TREM2 – Nasu-Hakola Disease

Nasu-Hakola disease, or polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), is a rare autosomal recessive leukodystrophy characterized by early‐onset presenile dementia, basal ganglia calcification, and multifocal bone cysts. Homozygous or compound heterozygous loss‐of‐function variants in the microglial receptor gene TREM2 underlie PLOSL by disrupting microglial signaling in the central nervous system and osteoclast differentiation in bone. The gene–disease link has been demonstrated in diverse populations, including Finnish, Japanese, Italian, Turkish, Chinese, and Iraqi families.

Genetic studies have identified biallelic TREM2 variants in at least 18 probands from 12 unrelated families, all presenting with the classic PLOSL phenotype. TREM2 mutations—such as c.97C>T (p.Gln33Ter) and splice-site changes—segregate recessively with disease and are absent in unaffected sibs, confirming autosomal recessive inheritance and high penetrance ([PMID:15883308], [PMID:38888203]).

Segregation analysis across multiple sibships shows concordant disease in all individuals homozygous or compound heterozygous for TREM2 variants, while heterozygous carriers remain asymptomatic or exhibit only subclinical neuroimaging changes, supporting a biallelic requirement for clinical PLOSL ([PMID:15966270]).

The variant spectrum includes >16 distinct alleles: nonsense (e.g., c.97C>T (p.Gln33Ter)), frameshift (c.313del (p.Ala105fs)), splice-site (c.482+2T>C), and missense substitutions affecting extracellular domains. Several founder alleles have been reported outside Finland and Japan.

Functional assays demonstrate that human TREM2-deficient pre-osteoclasts fail to mature into bone-resorbing osteoclasts ([PMID:17966394]), and TREM2 missense mutations impair microglial maturation and phagocytosis of apoptotic neurons in vitro ([PMID:24990881]). These data align with the neurodegenerative and skeletal phenotypes observed in PLOSL.

Although heterozygous TREM2 carriers may show basal ganglia hypoperfusion and visuospatial memory deficits on SPECT imaging, they do not develop overt PLOSL pathology, reinforcing the recessive loss-of-function mechanism ([PMID:15966270]).

In summary, TREM2 has a definitive ClinGen gene–disease association with Nasu-Hakola disease. Biallelic loss-of-function variants consistently cause PLOSL, and functional studies in osteoclast and microglial models corroborate the pathogenic mechanism. Key take-home: TREM2 sequencing should be included in molecular diagnostic panels for autosomal recessive early‐onset dementia with bone cysts.

References

• Neurology • 2005 • The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2 [PMID:15883308]
• Functional neurology • 2005 • Neuropsychological tests and functional nuclear neuroimaging provide evidence of subclinical impairment in Nasu-Hakola disease heterozygotes. [PMID:15966270]
• Advances in experimental medicine and biology • 2007 • The enigmatic function of TREM-2 in osteoclastogenesis. [PMID:17966394]
• Science translational medicine • 2014 • TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. [PMID:24990881]

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