Epilepsy Phenotypes of Vitamin B6-Dependent Diseases: An Updated Systematic Review

Abstract

Background: Vitamin B6-dependent epilepsies include treatable diseases responding to pyridoxine or pyridoxal-5Iphosphate (ALDH7A1 deficiency, PNPO deficiency, PLP binding protein deficiency, hyperprolinemia type II and hypophosphatasia and glycosylphosphatidylinositol anchor synthesis defects).

Patients and methods: We conducted a systematic review of published pediatric cases with a confirmed molecular genetic diagnosis of vitamin B6-dependent epilepsy according to PRISMA guidelines. Data on demographic features, seizure semiology, EEG patterns, neuroimaging, treatment, and developmental outcomes were collected.

Results: 497 published patients fulfilled the inclusion criteria. Seizure onset manifested at 59.8 ± 291.6 days (67.8% of cases in the first month of life). Clonic, tonic-clonic, and myoclonic seizures accounted for two-thirds of the cases, while epileptic spasms were observed in 7.6%. Burst-suppression/suppression-burst represented the most frequently reported specific EEG pattern (14.4%), mainly in PLPB, ALDH7A1, and PNPO deficiency. Pyridoxine was administered to 312 patients (18.5% intravenously, 76.9% orally, 4.6% not specified), and 180 also received antiseizure medications. Pyridoxine dosage ranged between 1 and 55 mg/kg/die. Complete seizure freedom was achieved in 160 patients, while a significant seizure reduction occurred in 38. PLP, lysine-restricted diet, and arginine supplementation were used in a small proportion of patients with variable efficacy. Global developmental delay was established in 30.5% of a few patients in whom neurocognitive tests were performed.

Conclusions: Despite the wide variability, the most frequent hallmarks of the epilepsy phenotype in patients with vitamin B6-dependent seizures include generalized or focal motor seizure semiology and a burst suppression/suppression burst pattern in EEG.

Keywords: ALDH7A1 deficiency; GPI anchor defects; PLPBP deficiency; PNPO deficiency; hyperprolinemia type II; metabolic epilepsies; pyridoxine-dependent epilepsies.

Figure 1

Flowchart reporting the selections of articles for this review.

Figure 2

Burst suppression EEG trace of a neonate with PNPO deficiency who was born at 37 weeks gestational age and presented with status epilepticus on the first day of life. The neonate was treated first with 40 mg/kg levetiracetam and then with 5 mg/kg phenobarbital with only partial response. Next, according to our institutional protocol, we administered pyridoxine 100 mg i.v., followed by a maintenance dosage of 30 mg/kg/day. The introduction of pyridoxin led to seizure freedom and EEG improvement. Highpass: 0.530 Hz, Lowpass: 70 Hz.

Figure 3

Continuous EEG trace of the same neonate of Figure 2 at age one week. Seizure freedom and EEG improvement after initiating pyridoxine treatment correlated with neurological improvement (less lethargic, needs less O2, better feeding). Highpass: 0.530 Hz, Lowpass: 70 Hz.

Figure 4

Symmetric spindles in sleep EEG in the same neonate of Figure 2 and Figure 3 at age two months under continued levetiracetam 15 mg/kg/day and pyridoxal phosphate 15 mg/kg/day.