Homozygous Duplication in the CHRNE in a Family with Congenital Myasthenic Syndrome 4C: 18-Year Follow Up.

BACKGROUND AND OBJECTIVES: Congenital myasthenic syndromes (CMSs) are rare inherited diseases characterized by muscle weakness and fatigability on exertion resulting from defects in the neuromuscular junctions. Mutations in 32 genes have been reported as the underlying causes of CMS, with mutations in the cholinergic receptor nicotinic epsilon subunit (CHRNE) being the most common cause of the disease. Methodology and Materials: This study investigated a large consanguineous family with multiple individuals suffering from abnormal fatigue and muscle weakness in the ocular and limb regions. Moreover, the affected individuals were followed up for 18 years to observe the clinical course of the disease. RESULTS: High-quality exome sequencing followed by bidirectional Sanger sequencing revealed a homozygous duplication variant (NM_000080.4: c.1220-8_1227dup) in the splice acceptor site of exon 11 of the CHRNE gene. This variant is predicted to cause frameshift and premature termination (p.Cys410ProfsTer51). Both parents had heterozygous duplication variants with no clinical symptoms. The personalized treatment of the affected individuals resulted in a marked improvement in the clinical symptoms. More than 80% of the disease symptoms in the affected individuals subsided after the use of pyridostigmine and salbutamol (4 mg). CONCLUSIONS: This is the first report of long-term follow up of cases with homozygous insertion (c.1220-8_1227dup) in the CHRNE gene. Furthermore, this report expands the phenotypic symptoms associated with the CHRNE mutation.

New Onset Multiple Sclerosis Post-COVID-19 Vaccination and Correlation With Possible Predictors in a Case-Control Study.

INTRODUCTION: Various inflammatory diseases have been associated with the administration of various vaccines. Several reports have associated vaccine administration with the demyelinating diseases of the central nervous system (CNS). However, no clear or strong scientific evidence exists to support the association of vaccine administration with the onset of demyelinating diseases. Some CNS demyelination diseases such as acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica spectrum disorders (NMOSD) were reported following the administration of COVID-19 vaccines. In this study, new onset multiple sclerosis (MS) following COVID-19 vaccine administration was reported. METHODS: In this longitudinal observational case-control study, a total of 65 participants were studied, who were divided into two groups. Group A included 32 MS patients who were diagnosed post-COVID-19 vaccine administration and group B included 33 participants who received COVID-19 vaccines and did not develop MS. Group B was used as a control. The Chi-square test and logistic regression analysis were carried out using Statistical Product and Service Solutions (SPSS) (IBM SPSS Statistics for Windows, Armonk, NY) software. RESULTS: Univariate and multivariate logistic regression analysis was performed and a significant correlation between the risk factors and the development of MS post-COVID-19 vaccination was identified. CONCLUSION: The risk factors, identified in this study, can be used as significant independent predictors for developing MS post-COVID-19 vaccinations.

An expansion of phenotype: novel homozygous variant in the MED17 identified in patients with progressive microcephaly and global developmental delay.

Global developmental delay (GDD) is a lifelong disability that affects 1-3% of the population around the globe. It is phenotypically variable and highly heterogeneous in terms of the underlying genetics. Patients with GDD are intellectually disabled (ID) manifesting cognitive impairment and deficient adaptive behavior. Here, we investigated a two-looped consanguineous family segregating severe ID, seizure, and progressive microcephaly. Magnetic resonance imaging (MRI) of the brain showed mild brain atrophy and myelination defect. Whole exome sequencing (WES) was performed on the DNA samples of two patients and a novel homozygous missense variant (Chr11:g0.93528085; NM_004268.5_c.871T > C; p. Trp291Gly) was identified in the MED17 gene. Sanger sequencing revealed that the identified variant is heterozygous in both parents and healthy siblings. This variant is conserved among different species, causes a non-conserved amino acid change, and is predicted deleterious by various in silico tools. The variant is not reported in population variant databases. MED17 (OMIM: 613668) encodes for the mediator of RNA polymerase II transcription complex subunit 17. Structure modeling of MED17 protein revealed that Trp291 is involved in different inter-helical interactions, providing structural stability. Replacement of Trp291Gly, a less hydrophobic amino acid loses the inter-helical interaction leading to a perturb variant of MED17 protein.

Clinical and genetic characterization of patients segregating variants in KPTN, MINPP1, NGLY1, AP4B1, and SON underlying neurodevelopmental disorders: Genetic and phenotypic expansion.

