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Early-onset vitamin B₆-dependent epilepsy due to pathogenic PLPBP variants in a premature infant: A case report and review of the literature.

ABSTRACT: 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.

SUBMITTER: Heath O

PROVIDER: S-EPMC7932866 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Early-onset vitamin B6-dependent epilepsy due to pathogenic PLPBP variants in a premature infant: A case report and review of the literature.

Heath Oliver O Pitt James J Mandelstam Simone S Kuschel Carl C Vasudevan Anand A Donoghue Sarah S

JIMD reports 20201115 1

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 ...[more]

PMID: 33728241

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Project description:ImportanceCopy number variation (CNV) is an important cause of neuropsychiatric disorders. Little is known about the role of CNV in adults with epilepsy and intellectual disability.ObjectivesTo evaluate the prevalence of pathogenic CNVs and identify possible candidate CNVs and genes in patients with epilepsy and intellectual disability.Design, setting, and participantsIn this cross-sectional study, genome-wide microarray was used to evaluate a cohort of 143 adults with unexplained childhood-onset epilepsy and intellectual disability who were recruited from the Toronto Western Hospital epilepsy outpatient clinic from January 1, 2012, through December 31, 2014. The inclusion criteria were (1) pediatric seizure onset with ongoing seizure activity in adulthood, (2) intellectual disability of any degree, and (3) no structural brain abnormalities or metabolic conditions that could explain the seizures.Main outcomes and measuresDNA screening was performed using genome-wide microarray platforms. Pathogenicity of CNVs was assessed based on the American College of Medical Genetics guidelines. The Residual Variation Intolerance Score was used to evaluate genes within the identified CNVs that could play a role in each patient's phenotype.ResultsOf the 2335 patients, 143 probands were investigated (mean [SD] age, 24.6 [10.8] years; 69 male and 74 female). Twenty-three probands (16.1%) and 4 affected relatives (2.8%) (mean [SD] age, 24.1 [6.1] years; 11 male and 16 female) presented with pathogenic or likely pathogenic CNVs (0.08-18.9 Mb). Five of the 23 probands with positive results (21.7%) had more than 1 CNV reported. Parental testing revealed de novo CNVs in 11 (47.8%), with CNVs inherited from a parent in 4 probands (17.4%). Sixteen of 23 probands (69.6%) presented with previously cataloged human genetic disorders and/or defined CNV hot spots in epilepsy. Eight nonrecurrent rare CNVs that overlapped 1 or more genes associated with intellectual disability, autism, and/or epilepsy were identified: 2p16.1-p15 duplication, 6p25.3-p25.1 duplication, 8p23.3p23.1 deletion, 9p24.3-p23 deletion, 10q11.22-q11.23 duplication, 12p13.33-13.2 duplication, 13q34 deletion, and 16p13.2 duplication. Five genes are of particular interest given their potential pathogenicity in the corresponding phenotypes and least tolerability to variation: ABAT, KIAA2022, COL4A1, CACNA1C, and SMARCA2. ABAT duplication was associated with Lennox-Gastaut syndrome and KIAA2022 deletion with Jeavons syndrome.Conclusions and relevanceThe high prevalence of pathogenic CNVs in this study highlights the importance of microarray analysis in adults with unexplained childhood-onset epilepsy and intellectual disability. Additional studies and comparison with similar cases are required to evaluate the effects of deletions and duplications that overlap specific genes.

Dataset Information

Early-onset vitamin B₆-dependent epilepsy due to pathogenic PLPBP variants in a premature infant: A case report and review of the literature.

Publications

Early-onset vitamin B<sub>6</sub>-dependent epilepsy due to pathogenic <i>PLPBP</i> variants in a premature infant: A case report and review of the literature.

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