P.83Vacuolar myopathy with valosin containing protein (VCP)-positive intranuclear and cytoplasmic inclusions: report of two cases with early and late childhood-onset disease

Abstract

Paediatric-onset protein aggregation and vacuolar myopathies (PAVM) are rare familial or sporadic disorders with marked clinicopathological and genetic heterogeneity. Extensive pathological analysis may be required to direct genetic testing. A multisystem proteinopathy (MSP) causing several phenotypes in adults including rimmed vacuolar myopathy, motor neurone disease, frontotemporal dementia and Paget disease of bone, unified by ubiquitin/TDP-43+ inclusions has been linked to mutations in VCP, HNRNPA2B1, HNRNPA1 and SQSTM1. Intranuclear/cytoplasmic VCP+ inclusions are present in most cases of VCP-MSP. VCP+ aggregates are hitherto not reported in other PAVM except sporadic inclusion body myositis and few neurodegenerative disorders. We describe two clinically diverse early and late-childhood onset cases with unifying muscle pathology resembling the classic VCP-MSP. PI, a 21-year-old male presented at 16y with aching pain in his left forearm and progressive left hand finger contractures. Remaining assessment was normal. PII, a 22-year old female presented at 9y with toe-walking and delayed motor milestones. Weakness progressed rapidly and ambulation was lost at 14y. She is now fully wheelchair-dependent, and on long-term non-invasive ventilation. PI: normal CK and EMG myopathic in the left forearm and intrinsic hand muscles. Muscle MRI showed oedema and fatty infiltration in the left forearm and finger flexors. PII: CK 409, EMG myopathic. Muscle biopsies (PI, PII): identical pathology resembling classic VCP-inclusion body myopathy with chronic myopathic/dystrophic changes, rimmed vacuoles, sarcoplasmic and intranuclear protein aggregates/inclusions (VCP/ubiquitin/TDP43+) and tubulofilamentous inclusions. Genetic studies to date are negative including whole exome sequencing in PII. Further genetic diversity may underpin the unifying VCP+ inclusion body pathology in these cases. Recruitment to other next-generation-sequencing platforms is underway.