COL4A1-related autosomal recessive encephalopathy in 2 Turkish children.

OBJECTIVE: This study presents the neurologic phenotypes of 2 brothers with a novel homozygous COL4A1 mutation that was identified in a large Turkish consanguineous cohort of neurogenetic diseases. METHODS: Whole-exome sequencing and bioinformatic analysis of consanguineous families with children affected by early-onset, neurogenetic disorders was performed using the RD-Connect Genome-Phenome Analysis Platform. We also performed clinical, EEG, and neuroimaging analyses in unaffected siblings and parents. RESULTS: We have identified a homozygous missense mutation in COL4A1 (p.Gly1278Ser, NM_001845.5:c.3832G>T) in 2 siblings affected by small vessel brain disease with periventricular leukoencephalopathy and ocular defects. Presenting symptoms included mild weakness, hemiparetic gait, pyramidal findings, and seizures, whereas their intellectual and behavioral functions were normal. Both parents and 5 of the siblings (3 boys and 2 girls) were heterozygous for the variant. They did not show any clinical or laboratory signs of small vessel disease. CONCLUSIONS: COL4A1 has previously been associated with dominant small vessel disease of the brain and other organs, manifesting with high penetrance in heterozygous mutation carriers. Our findings provide evidence that COL4A1-related encephalopathy can be inherited in an autosomal recessive manner, which is important for counseling, prognosis, and treatment. Genotype-phenotype correlations remain to be established

Severe neurodevelopmental disease caused by a homozygous TLK2 variant

Abstract: A distinct neurodevelopmental phenotype characterised mainly by mild motor and language delay and facial dysmorphism, caused by heterozygous de novo or dominant variants in the TLK2 gene has recently been described. All cases reported carried either truncating variants located throughout the gene, or missense changes principally located at the C-terminal end of the protein mostly resulting in haploinsufficiency of TLK2. Through whole exome sequencing, we identified a homozygous missense variant in TLK2 in a patient showing more severe symptoms than those previously described, including cerebellar vermis hypoplasia and West syndrome. Both parents are heterozygous for the variant and clinically unaffected highlighting that recessive variants in TLK2 can also be disease causing and may act through a different pathomechanism

Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease.

Microtubules help building the cytoskeleton of neurons and other cells. Several components of the gamma-tubulin (γ-tubulin) complex have been previously reported in human neurodevelopmental diseases. We describe two siblings from a consanguineous Turkish family with dysmorphic features, developmental delay, brain malformation, and epilepsy carrying a homozygous mutation (p.Glu311Lys) in TUBGCP2 encoding the γ-tubulin complex 2 (GCP2) protein. This variant is predicted to disrupt the electrostatic interaction of GCP2 with GCP3. In primary fibroblasts carrying the variant, we observed a faint delocalization of γ-tubulin during the cell cycle but normal GCP2 protein levels. Through mass spectrometry, we observed dysregulation of multiple proteins involved in the assembly and organization of the cytoskeleton and the extracellular matrix, controlling cellular adhesion and of proteins crucial for neuronal homeostasis including axon guidance. In summary, our functional and proteomic studies link TUBGCP2 and the γ-tubulin complex to the development of the central nervous system in humans

Neuromuscular disease genetics in underrepresented populations : increasing data diversity

