SQSTM1 variant in disorders of the frontotemporal dementia-amyotrophic lateral sclerosis spectrum: identification of a novel heterozygous variant and a review of the literature.

introductionAccumulating evidence shows that SQSTM1 plays a vital role in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which represent a neurodegenerative disease continuum. Here, we report a novel SQSTM1 variant in a patient presenting with progressive nonfluent aphasia (PNFA) and progressive bulbar palsy (PBP). Relevant literature about FTD and FTD-ALS caused by SQSTM1 mutation was reviewed to better understand its clinical features.

methodsWe collected data from a 66-year-old male patient with a novel heterozygous variant (c.995C > G, p.S332X) in the SQSTM1 gene who was diagnosed with PNFA and PBP and performed a PubMed literature search using the advanced research criteria: [("frontotemporal lobar degeneration") OR ("frontotemporal dementia") OR ("amyotrophic lateral sclerosis") OR ("motor neuron disease")] AND ("SQSTM1"). The clinical features of FTD and FTD-ALS related to SQSTM1 mutation were summarized based on previous cases and our new case.

resultsThe initial symptom of the current patient was progressive verb finding difficulties and effortful speech output, which developed into dysarthria and dysphagia in subsequent months. The results, including tongue atrophy, fasciculations, neurogenic changes, and mild left dominant hypometabolism of 18F-fluorodeoxyglucose PET in the frontal cortex, suggest the possibility of PNFA and PBP. A novel likely pathogenic heterozygous variant (c.995C > G, p.S332X) in the SQSTM1 gene was identified. The literature search revealed a total of 33 FTD and FTD-ALS cases related to the SQSTM1 mutation with detailed clinical information. The mean age of onset (including our patient) was 63.5 ± 9.7 years. bvFTD was the most common clinical phenotype. The missense mutation in the SQSTM1 gene coding region and the UBA domain involvement are its main genetic characteristics.

conclusionAlthough rare, mutations in SQSTM1 can lead to various clinical subtypes of FTD and FTD-ALS, including the rare combination of PNFA and PBP. Exon missense mutation is the main type of mutation, which is common in the UBA domain.