The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2
Abstract
Background Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), or Nasu-Hakola disease, is a presenile dementia associated with loss of myelin, basal ganglia calcification, and bone cysts. It is caused by recessively inherited mutations in two genes encoding subunits of a cell membrane-associated receptor complex: TREM2 and DAP12. The clinical course of PLOSL has not been characterized in a series of patients with TREM2 mutations. Methods The authors compare neurologic and neuroradiologic follow-up data of six patients carrying TREM2 mutations with PLOSL due to defective DAP12 genes. The authors review the known mutations in these two genes. Results Mutations in DAP12 and TREM2 result in a uniform disease phenotype. In Finnish and Japanese patients with PLOSL, DAP12 mutations predominate, whereas TREM2 is mutated more frequently elsewhere. Conclusions Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy should be considered in adult patients under age 50 years with dementia and basal ganglia calcification. Radiographs of ankles and wrists, and DNA test in uncertain cases, confirm the diagnosis.
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Neuropathological findings in Nasu-Hakola disease include loss of myelin and axons in the brain, with reactive astrocytosis and microglial activation.
“Neuropathological findings in NHD include loss of myelin and axons in the brain, with reactive astrocytosis and microglial activation [25].”
From TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis (2020) · cites this paper as [25]
NHD is characterized by loss of myelin and microglia activation in the CNS.
“NHD is characterized by loss of myelin and microglia activation in the CNS [25].”
From TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis (2020) · cites this paper as [25]
Nasu-Hakola disease (NHD) is a rare autosomal recessive leukoencephalopathy caused by a loss-of-function mutation of either TYROBP (DAP12) or TREM2 expressed in microglia.
“Nasu-Hakola disease (NHD) is a rare autosomal recessive leukoencephalopathy caused by a loss-of-function mutation of either TYROBP (DAP12) or TREM2 expressed in microglia.”
From Microglia express ABI3 in the brains of Alzheimer's disease and Nasu-Hakola disease (2017) · cites this paper as [1]
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TREM2 in Alzheimer’s Disease: Microglial Survival and Energy Metabolism
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A novel mutation in TREM2 gene causing Nasu-Hakola disease and review of the literature
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Role of microglia-neuron interactions in diabetic encephalopathy
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TREM2-Dependent Effects on Microglia in Alzheimer’s Disease
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The TREM2-DAP12 signaling pathway in Nasu–Hakola disease: a molecular genetics perspective
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RNA-Seq analysis implicates dysregulation of the immune system in schizophrenia
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A comprehensive profile of ChIP-Seq-based PU.1/Spi1 target genes in microglia.
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Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice
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TREM2 and sTREM2 in Alzheimer’s disease: from mechanisms to therapies
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TREM2 Variants and Neurodegenerative Diseases: A Systematic Review and Meta-Analysis
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Nasu–Hakola disease and primary microglial dysfunction
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Immunohistochemical characterization of microglia in Nasu‐Hakola disease brains
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Rare TREM2 variants associated with Alzheimer’s disease display reduced cell surface expression
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Exploring the Impact of TREM2 in Tumor-Associated Macrophages
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Nasu-Hakola disease with a splicing mutation of TREM2 in a Japanese family
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TREM2 ‐dependent microglial function is essential for remyelination and subsequent neuroprotection
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The Role of TREM2 in Alzheimer’s Disease and Other Neurological Disorders
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- Authors
- Klünemann, H. H., Ridha, B. H., Magy, L., Wherrett, J. R., Hemelsoet, D. M., Keen, R. W., De Bleecker, J. L., Rossor, M. N., Marienhagen, J., Klein, H. E., Peltonen, L., & Paloneva, J.
- Affiliations
- From the Departments of Psychiatry and Psychotherapy (Drs. Klünemann and Klein) and Nuclear Medicine (Dr. Marienhagen), University of Regensburg School of Medicine, Germany; Dementia Research Centre (Drs. Ridha and Rossor), National Hospital for Neurology and Neurosurgery, London, UK; Neurology Service (Dr. Magy), Dupuytren University Hospital, Limoges, France; Division of Neurology (Dr. Wherrett), Toronto Western Hospital and University of Toronto, Ontario, Canada; Department of Neurology (Drs....
- University of Toronto (CA)
- Venue
- Neurology
- Published
- 2005-05-10
- Volume
- 64
- Issue
- 9
- Pages
- 1502-1507
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- OpenAlex
- W2111606353
- Cited by
- 254
- References
- 24
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 12 · 2023: 31 · 2022: 16 · 2021: 13 · 2020: 18 · 2019: 14 · 2018: 15 · 2017: 21 · 2016: 14 · 2015: 11 · 2014: 19 · 2013: 12 · 2012: 6
- FWCI
- 3.02
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurology (publishedVersion)
- PubMed (publishedVersion)
- University of Regensburg Publication Server (University of Regensburg) (acceptedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- DIAL (Catholic University of Leuven) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Dermatological and Skeletal Disorders
- Keywords
- Nasu-Hakola disease, basal ganglia calcification, dementia, bone cysts, demyelination, early-onset dementia, genetic diagnosis, Finnish patients, Japanese patients
- MeSH terms
- Adult, Age Factors, Alzheimer Disease, Ankle Joint, Basal Ganglia Diseases, Bone and Bones, Bone Cysts, Bone Diseases, Calcinosis, Diagnosis, Differential, DNA Mutational Analysis, Female, Follow-Up Studies, Genetic Testing, Humans, Magnetic Resonance Imaging, Male, Membrane Glycoproteins, Membrane Proteins, Mutation, Receptors, Immunologic, Syndrome, Tomography, X-Ray Computed, Wrist Joint, Disease Progression, Genetic Predisposition to Disease, Adaptor Proteins, Signal Transducing
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