Vance et al. (2009) reported 8 families with ALS due to mutations in the FUS gene. Among 20 affected individuals, there was even gender distribution, the average age at onset was 44.5 years, and the average survival was ... Vance et al. (2009) reported 8 families with ALS due to mutations in the FUS gene. Among 20 affected individuals, there was even gender distribution, the average age at onset was 44.5 years, and the average survival was 33 months. The site of onset varied: it was cervical in 10, lumbar in 5, and bulbar in 3. No affected individual developed cognitive deficits. Detailed neuropathologic examination of 3 patients showed severe lower motor neuron loss in the spinal cord, and to a lesser degree in the brain stem, whereas dorsal horn neurons appeared unaffected. There was evidence of mild myelin loss in the dorsal columns, but only 1 case had major pallor of the corticospinal tracts. There was mild to moderate upper motor neuron loss in the motor cortex. FUS immunostaining showed large globular and elongated cytoplasmic inclusions in spinal cord motor neurons and dystrophic neurites in all cases. Hewitt et al. (2010) reported a 69-year-old man who presented with predominantly lower motor neuron ALS involving both the lower and upper limbs. He had marked proximal muscle wasting with fasciculations around the shoulder girdle and depressed reflexes. The lower limbs showed distal weakness, proximal fasciculations, and decreased reflexes. He had no family history of neurologic disease, and died of respiratory failure 42 months after symptom onset. Postmortem examination showed marked loss of lower motor neurons at all spinal levels, and neuronal and glial cytoplasmic inclusions that stained for FUS. Hewitt et al. (2010) also reported an unrelated man who had onset of a progressive muscular atrophy variant of motor neuron disease with upper limb onset at the age of 61 years. His brother presented with a similar pattern of disease at age 58, but DNA was not available. Postmortem examination of the first patient showed marked depletion of lower motor neurons with glial cytoplasmic and nuclear inclusions that stained for p62 (SQSTM1; 601530). There was FUS staining predominantly in the nucleus of neurons and glia, with some lower motor neurons showing strong cytoplasmic FUS expression. Yan et al. (2010) summarized the clinical features of 101 patients from 25 unrelated families with ALS6 who carried heterozygous mutations in the FUS gene. The average age at symptom onset was 43.6 years, which was earlier than that observed in patients with SOD1 (147450) or TARDBP (605078) mutations. Some patients with FUS mutations had onset in adolescence. The average duration of symptoms for those with FUS mutations was 3.4 years, with 88.6% of patients dying in less than 4 years, indicating a more rapid disease progression compared to those with SOD1 or TARDBP mutations. Approximately 33.3% of those with FUS mutations presented with bulbar onset, and some affected members of 3 families also developed frontotemporal dementia.
In 17 different families with ALS6, including 2 families previously reported by Sapp et al. (2003), Kwiatkowski et al. (2009) identified 13 different mutations in the FUS gene (see, e.g., 137070.0001-137070.0004), including 10 mutations in exon 15. One ... In 17 different families with ALS6, including 2 families previously reported by Sapp et al. (2003), Kwiatkowski et al. (2009) identified 13 different mutations in the FUS gene (see, e.g., 137070.0001-137070.0004), including 10 mutations in exon 15. One of the families was consanguineous and from Cape Verde, an island off the western coast of Africa; this family had a homozygous mutation (H517Q; 137070.0001) and showed autosomal recessive inheritance. All of the other families had heterozygous mutations and showed autosomal dominant inheritance. Another family had been reported by Sapp et al. (2003). Postmortem examination of 1 patient with the R521G mutation (137070.0002) showed loss of motor neurons in the anterior horn of the spinal cord and the hypoglossal nucleus. Immunostaining showed nuclear and cytoplasmic aggregation of FUS and diffuse ubiquitin positivity in nuclei in the patient tissue, but not control tissue, suggesting misfolding of a nuclear protein. In vitro RNA binding studies showed that the mutations did not affect binding of RNA oligomers. Vance et al. (2009) identified 3 FUS mutations in 9 families with ALS6. All of the mutations had also been found by Kwiatkowski et al. (2009). One of the families (F1) had been reported by Ruddy et al. (2003). Vance et al. (2009) demonstrated that wildtype endogenous FUS is predominantly localized to the nucleus. FUS mutations caused subcellular mislocalization with protein retention in the cytoplasm. Kwiatkowski et al. (2009) and Vance et al. (2009) estimated the frequency of FUS mutations to be about 5% in familial ALS. Belzil et al. (2009) identified heterozygous FUS mutations (see, e.g., 137070.0004-137070.0005) in 1 (1.25%) of 80 patients with familial ALS and in 3 (0.74%) of 405 patients with apparently sporadic ALS. Three of the 4 mutations occurred in exon 15. Age at onset ranged from 32 to 80 years, and none had cognitive impairment; the patients were of French and French Canadian origin. Ticozzi et al. (2009) identified 4 different FUS mutations, including 2 novel mutations, in 5 (4%) of 97 Italian patients with familial ALS. The authors noted that all affected individuals had early symptoms of symmetric weakness in the proximal muscles. One patient developed dementia. Corrado et al. (2010) identified 7 different missense mutations, including 6 novel mutations, in the FUS gene (see, e.g., 137070.0006 and 137070.0007) in 9 of 1,009 Italian patients with ALS, including 964 patients with sporadic disease. Two of the 9 patients with an FUS mutation had a family history of the disorder. In addition, 8 different deletions and 2 insertions were identified in 2 glycine-rich regions in exons 5 and 6, but these were also found in controls and believed to represent triplet repeat length polymorphisms. Overall, pathogenic FUS mutations were found in 0.7% of sporadic and 4.4% of familial ALS in this population. Hewitt et al. (2010) identified a heterozygous mutation in the FUS gene (137070.0008) in 2 (5%) of 42 patients with familial ALS. A different heterozygous mutation (137070.0006) was identified in 1 of 548 patients with sporadic ALS. Both mutations were located in the C-terminal region of the protein, which is important in regulating DNA and RNA binding. Hewitt et al. (2010) postulated that disruption of this region may disrupt subcellular distribution of FUS, in turn affecting transcription and RNA processing and conferring a toxic gain of function. Millecamps et al. (2010) identified 5 different FUS mutations in 7 (4.3%) of 162 French probands with familial ALS. All mutations were located in exon 15 of the FUS gene. One patient with a FUS mutation (R521C; 137070.0004) was also heterozygous for a mutation in the ANG gene (K17I; 105850.0002), which causes ALS9 (611895). Overall, FUS mutation carriers had an earlier age of disease onset and shorter life span due to a rapid disease progression compared to those with mutations in other ALS genes. The site of onset of FUS patients was in the arms (43%), legs (38%), or bulbar muscles (19%). One patient developed cognitive impairment 5 months after the onset of ALS. Waibel et al. (2010) identified 2 different heterozygous mutations in the FUS gene (see, e.g., R495X; 137070.0009) in 4 (6.8%) of 58 German families with ALS. No FUS mutations were found in 133 patients with sporadic disease. The authors sequenced only the C-terminal region of the gene encompassing exons 13 to 15. Yan et al. (2010) identified 16 heterozygous FUS mutations, including 11 novel mutations (see, e.g., 137070.0010), in 25 (5.6%) of 476 patients with familial ALS who did not have mutations in the SOD1 (147450) or TARDBP (605078) genes. All exons of the FUS gene were screened, but 12 of the 16 mutations occurred in exons 14 and 15. No mutations were found in 41 patients with sporadic ALS.