GBE1 – Adult Polyglucosan Body Disease

Adult polyglucosan body disease (APBD) is a late‐onset autosomal recessive leukodystrophy characterized by progressive spastic paraplegia, neurogenic bladder dysfunction, peripheral axonal neuropathy, and cognitive impairment. APBD results from deficiency of the glycogen branching enzyme 1 (GBE1), leading to accumulation of poorly branched glycogen (polyglucosan bodies) in central and peripheral nervous system tissues (PMID:10762170).

Genetic evidence for GBE1–APBD is robust, with over 50 unrelated probands carrying biallelic pathogenic variants identified in multinational cohorts (PMID:23034915). Segregation in consanguineous pedigrees confirms autosomal recessive inheritance, and recurrent founder alleles (p.Tyr329Ser) in Ashkenazi Jewish families have been documented in five kindreds (PMID:9851430). Deep intronic “gene‐trap” mutations explain manifesting heterozygotes, further supporting complete loss of enzyme activity as the disease mechanism (PMID:25665141).

The variant spectrum comprises missense and loss‐of‐function alleles, including recurrent c.1544G>A (p.Arg515His) and c.986A>C (p.Tyr329Ser) and private frameshift or splice‐site mutations (e.g., c.1280del (p.Gly427GlufsTer9)) (PMID:36456471). Founder and private alleles co‐segregate with disease, and no heterozygous carriers manifest symptoms when in trans with null alleles.

Functional assays demonstrate that missense variants drastically reduce GBE1 activity in patient lymphocytes and fibroblasts, while structural studies reveal misfolding of the p.Tyr329Ser enzyme. Recombinant expression and crystallography identify a non-catalytic binding cleft adjacent to the common APBD mutation, and peptide chaperones partially rescue enzyme activity in vitro (PMID:26199317). iPSC‐based models corroborate loss‐of‐function effects of novel VUS (e.g., p.Ile694Asn), establishing a clear genotype–biochemistry–phenotype correlation (PMID:38516405).

No substantial conflicting evidence has been reported. One heterozygous variant (Val160Ile) was found in both a patient and healthy controls, but lacked pathogenicity on enzyme assays and is considered a benign polymorphism (PMID:14755501).

In summary, biallelic GBE1 loss‐of‐function variants cause adult polyglucosan body disease via haploinsufficiency of glycogen branching activity. Genetic testing for GBE1 pathogenic alleles and enzyme assays provide definitive diagnosis. Early recognition allows accurate prognosis and genetic counseling.

Key Take-Home: GBE1 sequencing and enzyme activity measurement enable reliable diagnosis of APBD, supporting clinical management and genetic counseling.

References

• Annals of neurology • 2000 • Novel missense mutations in the glycogen-branching enzyme gene in adult polyglucosan body disease. PMID:10762170
• Annals of neurology • 1998 • Adult polyglucosan body disease in Ashkenazi Jewish patients carrying the Tyr329Ser mutation in the glycogen-branching enzyme gene. PMID:9851430
• Annals of neurology • 2012 • Adult polyglucosan body disease: Natural History and Key Magnetic Resonance Imaging Findings. PMID:23034915
• JAMA neurology • 2015 • Deep intronic GBE1 mutation in manifesting heterozygous patients with adult polyglucosan body disease. PMID:25665141
• The Journal of clinical investigation • 1996 • Hepatic and neuromuscular forms of glycogen storage disease type IV caused by mutations in the same glycogen-branching enzyme gene. PMID:8613547
• Human molecular genetics • 2015 • Structural basis of glycogen branching enzyme deficiency and pharmacologic rescue by rational peptide design. PMID:26199317
• Molecular genetics and metabolism reports • 2024 • Induced pluripotent stem cell (iPSC) modeling validates reduced GBE1 enzyme activity due to a novel variant, p.Ile694Asn, found in a patient with suspected glycogen storage disease IV. PMID:38516405

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