PLPBP Deficiency

CLINICAL CHARACTERISTICS

PLPBP deficiency is a treatable form of vitamin B-dependent early-onset epileptic encephalopathy. Seizure onset is typically in the neonatal period (i.e., within the first 28 days after birth), and rarely in childhood after the neonatal period. Seizures are unresponsive to (or only partly responsive to) anti-seizure medications (ASMs) but typically show an immediate positive response to vitamin B, given as either pyridoxine (PN) or pyridoxal 5'-phosphate (PLP). This therapy needs to be continued lifelong. In addition to vitamin B treatment, almost 60% of individuals require adjunct ASMs to achieve optimal seizure control. Although many individuals with PLPBP deficiency have normal motor, speech, and intellectual development, more than 50% have varying degrees of neurodevelopmental issues, including learning difficulties or intellectual disability (varying from mild to severe), delayed or absent speech development, or motor development abnormalities (most commonly mild hypotonia).

DIAGNOSIS/TESTING: The diagnosis of PLPBP deficiency is established in a proband with suggestive findings and biallelic pathogenic variants in identified by molecular genetic testing.

MANAGEMENT

There is no cure for PLPBP deficiency. Targeted therapy is lifelong pharmacologic treatment with either PN or PLP, and often with additional ASMs. Supportive care for neurodevelopmental issues typically includes specialists in multiple disciplines including neurology, developmental pediatrics, speech-language therapy, physical therapy, and occupational therapy. Regular examination by treating specialists is necessary to monitor existing manifestations, the individual's response to pharmacologic treatment and supportive care, and the emergence of new manifestations. Several ASMs (such as carbamazepine, valproate, phenytoin, and phenobarbitone) can cause a low plasma concentration of PLP. If the pathogenic variants have been identified in an affected family member, prenatal molecular genetic testing may be performed via amniocentesis or chorionic villus sampling in future pregnancies at risk in order to facilitate postnatal treatment of the newborn. When prenatal testing has not been performed on a pregnancy at risk, prompt diagnostic evaluation of the newborn is essential. While results of molecular genetic testing are pending, the options for management are either: (1) treatment with PN or PLP (whichever was effective in the affected sib); or (2) clinical and EEG monitoring with initiation of PN or PLP (whichever was effective in the affected sib) at the first sign of seizures or encephalopathy.

GENETIC COUNSELING

PLPBP deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual, irrespective of sex, has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.