DATA AVAILABILITY : At the end of the study, participants de-identified exome and genome data will be archived in the European Molecular Biology Laboratory European Bioinformatics Institute’s European Genome-Phenome Archive (EMBL EBI EGA), with community access to this and selected de-identified REDCap data managed via an ICGNMD Data Access Committee.Neuromuscular diseases (NMDs) affect ∼15 million people globally. In high income settings DNA-based diagnosis has transformed care pathways and led to gene-specific therapies. However, most affected families are in low-to-middle income countries (LMICs) with limited access to DNA-based diagnosis. Most (86%) published genetic data is derived from European ancestry. This marked genetic data inequality hampers understanding of genetic diversity and hinders accurate genetic diagnosis in all income settings. We developed a cloud-based transcontinental partnership to build diverse, deeply-phenotyped and genetically characterized cohorts to improve genetic architecture knowledge, and potentially advance diagnosis and clinical management. We connected 18 centres in Brazil, India, South Africa, Turkey, Zambia, Netherlands and the UK. We co-developed a cloud-based data solution and trained 17 international neurology fellows in clinical genomic data interpretation. Single gene and whole exome data were analysed via a bespoke bioinformatics pipeline and reviewed alongside clinical and phenotypic data in global webinars to inform genetic outcome decisions. We recruited 6001 participants in the first 43 months. Initial genetic analyses 'solved' or 'possibly solved' ∼56% probands overall. In-depth genetic data review of the four commonest clinical categories (limb girdle muscular dystrophy, inherited peripheral neuropathies, congenital myopathy/muscular dystrophies and Duchenne/Becker muscular dystrophy) delivered a ∼59% 'solved' and ∼13% 'possibly solved' outcome. Almost 29% of disease causing variants were novel, increasing diverse pathogenic variant knowledge. Unsolved participants represent a new discovery cohort. The dataset provides a large resource from under-represented populations for genetic and translational research. In conclusion, we established a remote transcontinental partnership to assess genetic architecture of NMDs across diverse populations. It supported DNA-based diagnosis, potentially enabling genetic counselling, care pathways and eligibility for gene-specific trials. Similar virtual partnerships could be adopted by other areas of global genomic neurological practice to reduce genetic data inequality and benefit patients globally.This work was supported by a Medical Research Council strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1. Additional ICGNMD support including travel and subsistence costs was received from the National Brain Appeal (UK Charity 290173) and University College London Global Engagement Funds. Fellowships for R.S.S.F. and K.N. were funded by the Guarantors of Brain (UK Charity 1197319). The authors acknowledge and are grateful for: conference bursaries from the World Muscle Society to R.S.S.F. S.R., K.N., O.Y.K., P.J.T., V.V.Y. S.V.D.M. and R.L. are members of the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-MND). M.P.K.: National Institute of Neurological Disorders and Stroke (1K23NS112463), American Association of Neuromuscular & Electrodiagnostic Medicine Development Award and Allen Foundation. D.B.: National Institute of Neurological Disorders and Stroke (K23NS117310) and support from Biogen for the KCTN1 Natural History Study. G.M.R.: University College London and UCLH Biomedical Research Centre funding, Health Education England and University College London Hospitals NHS Foundation Trust Innovation Fund. R.M.F., R.W.T. and K.P.: Wellcome core support (203105/Z/16/Z). R.M.F. received additional support from the Lily Foundation and the Leigh Syndrome International Consortium. A.T.: EU Horizon 2020 research and innovation Solve-RD project, No. 779257. F.H.W., M.S., M.B. and A.V.: South African Medical Research Council award ‘The genetics of Neuromuscular Diseases in South African patient populations: the ICGNMD study’. K.T. is funded by a J. C. Bose Fellowship, Science and Engineering Research Board (SERB) Department of Science and Technology, India. P.G. is supported by the Centre for DNA Fingerprinting and Diagnostics (CDFD) Core Research Grant, Department of Biotechnology, Government of India. R.H.: Wellcome award 109915/Z/15/Z, UK Medical Research Council award MR/N025431/1, the Lily Foundation, Evelyn Trust Research Grant (Ref 19/14), Action for A-T and UK Research and Innovation Newton Fund (MR/NO27302/1). P.F.C.: Wellcome awards 212219/Z/18/Z and 224486/Z/21/Z, UK Medical Research Council awards MC_PC_21046, MR/S035699/1 and MR/ S01165X/1, LifeArc Philanthropic Fund, NIHR BioResource for Translational Research in Common and Rare Diseases, Alzheimer’s Society, NIHR BioResource for Genes and Cognition and Leverhulme Trust. R.D.S.P.: UK Medical Research Council MR/ S002065/1 and MC_PC_21046, and the Lily Foundation. H.H.: UK Medical Research Council, Wellcome, UCLH Biomedical Research Centre (NIHR-BRC), Rosetrees Trust, and SOLVE-RD. M.M.R.: Wellcome grant G104817, National Institute of Neurological Disorders and Stroke and Office of Rare Diseases grants U54NS065712 and 1UOINS109403-01 and Muscular Dystrophy Association grant.https://www.edusoft.ro/brain/index.php/brainam2024Paediatrics and Child HealthSDG-03:Good heatlh and well-bein

Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice

Nonketotic Hyperglycinemia and Acquired Hydrocephalus

Nonketotic hyperglycinemia is an autosomal recessive disorder of glycine metabolism. Patients generally present in the neonatal period with lethargy, feeding difficulty, hypotonia, apnea, poorly controlled convulsions, and coma. Myoclonic seizures and burst suppression pattern on electroencephalography are major findings of disease, but development of hydrocephalus is not an expected finding. The present case is that of an infant with acquired hydrocephalus, psychomotor retardation, and myoclonic seizures in whom the final diagnosis was nonketotic hyperglycinemia. (C) 2009 by Elsevier Inc. All rights reserved

Parental attitude of mothers, iron deficiency anemia, and breath-holding spells

The aim of this study was to investigate the effect of family structure and the attitude of mothers on the development of breath-holding spells. The data of the Sociodemographic and Parental Attitude Research Instruments of 30 mothers of children with breathholding spells and of 30 mothers of healthy children were compared. The subjects were also evaluated for iron deficiency anemia and by age-related developmental test. No significant difference was observed between the two groups in the results of the Sociodemographic and Parental Attitude Research Instruments. Iron deficiency anemia was found to be significantly higher in the group of mothers of children with breathholding spells compared with the control group. This study suggests that iron deficiency anemia rather than behavioral or psychosocial problems of mothers plays a role in the development of breath-holding spells. (c) 2006 by Elsevier Inc. All rights reserved

Nonconvulsive status epilepticus and neurodevelopmental delay

Nonconvulsive status epilepticus is characterized by continuous or near continuous epileptiform discharges on electroencephalography without overt motor or sensory phenomena. It is a symptomatic condition related to a disease such as epileptic encephalopathy or a metabolic disorder. Children with isolated nonconvulsive status epilepticus rarely present with global neurodevelopmental delay. This report describes an 18-month-old male who presented with global neurodevelopmental delay and decreased alertness in whom electrical status epilepticus during sleep, which is a form of nonconvulsive status epilepticus, was determined. Metabolic investigations and cranial magnetic resonance imaging were normal. He began to achieve developmental milestones after treatment with valproic acid. Although rare, pediatric neurologists and pediatricians must be aware of this condition in making the differential diagnosis of global neurodevelopmental delay and decreased alertness. (c) 2006 by Elsevier Inc. All rights reserved