Summary Using exome sequencing, we identified a p.R191Q amino acid change in the valosin-containing protein (VCP) gene in an Italian family with autosomal dominantly inherited amyotrophic lateral sclerosis (ALS). Mutations in VCP have previously been identified in families with Inclusion Body Myopathy, Paget’s disease and Frontotemporal Dementia (IBMPFD). Screening of VCP in a cohort of 210 familial ALS cases and 78 autopsy-proven ALS cases identified four additional mutations including a p.R155H mutation in a pathologically-proven case of ALS. VCP protein is essential for maturation of ubiquitin-containing autophagosomes, and mutant VCP toxicity is partially mediated through its effect on TDP-43 protein, a major constituent of ubiquitin inclusions that neuropathologically characterize ALS. Our data broaden the phenotype of IBMPFD to include motor neuron degeneration, suggest that VCP mutations may account for ~1–2% of familial ALS, and represent the first evidence directly implicating defects in the ubiquitination/protein degradation pathway in motor neuron degeneration.

In the Discussion section, it is erroneously stated that the vacuolar protein sorting 54 protein (the gene responsible for motor neuron degeneration in the wobbler mouse) is the mouse homolog of the human valosin-containing protein. VCP and VPS54 are not structurally or functionally homologous.

Purpose Pre-fALS is a longitudinal study of individuals potentially at risk for developing familial amyotrophic lateral sclerosis (fALS). Our goals were to: 1) explore participants’ decisions whether or not to learn results of pre-symptomatic testing; 2) understand the psychosocial impact of these decisions; 3) assess preferences for receiving results by telephone or in-person. Methods The sample for this sub-study comprised 20 participants drawn randomly from autosomal dominant mutant SOD1 (mtSOD1) families in the Pre-fALS study. Twenty participants completed a semi-structured phone interview; prominent themes were identified and rated. Results Fourteen participants chose to learn results; 6 had mtSOD1 and 8 had wtSOD1. Of the 6 who initially elected non-disclosure, 3 were reconsidering their decision. Regardless of the results and method of counseling, participants had adapted well, at least in the short-term. Conclusion We recommend: 1) those considering pre-symptomatic genetic testing should undergo professional counseling to help decide whether to learn results; 2) discussion should include the option of telephone genetic counseling for those without easy access to in-person counseling; 3) those who initially decline to learn results should be offered the opportunity to learn their mutation status as their decision evolves.

Objective: It has been speculated that amyotrophic lateral sclerosis (ALS) is characterized by a premanifest period during which neurodegeneration precedes the appearance of clinical manifestations. Magnetic resonance spectroscopy (MRS) was used to measure ratios of neurometabolites in the cervical spine of asymptomatic individuals with a mutation in the SOD1 gene (SOD1ϩ) and compare their neurometabolic ratios to patients with ALS and healthy controls. Methods:A cross-sectional study of 1 H-MRS of the cervical spine was performed on 24 presymptomatic SOD1ϩ volunteers, 29 healthy controls, and 23 patients with ALS. All presymptomatic subjects had no symptoms of disease, normal forced vital capacity, and normal electromyographic examination. Relative concentrations of choline (Cho), creatine (Cr), myo-inositol (Myo), and N-acetylaspartate (NAA) were determined.Results: NAA/Cr and NAA/Myo ratios are reduced in both SOD1ϩ subjects (39.7%, p ϭ 0.001 and 18.0%, p ϭ 0.02) and patients with ALS (41.2%, p Ͻ 0.001 and 24.0%, p ϭ 0.01) compared to controls. Myo/Cr is reduced (10.3%, p ϭ 0.02) in SOD1ϩ subjects compared to controls, but no difference was found between patients with ALS and controls. By contrast, NAA/Cho is reduced in patients with ALS (24.0%, p ϭ 0.002), but not in presymptomatic SOD1ϩ subjects compared to controls. It has been speculated that amyotrophic lateral sclerosis (ALS) is characterized by a premanifest period during which neuronal degeneration precedes the appearance of clinical symptoms. Some evidence of this premanifest period has been derived from the superoxide dismutase (SOD1) mouse model of ALS in which there is a decline in the estimated motor unit number in advance of the appearance of symptoms. Conclusions:1 Limited data from a number of healthy individuals at risk for ALS by virtue of their carrying a mutation in the SOD1 gene (SOD1ϩ) suggest a decline in motor unit numbers several months in advance of the appearance of symptoms.