FUS/TLSgene mutations are the second most frequent cause of familial ALS in the Spanish population

Abstract

information on 85 patients in the 25 families studied, although there were approximately 144 affected individuals across four or fi ve generations in 60% of the families. The mean number of affected individuals per family was 5.7. Of the 30 families, fi ve had mutations in SOD1 (20), and mutations in FUS/TLS were identifi ed in two.Family F-19. The proband (IV:18) presented at 41 years of age for genetic screening. She had developed progressive weakness and wasting of the upper limbs (UL) over the preceding 11 months. Brain and cervical MRI were normal. EMG revealed active generalized denervation. Clinical examination revealed diffuse fasciculations and marked scapulohumeral amyotrophy in both arms. Six months later, proximal muscle involvement had worsened, with dropped head and predominant lower motor neuron (LMN) signs. Respiratory failure developed 25 months after clinical onset, and death occurred six months later.Her brother (IV:16) had died of ALS at 28 years of age, after a rapidly progressive (10 months) Patients and methods PatientsThe mean age of our FALS patient cohort was 49.3 (SD Ϯ 12.0) years. We had suffi cient clinical AbstractOur objective was to investigate the prevalence of FUS/TLS mutations in a Catalan familial ALS cohort undergoing a mutational study for SOD1 in 2006. We screened 25 probands from non-SOD1 families for FUS/TLS mutations. We identifi ed two FALS probands with FUS/TLS mutations. One carried a C-to-T transition at nucleotide position 1561 (c.1561C Ͼ T) producing a p.R521C sequence change at protein level. The phenotype was characterized by a young age at onset (38.2 years old), proximal limb girdle weakness, predominant lower motor neuron signs and dropped head. Survival time ranged from 10 to 36 months. Obligate asymptomatic carriers were detected. Our second ALS6 pedigree carried a C-to-T transition at nucleotide position 1528 (c.1528G Ͼ A) producing a p.K510E sequence change at protein level. The phenotype was of an early onset ( Ͻ 40 years old), predominant lower motor neuron disease with short survival (nine months). In conclusion, these are the fi rst two FUS/TLS mutations identifi ed in Spain. The prevalence of this form of FALS (8%) is similar to the Dutch and British populations. FUS/TLS mutations are the second most common cause of FALS in our population.

Screening of SOD1, FUS and TARDBP genes in patients with amyotrophic lateral sclerosis in central-southern China

“…Mutations in SOD1 were present in 20.0% of fALS patients and 1.9% of sALS patients, which is consistent with previous studies in western populations8, and indicates that SOD1 mutations play a key role in the pathology of ALS patients from different ethnicities. In addition, the frequency of FUS mutation was approximately 13.3% in fALS patients, which is consistent with reports from several other populations11121314, but is higher than the frequencies found in Catalan (8%)15, German (2.4–6.9%)1617, Italian (4.4%)12, and Belgian (2.9%)18 populations. This difference may be due to small sample sizes and the differing ethnicities of fALS patients.…”

De novo FUS mutations are the most frequent genetic cause in early-onset German ALS patients

“…An overview of clinical symptoms of all patients is given in (Blair et al, 2010;Syriani et al, 2011). One patient was reported to have a history of impaired mental development during childhood.…”

“…One very interesting clinical feature observed in patients with a FUS mutation was a functionally disabling dropped-head syndrome, which emerged in two patients in the course of the disease and one patient even displayed it as the first symptom. This symptom had been described before in ALS patients carrying a FUS mutation (Blair et al, 2010;Syriani et al, 2011), while in "classical" ALS cases, it is not a common feature. Mental retardation or learning difficulties were described before in some patients with early-onset FUS-associated ALS (Zou et al, 2013).…”

TARDBPandFUSMutations Associated with Amyotrophic Lateral Sclerosis: Summary and Update

“…The first two reports suggested that FUS mutations might only be associated with FALS [Kwiatkowski et al, ; Vance et al, ]. However, several recent reports identified FUS mutations in SALS patients, including the most common variants p.R521C and p.R521H (Table ) [Belzil et al, ; Blair et al, ; Broustal et al, ; Chiò et al, ; Corrado et al, ; Drepper et al, ; Groen et al, ; Kwiatkowski et al, ; Lai et al, ; Millecamps et al, ; Rademakers et al, ; Sproviero et al, ; Suzuki et al, ; Syriani et al, ; Ticozzi et al, ; Tsai et al, ; van Blitterswijk et al, ; Vance et al, ; Van Damme et al, ; Van Langenhove et al, ; Yamamoto‐Watanabe et al, ; Yan et al, ; Zou et al, ].…”