Neurodevelopmental disorders (NDDs) are heterogeneous genetic conditions of the central nervous system (CNS). Primary phenotypes of NDDs include epilepsy, loss of developmental skills, abnormal movements, muscle weakness, ocular anomalies, hearing problems, and macro- or microcephaly. NDDs occur due to variants in genes encoding proteins involved in the structure and function of CNS, thus interrupting its normal physiological role. In the study presented here, four consanguineous families (A-D), with members showing neurodevelopmental symptoms, were recruited for clinical and genetic characterization of the phenotypes. Clinical examinations, including Seguin Form Board Test (SFBT), Vineland Social Maturity Scale (VSMS), brain Magnetic Resonance Imaging (MRI), Electroencephalogram (EEG), Electromyography (EMG), Nerve Conduction Velocity (NCV), and Magnetic Resonance Spectroscopy, were employed to characterize the disease phenotypes. Whole exome sequencing (WES) followed by Sanger sequencing was employed to search for the genetic basis of the neurological symptoms observed in four families (A-D). Two of these families (A, B) were of Saudi Arabian origin, and two others (C, D) were of Pakistan origin. Two homozygous missense (KPTN: NM_007059.4:c.301T>G: NP_008990.2; p.(Phe101Val) and MINPP1:NM_001178118.2:c.1202G>A: NP_001171588.1; p.(Arg401Gln)) variants in families A and B, respectively, and two homozygous nonsense (NGLY1:NM_018297.3:c.1534_1541dup: NP_060767.2; p.(Ser515LysfsTer51) and AP4B1:NM_001253852:c.1668G>A: NP_001240781.1; p.(Trp556X)) variants in families C and D, respectively, were identified. Interestingly, additional heterozygous nonsense variant in SON: NM_138927.2: c.5753_5756del: NP_620305.3; p.(Val1918GlufsTer87) and a homozygous variant in FLG (FLG: NM_002016.2:c.7339C>T: NP_002007.1; p.(Arg2447X) were detected in families A and D, respectively. Further, we determined the deleteriousness of each variant through computational approaches. The present study expands the phenotypic and genetic spectrum of NDD-associated genes (KPTN, MINPP1, NGLY1, and AP4B1). Moreover, additional nonsense variants (SON: c.5753_5756del and FLG: c.7339C>T) identified in two families segregating with the phenotype might explain the phenotypic variability and severity in our patients.

Association of SORD mutation with autosomal recessive asymmetric distal hereditary motor neuropathy.

BACKGROUND: The aim of this study was to identify the underlying genetic defect in a family segregating autosomal recessive asymmetric hereditary motor neuropathy (HMN). Asymmetric HMN has not been associated earlier with SORD mutations. METHODS: For this study, we have recruited a family and collected blood samples from affected and normal individuals of a family. Detailed clinical examination and electrophysiological studies were carried out. Whole exome sequencing was performed to detect the underlying genetic defect in this family. The potential variant was validated using the Sanger sequencing approach. RESULTS: Clinical and electrophysiological examination revealed asymmetric motor neuropathy with normal nerve conduction velocities and action potentials. Genetic analysis identified a homozygous mononucleotide deletion mutation (c.757delG) in a SORD gene in a patient. This mutation is predicted to cause premature truncation of a protein (p.A253Qfs*27). CONCLUSIONS: Interestingly, the patient with homozygous SORD mutation demonstrates normal motor and nerve conduction velocities and action potentials. The affected individual describes in this study has a unique presentation of asymmetric motor neuropathy predominantly affecting the right side more than the left as supported by the clinical examination. This is the first report of SORD mutation from Saudi Arabia and this study further expands the phenotypic spectrum of SORD mutation.

A homozygous missense variant in the MLC1 gene underlies megalencephalic leukoencephalopathy with subcortical cysts in large kindred: Heterozygous carriers show seizure and mild motor function deterioration.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy characterized by epileptic seizures, macrocephaly, and vacuolization of myelin and astrocyte. The magnetic resonance imaging of the brain of MLC patients shows diffuse white-matter anomalies and the occurrence of subcortical cysts. MLC features have been observed in individuals having mutations in the MLC1 or HEPACAM genes. In this study, we recruited a six generation large kindred with five affected individuals manifesting clinical features of epileptic seizures, macrocephaly, ataxia, and spasticity. In order to identify the underlying genetic cause of the clinical features, we performed whole-genome genotyping using Illumina microarray followed by detection of loss of heterozygosity (LOHs) regions. One affected individual was exome sequenced as well. Homozygosity mapping detected several LOH regions due to extensive consanguinity. An unbiased and hypothesis-free exome data analysis identified a homozygous missense variant (NM_015166.3:c.278C>T) in the exon 4 of the MLC1 gene. The variant is present in the LOH region on chromosome 22q (50 Mb) and segregates perfectly with the disorder within the family in an autosomal recessive manner. The variant is present in a highly conserved first cytoplasmic domain of the MLC1 protein (NM_015166.3:p.(Ser93Leu)). Interestingly, heterozygous individuals show seizure and mild motor function deterioration. We propose that the heterozygous variant in MLC1 might disrupt the functional interaction of MLC1 with GlialCAM resulting in mild clinical features in carriers of the variant.

Public Awareness of Ischemic Stroke in Medina city, Kingdom of Saudi Arabia.

OBJECTIVES: To assess social awareness of ischemic stroke amongst Saudi citizens in Medina city. METHODS: In a cross-sectional study conducted between February and September 2019, we used a validated questionnaire to conduct face-to-face interviews and collect data, at 4 shopping malls and 5 supermarkets in Medina city, KSA. RESULTS: Five hundred and nineteen participants completed the questionnaire. Of the respondents, 57.4% correctly defined stroke, 42.6% correctly chose ≥2 stroke signs and made ≤one mistake, 23.1% knew of blood clot-dissolving drugs, 32.8% correctly identified ≥ 4 risk factors with ≤ one mistake, 85.93% knew that going to the Emergency Room (ER) was the correct action, and 35.84% identified ≥ 3 post-discharge requirements, with ≤one mistake. Most participants (65.77%) cited internet and social media as information sources. In the univariate comparison, older age (p<0.001) and family history of stroke (p=0.001) better predicted stroke knowledge. In a multivariate logistic regression, the only predictor for stroke recognition was the educational level. The gender and family history were predictors for stroke signs knowledge. Educational level and the family history of stroke were predictors for risk factors knowledge respectively. CONCLUSION: We observed a significant stroke knowledge deficit in our Saudi cohort, thus there is a need to increase public awareness about stroke risk factors, warning signs and emphasizing prevention approaches.