Hussein Kamel

Neurocysticercosis in Qatari patients: Case reports

Neurocysticercosis is the most common parasitic infection of the central nervous system. It is a major cause of seizures in developing countries, especially in the Indian subcontinent and most of Asia, Latin America and Africa. It is increasing in prevalence in Muslim countries, especially in the Gulf region reflecting the demographics of these countries which rely heavily on labourers from highly endemic areas. Infections among Muslims in non-endemic regions are increasing. We describe one prospective case report of a Qatari male who presented with seizures and was found to have neurocysticercosis, and three retrospective cases of this infection among Qatari Muslims, who were admitted to a tertiary care hospital over the past 10 years.

Loss-of-Function Mutation in APC2 Causes Sotos Syndrome Features

Sotos syndrome, characterized by intellectual disability and characteristic facial features, is caused by haploinsufficiency in the NSD1 gene. We conducted an etiological study on two siblings with Sotos features without mutations in NSD1 and detected a homozygous frameshift mutation in the APC2 gene by whole-exome sequencing, which resulted in the loss of function of cytoskeletal regulation in neurons. Apc2-deficient (Apc2-/-) mice exhibited impaired learning and memory abilities along with an abnormal head shape. Endogenous Apc2 expression was downregulated by the knockdown of Nsd1, indicating that APC2 is a downstream effector of NSD1 in neurons. Nsd1 knockdown in embryonic mouse brains impaired the migration and laminar positioning of cortical neurons, as observed in Apc2-/- mice, and this defect was rescued by the forced expression of Apc2. Thus, APC2 is a crucial target of NSD1, which provides an explanation for the intellectual disability associated with Sotos syndrome.

Nonsense mutation in the WDR73 gene is associated with Galloway-Mowat syndrome

Background Neuroanatomical defects are often present in children with severe developmental delay and intellectual disabilities. Few genetic loci have been associated with disorders of neurodevelopment. Our objective of the present study was to analyse a consanguineous Arab family showing some of the hallmark signs of a rare cerebellar hypoplasia-related neurodevelopmental syndrome as a strategy for discovering a causative genetic mutation. Methods We used whole exome sequencing to identify the causative mutation in two female siblings of a consanguineous Arab family showing some of the hallmark signs of a cerebellar-hypoplasia-related neurodevelopmental disorder. Direct Sanger sequencing was used to validate the candidate mutations that cosegregated with the phenotype. Gene expression and loss of function studies were carried out in the zebrafish model system to examine the role of the candidate gene in neurodevelopment. Results Patients presented with severe global developmental delay, intellectual disability, hypoplasia of the cerebellum and biochemical findings suggestive of nephrotic disease. Whole exome sequencing of the two patients revealed a shared nonsense homozygous variant in WDR73 (p.Q235X (c.703C>T)) resulting in loss of the last 144 amino acids of the protein. The variant segregated according to a recessive mode of inheritance in this family and was absent from public and our inhouse databases. We examined the developmental role of WDR73 using a loss-of-function paradigm in zebrafish. There was a significant brain growth and morphogenesis defect in wdr73 knockdown embryos resulting in a poorly differentiated midbrain and cerebellum. Conclusions The results provide new insight into the functional role of WDR73 in brain development and show that perturbation of its function in an inherited disorder in humans is associated with cerebellar hypoplasia as well as nephrotic disease, consistent with Galloway-Mowat Syndrome.

Mutation in non-coding RNA, RNU12 causes early-onset cerebellar ataxia.

Exome sequences account for only 2% of the genome and may overlook mutations causing disease. To obtain a more complete view, whole genome sequencing (WGS) was analyzed in a large consanguineous family in which members displayed autosomal recessively inherited cerebellar ataxia manifesting before 2 years of age.

W44X mutation in the WWOX gene causes intractable seizures and developmental delay: a case report

BackgroundWW domain containing oxidoreductase (WWOX) gene was cloned in 2000; alteration has been seen in many cancer cells. It acts as a tumor suppresser by blocking cell growth and causing apoptosis. WWOX protein showed different expression of mice brain and spinal cord, for which deletion causes seizure and early death.Case presentationClinical and molecular characteristics of a consanguineous family show a homozygous mutation of WWOX gene at specific bases, causing a debilitating syndrome characterized by growth retardation, intractable epilepsy, intellectual disability, and early death.Using Whole Exome Sequencing (WES), a novel homozygous mutation in the WWOX gene is identified in a consanguineous Arab family from Qatar with two daughters who presented with intractable seizure and developmental delay.ConclusionThe study presents the importance of human WWOX gene for brain development and the association between gene mutation and epileptic encephalopathy. It also highlights the power of WES particularly in clinically challenging cases.

