Childhood-related neural genotype–phenotype in ATP1A3 mutations: comprehensive analysis

Muthaffar Osama Y.,Alqarni Asma,Shafei Jumana A.,Bahowarth Sarah Y.,Alyazidi Anas S.,Naseer Muhammad Imran 한국유전학회 2024 Genes & Genomics Vol.46 No.4

Background ATP1A3 is a gene that encodes the ATPase Na + /K + transporting subunit alpha-3 isoenzyme that is widely expressed in GABAergic neurons. It maintains metabolic balance and neurotransmitter movement. These pathways are essential for the proper functioning of the nervous system. A mutation in the ATP1A3 gene demonstrates remarkable genotype–phenotype heterogeneity. Objectives To provide insight into patients with ATP1A3 mutation. Material and methods These cases were identified using next generation sequencing. The patients' clinical and genetic data were retrieved. Detailed revision of the literature was conducted to illustrate and compare findings. The clinical, genetical, neuroimaging, and electrophysiological data of all pediatric patients were extracted. Results The study included 14 females and 12 males in addition to two novel females cases. Their mean current age is 6.3 ± 4.24 years. There were 11.54% preterm pregnancies with 5 cases reporting pregnancy complications. Mean age of seizure onset was 1.07 ± 1.06 years. Seizure semiology included generalized tonic–clonic, staring spells, tonic–clonic, and others. Levetiracetam was the most frequently used Anti-seizure medication. The three most frequently reported classical symptoms included alternating hemiplegia of childhood (50%), cerebellar ataxia (50%), and optic atrophy (23.08%). Non-classical symptoms included dystonia (73.08%), paroxysmal dyskinesias (34.62%), and encephalopathy (26.92%). Developmental delay was reported among 84.62% in cognitive, 92.31% in sensorimotor, 80.77% in speech, and 76.92% in socioemotional. EEG and MRI were non-specific. Conclusion Our study demonstrated high heterogeneity among patients with pathogenic variants in the ATP1A3 gene. Such variation is multifactorial and can be a predisposition of wide genetic and clinical variables. Many patients shared few similarities in their genetic map including repeatedly reported de novo, heterozygous, mutations in the gene. Clinically, higher females prevalence of atypical presentation was noted. These findings are validated with prior evidence and the comprehensive analysis in this study. Background ATP1A3 is a gene that encodes the ATPase Na + /K + transporting subunit alpha-3 isoenzyme that is widely expressed in GABAergic neurons. It maintains metabolic balance and neurotransmitter movement. These pathways are essential for the proper functioning of the nervous system. A mutation in the ATP1A3 gene demonstrates remarkable genotype–phenotype heterogeneity. Objectives To provide insight into patients with ATP1A3 mutation. Material and methods These cases were identified using next generation sequencing. The patients' clinical and genetic data were retrieved. Detailed revision of the literature was conducted to illustrate and compare findings. The clinical, genetical, neuroimaging, and electrophysiological data of all pediatric patients were extracted. Results The study included 14 females and 12 males in addition to two novel females cases. Their mean current age is 6.3 ± 4.24 years. There were 11.54% preterm pregnancies with 5 cases reporting pregnancy complications. Mean age of seizure onset was 1.07 ± 1.06 years. Seizure semiology included generalized tonic–clonic, staring spells, tonic–clonic, and others. Levetiracetam was the most frequently used Anti-seizure medication. The three most frequently reported classical symptoms included alternating hemiplegia of childhood (50%), cerebellar ataxia (50%), and optic atrophy (23.08%). Non-classical symptoms included dystonia (73.08%), paroxysmal dyskinesias (34.62%), and encephalopathy (26.92%). Developmental delay was reported among 84.62% in cognitive, 92.31% in sensorimotor, 80.77% in speech, and 76.92% in socioemotional. EEG and MRI were non-specific. Conclusion Our study demonstrated high heterogeneity among patients with pathogenic variants in the ATP1A3 gene. Such variation is multifactorial and can be a predisposition of wide genetic and clinical variables. Many patients shared few similarities in their genetic map including repeatedly reported de novo, heterozygous, mutations in the gene. Clinically, higher females prevalence of atypical presentation was noted. These findings are validated with prior evidence and the comprehensive analysis in this study.

