那須・ハコラ病

Provided herein are novel compounds as TREM2 agonists, pharmaceutical compositions, use of such compounds in treating Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Nasu-Hakola disease, and stroke, and processes for preparing such compounds.

Nasu-Hakola disease is a rare autosomal recessive disorder characterized by progressive cognitive decline and bone cyst formation and is commonly associated with triggering receptor expressed on myeloid cells 2 (TREM2) variants. Herein, we report a novel TREM2 frameshift variant in a middle-aged man from a consanguineous Chinese family who presented with early-onset dementia and right ankle pain. Neuroimaging and skeletal examinations revealed cerebral atrophy and bone cystic lesions. Whole-exome sequencing followed by Sanger confirmation identified a homozygous TREM2 c.257del (p.D86Afs*103) variant. The patient was diagnosed with Nasu-Hakola disease, and his cognitive deterioration continued despite treatment with donepezil and memantine. Functional assays in human embryonic kidney 293T cells demonstrated preserved mRNA expression of the mutant construct but markedly reduced protein levels compared with that of wild-type. We also conducted a descriptive literature review of 54 previously reported cases of homozygous or compound heterozygous TREM2 variants to highlight the variability in neurodegenerative and skeletal phenotypes. To the best of our knowledge, this is the first report of a TREM2 c.257del variant in a Chinese family. Our findings expand the mutational spectrum of Nasu-Hakola disease and highlight substantial phenotypic heterogeneity, emphasizing the importance of early genetic testing in patients with unexplained early-onset dementia, even in the absence of bone lesions.

Provided herein are novel compounds as TREM2 modulators, pharmaceutical compositions, use of such compounds in treating Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Nasu-Hakola disease, and processes for preparing such compounds.

Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder characterized by progressive dementia and multiple bone cysts. The known pathogenic genes include TYRO protein tyrosine kinase binding protein (TYROBP) on chromosome 19q13.1 and triggering receptor expressed on myeloid cells 2 (TREM2) on chromosome 6p21.1. Until now, no case related to TYROBP gene mutation has been reported in the Chinese population. We report a 39-year-old Chinese Han patient who presented with early-onset dementia and cystic bone lesions. Brain magnetic resonance imaging showed extensive cerebral atrophy with ventricular enlargement and diffuse, symmetric white matter lesions. Whole-exome sequencing identified a nonsense mutation, c.214C > T (p.Arg72Ter), in the TYROBP gene. Minigene experiments suggested that this variant may partially affect TYROBP splicing, providing supplementary transcript-level evidence for NHD. This is the first genetically confirmed case of NHD associated with a homozygous TYROBP c.214C > T (p.Arg72Ter) variant in the Chinese population. Our findings expand the mutation spectrum of NHD and provide new reference evidence for its molecular diagnosis and genetic counseling.