GYG1 – Polyglucosan Body Myopathy Type 2

Glycogenin-1, encoded by GYG1, is critical for the initiation of glycogen biosynthesis. Biallelic loss-of-function or deleterious missense variants in GYG1 underlie autosomal recessive polyglucosan body myopathy type 2 (PGBM2). Affected individuals present with slowly progressive proximal and axial muscle weakness, often sparing cardiac function.

Six unrelated probands (one homozygous frameshift; one homozygous missense; two siblings; two compound heterozygotes) have been reported to date (PMID:29422440; PMID:26255073; PMID:29143313; PMID:31791869). Segregation analysis in one family confirmed Mendelian segregation in two affected siblings (PMID:29143313).

The variant spectrum includes truncating alleles such as c.487del (p.Asp163ThrfsTer5) (PMID:29422440) and c.631del (p.Val211CysfsTer30) (PMID:31791869), splice-site c.144-2A>G (PMID:31791869), and deleterious missense changes: c.634C>T (p.His212Tyr) (PMID:26255073), c.403G>A (p.Gly135Arg) (PMID:29143313), and c.304G>C (p.Asp102His) (PMID:31791869).

Functional assays demonstrate that missense variants impair autoglucosylation activity in vitro and that truncating alleles abolish protein expression in patient muscle fibers. Histopathology shows PAS-positive, α-amylase-resistant polyglucosan inclusions with vacuolar myopathy (PMID:29422440; PMID:26255073). Muscle MRI reveals selective involvement of limb-girdle and paraspinal muscles.

Pathogenicity is mediated by loss of glycogenin-1 primer activity, leading to abnormal glycogen chain elongation and polyglucosan accumulation. There is no evidence for dominant-negative effects, and compensation by glycogenin-2 is insufficient in skeletal muscle.

Collectively, the genetic and experimental data support a Strong gene–disease association for GYG1 and PGBM2. Genetic testing for GYG1 variants and muscle biopsy with PAS staining should be considered in unexplained limb-girdle myopathies. Key take-home: biallelic GYG1 variants cause autosomal recessive progressive myopathy with characteristic polyglucosan storage.

References

• Neuromuscular disorders : NMD • 2018 • GYG1 causing progressive limb girdle myopathy with onset during teenage years (polyglucosan body myopathy 2). PMID:29422440
• Neuromuscular disorders : NMD • 2015 • Muscle pathology and whole-body MRI in a polyglucosan myopathy associated with a novel glycogenin-1 mutation. PMID:26255073
• Acta neurologica Scandinavica • 2018 • Polyglucosan myopathy and functional characterization of a novel GYG1 mutation. PMID:29143313
• Neuromuscular disorders : NMD • 2019 • Functional characterization of GYG1 variants in two patients with myopathy and glycogenin-1 deficiency. PMID:31791869

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