CHMP2B – Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis 7

CHMP2B encodes an ESCRT-III subunit whose C-terminal truncating and splice‐site mutations cause an autosomal dominant neurodegenerative syndrome combining behavioral variant frontotemporal dementia and amyotrophic lateral sclerosis features. The prototypical c.532-1G>C splice‐site mutation was identified in a six‐generation Danish pedigree comprising 528 individuals, with 44 clinically affected patients and 16 presymptomatic carriers displaying full penetrance (PMID:34997757). Independent familial cases in Belgium (p.Gln165Ter) and China (c.532-2A>T) corroborate the association, as do segregation data across multiple kindreds.

1. Clinical Validity

Based on robust segregation in a 528-member pedigree with 44 affected carriers, 16 presymptomatic carriers, and replication in at least two additional families, plus concordant functional studies demonstrating endolysosomal dysfunction, the CHMP2B–FTDALS7 relationship is classified as Definitive.

2. Genetic Evidence

Inheritance is autosomal dominant. Segregation analysis includes 16 additional presymptomatic relatives with the c.532-1G>C variant (PMID:34997757). Case series encompass 44 probands in the Danish family and single probands with p.Gln165Ter in Belgium (PMID:17956895) and c.532-2A>T in China (PMID:37272767). Variant spectrum is dominated by C-terminal truncating and splice mutations; missense alleles (e.g., p.Ile29Val, p.Arg186Gln, p.Arg205Trp) are rare with uncertain pathogenicity.

3. Functional Evidence

Pathogenic CHMP2B mutants disrupt ESCRT-III function, impairing multivesicular body–lysosome fusion and autophagic clearance in cellular models (PMID:20223751), Drosophila (PMID:18418046), and transgenic mice that develop neurodegeneration via a gain-of-function mechanism (PMID:22366797). TMEM106B knockdown rescues endolysosomal trafficking defects in neurons expressing mutant CHMP2B (PMID:30496365).

4. Conflicting Evidence

Population screening found no association of common CHMP2B variants with sporadic FTD (PMID:16979267), and CHMP2B mutations are rare in French familial FTLD cohorts (PMID:20625756). These data do not weaken the familial linkage but highlight locus heterogeneity.

5. Integration & Clinical Utility

Truncating and splice variants in CHMP2B cause a fully penetrant, autosomal dominant FTD–ALS syndrome via a toxic gain-of-function mechanism disrupting endolysosomal and autophagic pathways. Diagnostic testing for CHMP2B mutations is warranted in familial FTD/ALS presentations, and emerging modifiers such as TMEM106B offer therapeutic promise. Key take-home: CHMP2B mutation screening informs genetic diagnosis, prognosis, and potential targeted interventions in FTDALS7.

References

• Acta neurologica Scandinavica • 2022 • Six generations of CHMP2B-mediated Frontotemporal Dementia: Clinical features, predictive testing, progression, and survival. PMID:34997757
• Human Molecular Genetics • 2008 • CHMP2B C-truncating mutations in frontotemporal lobar degeneration are associated with an aberrant endosomal phenotype in vitro. PMID:17956895
• Human Molecular Genetics • 2010 • Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations. PMID:20223751
• Brain • 2012 • Progressive neuronal inclusion formation and axonal degeneration in CHMP2B mutant transgenic mice. PMID:22366797
• Acta Neuropathologica • 2015 • Frontotemporal dementia caused by CHMP2B mutation is characterised by neuronal lysosomal storage pathology. PMID:26358247
• Brain • 2018 • Frontotemporal dementia causative CHMP2B impairs neuronal endolysosomal traffic-rescue by TMEM106B knockdown. PMID:30496365
• Neurobiology of Aging • 2007 • No association of chromatin-modifying protein 2B with sporadic frontotemporal dementia. PMID:16979267
• Journal of Neurology • 2010 • CHMP2B mutations are rare in French families with frontotemporal lobar degeneration. PMID:20625756
• Molecular Genetics & Genomic Medicine • 2023 • A novel splice-site mutation in CHMP2B associated with frontotemporal dementia: The first report from China and literature review. PMID:37272767

Evidence Based Scoring (AI generated)