Plasma Physics

Contains reports on three research projects.United States Atomic Energy Commission under Contract AT(30-1)-184

Plasma Physics

Contains research objectives and reports on two research projects.United States Atomic Energy Commission under Contract AT(30-1)-184

Plasma Physics

Contains reports on five research projects.United States Atomic Energy Commission (Contract AT(30-1)-1842)Project MACAdvanced Research Agency, Department of Defense, under Office of Naval Research Contract Nonr-4102(01

Plasma Physics

Contains reports on five research projects.United States Atomic Energy Commission (Contract AT(30-1)-1842

Plasma Physics

Contains reports on seven research projects.United States Atomic Energy Commission under Contract AT(30-1)-1842Joint Services Electronics Programs (U.S. Army, U.S. Navy, and U.S. Air Force) under Contract DA 28-043-AMC-02536(E

The genotypic spectrum of ALDH7A1 mutations resulting in pyridoxine dependent epilepsy: a common epileptic encephalopathy

Pyridoxine dependent epilepsy (PDE) is a treatable epileptic encephalopathy characterized by a positive response to pharmacologic doses of pyridoxine. Despite seizure control, at least 75% of individuals have intellectual disability and developmental delay. Current treatment paradigms have resulted in improved cognitive outcomes emphasizing the importance of an early diagnosis. As genetic testing is increasingly accepted as first tier testing for epileptic encephalopathies, we aimed to provide a comprehensive overview of ALDH7A1 mutations that cause PDE. The genotypes, ethnic origin, and reported gender was collected from 185 subjects with a diagnosis of PDE. The population frequency for the variants in this report and the existing literature were reviewed in the Genome Aggregation Database (gnomAD). Novel variants identified in population databases were also evaluated through in silico prediction software and select variants were over-expressed in an E.coli-based expression system to measure α-aminoadipic semialdehyde dehydrogenase activity and production of α-aminoadipic acid. This study adds 47 novel variants to the literature resulting in a total of 165 reported pathogenic variants. Based on this report, in silico predictions, and general population data, we estimate an incidence of approximately 1:64,352 live births. This report provides a comprehensive overview of known ALDH7A1 mutations that cause PDE, and suggests that PDE may be more common than initially estimated. Due to the relative high frequency of the disease, the likelihood of under-diagnosis given the wide clinical spectrum and limited awareness among clinicians as well as the cognitive improvement noted with early treatment, newborn screening for PDE may be warranted

The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT

International audiencePurpose: The study's purpose was to delineate the genetic mutations that cause classic nonketotic hyperglycinemia (NKH). Methods: Genetic results, parental phase, ethnic origin, and gender data were collected from subjects suspected to have classic NKH. Mutations were compared with those in the existing literature and to the population frequency from the Exome Aggregation Consortium (ExAC) database. Results: In 578 families, genetic analyses identified 410 unique mutations, including 246 novel mutations. 80% of subjects had mutations in GLDC. Missense mutations were noted in 52% of all GLDC alleles, most private. Missense mutations were 1.5 times as likely to be pathogenic in the carboxy terminal of GLDC than in the amino terminal part. Intragenic copy-number variations (CNVs) in GLDC were noted in 140 subjects, with biallelic CNVs present in 39 subjects. The position and frequency of the breakpoint for CNVs correlated with intron size and presence of Alu elements. Missense mutations, most often recurring, were the most common type of disease-causing mutation in AMT. Sequencing and CNV analysis identified biallelic pathogenic mutations in 98% of subjects. Based on genotype, 15% of subjects had an attenuated phenotype. The frequency of NKH is estimated at 1:76,000. Conclusion: The 484 unique mutations now known in classic NKH provide a valuable overview for the development of genotype-based therapies