Rare neurological channelopathies--networks to study patients, pathogenesis and treatment

Abstract

Each of the thousands of rare neurological diseases requires a widely distributed network of centres, investigators and patients, so as to foster multidisciplinary investigations and involve sufficient numbers of patients in the discovery of disease pathogenesis and novel treatment. In this Review, we highlight the value of this collaborative approach in patient-oriented research into rare neurological channelopathies. Two networks, the Consortium for Clinical Investigations of Neurological Channelopathies (CINCH) and the Clinical Research Consortium for Studies of Cerebellar Ataxias (CRC-SCA), provide a link between patients with rare channelopathies and investigators who are studying disease pathogenesis and developing novel treatments. Interactions between patients, researchers and advocacy groups promote shared agendas that benefit patient education and recruitment, research collaboration and funding, and training and mentoring of junior investigators who are attracted to the study of the diseases that provide the focus for the two networks. Here, we discuss how linkage of national and international centres has enabled recruitment of study participants, provided opportunities for novel studies of pathogenesis, and facilitated successful clinical trials.

Figure 1|. Timeline of molecular and clinical research in SCA.

SCA research began with the classification of autosomal dominant cerebellar ataxias in 1982. Key clinical events are in grey boxes, and key molecular events in SCA research are in purple boxes. Mapping of the first SCA locus (SCA1) in 1989 and identification of an expanded polyglutamine-encoding CAG repeat in the ATXN1 gene 4 years later heralded the molecular era, leading the way to the identification of an ever-increasing number of mutations and genes (italicized) that define SCA. Polymorphic repeat expansions are indicated in parentheses alongside many of the genes; those without parentheses are affected by point mutations or small indel mutations. Sporadic empirical clinical trials resulted largely in disappointing or uncertain results in the past, but the recent molecular advances facilitated coordinated efforts to investigate natural history, genetic modifiers and biomarkers of the SCAs. These studies have renewed hope for international multicentre clinical trials, which would be necessary for securing a large enough sample size to test disease-modifying therapeutics. CAG, Cooperative Ataxia Group; CRC-SCA, Clinical Research Consortium for Spinocerebellar Ataxias; ESMI, European Spinocerebellar Ataxia Type 3/Machado–Joseph Disease Initiative; ICARS, International Cooperative Ataxia Rating Scale; JPND, European Union-supported Joint Program in Neurodegenerative Disease; SCA, spinocerebellar ataxia.

Figure 2|. Timeline of molecular and clinical research in neurological channelopathies.

The purple boxes show key discoveries of human channelopathies that were the focus of CINCH, with the defective genes in italics. The identification of mutations in the SCN4A gene in hyperkalaemic periodic paralysis marked the first demonstration that genetic defects in an ion channel gene could cause human disease. The discovery of mutations in the CLCN1 gene in myotonia congenita was followed by the genetic characterization of other nondystrophic myotonia syndromes. EA1 and EA2 (allelic to SCA6) are channelopathies that affect the CNS. Andersen–Tawil syndrome manifests with periodic paralysis and cardiac arrhythmia. Founding of the patient support groups and key clinical trials are shown in grey boxes. CINCH, Consortium for Clinical Investigations of Neurological Channelopathies; EA, episodic ataxia; RCT, randomized control trial; SCA6, spinocerebellar ataxia type 6.