ESPE Abstracts

Introduction: Mutations of the SCN8A gene, which encodes a neuronal voltage-gated sodium channel are associated with an epileptic encephalopathy of varying severity and neurodevelopmental delay. A few cases are reported, where epileptic encephalopathy due to SCN8A mutations have been associated with multiple fractures and bone loss suggestive of juvenile osteoporosis.

Case Presentation: Two girls, aged 19-months were referred for evaluation of recurrent fractures associated with seizures. They were monochorionic, diamniotic twins from a consanguineous marriage (common great-grandmother on paternal and maternal sides), with marginal prematurity (35 weeks) and low birth weight (First twin (T1) 1.4 kg, second twin (T2) 1.2 kg). They were well up to 6 months of age, when both developed generalized seizures with developmental arrest/regression. They were commenced on sodium valproate and steroids. Seizures were not completely controlled, and both T1 and T2 were noted to have fractures of upper/ lower limbs following tonic-clonic seizures. There were no features suggestive of trauma or non-accidental-injury. Both had blue sclerae, delayed teeth eruption, and paucity of limb movements with fussiness on handling. Skeletal survey in both showed multiple long bone fractures at different stages of healing, wedge fractures of the vertebrae, and osteopenia. Their serum calcium, phosphate, alkaline phosphatase, PTH and vitamin D levels were normal. Dual-energy X-ray absorptiometry (DXA) scans were performed to determine any underlying bone-fragility. Both children had similar whole body bone mineral content and bone mineral density, and interpretation was confounded by lack of age/sex/ population specific normative data. Considering the frequency of fractures, with vertebral fractures, we decided to commence intravenous (IV) bisphosphonate (zolendronic acid) therapy. Subsequently, genetic testing by whole exome sequencing revealed a pathogenic heterozygous mutation in SCN8A gene (c.5615G>A9p. Arg1872Gln). There were no new fractures in the six months following IV bisphosphonate, and parents reported improvement in general handling and activity levels. IV bisphosphonate was repeated after a 3-month interval, and both children have been fracture free for nearly one year to date. We plan to continue IV zolendronic acid for two years, and decide on longer term therapy based on clinical course and repeat DXA scans.

Conclusion: This is the first report of twins presenting with seizures and fractures due to a SCN8A gene mutation. IV bisphosphonate therapy led to clinical improvement and prevention of further fractures in both children. Thus, we suggest that bisphosphonate therapy may be a useful a therapeutic option for juvenile osteoporosis associated with SCN8A mutations.