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

Abstract

Vitamin B6‐responsive epilepsies are a group of genetic disorders including ALDH7A1 deficiency, PNPO deficiency, and others, usually causing neonatal onset seizures resistant to treatment with common antiepileptic drugs. Recently, biallelic mutations in PLPBP were shown to be a novel cause of vitamin B6‐dependent epilepsy with a variable phenotype. The different vitamin B6‐responsive epilepsies can be detected and distinguished by their respective biomarkers and genetic analysis. Unfortunately, metabolic biomarkers for early detection and prognosis of PLPBP deficiency are currently still lacking. Here, we present data from two further patients with vitamin B6‐dependent seizures caused by variants in PLPBP, including a novel missense variant, and compare their genotype and phenotypic presentation to previously described cases. Hyperglycinemia and hyperlactatemia are the most consistently observed biochemical abnormalities in pyridoxal phosphate homeostasis protein (PLPHP) deficient patients and were present in both patients in this report within the first days of life. Lactic acidemia, the neuroradiological, and clinical presentation led to misdiagnosis of a mitochondrial encephalopathy in two previously published cases with an early fatal course. Similarly, on the background of glycine elevation in plasma, glycine encephalopathy was wrongly adopted as diagnosis for a patient in our report. In this regard, lactic acidemia as well as hyperglycinemia appear to be diagnostic pitfalls in patients with vitamin B6‐responsive epilepsies, including PLPHP deficiency. Synopsis In vitamin B6‐responsive epilepsies, including PLPHP deficiency, there are several diagnostic pitfalls, including lactic acidemia as well as hyperglycinemia, highlighting the importance of a pyridoxine trial, and genetic testing.

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

“…Prematurity has been reported in the PLP and PN responsive epilepsies, presenting in 18% of ATQ deficiency patients and 46% to 50% of patients with PNPO deficiency 18‐20 . This also seems to be a feature of EPVB6D with prematurity reported in eight patients (27%), including our patient 4,8,9,11 . Other pregnancy complications (IUGR, 4 abnormal movements 4,8,13 ) and fetal distress (nonreassuring CTG, 4,8 meconium stained liquor 4,8,11 ) occurred in up to half of all cases.…”

“…The splice‐variant c.207+1G>T was described in a Chinese patient with pyridoxine‐dependent epilepsy 12 . An alternative nucleotide change at the same position, c.207+1G>A, has strong evidence for pathogenicity and has been reported in two other individuals 4,11 . The second variant, c.722G>A; p.(Arg241Gln), is a missense variant previously reported in two unrelated individuals with EPVB6D and milder phenotypes 4,5,8 .…”

“…and c.722G>A; p.(Arg241Gln). As summarized in Table 1, 14 missense, 3 nonsense, 2 frameshift, and 3 splice site pathogenic PLPBP variants have been reported to date 4,5,8‐12 . Loss‐of‐function is the likely mechanism of disease for this gene, with splice site, nonsense and frameshift mutations often resulting in more severe phenotypes 8,16 .…”

“…The phenotype is dominated by neonatal‐onset refractory seizures. Seventy‐eight percent of affected infants had seizures in their first week of life, and in all of those born prematurely, seizures developed within 24 hours of life 4,8,9,11 . Prematurity has been reported in the PLP and PN responsive epilepsies, presenting in 18% of ATQ deficiency patients and 46% to 50% of patients with PNPO deficiency 18‐20 .…”

“…Forty‐four cases of EPVB6D have been reported in humans, 4,5,8‐13 with a clinical picture dominated by neonatal‐onset intractable seizures responsive to pyridoxine and/or PLP, microcephaly, structural brain abnormalities and lactic acidosis. Unlike other causes of B 6 ‐dependent epilepsies, there is no specific biomarker for this disorder 5 …”