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ObjectiveTo define the natural history of the C9orf72 amyotrophic lateral sclerosis (C9ALS) patient population, develop disease biomarkers, and characterize patient pathologies.MethodsWe prospectively collected clinical and demographic data from 116 symptomatic C9ALS and 12 non–amyotrophic lateral sclerosis (ALS) full expansion carriers across 7 institutions in the United States and the Netherlands. In addition, we collected blood samples for DNA repeat size assessment, CSF samples for biomarker identification, and autopsy samples for dipeptide repeat protein (DPR) size determination. Finally, we collected retrospective clinical data via chart review from 208 individuals with C9ALS and 450 individuals with singleton ALS.ResultsThe mean age at onset in the symptomatic prospective cohort was 57.9 ± 8.3 years, and median duration of survival after onset was 36.9 months. The monthly change was −1.8 ± 1.7 for ALS Functional Rating Scale–Revised and −1.4% ± 3.24% of predicted for slow vital capacity. In blood DNA, we found that G4C2 repeat size correlates positively with age. In CSF, we observed that concentrations of poly(GP) negatively correlate with DNA expansion size but do not correlate with measures of disease progression. Finally, we found that size of poly(GP) dipeptides in the brain can reach large sizes similar to that of their DNA repeat derivatives.ConclusionsWe present a thorough investigation of C9ALS natural history, providing the basis for C9ALS clinical trial design. We found that clinical features of this genetic subset are less variant than in singleton ALS. In addition, we identified important correlations of C9ALS patient pathologies with clinical and demographic data.

We examined the biology of AMPA/kainate-induced motor neuron degeneration using dissociated spinal cord cultures and motor neuron-specific antibodies which enable characterization of individual motor neurons in culture. Cobalt, which is thought to pass through Ca2+-permeable AMPA/kainate receptors following kainate exposure, labeled motor neurons in spinal cord cultures. The analysis of AMPA subunit distribution in dissociated motor neurons revealed a unique pattern of glutamate receptor (GluR) subunits in those cells; the GluR1 subunit was found in all spinal cord neurons, but the GluR2 subunit was not found in identified dissociated motor neurons. These data suggest that selective sensitivity of motor neurons to non-NMDA receptor activation is due, at least in part, to the presence of Ca2+-permeable AMPA/kainate receptors.

Two double-blinded, placebo-controlled clinical trials of riluzole have now been carried out in more than 1,100 patients with ALS. The results of both studies show a modest benefit in prolonging survival that is statistically significant. These results led to the availability of this drug by the Food and Drug Administration for use in the United States beginning in early 1996. This is the first drug that has been available for ALS. It begins a new era in both basic and clinical research in an attempt to find a cure for this disease.

Idiopathic recurring stupor (IRS) is a disease of unknown pathogenesis presenting with recurrent stuporous states. We describe three IRS patients in whom there were no metabolic, toxic, or structural brain dysfunctions. Ictal EEGs were characterized by fast (14- to 16-Hz), unreactive background activity. Flumazenil, a benzodiazepine receptor antagonist, promptly resolved the clinical and EEG picture. In all patients, ictal plasma determination showed a marked increase in benzodiazepine-like activity identified as endozepine-4. IRS may be due to an unexplained excess of endozepine-4.