P.21Genetic analysis of first-degree relatives with inclusion body myositis

Abstract

Inclusion body myositis (IBM) is a sporadic clinicopathologically defined myopathy characterised by finger flexor and quadriceps weakness, along with the histological triad of endomysial autoaggressive inflammation, rimmed vacuoles and protein aggregates. Rare familial occurrences of IBM have however been reported. We have identified 3 such families. Families 1 and 2 consisted of pairs of affected siblings, while family 3 consisted of a mother and her two children. The onset of symptoms was between 55 and 73 years. Patients displayed finger flexion greater than shoulder abduction and/or quadriceps greater than iliopsoas weakness. One individual in family 3 developed amyotrophic lateral sclerosis (ALS) 5 years after the diagnosis of IBM. An autoaggressive endomysial inflammatory infiltrate was present in all patients, while congophilic inclusions and rimmed vacuoles were observed in 6 and 5 patients, respectively. Anti-cytosolic 5′-nucleotidase 1A (cN1A) antibodies were present in the only 2 patients tested. Whole genome sequencing was performed in all patients and failed to identify causative variants in well-characterised Mendelian myopathy genes, including myopathies with rimmed vacuoles. The two siblings of family 1 both carried a heterozygous frameshift variant in TANK binding kinase 1 (TBK1). In the other 2 families, no candidate variant has so far been identified. Loss-of-function variants in TBK1 have recently been reported to cause ALS. TBK1 is a ubiquitously-expressed protein kinase known to regulate autophagy, mitophagy, neuroinflammation and adipose tissue energy metabolism. Several of these pathways have been hypothesised to play a role in the development of IBM. Further research is therefore warranted to explore the role of TBK1 in the pathogenesis of both familial and sporadic IBM.