Case Report: Early-Onset Behavioral Variant Frontotemporal Dementia in Patient With Retrotransposed Full-Length Transcript of Matrin-3 Variant 5

Abstract

Frontotemporal dementia (FTD) rarely occurs in individuals under the age of 30, and genetic causes of early-onset FTD are largely unknown. The current report follows a 27 year-old patient with no significant past medical history presenting with two years of progressive changes in behavior, rushed speech, verbal aggression, and social withdrawal. MRI and FDG-PET imaging of the brain revealed changes maximally in the frontal and temporal lobes, which along with the clinical features, are consistent with behavioral variant FTD. Next generation sequencing of a panel of 28 genes associated with dementia and amyotrophic lateral sclerosis (ALS) initially revealed a duplication of exon 15 in Matrin-3 (MATR3). Whole genome sequencing determined that this genetic anomaly was, in fact, a sequence corresponding with full-length MATR3 variant 5 inserted into chromosome 12, indicating retrotransposition from a messenger RNA intermediate. To our knowledge, this is a novel mutation of MATR3, as the majority of mutations in MATR3 linked to FTD-ALS are point mutations. Genomic DNA analysis revealed that this mutation is also present in one unaffected first-degree relative and one unaffected second-degree relative. This suggests that the mutation is either a disease-causing mutation with incomplete penetrance, which has been observed in heritable FTD, or a benign variant. Retrotransposons are not often implicated in neurodegenerative diseases; thus, it is crucial to clarify the potential role of this MATR3 variant 5 retrotransposition in early-onset FTD.

An Indonesian elderly with primary progressive aphasia and behavioral variant of frontotemporal dementia: A case report and review article

“…Risperidone and olanzapine have some documented utility in treating behavioral disturbance (agitation or impulsivity) compared with other antipsychotics [ [8] , [9] , [10] ]. However, these medications could have side effects and increase mortality risk in patients with FTD [ 10 , 15 ].…”

Duplication of exons 15 and 16 in Matrin-3: a phenotype bridging amyotrophic lateral sclerosis and immune-mediated disorders

“…Some mutational variants cause an aggressive phenotype leading to death in 2 years, while others, such as p.Phe115Cys and p.Ser707Leu, cause a phenotype with variable rate of progression within the ALS-FTD spectrum [1,2]. Pure frontotemporal dementia in a 27-year-old patient was associated to variant 5 MATR-3 cDNA insertion into Chromosome 12 likely due to retrotransposition [3]. To add complexity, one of the most common missense variants, p.Ser85Cys, previously associated with autosomal dominant vocal cord pharyngeal distal myopathy and distal myopathy, was later recognized in a large familial ALS pedigree with an unusually slow disease progression and evident upper motor neuron (UMN) signs [2].…”

Multisystem Proteinopathy Due to VCP Mutations: A Review of Clinical Heterogeneity and Genetic Diagnosis

“…MATR3 mutations are linked to familial myopathy with ALS [ 28 ], as well as sporadic ALS disease [ 29 , 30 ]. It was also suggested that some of the familial ALS patients may have had associated dementia, though the clinical presentation was not described [ 28 ]; the presence of FTD associated with MATR3 mutations is at best very rare [ 31 ] and there is only a single well-described case in the literature [ 32 ]. There are no cases reported of MATR3 mutations with PDB.…”