Osteoporosis Associated with SCN8A Mutation

A 26-year-old man was evaluated for an elevated serum bone-specific alkaline phosphatase (BSAP). His medical history was significant for a neurodevelopmental disorder with generalized epilepsy. Symptoms included chronic pain in the ankles, hands, and right ribs, and a progressive decline in physical activity. Vitamin D deficiency was discovered, but the elevated BSAP persisted despite vitamin D replacement. Imaging studies reported diffusely increased scintigraphic uptake in the axial and appendicular skeleton, and low bone mineral density, but no radiographic sclerotic or lytic lesions. Genetic screening revealed a heterozygous pathogenic variant in the sodium voltage-gated channel α subunit 8 gene (SCN8A) (c.2924 T>A; p.L975*). Loss-of-function mutations in SCN8A are responsible for neurologic disease and bone loss. Expression analysis revealed that SCN8A was present in human osteoblasts and osteocytes, but not in osteoclasts, suggesting that the voltage-gated sodium channel, Nav1.6, encoded by SCN8A, may have direct actions in bone. The patient was subsequently prescribed alendronate, resulting in a lower alkaline phosphatase and symptomatic improvement in bone pain.