Polyglucosan Body Myopathy 1 With Or Without Immunodeficiency

A number sign (#) is used with this entry because polyglucosan body myopathy-1 (PGBM1) is caused by homozygous or compound heterozygous mutation in the RBCK1 gene (610924) on chromosome 20p13.

Description

Polyglucosan body myopathy-1 is an autosomal recessive disorder characterized by onset in childhood of progressive proximal muscle weakness, resulting in difficulties in ambulation. Most patients also develop progressive dilated cardiomyopathy, which may necessitate cardiac transplant in severe cases. A small subset of patients present with severe immunodeficiency and a hyperinflammatory state in very early childhood (summary by Boisson et al., 2012 and Nilsson et al., 2013).

Genetic Heterogeneity of Polyglucosan Body Myopathy

See also PGBM2 (616199), caused by mutation in the GYG1 gene (603942) on chromosome 3q24.

Clinical Features

Boisson et al. (2012) reported 2 sisters and an unrelated boy with a complex phenotype characterized by primary immunodeficiency, a hyperinflammatory state, and cardiac and skeletal muscle amylopectinosis. All 3 patients presented with recurrent infections in early infancy associated with episodic fevers and evidence of systemic inflammation, often with lymphadenopathy. One patient had hepatosplenomegaly. The patients had invasive infections, septicemia, pneumonias, pyelonephritis, and gastrointestinal inflammation. In early childhood, all patients developed cardiomyopathy with congestive heart failure as well as progressive muscle weakness. Cardiac and skeletal muscle biopsy showed amylopectin-like deposits reminiscent of a glycogen storage disease. All patients also had severe failure to thrive. Immunologic workup in the 2 sisters showed memory B-cell deficiency and hyper-IgA syndrome, whereas workup in the boy showed leukocytosis, low IgA, and defective T-cell proliferation in response to CD3. The patients all died between ages 3.5 and 8 years.

Nilsson et al. (2013) reported 10 individuals from 8 families of various ethnic backgrounds with early-onset polyglucosan body myopathy without immunodeficiency, including 2 sibs who had previously been reported by Schoser et al. (2008) and 1 patient previously reported by de La Blanchardiere et al. (1994). Between 4 and 17 years of age, all 10 patients developed slowly progressive proximal leg muscle weakness resulting in difficulties in ambulation. Six patients who were homozygous or compound heterozygous for truncating mutations developed rapidly progressive dilated cardiomyopathy in adolescence, resulting in heart transplant in 4 patients and death in 1. Patients with a missense mutation had an apparently milder phenotype, with less muscle weakness and either later onset of cardiomyopathy or lack of cardiac involvement. Two patients had liver involvement with storage of polyglucosan, and 3 had abnormal liver enzymes but no apparent polyglucosan storage. One patient had some evidence of immune dysfunction, manifest as recurrent pharyngitis, lymphadenopathy, enteritis, and psoriasis, but immunologic workup did not reveal any dysfunction. None of the other patients had signs of severe immunodeficiency. Muscle fibers from heart and skeletal muscle showed accumulation of periodic acid-Schiff (PAS)-positive inclusions that differed from normal glycogen and consisted of partly filamentous material, consistent with polyglucosan.

Wang et al. (2013) reported 3 patients from 2 unrelated families with childhood onset of progressive muscle weakness and cardiomyopathy due to amylopectinosis. Growth and development were normal. The authors were unable to detect any evidence of immunodeficiency or autoinflammation in these patients.

Inheritance

The transmission pattern of early-onset polyglucosan myopathy in the families reported by Boisson et al. (2012) and Nilsson et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 French sisters and an Italian patient with early-onset polyglucosan myopathy with immunodeficiency, Boisson et al. (2012) identified homozygous or compound heterozygous truncating mutations in the RBCK1 gene (610924.0001 and 610924.0002). One allele of the French sisters carried a 32-kb deletion on chromosome 20p13 encompassing the last 3 exons of TRIB3 (607898) and the first 4 exons of RBCK1; TRIB3 mRNA levels were normal. The mutations were found by genomewide investigation for copy number variations and by whole-exome sequencing. Patient fibroblasts showed decreased expression of RBCK1 as well as 2 other components of the linear ubiquitin chain assembly complex (LUBAC), which could be restored by expression of wildtype RBCK1. Patient fibroblasts showed impaired NFKB (see 164011) activation with weak induction of genes targeted by TNF (191160) and IL1B (147720). M Transcriptional profiles of patient leukocytes, particularly monocytes, indicated hyperactivation with enhanced responses to IL1B. The consequences of RBCK1 and LUBAC deficiencies for IL1B responses thus differed between cell types, consistent with the unique association of autoinflammation and immunodeficiency in these patients.

In 10 patients from 8 unrelated families with early-onset polyglucosan body myopathy without evidence of severe immunodeficiency, Nilsson et al. (2013) identified homozygous or compound heterozygous mutations in the RBCK1 gene (see, e.g., 610924.0003-610924.0006). The mutations in the first family were found by whole-exome sequencing; subsequent mutations were found in 8 of 32 additional patients with polyglucosan storage disease who were screened for mutations in the RBCK1 gene. The mutations were predicted to result in a loss of function, but functional studies were not performed. Nilsson et al. (2013) noted that most of the mutations in their cohort affected the middle or C-terminal part of RBCK1, whereas those reported by Boisson et al. (2012) in patients with immunodeficiency affected the N-terminal region.

In 3 patients from 2 unrelated families with PGBM1, Wang et al. (2013) identified biallelic truncating mutations in the RBCK1 gene (see, e.g., 610924.0007 and 610924.0008). Functional studies were not performed.