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

Abstract

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.

Frontotemporal dementia presentation in patients with heterozygous p.H157Y variant ofTREM2

“…The neuropsychological presentation consisted of insidious onset with personality changes, disinhibited behaviour, executive dysfunction and emotional disorders, resembling bvFTD. Similar findings were obtained by Samanci et al , who revealed bvFTD-like clinical features in 14 patients carrying several pathogenic TREM2 variants 59. Furthermore, Guerreiro et al reported compound heterozygous missense mutations (p.Y38C and p.D86V) associated with personality and behavioural changes at an early age in a Turkish family.…”

“…Similar findings were obtained by Samanci et al , who revealed bvFTD-like clinical features in 14 patients carrying several pathogenic TREM2 variants. 59 Furthermore, Guerreiro et al reported compound heterozygous missense mutations (p.Y38C and p.D86V) associated with personality and behavioural changes at an early age in a Turkish family. This case showed cortical atrophy with periventricular white matter disease, culminating in severe dementia.…”

MonoallelicTYROBPdeletion is a novel risk factor for Alzheimer’s disease

“…Intriguingly, genetic silencing or pharmacological inhibition of PSAT1 in mouse osteoclasts leads to an impairment in osteoclast multinucleation ( 27 ), similar to that observed in monocyte-derived osteoclasts of NHD patients ( 29 ). Interestingly, some deleterious biallelic TREM2 variants lead to frontotemporal dementia without bone involvement ( 6, 7 ). Together, this evidence suggests that DAP12 encoded by TYROBP may be more critical for the osteoclast function than TREM2.…”

Nasu-Hakola Disease With Stroke-like Attack

“…It is a fatal disease that usually presents with early onset dementia during the fourth decade of life along with behavioral symptoms mimicking the behavioral variant of frontotemporal dementia. 1 Paloneva et al 2 first described the association between TREM2 variants and NHD. A number of rare TREM2 variants, including those causing NHD, are known to increase the risk of Alzheimer disease 3 and other neurodegenerative diseases, including frontotemporal dementia, Parkinson disease, and amyotrophic lateral sclerosis.…”

“…Homozygous mutations in triggering receptor expressed on myeloid cells 2 (TREM2) gene are known to cause Nasu-Hakola disease (NHD) or Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy-2 (OMIM 605086) characterized with multifocal bone cysts, progressive presenile dementia of frontal lobe type, and sometimes epileptic seizures. It is a fatal disease that usually presents with early onset dementia during the fourth decade of life along with behavioral symptoms mimicking the behavioral variant of frontotemporal dementia 1. Paloneva et al2 first described the association between TREM2 variants and NHD.…”