Intrafamilial clinical heterogeneity of CSPP1-related ciliopathy

Intrafamilial Clinical Heterogeneity of CSPP1-Related Ciliopathy Tawfeg Ben-Omran,* Reem Alsulaiman, Hussein Kamel, Ranad Shaheen, and Fowzan S. Alkuraya* Department of Pediatrics, Section of Clinical and Metabolic Genetics, Doha, Qatar Department of Radiology, Hamad Medical Corporation, and Weill Cornell Medical College, Doha, Qatar Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia

Whole genome sequencing identifies a novel occludin mutation in microcephaly with band-like calcification and polymicrogyria that extends the phenotypic spectrum

Whole Genome Sequencing Identifies a Novel Occludin Mutation in Microcephaly With Band-Like Calcification and Polymicrogyria That Extends the Phenotypic Spectrum Mahmoud F. Elsaid, Hussein Kamel, Nader Chalhoub, Nahla Abdel Aziz, Khalid Ibrahim, Tawfeg Ben-Omran, Binu George, Eman Al-Dous, Yasmin Mohamoud, Joel A. Malek, M. Elizabeth Ross, and Alice Abdel Aleem* Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar Weill Cornell Medical College, Qatar Department of Radiology, Hamad Medical Corporation, Doha, Qatar Laboratories Neurogenetics, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar Center for Neurogenetics, Brain & Mind Research Institute, Weill Cornell Medical College, New York National Research Center, Cairo, Egypt Genomics Core, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar Department of Neurology, Brain & Mind Research Institute, Weill Cornell Medical College, New York

Non-truncating LIFR mutation: Causal for prominent congenital pain insensitivity phenotype with progressive vertebral destruction?

We present a Qatari family with two children who displayed a characteristic phenotype of congenital marked pain insensitivity with hypohidrosis and progressive aseptic destruction of joints and vertebrae resembling that of hereditary sensory and autonomic neuropathies (HSANs). The patients, aged 10 and 14, remained of uncertain genetic diagnosis until whole genome sequencing was pursued. Genome sequencing identified a novel homozygous C65S mutation in the LIFR gene that is predicted to markedly destabilize and alter the structure of a particular domain and consequently to affect the functionality of the whole multi‐domain LIFR protein. The C65S mutant LIFR showed altered glycosylation and an elevated expression level that might be attributed to a slow turnover of the mutant form. LIFR mutations have been reported in Stüve–Wiedemann syndrome (SWS), a severe autosomal recessive skeletal dysplasia often resulting in early death. Our patients share some clinical features of rare cases of SWS long‐term survivors; however, they also phenocopy HSAN due to the marked pain insensitivity phenotype and progressive bone destruction. Screening for LIFR mutations might be warranted in genetically unresolved HSAN phenotypes.

Neuro-imaging evaluation after the first afebrile seizure in children: A retrospective observational study

PURPOSE To evaluate the role of neuro-imaging in children presenting with the first afebrile seizure and determine factors that influence the outcome of imaging in a large paediatric emergency centre. METHOD This is a retrospective review of the medical records of all patients presenting with the first non-febrile seizure to a large paediatric emergency centre in the state of Qatar. Seizure classification followed the current ILAE classification system. Imaging was undertaken in our tertiary hospital and all images were reviewed by experienced neuro-radiologists. Student t test was used for statistical analysis. RESULTS Ninety-six children underwent neuro-imaging following the first afebrile seizure. Of them, thirty-two patients (33%) were reported to have abnormalities. Children below the age of two demonstrated a significantly higher percentage of abnormal imaging (59%); (p=0.002). Children presenting with prolonged seizures showed a high percentage of imaging abnormalities (58%); (p=0.003). Children with focal seizures demonstrated a higher percentage of imaging abnormality compared to those presenting with generalized seizures (35% vs 31%). This difference did not reach statistical significance. CONCLUSION Children below the age of two demonstrated significantly higher percentages of abnormal imaging (59%), as did children presenting with status epilepticus (58%). Neuro-imaging should be considered in infants and those with focal or prolonged seizures. Neuro-imaging informed decision making in 6-8% of children.

Homozygous Nonsense Mutation in SCHIP1/IQCJ-SCHIP1 Causes a Neurodevelopmental Brain Malformation Syndrome

We report a consanguineous Arab family with 3 affected siblings who display a disorder of global developmental delay, learning difficulties, facial dysmorphism, hearing impairments, and cataract. The clinical phenotype was associated with characteristic brain magnetic resonance imaging (MRI) features of axonal guidance defects involving anterior commissure agenesis as well as scattered areas of polymicrogyria‐cobblestone complex. Whole genome sequencing revealed a novel nonsense mutation (159609921C>T) that segregated in the family consistent in an autosomal recessive pattern. This mutation located in the C‐terminal region shared by the Schwanomin‐Interacting Protein1 (SCHIP1) isoforms including the IQCJ‐SCHIP1. The in vitro expression of SCHIP1 and IQCJ‐SCHIP1 truncated mutant isoforms (NM_001197109.1; p.R209* and NM_001197114.1; p.R501*, respectively) were markedly reduced as compared to their full‐length versions suggesting protein stability/folding impairment. The pathogenic nature of this mutation is supported by a previously reported mouse knockout of Schip1 isoforms, which phenocopied the human axon guidance abnormality. This is the first report of a SCHIP1/IQCJ‐SCHIP1 point mutation in humans associated with a neurological‐developmental phenotype.