PLPBP mutations cause variable phenotypes of developmental and epileptic encephalopathy

Abstract

SummaryObjectiveVitamin B6–dependent epilepsies are treatable disorders caused by variants in several genes, such as ALDH7A1,PNPO, and others. Recently, biallelic variants in PLPBP, formerly known as PROSC, were identified as a novel cause of vitamin B6–dependent epilepsies. Our objective was to further delineate the phenotype of PLPBP mutation.MethodsWe identified 4 unrelated patients harboring a total of 4 variants in PLPBP, including 3 novel variants, in a cohort of 700 patients with developmental and epileptic encephalopathies. Clinical information in each case was collected.ResultsEach patient had a different clinical course of epilepsy, with seizure onset from the first day of life to 3 months of age. Generalized tonic–clonic seizures were commonly noted. Myoclonic seizures or focal seizures were also observed in 2 patients. Interictal electroencephalography showed variable findings, such as suppression burst, focal or multifocal discharges, and diffuse slow activity. Unlike previous reports, all the patients had some degree of intellectual disability, although some of them had received early treatment with vitamin B6, suggesting that different mutation types influence the severity and outcome of the seizures.Significance PLPBP variants should be regarded as among the causative genes of developmental and epileptic encephalopathy, even when it occurs after the neonatal period. Early diagnosis and proper treatment with pyridoxine or pyridoxal phosphate is essential to improve the neurologic prognosis in neonates or young children with poorly controlled seizures.

Diagnostic pitfalls in vitamin B6‐dependent epilepsy caused by mutations in the PLPBP gene

“…Here, we describe two additional patients with PLPBP ‐associated vitamin B6‐dependent epilepsy caused by homozygous variants in PLPBP , including a novel missense variant, c.121C>T, p.(Arg41Trp) and a splice‐site variant c.207+1G>A, which was previously identified in compound heterozygous state with another splice‐site variant . Pathogenicity of p.(Arg41Trp) is supported by the previous identification of the substitution of arginine 41 by glutamine in five patients with relatively mild clinical severity of vitamin B6‐dependent epilepsy due to PLPBP variants (four homozygous, one compound heterozygous) . Overall, 13 missense and 7 splice‐site and null (nonsense and frameshift) variants in PLPBP have been identified .…”

“…In contrast, the patients reported by Plecko et al were all treated with PN and had decent seizure control in at least three out of four cases . Three of four patients reported by Shiraku et al were treated with PN and in the latest study only one of three patients who switched from PN to PLP had improved seizure control . While these clinical data do not offer indication for superior effectiveness of either PN or PLP, studies in plpbp −/− zebrafish larvae showed a more remarkable effect of PN on the epileptic phenotype and survival with a clear dose‐dependency .…”

“…Hyperglycinemia and hyperlactatemia are the most consistently observed biochemical abnormalities in PLPHP deficient patients. To this date, hyperglycinemia and hyperlactatemia has been described in 6 and 10 of the 28 published cases, respectively (parameters were not determined in 8 and 11 patients, respectively). Interestingly, hyperglycinemia and lactic acidemia were also present in both patients in this report within the first days of life, the latter reaching 8.1 and 8.9 mmoL/L as peak concentrations within the first day of life and normalizing within 3 to 4 days (patient 1 and 2, respectively).…”

“…To date, 30 patients with PLPHP deficiency have been described, including this report, with four patients with early demise (age range of surviving patients 5 months to 30 years, median age 5 years). Developmental delay (DD) and varying degrees of intellectual disability (ID) are common but not a constant feature of this condition (description of DD in 15/25 patients, normal development in 9/25 patients, and some degree of ID in 11/25 patients, normal learning in 5/25 patients).…”

“…So far, 28 cases of vitamin B6‐dependent epilepsy caused by PLPBP variants have been described . Neonatal onset seizures are the dominating feature in this patient group.…”