A novel homozygous frameshift variant in the MCPH1 gene causes primary microcephaly in a consanguineous Saudi family

Muhammad Imran Naseer,Mahmood Rasool,Osama Yousef Muthaffar,Abdulrahman J. Sabbagh,Adeel G. Chaudhary,Mohammad H. Al‑Qahtani 한국유전학회 2017 Genes & Genomics Vol.39 No.12

Primary microcephaly (MCPH) is a rare developmental defect characterized by impaired cognitive functions, retarded neurodevelopment and reduced brain size. It is genetically heterogeneous and so far more than 17 genes associated with this disease have been identified. Primary microcephaly type 1 (MCPH1) gene encodes a protein called microcephalin, which is implicated in chromosome condensation and DNA damage induced cellular responses. It is suggested to play a role in neurogenesis and regulation of the size of the cerebral cortex. Whole exome sequencing revealed a novel, homozygous frameshift mutation (c.373_374delAA) in MCPH1 gene in exon 5 resulting in frameshift change from p.Lys125Glusfs*7. Our report presents the results of the simultaneous analysis of the trio exome data of both unaffected parents and their affected son. A homozygous frameshift variant in the MCPH1 gene was identified as a plausible candidate causal variant for the clinical phenotype in this family.

Enhanced PEC characteristics of pre-annealed CuS film electrodes by metalloporphyrin/polymer matrices

Zyoud, Ahed,AlKerm, Rana S.,Alkerm, Rola S.,Abdelhadi, Doa׳,H.,Park, DaeHoon,Helal, Mohammed H.S.,Campet, Guy,Muthaffar, Reham W.,Kwon, Hansang,Hilal, Hikmat S. North-Holland 2016 Solar Energy Materials and Solar Cells Vol. No.

<P><B>Abstract</B></P> <P>High conversion efficiency (<I>η</I>) values have been obtained from modified CuS film electrodes electrochemically deposited onto Glass/FTO. The modification involved pre-annealing the film followed by coating with tetra(-4-pyridyl)porphyrinato manganese (MnTPyP<SUP>+</SUP>) ions embedded inside a polyethylene (PE) matrix. The Glass/FTO/CuS/MnTPyP/PE electrodes exhibited enhanced photo-electrochemical (PEC) characteristics under solar simulated illumination (5.6mW/cm<SUP>−2</SUP>) in aqueous media, compared to the as-prepared Glass/FTO/CuS films which showed no PEC activity. Up to 17.4% efficiency and 85% fill factor (FF) values were obtained from the modified film electrodes. Such characteristics have not been widely known for metal chalcogenide based film electrodes before. Different pre-annealing temperatures were attempted and the 250°C temperature, followed by quenching, showed favorable results. Different aqueous redox couples were studied and the environmentally safe FeCl<SUB>2</SUB>/FeCl<SUB>3</SUB> aqueous system showed highest PEC characteristics. Effect of pre-annealing on film electrode characteristics is discussed. The MnTPyP/PE matrix behaves as charge transfer catalyst for the holes across the CuS film/liquid junction.</P> <P><B>Highlights</B></P> <P> <UL> <LI> CuS film electrodes were coated with metalloporphyrinato manganese(III)/polyethylene matrices. </LI> <LI> High PEC characteristics have been exhibited by the modified electrodes. </LI> <LI> Modification enhanced both film electrode stability and efficiency together. </LI> <LI> The matrix behaved as charge transfer catalyst for holes at the solid/liquid interface. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>Annealing CuS film electrodes at moderate temperatures (preferably at 250°C) affects CuS film morphology and spectral properties, and coating with metalloporphyrin/polymer matrices enhanced their PEC efficiency and stability.</P> <P>[DISPLAY OMISSION]</P>