RBCK1 — Polyglucosan Body Myopathy 1 With or Without Immunodeficiency

Polyglucosan body myopathy 1 (PGBM1, MONDO:0014389) is a rare autosomal recessive disorder caused by biallelic variants in RBCK1 (RBCK1). Affected individuals accumulate polyglucosan in skeletal and cardiac muscle, leading to progressive muscle weakness (HP:0003323) and loss of ambulation (HP:0002505), often with cardiomyopathy and variable immunodeficiency.

Five unrelated probands[PMID:37102570][PMID:38922716][PMID:33413275][PMID:38329383] have been reported with biallelic RBCK1 variants, including compound heterozygous nonsense and synonymous splicing alleles[PMID:37102570], a homozygous missense c.1411G>A (p.Glu471Lys)[PMID:33413275], and a homozygous frameshift c.598_599insT (p.Pro200LeufsTer15)[PMID:38329383]. These variants span loss-of-function classes (nonsense, frameshift, splice) and missense alleles, consistent with recessive inheritance.

Segregation analysis in multiple families demonstrated that heterozygous carriers are asymptomatic, with affected individuals homozygous or compound heterozygous for pathogenic alleles and no additional unrelated affected relatives identified[PMID:38922716][PMID:38329383].

Muscle histopathology shows characteristic periodic acid–Schiff–positive polyglucosan inclusions and reduced HOIL-1 and HOIP protein levels in patient tissue[PMID:33413275]. Functional assays of RBCK1 reveal that it encodes an E3 ubiquitin ligase whose activity is abolished by pathogenic truncating variants, and is regulated by splice variants in vitro[PMID:18303026].

The pathogenic mechanism is loss of function of the LUBAC complex due to RBCK1 deficiency, leading to glycogen clearance failure and myopathic and cardiac pathology. Variant location modulates immunological involvement, with N-terminal variants more often associated with immunodeficiency[PMID:38329383][PMID:38922716].

Collectively, the genetic and experimental data support a strong autosomal recessive association between RBCK1 and PGBM1. Genetic testing for RBCK1 should be considered in patients with unexplained polyglucosan myopathy to enable early diagnosis and tailored management.

References

• Clinical Genetics • 2023 • A synonymous codon variant altering splicing of RBCK1 expands the phenotype and genotype spectra of polyglucosan body myopathy 1. PMID:37102570
• Neuropathology • 2025 • Phenotypic and genotyping spectrum of two Iranian cases with RBCK1-associated polyglucosan body myopathy. PMID:38922716
• BMC Musculoskeletal Disorders • 2021 • Polyglucosan body myopathy 1 may cause cognitive impairment: a case report from China. PMID:33413275
• ESC Heart Failure • 2024 • A novel likely pathogenic homozygous RBCK1 variant in dilated cardiomyopathy with muscle weakness. PMID:38329383
• The Journal of Biological Chemistry • 2008 • Identification of ubiquitin ligase activity of RBCK1 and its inhibition by splice variant RBCK2 and protein kinase Cbeta. PMID:18303026

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