Juvenile-onset Sporadic Amyotrophic Lateral Sclerosis with a Frameshift <i>FUS</i> Gene Mutation Presenting Unique Neuroradiological Findings and Cognitive Impairment

Abstract

A 24-year-old Japanese woman developed anterocollis, weakness of the proximal arms, and subsequent cognitive impairment. A neurological examination revealed amyotrophic lateral sclerosis (ALS) without a family history. Systemic muscle atrophy progressed rapidly. Cerebral MRI clearly exhibited high signal intensities along the bilateral pyramidal tracts. An analysis of the FUS gene revealed a heterozygous two-base pair deletion, c.1507-1508delAG (p.G504WfsX515). A subset of juvenile-onset familial/sporadic ALS cases with FUS gene mutations reportedly demonstrates mental retardation or learning difficulty. Our study emphasizes the importance of conducting a FUS gene analysis in juvenile-onset ALS cases, even when no family occurrence is confirmed.

The investigation of genetic and clinical features in Chinese patients with juvenile amyotrophic lateral sclerosis

“…It is well accepted that severe clinical phenotype and aggressive course are associated with JALS patients carrying FUS mutations. In reviewing previous literatures, we found that the disease progression of JALS patients with FUS mutation in the present study is dramatically slower (a mean disease duration of 58.2 months) than previously reported JALS cases harboring FUS mutations with an average disease duration of 16.32 ± 8.65 months (Table ). Other factors may affect the estimation of survival time, such as the delayed time between onset of symptoms and diagnosis of ALS, and the intervention time of mechanical ventilation.…”

“…Other as yet unidentified factors that may influence the interfamilial phenotypic variation need to be further explored in JALS.It is well accepted that severe clinical phenotype and aggressive course are associated with JALS patients carrying FUS mutations. In reviewing previous literatures, we found that the disease progression of JALS patients with FUS mutation in the present study is dramatically slower (a mean disease duration of 58.2 months) than previously reported JALS cases harboring FUS mutations with an average disease duration of 16.32 AE 8.65 months3,[11][12][13][14][21][22][23][24][25][26][27][28][29][30][31]…”

Dendritic Homeostasis Disruption in a Novel Frontotemporal Dementia Mouse Model Expressing Cytoplasmic Fused in Sarcoma

“…FUS proteinopathy defines the majority of tau- and TDP-43-negative cases of frontotemporal dementia ( Urwin et al, 2010 ). Several FUS mutations have been reported to be linked to familial ALS with features of frontotemporal dementia ( Yan et al, 2010 ), and juvenile-onset ALS with cognitive impairment ( Hirayanagi et al, 2016 ). To explore the molecular mechanism underlying FUS proteinopathy in FTD, we examined tg mice overexpressing Myc-tagged exogenous ΔNLS-FUS under Thy-1 promoter, which developed progressive motor weakness from 20 weeks of age and formed ubiquitin/p62-positive cytoplasmic aggregates from 6 months of age ( Shiihashi et al, 2016 ).…”

Cognitive dysfunction in hereditary spastic paraplegias and other motor neuron disorders

“…FUS and UBQLN2 mutations have been linked with adult-onset ALS with frontotemporal dementia, 27 , 28 but only the first type is allegedly associated with mental retardation in JALS reports. 29 , 30 A JALS/dementia cluster has also been described in Dutch patients, corresponding to an unidentified autosomal recessive form (OMIM %205200). 31 , 32 Regarding behavioral changes, JALS type 2 patients had features of pseudobulbar affect in a Tunisian family.…”