Nasu Hakola Disease: A Rare Cause of Dementia and Cystic Bone Lesions, Report of a New Turkish Family

Köseoğlu, Emel; Tepgeç, Fatih; Yetkin, Mehmet Fatih; Uyguner, Zehra Oya; Ekinci, Ayten; Abdülrezzak, Ümmühan; Hanağası, Haşmet

doi:10.5152/npa.2017.19484

Cited by 8 publications

(8 citation statements)

References 15 publications

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“…There are few case reports on FDG-PET and single-photon emission computed tomography findings in NHD patients, which described global hypometabolism or hypoperfusion in the cortex and basal ganglia [31,[41][42][43]. FDG-PET was available in three of our patients, and all had hypometabolism in basal ganglia and parietal lobe as well as hypometabolism in various cortical areas.…”

Section: Discussionmentioning

confidence: 93%

TREM2 variants as a possible cause of frontotemporal dementia with distinct neuroimaging features

Samancı

Bılgıç

Gelişin

et al. 2021

Euro J of Neurology

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Background and purpose: Nasu-Hakola disease (NHD) is a rare, autosomal recessive disorder characterized by skeletal and neurological symptoms. Behavioral symptoms with cognitive impairment may mimic the behavioral variant of frontotemporal dementia (bvFTD) and other early-onset dementias. Our patients were analyzed and the literature was reviewed to delineate neurological and neuroimaging findings suggestive of NHD.Method: Fourteen patients carrying a pathogenic mutation in the TREM2 gene were found in our database. Demographic, clinical, laboratory and radiological data were retrieved and analyzed. Results:The presenting clinical picture was behavioral changes with cognitive decline resembling bvFTD in all patients. The mean age was 37.1 ± 4.97 years and the mean duration of the disease was 8.9 ± 3.51 years. Only two patients had typical bone cysts.Seven patients had bilateral calcification of the basal ganglia in computed tomography of the brain. Magnetic resonance imaging of the brain revealed severe atrophy of the corpus callosum, enlargement of the ventricles, atrophy of the caudate nuclei and periventricular white matter changes in all patients. Symmetrical global atrophy of the brain mainly affecting frontoparietal and lateral temporal regions were observed in all cases, and 13 patients had atrophy of the hippocampus. Cerebrospinal fluid examination of 10 patients showed elevated protein levels in six and the presence of oligoclonal bands in four patients. Conclusion:A combination of white matter changes, enlarged ventricles, atrophy of the caudate nuclei and thinning of the corpus callosum in magnetic resonance imaging strongly suggests NHD in patients with FTD syndrome. Molecular genetic analysis should be performed in suspected cases, and families should receive genetic counseling.

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Section: Discussionmentioning

confidence: 93%

TREM2 variants as a possible cause of frontotemporal dementia with distinct neuroimaging features

Samancı

Bılgıç

Gelişin

et al. 2021

Euro J of Neurology

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“…Although these KO studies validated TREM2 as a key and central player for microglia in the pathogenesis of AD, they did not address how missense mutations in the protein could modify the risk of developing LOAD with age. Furthermore, a caveat with the interpretation of functional endpoints from AD models crossed with Trem2 KO mice is that loss of TREM2 function (or its binding partner DAP12) in humans results in Nasu-Hakola disease, a white matter-targeting age-dependent neurodegenerative disease [ 63 ], suggesting that absence of TREM2 has detrimental effects on the brain in the absence of plaques.…”

Section: Discussionmentioning

confidence: 99%

A Trem2R47H mouse model without cryptic splicing drives age- and disease-dependent tissue damage and synaptic loss in response to plaques

