PNPO was first reported in relation to autosomal recessive pyridoxal phosphate-responsive seizures in 2005 (Mills et al., 2005, PMID: 15772097). Pyridoxal phosphate-responsive seizures (MONDO: 0012407) is characterized by neonatal-onset severe seizures commonly observed within the first several hours to days of life, and subsequent encephalopathy. Developmental delay, intellectual disability, hypotonia, erratic eye movements, etc are also observed in patients with variants in PNPO. Fourteen variants (missense and frameshift) that have been reported in twenty-six probands in nine publications (PMIDs: 15772097, 23430561, 18485777, 24266778, 24658933, 24645144, 25296925, 28133863, 28985901) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by animal models and a rescue (PMIDs: 15772097, 31261385, 31616300, 31759955). Chi et al., 2019 (PMID: 31261385) demonstrated cell-type specific expression in sugarlethal drosophila with the previously identified variant c.95C>A is a valid model for PNPO-deficiency induced epilepsy. Ciapaite et al., 2020 (PMID: 31759955) used CRISPR/Cas9 gene editing to generate Pnpo-deficient zebrafish in which locomotion analysis demonstrated that these zebrafish developed seizures and only 38% survived. Even though the default points for animal models is 2 points, the ClinGen Epilepsy GCEP has decided to downgrade evidence in Chi et al., 2019 and Ciapaite et al., 2020 to 1 point because they are non-mammalian model systems. An additional line of experimental evidence (rescue) was published by Chen et al., 2019 (PMID: 31616300). In summary, PNPO is definitively associated with autosomal recessive pyridoxal phosphate-responsive seizures. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on 12/15/2020 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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