A novel mutation in TREM2 gene causing Nasu-Hakola disease and review of the literature

Nasu-hakola disease (NHD) is a rare disease characterized by bone cysts and fractures, frontal lobe syndrome, and progressive presenile dementia. NHD may be the prototype of primary microglial disorders of the CNS or, as they have been coined, “microgliopathies”. Mutations in TREM2 and TYROBP genes are known to cause NHD. Interestingly, recent evidence-associated rare genetic variants of TREM2 gene with increased risk of Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, and Parkinson's disease. Here, we report a 33-year-old Greek female with phenotype suggestive of NHD. Full gene sequencing of the TREM2 and TYROBP genes revealed a novel mutation in exon 2 of TREM2 gene, namely c.244G>T (p.W50C) and heterozygosity in the parents and her brother. This report extends the range of TREM2 mutations that cause NHD phenotype. In addition, we provide a comprehensive review of all reported in the literature TREM2 gene mutations and the respective wide spectrum of clinical manifestations that highlights the importance of considering TREM2 gene mutations in a variety of neurodegenerative phenotypes.