Vitamin B6‐dependent epilepsies are a heterogeneous group of disorders characterized by decreased availability of the active cofactor pyridoxal‐5′‐phosphate (PLP). While pathogenic variants in ALDH7A1 or PNPO genes account for most cases of these disorders, biallelic pathogenic variants in PLPBP have been shown to cause a form of early onset vitamin B6‐dependent epilepsy (EPVB6D). PLPBP is thought to play a role in the homeostatic regulation of vitamin B6, by supplying PLP to apoenzymes while limiting side‐reaction toxicity related to excess unbound PLP. Neonatal‐onset intractable seizures that respond to pyridoxine and/or PLP are a predominant feature of EPVB6D in humans. Unlike other causes of vitamin B6‐dependent epilepsies; however, a specific biomarker for this disorder has yet to be identified. Here we present data from a premature infant found to have pathogenic variants in PLPBP and propose that prematurity may provide an additional clue for early consideration of this diagnosis. We discuss these findings in context of previously published genotypic, phenotypic, and metabolic data from similarly affected patients.
Pyridine Nucleotide-Disulfide Oxidoreductase Domain 2 (PYROXD2; previously called YueF) is a mitochondrial inner membrane/matrix-residing protein and is reported to regulate mitochondrial function. The clinical importance of PYROXD2 has been unclear, and little is known of the protein’s precise biological function. In the present paper, we report biallelic variants in PYROXD2 identified by genome sequencing in a patient with suspected mitochondrial disease. The child presented with acute neurological deterioration, unresponsive episodes, and extreme metabolic acidosis, and received rapid genomic testing. He died shortly after. Magnetic resonance imaging (MRI) brain imaging showed changes resembling Leigh syndrome, one of the more common childhood mitochondrial neurological diseases. Functional studies in patient fibroblasts showed a heightened sensitivity to mitochondrial metabolic stress and increased mitochondrial superoxide levels. Quantitative proteomic analysis demonstrated decreased levels of subunits of the mitochondrial respiratory chain complex I, and both the small and large subunits of the mitochondrial ribosome, suggesting a mitoribosomal defect. Our findings support the critical role of PYROXD2 in human cells, and suggest that the biallelic PYROXD2 variants are associated with mitochondrial dysfunction, and can plausibly explain the child’s clinical presentation.
FREQUENCY AND TENESMUS IN ACUTE CYSTITIS. ov. 29 19'3 poinit of thle left shoulder, in tlle region supplied by tlle fourttlh cervical nlerve. For tlle last two miiontlhs the temperature was constantly raised, generally reaching 1030 at 6 p.m. The pu's r was little affected as regards frequelncy until cardiac weakness app)eared in tlle last few wecks. Faecal examitcttions slhGwed an unusual iinumlber of microbic elileimts and an unusual type of coliformii bacillus, _ M AM-AM PPM At4 m 7w 1610 2 6|0102 92.6 2 6 I t 2 602L 26 _ 6 s0r 7?e~~~~~~~t e lie exstd 1 0 0 . 0 t@i f f buthe e_le were_is In t lat peri pneriod Plissee _ yniN ; _taSsof cirrh |osi ofc fats were not digested and bile was deficient. Urobilin was in excess in the urine. Initestinal antiseptics-for exam)ple, salol, paraffin, etc.-were administered from thle start, but produced no benefit. N7ecropsy. A post-?nortcm examiiiat.on by Dr. Spilsbtury showed the folloWing condition: Exernal.Tllere was somlie oedenia of the lower extrenmities and scrotulmii. Tlle abdomen was ratlher distended. It tecrna 1.Heart. All cavities dilated; muscle showed nlicroscopically mnarked brown atrophy. Lungs: Partly compressed by diaphragm; they also slhowed passive congestion and enmplhysema. Tlhe peritoneumn contained 3 to 5 pints oI clear ascitic fluid. Liver: of about normal size, but increased weiglht. There was some surface irreoularitv, but little tllickeninig of capsule. On section, tlle organ was very firm and dry. Tlle cut surface lhad a mottled appearance, reddislh and grev areas alternating.The organ did not appear greasy. No fibrous network could be detected -with certainty. The gall bladder was normal, and contained pale and watery bile; tlle bile ducts were normal. Microscopically the organl was traversed by numerous broad, and in places interlacina areas in which tlle liver cells were undergoing atrophy, and many had disappeared, the wide spaces between the cells being occupied by greatly dilated blood capillaries, which are not easily seen, owing to post-mortem changes.In the meshes of this interlacing network were islands of liver cells wllich exllibited marked hypertropliic cllaniges, tlle cells being of larae size and stainiing deeply, and some having two niuclei apiece. These changes were not very regularlv disposed, btut the atroplhic areas appeared to be chiefly in tlle central, the hypertrophic clhiefly in the peripheral, zones of the lobules. All the liver cells contained some excess of pigment. Fatty infiltration wvas exhibited by some of thle hlypertrophied cells, but the atrophlied cells contained no fat. Thlere w^as a little recenlt fibrous thlickiening of thle capsulle, butt none of thle portal areas, except aroulnd some of the larger bile ducts; there wvas. howvever,, some thickienling of the walls of the lhepatic vein tributaries. Tllere w+erc no uyxoniiatous degenerations in the organi, practically no round-celled infiltration of it, and nothing to suggest an infective proccss.There wvas no true cirrlhosis or biliary cirrhosis, btIt a widesp...
Optical genome mapping (OGM) is a promising alternative to traditional cytogenetic approaches. The technique evaluates ultra-high molecular weight DNA, allowing high resolution and genome wide assessment of structural and copy number variants (CNVs). OGM (Saphyr, Bionano Genomics) was utilised to analyse 50 patients with a variety of haematological malignancies (AML, B-ALL, MDS/MPN, MM, CML, CMML, T-ALL, PV, MF, CLL, and lymphoma). Variant concordance with the current standard genomic techniques of FISH, SNP-microarray and G-banded karyotype was evaluated. Concordance of OGM genomic variation with FISH was 73% overall and 100% for fusions. G-banded karyotype concordance was 92%. Concordance with SNP-microarray was significantly lower (27%). The majority of discordance was due to changes in minor clonal populations or small CNVs not being detected by OGM. The evaluation of B-allele frequency was not available, but is important for the confirmation of CNVs, detection of low clonal events, estimating clone size and for the detection of loss of heterozygosity. OGM using the Bionano Saphyr system has the capacity to detect structural and copy number variants in one assay. However, the sensitivity of the assay to detect small clones and small CNVs is currently not comparable to standard techniques.
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