Tran

Kawauchi

Kramár

et al. 2023

Mol Neurodegeneration

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Background The TREM2 R47H variant is one of the strongest genetic risk factors for late-onset Alzheimer’s Disease (AD). Unfortunately, many current Trem2R47H mouse models are associated with cryptic mRNA splicing of the mutant allele that produces a confounding reduction in protein product. To overcome this issue, we developed the Trem2R47H NSS (Normal Splice Site) mouse model in which the Trem2 allele is expressed at a similar level to the wild-type Trem2 allele without evidence of cryptic splicing products. Methods Trem2R47H NSS mice were treated with the demyelinating agent cuprizone, or crossed with the 5xFAD mouse model of amyloidosis, to explore the impact of the TREM2 R47H variant on inflammatory responses to demyelination, plaque development, and the brain’s response to plaques. Results Trem2R47H NSS mice display an appropriate inflammatory response to cuprizone challenge, and do not recapitulate the null allele in terms of impeded inflammatory responses to demyelination. Utilizing the 5xFAD mouse model, we report age- and disease-dependent changes in Trem2R47H NSS mice in response to development of AD-like pathology. At an early (4-month-old) disease stage, hemizygous 5xFAD/homozygous Trem2R47H NSS (5xFAD/Trem2R47H NSS) mice have reduced size and number of microglia that display impaired interaction with plaques compared to microglia in age-matched 5xFAD hemizygous controls. This is associated with a suppressed inflammatory response but increased dystrophic neurites and axonal damage as measured by plasma neurofilament light chain (NfL) level. Homozygosity for Trem2R47H NSS suppressed LTP deficits and loss of presynaptic puncta caused by the 5xFAD transgene array in 4-month-old mice. At a more advanced (12-month-old) disease stage 5xFAD/Trem2R47H NSS mice no longer display impaired plaque-microglia interaction or suppressed inflammatory gene expression, although NfL levels remain elevated, and a unique interferon-related gene expression signature is seen. Twelve-month old Trem2R47H NSS mice also display LTP deficits and postsynaptic loss. Conclusions The Trem2R47H NSS mouse is a valuable model that can be used to investigate age-dependent effects of the AD-risk R47H mutation on TREM2 and microglial function including its effects on plaque development, microglial-plaque interaction, production of a unique interferon signature and associated tissue damage.

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“…Although these KO studies validated TREM2 as a key and central player for microglia in the pathogenesis of AD, they did not address how missense mutations in the protein could modify the risk of developing LOAD with age. Furthermore, a caveat with the interpretation of functional endpoints from AD models crossed with TREM2 KO mice is that loss of TREM2 function (or its binding partner DAP12) in humans results in Nasu-Hakola disease, a white matter-targeting age- dependent neurodegenerative disease (Koseoglu et al, 2018), suggesting that absence of TREM2 has detrimental effects on the brain in the absence of plaques.…”

Section: Discussionmentioning

confidence: 99%

A Trem2*R47H mouse model without cryptic splicing drives age- and disease-dependent tissue damage and synaptic loss in response to plaques

Tran¹,

Kawauchi

Rezaie³

et al. 2022

Preprint

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Genome-Wide Association Studies revealed the TREM2 R47H variant as one of the strongest genetic risk factors for late-onset Alzheimer's Disease (AD). Unfortunately, many current TREM2*R47H mouse models are associated with cryptic mRNA splicing of the mutant allele that produces a confounding reduction in protein product. We have developed the Trem2R47H NSS (Normal Splice Site) mouse model where the Trem2 allele is expressed at a similar level to the wild-type Trem2 allele, without evidence of cryptic splicing products, and appropriate inflammatory responses to cuprizone challenge. Utilizing the 5xFAD mouse model, we report age- and disease-dependent changes in response to pathology. At an early disease stage (4 mo), homozygous Trem2R47H NSS; hemizygous 5xFAD (Trem2R47H NSS ; 5xFAD) mice have reduced size and number of microglia plus impaired interaction with plaques, that is associated with increased dystrophic neurites and axonal damage detected through plasma neurofilament light chain (NfL) level and suppressed inflammation. However, homozygosity for Trem2R47H NSS suppressed LTP deficits and presynaptic puncta loss caused by the 5xFAD transgene array. At a more advanced disease stage (12 mo,) Trem2R47H NSS ; 5xFAD mice no longer display impaired plaque-microglia interaction or suppressed inflammatory gene expression, although NfL levels remain elevated, and a unique interferon-related gene expression signature is seen. Furthermore, (age) Trem2R47H NSS ; 5xFAD mice also display robust LTP deficits and exacerbated presynaptic loss. Collectively, we provide a Trem2R47H variant mouse without cryptic splicing, and demonstrate it has disease stage dependent effects when combined with a plaque bearing model, with an initial loss of function that ultimately resolves, giving rise to a unique interferon signature and associated tissue damage.

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Nasu Hakola Disease: A Rare Cause of Dementia and Cystic Bone Lesions, Report of a New Turkish Family

Cited by 8 publications

References 15 publications

TREM2 variants as a possible cause of frontotemporal dementia with distinct neuroimaging features

TREM2 variants as a possible cause of frontotemporal dementia with distinct neuroimaging features

A Trem2R47H mouse model without cryptic splicing drives age- and disease-dependent tissue damage and synaptic loss in response to plaques

A Trem2*R47H mouse model without cryptic splicing drives age- and disease-dependent tissue damage and synaptic loss in response to plaques

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