8 August 2010. Amyotrophic lateral sclerosis is tragic when it hits in late or middle age, but a rare juvenile form of the disease is all the more devastating because it attacks people in their late teens and early twenties. “Juvenile ALS is a relatively overlooked entity,” wrote Eric Huang, of the University of California in San Francisco, in an e-mail to ARF. Researchers do not know why the disease manifests so early, or even if it has the same cause as later-onset ALS (Gouveia and de Carvalho, 2007). A pair of recent papers suggests juvenile ALS shares some features, namely mutations in the gene fused in sarcoma (FUS), with late-onset ALS. FUS mutations appear at a high frequency in juvenile ALS cases.
In the July 28 Neurology online, researchers led by Olaf Ansorge at the John Radcliffe Hospital in Oxford, UK, report findings from four cases of juvenile ALS with basophilic inclusions. These filamentous, protein aggregates are common in juvenile ALS, whereas inclusions in late-onset ALS tend not to be basophilic (Matsumoto et al., 1993). The young patients showed their first motor symptoms between 17 and 22 years of age. After autopsy, the study authors discovered all had basophilic, intraneuronal protein deposits in motor neurons and the motor cortex. These inclusions contained FUS, but not TDP-43, another aggregation-prone protein commonly linked to ALS. Although these people had no family history of motor neuron disease, gene sequencing of three of the four cases identified FUS mutations. One patient had a four-base pair deletion, predicted to cause a frameshift in the last eight amino acids of the protein. Two others carried a P525L mutation, which has been found in familial (see ARF related news story on Kwiatkowski et al., 2009) as well as sporadic (Chiò et al., 2010) ALS.
In an editorial accompanying the Neurology paper, David Munoz of St. Michael’s Hospital in Toronto, Canada, cited the lack of a family history of motor neuron disease as one of the most interesting results in the paper. It suggests, Munoz wrote, that people with juvenile ALS may carry newly arisen FUS mutations. “The practicing neurologist cannot safely assume that the absence of family history negates the need for genetic screening,” he wrote.
Two more cases of juvenile ALS with basophilic inclusions were described in the May 25 Brain Pathology online. First author Huang, senior author Catherine Lomen-Hoerth, also at UCSF, and colleagues reported that one of the young women carried the FUS P525L mutation, although neither of her parents did. The other woman had wild-type FUS. At autopsy, both evinced abnormal FUS-containing aggregates in motor neurons and the cortex.
The prevalence of FUS pathology in juvenile ALS contrasts with sporadic late-onset ALS, Huang and colleagues wrote, where TDP-43 pathology is generally prevalent. In fact, FUS aggregates are usually associated with frontotemporal dementia with basophilic inclusions (Urwin et al., 2010). Therefore, the research suggests both a similarity between juvenile and late-onset ALS, in that both are linked to FUS mutations, as well as a difference in that the pathological inclusions are distinct.
The cause of juvenile ALS remains unclear, Huang told ARF, but the FUS P525L mutation is particularly common in young-onset cases. In another recent study, he noted, FUS-P525L had a high propensity to leave its normal nuclear location for the cytoplasm (see ARF related news story on Dormann et al., 2010), and that localization might be related to its early pathology.
Another paper published online by Neurology July 28 suggests FUS mutations may cause early ALS. Researchers working at the Northwestern University Feinberg School of Medicine laboratory of Teepu Siddique found several new FUS mutations in people with the late-onset form of the disease. They reported that people with FUS mutations tended to show disease at an earlier age than did people with mutations in TDP-43 or SOD1, another gene linked to ALS.—Amber Dance.
Bäumer D, Hilton D, Paine SML, Turner MR, Lowe J, Talbot K, Ansorge O. Juvenile ALS with basophilic inclusions is a FUS proteinopathy with FUS mutations. Neurology. 2010 Jul 28. Abstract
Huang EG, Zhang J, Geser F, Trojanowski JQ, Strober JB, Dickson DW, Brown Jr RH, Shapiro BE, Lomen-Hoerth C. Extensive FUS-immunoreactive pathology in juvenile amyotrophic lateral sclerosis with basophilic inclusions. Brain Pathol. 2010 May 25. Abstract
Munoz DB. FUS mutations in sporadic juvenile ALS. Another step toward understanding ALS pathogenesis. Neurology. 2010 Jul 28. Abstract
Yan J, Deng HX, Siddique N, Fecto F, Chen W, Yang Y, Liu E, Donkervoort S, Zheng JG, Shi Y, Ahmeti KB, Brooks B, Engel WK, Siddique T. Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia. Neurology. 2010 Jul 28. Abstract