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Episodic Ataxia Type 1: a Neuronal Potassium Channelopathy

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Episodic Ataxia Type 1: a Neuronal Potassium Channelopathy Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics Episodic Ataxia Type 1: A Neuronal Potassium Channelopathy Sanjeev Rajakulendran,* Stephanie Schorge,* Dimitri M. Kullmann,† and Michael G. Hanna* *Department of Molecular Neuroscience, Centre for Neuromuscular Disease, and †Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, United Kingdom Summary: Episodic ataxia type 1 is a paroxysmal neurological model for understanding more common paroxysmal disorders, disorder characterized by short-lived attacks of recurrent mid- such as epilepsy and migraine. This review examines our cur- line cerebellar dysfunction and continuous motor activity. Mu- rent understanding of episodic ataxia type 1, focusing on its tations in KCN1A, the gene encoding Kv1.1, a voltage-gated clinical and genetic features, pathophysiology, and treatment. neuronal potassium channel, are associated with the disorder. Key Words: Episodic ataxia, channelopathies, myokymia, Although rare, the syndrome highlights the fundamental fea- potassium channel. tures of genetic ion-channel diseases and serves as a useful INTRODUCTION The voltage-gated potassium channel Kv1.1, which is encoded by the KCNA1 gene associated with EA-1,11–18 Dysfunction of neuronal ion channels is now under- contributes to the regulation of neuronal excitability and stood to cause a number of paroxysmal neurological is widely expressed in the nervous system. With the diseases.1–5 With advances in molecular biology and the identification and characterization of newer mutations of completion of the human genome project, these geneti- KCNA1 in EA-1 kindreds, the phenotypic spectrum of cally determined channelopathies are increasingly recog- the disorder has widened considerably beyond the orig- nized in clinical practice. inal description of a purely cerebellar syndrome. This The episodic ataxias are inherited syndromes charac- review examines the protean clinic manifestations of terized by intermittent cerebellar dysfunction in individ- EA-1. The mechanistic link between genotype and phe- uals with otherwise essentially normal brain func- notype is further considered, along with an outline of the tion.2,6–10 Two main forms are recognized, episodic molecular and cellular processes involved. ataxia type 1 and type 2 (EA-1 and EA-2), both of which are autosomal dominant. The episodic ataxias exemplify the phenomenon of phenotypic convergence, in that CLINICAL FEATURES EA-1 is caused by mutations in the voltage-gated potas- sium channel gene, KCNA1,11–18 but mutations in the In 1975, Van Dyke et al.27 first described a family in gene CACNA1A, which encodes the voltage-gated P/Q- which 11 members over three generations experienced type calcium channel, are associated with EA-2.19–26 periodic ataxia and continuous muscle movement. The Although individually rare, these disorders have pro- onset of the disorder was between the ages of 2 and 12 vided unprecedented insight into the complex interplay years, and the affected individuals experienced attacks of of ion channels and neuronal circuits, and have raised the generalized ataxia, jerking movements of the head, stiff- possibility that mutations in ion channels underlie some ening of the body, and carpal spasms, as well as subjec- of the more common neurological diseases such as epi- tive sensations including vertigo, dizziness, blurred vi- lepsy and migraine. sion, and diplopia. These attacks would last on average 3 minutes and would be provoked by anxiety, excitement, fatigue, hunger, and voluntary movement (kinesigenic Address correspondence and reprint requests to: Michael G. Hanna, stimulation). BSc(Hons) MD, FRCP, Centre for Neuromuscular Disease, Depart- Hanson et al.28 subsequently described in 1976 an- ment of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, United King- other family, in which the mother and her two children dom. E-mail: [email protected]. had intermittent attacks of shaking and titubation with 258 Vol. 4, 258–266, April 2007 © The American Society for Experimental NeuroTherapeutics, Inc. EPISODIC ATAXIA TYPE 1 259 dysarthria and abnormal hand posturing. The mother, tween families and between individuals of the same fam- who was born with a clubfoot, described having had ily. Although the full spectrum of phenotypic variations episodes of shaking since the age of 4 or 5 years. Epi- remains to be established, a number of core clinical sodes occurred several times a month and lasted 10 min- features have emerged. utes. During these episodes, her legs would feel weak, Clinically, EA-1 usually declares itself in the first or her voice would become