MITOCHONDRIAL DISEASES & METABOLIC MYOPATHIES: P.318 RBCK1-related disease: A rare multisystem disorder with polyglucosan storage, autoinflammation, recurrent infections, skeletal, and cardiac myopathy

Abstract

Homozygous or compound heterozygous pathogenic variants in RBCK1 (OMIM #610924) cause a systemic condition characterised by polyglucosan storage. Current knowledge of RBCK1-related disease is based on a few case reports. All of the 21 previously reported patients had cardiac and/or skeletal muscle myopathy. A proportion of patients may also present with immunodeficiency and auto-inflammation. We report here four additional patients (P1-P4), from three kindreds, including two sisters (P1, P2) with homozygous or compound heterozygous mid-domain variants in RBCK1. P1 first presented in early childhood with delayed motor milestones. She developed juvenile arthritis, early-onset cardiomyopathy requiring transplant, recurrent multisystem infections, inflammatory bowel disease, respiratory involvement and a proximal myopathy. She developed Hodgkin lymphoma treated with chemotherapy, and died of respiratory complications. P2, similar to the younger sister (P1) presented with childhood-onset proximal myopathy and recurrent multisystem infections. Cardiomyopathy developed in her teens and worsened following twin pregnancy requiring transplant. Both P1 and P2 were confirmed to have a homozygous pathogenic variant in RBCK1 (mid-domain). P3 presented in childhood with abdominal pain, hepatosplenomegaly, abnormal liver function and fatty liver. He showed mild proximal weakness and running difficulties. He presented with acute cardiac failure at 15 years and died following deterioration of his liver and cardiac function. Genetic testing revealed compound heterozygous pathogenic variants in RBCK1. P4 presented with early childhood-onset proximal myopathy. Cardiomyopathy was diagnosed at age 10, progressing to end-stage cardiac failure requiring transplant at 17 years. He had recurrent chest infections. By age 33 he was wheelchair-bound due to progressive myopathy and died following valvular heart surgery. Genetic testing confirmed compound heterozygous variants in RBCK1. Retrospective analysis of biopsies/explants revealed extensive polyglucosan storage in skeletal muscle (P3, P4), heart (P1, P2, P4), gut and lung (P1). Liver biopsy in P3 showed fatty change and portal fibrosis. In summary our cases with RBCK1 disease present with a phenotype spanning the entire spectrum of the condition, including skeletal and cardiac myopathy, combined immunodeficiencies and auto-inflammation.