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

Abstract

Objective: To describe a new phenotype and the diagnostic workup of a vitamin-B6-dependent epilepsy due to PLPBP deficiency in an infant with early-onset epilepsy at age 5 ½ months. Methods: Following immediate and impressive clinical response to treatment with pyridoxine, metabolic screening for vitamin-B6-dependent epilepsies and targeted next generation sequencing (NGS) - based gene panel analysis were performed. Potentially pathogenic variants were confirmed by Sanger sequencing in the patient and variants were analyzed in both parents to confirm bi-allelic inheritance. The clinical phenotype and course of disease were compared to the 44 cases reported in the literature, harboring variants in PLPHP and with cases of vitamin-B6-dependent epilepsy due to other known causative genes. Results: levels of alpha-aminoadipic-semialdehyde in urine and amino acids were normal. Two inherited pathogenic variations in PLPHP were found in compound heterozygosity, including one novel deletion. Conclusions: We here describe a previously unreported individual harboring bi-allelic pathogenic PLPHP variants presenting with paroxysmal eye-head-movements followed by epileptic spasms and an almost normal interictal electroencephalogram (EEG), thus expanding the clinical spectrum of PLPBP deficiency. 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. PLPHP should be included systematically in NGS epilepsy gene panels.

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

“…Infantile spasms associated with hypsarrhythmia accounted for a lower number of initial electroclinical patterns in all vitamin B6 diseases, suggesting that supplementation with pyridoxine or PLP should be considered as second-line treatment, after ACTH and vigabatrin, in these cases [ 92 , 99 ]. Epileptic spasms were also recently reported without an associated hypsarrhythmia in a 5-month-old infant presenting with combined paroxysmal eye-movement disorders and carrying a previously unreported bi-allelic pathogenic PLPBP variant [ 100 ].…”