Van Deerlin VM, Leverenz JB, Bekris LM, et al. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol. 2008;7: 409-416.

In amyotrophic lateral sclerosis (ALS), a primary component of the ubiquitinated inclusions characteristic of the disease is TDP-43, an RNA- and DNA-binding protein. This protein is also a major component in frontotemporal lobar degeneration (FTLD) with ubiquitin inclusions (FTLD-U), which encompasses various neurodegenerative disorders and is believed to be the most common nonmotor deficit in patients with ALS. TDP-43 has several functions and is encoded by the TAR DNA-binding protein gene (TARDBP) on chromosome 1. With these considerations in mind, investigators conducted a study to determine whether TARDBP might be a candidate disease gene for familial ALS not associated with superoxide dismutase mutations (which account for only about 20% of familial cases).

Sequencing of TARDBP was undertaken in 259 patients with ALS, FTLD, or both, as well as in 276 neurologically healthy controls. Two novel genetic variants in the C-terminal TARDBP, which would encode the Gly290A1a and Gly298Ser forms of TDP-43, were found in 2 kindreds with familial ALS. Evidence showed that these variants play a pathogenic role, because they cosegregated with disease in both families and were absent in controls. Moreover, the variants were associated with TDP-43 neuropathology in 2 members of these families for whom central nervous system tissue was available from autopsy.

The authors commented that these findings further implicate TDP-43 as an active participant in TDP-43 proteinopathies (a class that includes ALS and FTLD-U), rather than simply as an “innocent bystander.”

Mikol DD, Barkhof F, Chang P, et al. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicenter, randomized, parallel, open-label trial. Lancet Neurol. 2008;7:903-914.

Data from the REGARD study have shown no significant differences between subcutaneous (SC) interferon and glatiramer acetate in 764 patients with relapsing-remitting multiple sclerosis (RRMS). In this open-label, parallel-group study, the time to first relapse at 96 weeks (the primary endpoint) occurred in similar proportions of patients randomized to the 2 therapies (hazard ratio for SC interferon vs glatiramer acetate, 0.94 [95% confidence interval, 0.74 to 1.21]; P=0.64). Safety outcomes were also similar and were consistent with the known profiles of both drugs.