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Objective: To investigate possible effects of the C9orf72 repeat expansion before disease onset, we assessed brain morphology in asymptomatic carriers. Methods: Aiming to diminish the effects of genetic variation between subjects, apart from the C9orf72 repeat expansion, 16 carriers of the repeat expansion were compared with 23 noncarriers from the same large family with a history of amyotrophic lateral sclerosis (ALS). Cortical thickness, subcortical volumes, and white matter connectivity, as assessed from high-resolution T1-weighted and diffusion-weighted MRIs, were evaluated. For comparison, we included 14 C9orf72 carriers with ALS and 28 healthy, unrelated controls. Results: We found temporal, parietal, and occipital regions to be thinner (p , 0.05) and the left caudate and putamen to be smaller (p , 0.05) in asymptomatic carriers compared with noncarriers. Cortical thinning of the primary motor cortex and decreased connectivity of white matter pathways (global, corticospinal tract, and corpus callosum) were observed in patients with C9orf72-associated ALS, but not in asymptomatic carriers. Conclusions: Asymptomatic C9orf72 carriers show cortical and subcortical differences compared with noncarriers from the same family, possibly effects of the C9orf72 repeat expansion on the brain. Of note, changes in the primary motor regions and motor-related tracts were found exclusively in patients with ALS, indicating that such motor changes may be a disease phenomenon.

Item does not contain fulltext OBJECTIVE: To assess the frequency and phenotype of hexanucleotide repeat expansions in C9ORF72 in a large cohort of patients of Dutch descent with familial (fALS) and sporadic (sALS) amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS). METHODS: Included were 78 patients with fALS, 1,422 with sALS, 246 with PMA, and 110 with PLS, and 768 control subjects. Repeat expansions were determined by a repeat primed PCR. Familial aggregation of dementia and Parkinson disease (PD) was examined among patients with ALS who carried the repeat expansion. RESULTS: The expanded repeat was found in 33 (37%) of all patients with fALS, in 87 (6.1%) patients with sALS, in 4 (1.6%) patients with PMA, and in 1 (0.9%) patient with PLS. None of the controls carried the mutation. Patients with ALS with the repeat expansion had an earlier age at onset (median 59.3 vs 61.9 years, hazard ratio 1.55, p = 5 x 10(-5)) and shorter survival (median 2.5 vs 2.7 years, hazard ratio 1.46, p = 8 x 10(-4)). Dementia, but not PD, occurred nearly twice as often in relatives of patients with the expansion compared to all patients with ALS or controls (p = 9 x 10(-4)). CONCLUSIONS: The hexanucleotide repeat expansion in C9ORF72 is a major cause of fALS and apparently sporadic ALS in the Netherlands. Patients who carry the repeat expansion have an earlier onset, shorter survival, and familial aggregation of dementia. These results challenge the classic definition of fALS and may justify genetic testing in patients with sALS.

Several studies have reported on the possible association between the risk of developing amyotrophic lateral sclerosis (ALS) and employment in the electrical industry, which may be related to extremely low frequency electromagnetic field (ELF-EMF) exposure or the risk of experiencing an electric shock, although no direct association has been proven.1 Three previous studies reported on ALS risk related to living near power lines, an important source of ELF-EMF exposure for the general population.2–4 These studies reported a null finding but had some shortcomings as they were based on registry data and had no detailed clinical data available. We therefore performed a large population-based case-control study with detailed phenotypic data to assess the relation between residential exposure to ELF-EMF from power lines and the risk of ALS. Acknowledgment: The authors thank Petra Berk, PhD (University Medical Center Utrecht), Hermieneke Vergunst (University Medical Center Utrecht), and Dorien Standaar (Amsterdam Medical Center) for technical assistance; all neurologists, consultants in rehabilitation medicine, and other health care providers for enrolling patients with ALS; and the patients with ALS and controls.