slurred and she would develop second decade of life. Patients experience disabling at- a tremor of the head. In addition, she had continuous tacks of midline cerebellar dysfunction, manifesting as rippling muscle movements in her legs, fine twitching of truncal and limb ataxia, dysarthria, and visual symptoms her eyelids, and a tremor involving her hands at rest. Her such as oscillopsia and visual blurring. These symptoms two children were both born with abnormal posture of are often accompanied by nausea and headache. A coarse the feet. At birth, both the children’s hands were clamped tremor of the arms and head titubation are clinically shut and described as difficult to pry open. They both evident in certain kindreds. These attacks are triggered went on to develop intermittent episodes of shaking, loss by physical and emotional stress, chemical stressors, of balance, slurred speech, and stiffening of the body. startle, and sudden postural changes and can last from Brunt and Van Weerdan10 in 1990 described the larg- seconds to minutes. The frequency of these ataxic spells est family known to date affected by paroxysmal ataxia can vary among individuals, from recurrent daily ictal and continuous myokymia. Twenty-eight members over episodes to infrequent attacks occurring a few times a five generations were diagnosed as having the condition. year. The episodes terminate spontaneously. Some pa- The onset, frequency, nature of attacks, and precipitants tients find that resting or sleeping at the onset helps were comparable with previously described families.8,26 curtail the episode. Interictally, patients are asymptom- Within the family, there was inter-individual variation atic, with a normal neurological examination. The dis- with respect to symptoms, duration, and intensity. For ease is nonprogressive, and the attack frequency com- example, one boy for many years had attacks of ataxia monly decreases with age. exclusively during intercurrent illness. The presence of The second cardinal feature of EA-1 is the presence myokymia was also variable. Close examination of half of continuous interictal motor activity in the form of the members demonstrated fine rippling of the muscles, myokymia or neuromyotonia that is a consequence of and in another one fourth, myokymia was evident as peripheral nerve hyperexcitability. The term myokymia small lateral finger movements. In all of the affected denotes spontaneous skeletal muscle contractions that family members who had EMG examinations, myokymic produce a rippling quality. These fine, rippling move- discharges were clearly demonstrated. ments of muscle can be observed in the limbs and around Since the description of the first EA-1 kindred by Van the eyes, and are also evident as small-amplitude side- Dyke et al.,27 a further 19 unrelated families have been to-side movements of the fingers in the outstretched described in the literature.8,11–18,28–31 Within this group, hands. Myokymia in EA-1 patients is often subclinical, more than 100 individuals have been identified as having although invariably evident on electromyography studies the phenotype of episodic ataxia and myokymia, the two (FIG. 1). cardinal features of EA-1. It is becoming increasingly Episodic ataxia type 2 is the other well-characterized apparent that wide phenotypic differences exist both be- paroxysmal cerebellar disorder.2,6,32,33 Although it has FIG. 1. Electromyographic tracing of myokymia. Neurotherapeutics, Vol. 4, No. 2, 2007 260 RAJAKULENDRAN ET AL. similarities to EA-1, several features help to distinguish marked kyphoscoliosis, elbow contractures, and shorten- it. First, EA-2 is more prevalent. The duration of the ing of the Achilles tendon. His EMG demonstrated attack in EA-2 is measured in hours to days, and each marked generalized myokymia. The boy’s mother pre- ictus is commonly associated with nausea, vomiting, ver- sented some years later with typical features of EA-1. On tigo, and occasionally diplopia. More than half of pa- examination, she had myokymia and mild skeletal ab- tients with EA-2 experience a severe migrainous head- normalities. ache during an attack. The migrainous component is This family38 was found to have the same mutation as notable, in that familial hemiplegic migraine is an allelic another family17 with EA-1 accompanied by contractures disorder of the P/Q-type calcium channel34,35 and pa- and epilepsy (see next section). Recently, a 10-year-old tients often have overlapping features. Weakness during girl with EA-1 was found to have distal weakness with or preceding an attack has also been described. Although paresis of the extensors of the feet and prolonged spells myokymia is not a feature in EA-2, patients often de- of limb stiffness lasting up to 12 hours.39 There is
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