TREM2 – Frontotemporal Dementia

Biallelic mutations in TREM2 (HGNC:17761) have been identified in multiple consanguineous families presenting with frontotemporal dementia (MONDO:0017276)–like syndromes without the bone cysts characteristic of Nasu–Hakola disease. These patients exhibit early-onset behavioral changes, language impairment, and progressive cognitive decline, confirming a recessive inheritance pattern for TREM2-related FTD (PMID:23870839; PMID:24910390).

Genetic studies report at least four unrelated probands harboring homozygous or compound heterozygous TREM2 variants—p.Thr66Met, p.Arg47Cys, c.391+1G>A, and other loss-of-function alleles—in Turkish, Italian, Chinese, and chorea-associated families, with segregation in multiple affected sib pairs (PMID:23870839; PMID:24910390; PMID:30797549; PMID:29578490).

The inheritance mode is autosomal recessive, with at least two sibs per family demonstrating concordant disease.

The variant spectrum includes missense changes affecting the Ig-like domain and canonical splice-site mutations.

A representative allele is c.197C>T (p.Thr66Met), which disrupts receptor maturation and surface expression in homozygous carriers (PMID:24910390).

Functional assays reveal that FTD-linked TREM2 missense mutations impair ectodomain shedding, reduce cell surface localization, and abolish microglial phagocytic activity, aligning with disease pathology (PMID:24990881).

Heterozygous rare variants such as p.R47H raise Alzheimer’s disease risk but do not cause FTD in isolation, underscoring the specificity of biallelic TREM2 loss-of-function for recessive FTD phenotypes.

Integrating genetic and experimental data, TREM2 loss-of-function is a moderate-strength cause of autosomal recessive FTD, with clear implications for molecular diagnosis and potential therapeutic targeting of microglial dysfunction.

Key Take-home: Screening for biallelic TREM2 variants is warranted in patients with early-onset, recessive frontotemporal dementia without bone involvement.

References

• Neurobiology of Aging • 2013 • Novel compound heterozygous mutation in TREM2 found in a Turkish frontotemporal dementia-like family. PMID:23870839
• Neurobiology of Aging • 2014 • Homozygous TREM2 mutation in a family with atypical frontotemporal dementia. PMID:24910390
• Neurobiology of Aging • 2020 • A novel homozygous mutation in TREM2 found in a Chinese early-onset dementia family with mild bone involvement. PMID:30797549
• Journal of Alzheimer's Disease • 2018 • Frontotemporal Dementia and Chorea Associated with a Compound Heterozygous TREM2 Mutation. PMID:29578490
• Science Translational Medicine • 2014 • TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. PMID:24990881

Evidence Based Scoring (AI generated)