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.

Keywords: PLPBP; PROSC; vitamin B6‐dependent early‐onset epilepsy.

FIGURE 1

Pyridoxine metabolism. IP, intestinal phosphatases; PK, pyridoxine kinase; PLP, Des PLP dependent enzymes; PLP, pyridoxal 5′‐phosphate. PLPBP binds PLP and might participate in storage of PLP

FIGURE 2

Brain MRI features. First row: axial T2 sequence; second row: axial T1 sequence; third‐row: coronal T2 sequence. A, Patient A at 2 months almost normal with mild delayed myelination. Increased subarachnoid spaces. B, Patient B at day 3 delayed myelination with temporal cysts and broad gyration with increased subarachnoid spaces and cortico‐subcortical atrophy. C, Patient C at 10 months mild delayed myelination, increased subarachnoid spaces, and cortico/subcortical atrophy. D, patient D at 1‐month broad gyration, delayed myelination, temporal cysts increased subarachnoid spaces, and cerebral atrophy. E: patient E at day 3 broad gyration, delayed myelination, temporal cysts, increased subarachnoid spaces, and cortico‐subcortical atrophy