New insights into the pathogenesis and therapeutics of episodic ataxia type 1

Abstract

Episodic ataxia type 1 (EA1) is a K+ channelopathy characterized by a broad spectrum of symptoms. Generally, patients may experience constant myokymia and dramatic episodes of spastic contractions of the skeletal muscles of the head, arms, and legs with loss of both motor coordination and balance. During attacks additional symptoms may be reported such as vertigo, blurred vision, diplopia, nausea, headache, diaphoresis, clumsiness, stiffening of the body, dysarthric speech, and difficulty in breathing. These episodes may be precipitated by anxiety, emotional stress, fatigue, startle response or sudden postural changes. Epilepsy is overrepresented in EA1. The disease is inherited in an autosomal dominant manner, and genetic analysis of several families has led to the discovery of a number of point mutations in the voltage-dependent K+ channel gene KCNA1 (Kv1.1), on chromosome 12p13. To date KCNA1 is the only gene known to be associated with EA1. Functional studies have shown that these mutations impair Kv1.1 channel function with variable effects on channel assembly, trafficking and biophysics. Despite the solid evidence obtained on the molecular mechanisms underlying EA1, how these cause dysfunctions within the central and peripheral nervous systems circuitries remains elusive. This review summarizes the main breakthrough findings in EA1, discusses the neurophysiological mechanisms underlying the disease, current therapies, future challenges and opens a window onto the role of Kv1.1 channels in central nervous system (CNS) and peripheral nervous system (PNS) functions.

A de novo <b><i>KCNA1</i></b> Mutation in a Patient with Tetany and Hypomagnesemia

“…The majority of the mutations result in reduced channel function, weakened surface expression, or changes in the biophysical characteristics that lead to a dominant-negative effect upon association with wild-type subunits [14]. The latter is also observed in our study.…”

“…KCNA1 mutations have been widely described as cause for EA1, with thus far 38 different mutations involved [13, 14]. The majority of the mutations result in reduced channel function, weakened surface expression, or changes in the biophysical characteristics that lead to a dominant-negative effect upon association with wild-type subunits [14].…”

Dominant‐negative mutation p.Arg324Thr in KCNA1 impairs Kv1.1 channel function in episodic ataxia

“…However, the specific functional consequences of mutations do not fully correlate with the clinical phenotype of patients, but instead show phenotypic variability. Thus, mutations in KCNA1 have been identified in a wide phenotypic spectrum, which includes large differences in severity and frequency in EA1 attacks, epilepsy with myokymia, isolated neuromyotonia, persistent cerebellar dysfunction with cognitive delay, and hypomagnesemia among others . Here we report the clinical, genetic, and functional study of KCNA1 /Kv1.1 in a family with EA1 and identify the novel mutation p.Arg324Thr that results in reduced potassium currents and changes in the voltage‐dependence of activation and inactivation.…”

Potassium Channel Candidate Genes Predict the Development of Secondary Lymphedema Following Breast Cancer Surgery

“…Voltage-gated K+ channels may regulate the frequency and the amplitude of the spontaneous smooth muscle contractions in lymphatic collectors and ducts (Telinius et al, 2014). Polymorphisms in KCNA1 have been linked to episodic ataxia and myokymia (D’Adamo et al, 2015). KCNA1 rs4766311, located in the 3′ untranslated region of the gene, has no known function.…”