Treatable newborn and infant seizures due to inborn errors of metabolism

Abstract

About 25% of seizures in the neonatal period have causes other than asphyxia, ischaemia or intracranial bleeding. Among these are primary genetic epileptic encephalopathies with sometimes poor prognosis and high mortality. In addition, some forms of neonatal infant seizures are due to inborn errors of metabolism that do not respond to common AEDs, but are amenable to specific treatment. In this situation, early recognition can allow seizure control and will prevent neurological deterioration and long‐term sequelae. We review the group of inborn errors of metabolism that lead to newborn/infant seizures and epilepsy, of which the treatment with cofactors is very different to that used in typical epilepsy management.

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

“…Other PN-or PLP-responsive seizure disorders include neonatal hypophosphatasia (MIM# 241500), hyperphosphatasia with mental retardation syndrome (Mabry syndrome; MIM# 239300), and hyperprolinemia type 2 (MIM# 239510). 3 Recently, biallelic mutations in the PLPBP gene (previously known as PROSC (proline synthetase co-transcribed homolog [bacterial]) were shown to be a novel cause of vitamin B6-dependent epilepsy (MIM# 617290). 4,5 Its gene product, termed pyridoxal phosphate homeostasis protein (PLPHP), is believed to be involved in PLP homeostasis.…”

“…P6C may immobilize PLP by formation of a condensation product resulting in PLP deficiency. Other PN‐ or PLP‐responsive seizure disorders include neonatal hypophosphatasia (MIM# 241500), hyperphosphatasia with mental retardation syndrome (Mabry syndrome; MIM# 239300), and hyperprolinemia type 2 (MIM# 239510) …”

“…Different vitamin B6‐dependent epilepsies can be detected and distinguished by their respective biomarkers and genetic analysis. In PDE, for example, elevated α‐AASA, P6C, and pipecolic acid concentrations can be detected in the cerebrospinal fluid (CSF), urine and plasma, and serve as biomarkers . However, no specific biomarkers have been identified for patients with pathogenic PLPBP variants …”

Confirmation of mutations inPROSCas a novel cause of vitamin B6-dependent epilepsy

“…Hitherto known biochemical mechanisms underlying vitamin-B 6 -dependent epilepsies were impaired formation or transport of pyridoxal 5’-phosphate (PLP) or its inactivation by small accumulating compounds 2 . PROSC encodes a PLP-binding protein and mutations most probably lead to impaired cellular PLP homeostasis 1.…”

The value of plasma vitamin B6 profiles in early onset epileptic encephalopathies

“…Antiquitin (ATQ) deficiency (OMIM#266100) and hyperprolinemia type II (OMIM#239510) result in inactivation of PLP, whereas pyridox(am) ine 5'-phosphate oxidase (PNPO) deficiency (OMIM#610090) leads to reduced formation of PLP; congenital hypophosphatasia (tissue non-specific alkaline phosphat a s e ( T N S A L P ) d e f i c i e n c y, O M I M # 2 4 1 5 0 0 ) o r hyperphosphatasia result in its impaired cellular uptake (Campistol and Plecko 2015). All these disorders can present with seizures and are a meanwhile well-defined group of vitamin B 6 -dependent epilepsies that are amenable to specific treatment.…”