A founder mutation in the PLPBP gene in families from Saguenay‐Lac‐St‐Jean region affected by a pyridoxine‐dependent epilepsy

Abstract

Pyridoxine‐dependent epilepsy (PDE) is a relatively rare subgroup of epileptic disorders. They generally present in infancy as an early onset epileptic encephalopathy or seizures, refractory to standard treatments, with rapid and variable responses to vitamin B6 treatment. Whole exome sequencing of three unrelated families identified homozygous pathogenic mutation c.370_373del, p.Asp124fs in PLPBP gene in five persons. Haplotype analysis showed a single shared profile for the affected persons and their parents, leading to a hypothesis about founder effect of the mutation in Saguenay‐Lac‐St‐Jean region of French Canadians. All affected probands also shared one single mitochondrial haplotype T2b3 and two rare variations in the mitochondrial genome m.801A>G and m.5166A>G suggesting that a single individual female introduced PLPBP mutation c.370_373del, p.Asp124fs in Quebec. The mutation p.Asp124fs causes a severe disease phenotype with delayed myelination and cortical/subcortical brain atrophy. The most noteworthy radiological finding in this Quebec founder mutation is the presence of the temporal cysts that can be used as a marker of the disease. Also, both patients, who are alive, had a history of prenatal supplements taken by their mothers as antiemetic medication with high doses of pyridoxine. In the context of suspected PDE in patients with neonatal refractory seizures, treatment with pyridoxine and/or Pyridoxal‐5‐phophate has to be started immediately and continued until the results of genetic analysis received. Even with early appropriate treatment, neurological outcome of our patient is still poor.

Infantile Spasms without Hypsarrhythmia and Paroxysmal Eye–Head Movements in an Infant with a Pyridoxine-Dependent Epilepsy due to PLPBP/PLPHP Deficiency

“…In patients with PLPBP deficiency, various seizure types have been described including focal and generalized clonic, tonic and myoclonic seizures. Only two patients developed epileptic spasms after neonatal onset of other seizure types; one associated with modified hypsarrhythmia and one with multifocal and generalized epileptic discharges 3,8 . Other clinical features may comprise global developmental impairment, congenital or secondary microcephaly and unspecific symptoms such as irritability, gastrointestinal symptoms, anemia and lactic acidosis.…”

“…This warrants consideration of vitamin-B6-dependent epilepsies in patients with early-onset epilepsy, including epileptic spasms, and eye movement disorders also beyond the neonatal period even when metabolic screening for vitamin-B6-dependent epilepsies is negative. responsive to B6 (pyridoxine) or its activated form, PLP [1][2][3][4] . In contrast to antiquitin-, PNPO-or TNSALP-deficiency, PLPBP-deficiency has no biomarker in blood, cerebrospinal fluid (CSF) or urine, as it is a non-enzymatic protein and is assumed to be responsible for intracellular PLP homeostasis 5 .…”

“…Only two patients developed epileptic spasms after neonatal onset of other seizure types; one associated with modified hypsarrhythmia and one with multifocal and generalized epileptic discharges. 3,8 Other clinical features may comprise global developmental impairment, congenital or secondary microcephaly, and unspecific symptoms such as irritability, gastrointestinal symptoms, anemia, and lactic acidosis. Additionally, variable paroxysmal eye movements have been described.…”

Portrait of autosomal recessive diseases in the French‐Canadian founder population of Saguenay‐Lac‐Saint‐Jean

“…All patients from SLSJ presented with metabolic acidosis (severe lactic and pyruvate acidosis), and a high level of creatine kinase. They had early delayed brain myelination and cortical/subcortical brain atrophy, as well as cystic formations in the frontal and temporal lobes (Pal et al, 2021). consanguinity was found in two kindreds (Pelletier et al, 1986).…”

“…Three of them are already deceased (at 13, 19 days and 5 months respectively), and the two survivors have severe developmental delay and autism spectrum disorder. This series of patients was diagnosed at Centre Hospitalier de l'Université Laval (CHUL) and have already been published byPal et al (2021).…”