Saad Abu Elila University Hospital, Khartoum, Sudan during the period January - July 2013. All patients with epilepsy who presented to the clinic during the study period were assessed for ADHD using psychometric questionnaire. According to the interpretation guide, the degree of probability of ADHD was identified. Out of 720 patients with epilepsy 77(10.6%) were identified as having ADHD. Of these 50 (19.50%) patients had a high probability of having ADHD, 29 (37.70%) above average, 29 (37.70%) average and 4 (5.20%) had low ADHD spectrum.

Sudanese female doctors in paediatrics.

Though the number of female medical graduates has increased throughout the world, their postgraduate professional achievements are said to be suboptimal. Our aim is to look into the achievements of Sudanese female pediatricians and compare them with their male counterparts. A cross sectional study was undertaken using a questionnaire involving pediatricians working in the universities and Ministry of Health, Sudan. Ninety five (65.1%) out of 146 pediatricians responded; 73 (76.8%) were females and 22 (23.2%) were males. Thirty (41%) Of the females were in the academic career. Only 2 (8.3%) out of 24 assistant professors were promoted to associate professors and non of the four associate professors managed to become a professor compared to 68% and 25% among males, respectively. Twenty three (76.6%) of females compared to 31% of males had no publications. Nineteen out of 21 females (90.4%) who have been offered training opportunities abroad declined the offer for family reasons. Fifty four (93%) female pediatricians declined to work outside the capital state. No nursery facilities were available at work place. The main reasons for inadequate achievements included family issues, cultural obstacles, lack of mentorships and unsatisfying work environment and facilities. Suggestions were put forward to improve on these problems. Though female doctors are the majority of undergraduate and graduate students in Sudan, their professional and academic achievements after specialization are not optimal mainly for socio-cultural reasons and these need to be addressed.