No abstract

An orally administered, fixed-dose coformulation of sodium phenylbutyratetaurursodiol (PB-TURSO) significantly slowed functional decline in a randomized, placebo-controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long-term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB-TURSO or placebo. Participants completing the 6-month (24-week) randomized phase were eligible to receive PB-TURSO in the open-label extension. An all-cause mortality analysis (35-month maximum follow-up post-randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of followup of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB-TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34-0.92; P = .023). Initiation of PB-TURSO treatment at baseline resulted in a 6.5-month longer median survival as compared with placebo. Combined with results from CEN-TAUR, these results suggest that PB-TURSO has both functional and survival benefits in ALS.

Patients with amyotrophic lateral sclerosis (ALS) often have questions about why they developed the disease and the likelihood that family members will also be affected. In recent years, providing answers to these questions has become more complex with the identification of multiple novel genes, the newly recognized etiologic link between ALS and frontotemporal dementia (FTD), and the increased availability of commercial genetic testing. A genetic diagnosis is particularly important to establish in the era of emerging gene-based therapies, such as SOD1 antisense oligonucleotide trials. In the span of a few years, ALS genetic testing options have progressed from testing of a single gene to multigene next-generation sequencing panels and whole-exome sequencing. This article provides suggestions for genetic counseling and genetic testing for ALS in this new environment.Genet Med 19 3, 267-274.

Objective To describe the unique phenotype and genetic findings in a 57-year-old female with a rare form of congenital myasthenic syndrome (CMS) associated with longstanding muscle fatigability, and to investigate the underlying pathophysiology. Methods We used whole-cell voltage clamping to compare the biophysical parameters of wild-type and Arg1457His-mutant Nav1.4. Results Clinical and neurophysiological evaluation revealed features consistent with CMS. Sequencing of candidate genes indicated no abnormalities. However, analysis of SCN4A, the gene encoding the skeletal muscle sodium channel Nav1.4, revealed a homozygous mutation predicting an arginine-to-histidine substitution at position 1457 (Arg1457His), which maps to the channel’s voltage sensor, specifically D4/S4. Whole-cell patch clamp studies revealed that the mutant required longer hyperpolarization to recover from fast inactivation, which produced a profound use-dependent current attenuation not seen in the wild type. The mutant channel also had a marked hyperpolarizing shift in its voltage dependence of inactivation as well as slowed inactivation kinetics. Interpretation We conclude that Arg1457His compromises muscle fiber excitability. The mutant fast-inactivates with significantly less depolarization, and it recovers only after extended hyperpolarization. The resulting enhancement in its use dependence reduces channel availability, which explains the patient’s muscle fatigability. Arg1457His offers molecular insight into a rare form of CMS precipitated by sodium channel inactivation defects. Given this channel’s involvement in other muscle disorders such as paramyotonia congenita and hyperkalemic periodic paralysis, our study exemplifies how variations within the same gene can give rise to multiple distinct dysfunctions and phenotypes, revealing residues important in basic channel function.

Intravenous immunoglobulin (IVIG) is a therapeutic biologic agent that has been prescribed for over two decades to treat various neuromuscular conditions. Most of the treatments are given off-label, as little evidence from large randomized trials exists to support its use. Recently, IGIV-C has received an indication for the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP). Because of the lack of evidence, an ad hoc committee of the AANEM was convened to draft a consensus statement on the rational use of IVIG for neuromuscular disorders. Recommendations were categorized as Class I-IV based on the strength of the medical literature. Class I evidence exists to support the prescription of IVIG to treat patients with Guillain-Barré syndrome (GBS), CIDP, multifocal motor neuropathy, refractory exacerbations of myasthenia gravis, Lambert-Eaton syndrome, dermatomyositis, and stiff person syndrome. Treatment of Fisher syndrome, polymyositis, and certain presumed autoimmune neuromuscular disorders is supported only by Class IV studies, whereas there is no convincing data to substantiate the treatment of inclusion body myopathy (IBM), idiopathic neuropathies, brachial plexopathy, or diabetic amyotrophy using IVIG. Treatment with IVIG must be administered in the context of its known adverse effects. There is little evidence to advise the clinician on the proper dosing of IVIG and duration of therapy.