# Nasu-Hakola Disease Presenting as Rapidly Progressive Dementia With Seizures: A TREM2 Mutation Case Without Skeletal Involvement

## TL;DR

A rare genetic disorder causing neurological symptoms was diagnosed in a woman without skeletal issues, highlighting the importance of genetic testing in dementia cases.

## Contribution

This case highlights TREM2 mutation causing Nasu-Hakola disease without skeletal involvement, expanding clinical recognition.

## Key findings

- A TREM2 gene mutation was identified in a patient with progressive dementia and seizures but no skeletal lesions.
- Neuroimaging and genetic testing confirmed Nasu-Hakola disease despite absence of typical bone involvement.
- The case emphasizes the importance of genetic testing in atypical early-onset dementia presentations.

## Abstract

Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder caused by mutations in the TYROBP or TREM2 genes. It is characterised by the unique combination of neurological and skeletal manifestations. However, isolated neurological variants without bone involvement have been described. A 38-year-old woman presented with a two-year history of progressive cognitive decline, reduced speech output, inappropriate emotional behaviour, recurrent generalised tonic-clonic seizures, gait unsteadiness, and loss of self-care abilities. Neurological examination revealed Parkinsonian features, cerebellar signs, brisk reflexes, and frontal release signs. Laboratory investigations for metabolic, autoimmune, and infectious aetiology were normal. Brain MRI demonstrated diffuse cortical atrophy, periventricular T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities, and bilateral globus pallidus calcification. Skeletal radiographs showed generalised osteopenia without cystic lesions. Clinical exome sequencing detected a homozygous c.371T>G mutation in the TREM2 gene (exon 2), confirming the diagnosis of Nasu-Hakola disease. NHD is typically described to progress in four stages, starting from a latent asymptomatic phase to sequential bone and neurological involvement. While bone involvement is a classical feature, this case emphasises isolated neurological involvement associated with TREM2 mutations. Furthermore, this case highlights the importance of neuroimaging combined with next-generation sequencing in patients with early-onset dementia with atypical features like generalised seizures and Parkinsonism. Nasu-Hakola disease should be considered in the differential diagnosis of presenile dementia, even in the absence of skeletal manifestations. Early recognition through genetic testing facilitates accurate diagnosis, appropriate counselling, and avoidance of unnecessary investigations.