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.

A Rare Presentation Characterized by Epileptic Spasms in ALDH7A1, Pyridox(am)ine-5′-Phosphate Oxidase, and PLPBP Deficiency

“…In the etiologies of infantile spasms, especially genetic etiology, PDE, PNPO deficiency, and PLPBP deficiency account for only a rare proportion. Moreover, in international reports, the seizure type of ES accounted for a similar proportion of the three genetic mutations associated with vitamin B6–dependent epilepsy ( Basura et al, 2009 ; Bennett et al, 2009 ; Mills et al, 2010 ; Scharer et al, 2010 ; Yeghiazaryan et al, 2012 ; Pérez et al, 2013 ; Tlili et al, 2013 ; Mills et al, 2014 ; Guerin et al, 2015 ; Mefford et al, 2015 ; van Karnebeek et al, 2016 ; Al Teneiji et al, 2017 ; Olson et al, 2017 ; Xue et al, 2017 ; Falsaperla et al, 2018 ; Heath et al, 2020 ; Jiao et al, 2020 ; Mohanlal et al, 2020 ). In our cohort, four out of the 54 patients with PDE showed ES, a rate that is less than internationally reported ( Basura et al, 2009 ; Bennett et al, 2009 ; Mills et al, 2010 ; Scharer et al, 2010 ; Yeghiazaryan et al, 2012 ; Pérez et al, 2013 ; Tlili et al, 2013 ; Mefford et al, 2015 ; van Karnebeek et al, 2016 ; Al Teneiji et al, 2017 ; Falsaperla et al, 2018 ; Jiao et al, 2020 ).…”

“…In 2016, biallelic pathogenic variants in PLPBP have been shown to cause a form of early onset vitamin B6–dependent epilepsy (OMIM: 610090) ( Darin et al, 2016 ; Plecko et al, 2017 ). So far, more than 300 cases of PDE, 87 cases of PNPO deficiency, and 44 cases of PLPBP deficiency have been reported, respectively ( Heath et al, 2020 ; Jiao et al, 2020 ; Alghamdi et al, 2021 ).…”

“…From a clinical point of view, literature data reported various types of seizures in patients with vitamin B6–dependent epilepsy, including focal seizures, generalized tonic-clonic seizures (GTCS), myoclonic seizures, and epileptic spasms (ES) ( Yeghiazaryan et al, 2012 ; Falsaperla et al, 2018 ; Heath et al, 2020 ; Jiao et al, 2020 ; Alghamdi et al, 2021 ). In terms of ES, of the cases for which clinical data were available, 14% (27/188) of patients with PDE presented as ES ( Basura et al, 2009 ; Bennett et al, 2009 ; Mills et al, 2010 ; Scharer et al, 2010 ; Yeghiazaryan et al, 2012 ; Pérez et al, 2013 ; Tlili et al, 2013 ; Mefford et al, 2015 ; van Karnebeek et al, 2016 ; Al Teneiji et al, 2017 ; Falsaperla et al, 2018 ; Jiao et al, 2020 ).…”

“…In terms of ES, of the cases for which clinical data were available, 14% (27/188) of patients with PDE presented as ES ( Basura et al, 2009 ; Bennett et al, 2009 ; Mills et al, 2010 ; Scharer et al, 2010 ; Yeghiazaryan et al, 2012 ; Pérez et al, 2013 ; Tlili et al, 2013 ; Mefford et al, 2015 ; van Karnebeek et al, 2016 ; Al Teneiji et al, 2017 ; Falsaperla et al, 2018 ; Jiao et al, 2020 ). In PNPO deficiency and PLPBP deficiency, the proportion was 10% (5/50) and 14% (5/36), respectively ( Mills et al, 2014 ; Guerin et al, 2015 ; Olson et al, 2017 ; Xue et al, 2017 ; Heath et al, 2020 ; Mohanlal et al, 2020 ). To date, we have collected 54 cases of PDE, 13 cases of PNPO deficiency, and 2 cases of PLPBP deficiency.…”

Metabolic Seizures

“…The majority of patients remained seizure-free whether on pyridoxine or upon switching to pyridoxal phosphate. Diagnosis is molecularly confirmed by identifying mutations in the PLPBP gene ( 47 ).…”