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Episodic Neurologic Disorders: Syndromes, Genes, and Mechanisms

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Episodic Neurologic Disorders: Syndromes, Genes, and Mechanisms NE36CH02-Russell ARI 7 June 2013 15:4 Episodic Neurologic Disorders: Syndromes, Genes, and Mechanisms Jonathan F. Russell,1,2,3 Ying-Hui Fu,1 and Louis J. Pta´cekˇ 1,2,3 1Department of Neurology, 2Medical Scientist Training Program, 3Howard Hughes Medical Institute, School of Medicine, University of California, San Francisco, California 94158; email: [email protected], [email protected], [email protected] Annu. Rev. Neurosci. 2013. 36:25–50 Keywords First published online as a Review in Advance on paroxysmal, neurogenetics, Mendelian, exome sequencing, April 29, 2013 channelopathy, synaptopathy The Annual Review of Neuroscience is online at neuro.annualreviews.org Abstract This article’s doi: Many neurologic diseases cause discrete episodic impairment in con- 10.1146/annurev-neuro-062012-170300 trast with progressive deterioration. The symptoms of these episodic Copyright c 2013 by Annual Reviews. disorders exhibit striking variety. Herein we review what is known of the by Louis Ptacek on 07/19/13. For personal use only. All rights reserved phenotypes, genetics, and pathophysiology of episodic neurologic disor- ders. Of these, most are genetically complex, with unknown or polygenic inheritance. In contrast, a fascinating panoply of episodic disorders ex- hibit Mendelian inheritance. We classify episodic Mendelian disorders Annu. Rev. Neurosci. 2013.36:25-50. Downloaded from www.annualreviews.org according to the primary neuroanatomical location affected: skeletal muscle, cardiac muscle, neuromuscular junction, peripheral nerve, or central nervous system (CNS). Most known Mendelian mutations al- ter genes that encode membrane-bound ion channels. These mutations cause ion channel dysfunction, which ultimately leads to altered mem- brane excitability as manifested by episodic disease. Other Mendelian disease genes encode proteins essential for ion channel trafficking or sta- bility. These observations have cemented the channelopathy paradigm, in which episodic disorders are conceptualized as disorders of ion chan- nels. However, we expand on this paradigm to propose that dysfunction at the synaptic and neuronal circuit levels may underlie some episodic neurologic entities. 25 NE36CH02-Russell ARI 7 June 2013 15:4 transient ischemic attack, syncope, epilepsy, Contents and migraine (Figure 1). Aside from these four diseases, which are complex and common, there INTRODUCTION.................. 26 exist a myriad of symptomatically similar dis- COMPLEXDISORDERS............ 26 eases that are complex but rare. Of these, many Four Common Complex Disorders . 27 are in fact progressive neurologic disorders that A Myriad of Rare Complex happen to feature episodic symptoms but are Disorders....................... 28 not primarily episodic in nature. However, oth- MENDELIAN DISORDERS. 30 ers are indeed primarily episodic. In this review, GeneralCharacteristics............ 30 we focus on those complex, rare disorders with SkeletalMuscle.................... 31 autoimmune etiology because they have pro- CardiacMuscle.................... 34 vided substantial pathophysiological insight. Neuromuscular Junction . 35 For the same reason, the remaining bulk PeripheralNerve.................. 35 of our review focuses on episodic neurologic CentralNervousSystem........... 36 disorders that are Mendelian (Figure 1). Each BEYOND THE is rare. For these disorders, single gene muta- CHANNELOPATHY tions are sufficient to cause disease. However, PARADIGM...................... 40 even in these genetic diseases, environmental factors can still be important in triggering attacks. Over the past two decades, medical geneticists have extensively clarified the known INTRODUCTION phenotypes, identified many novel phenotypes, Whereas many diseases of the nervous system and pinpointed scores of disease genes. In many cause progressive deterioration, a sizable cases, disease gene discovery has directly led to fraction of them are predominantly episodic in pathophysiological insight and, in a few cases, nature. In this subset of disorders, a patient’s even novel treatments. We organize these di- neurologic function is impaired during an verse disorders on the basis of the primary neu- episode (also known as an attack). Although roanatomical location affected: skeletal muscle, some patients may suffer from superimposed, cardiac muscle, neuromuscular junction chronic neurologic dysfunction, between (NMJ), peripheral nerve, or CNS. As much as attacks patients are usually completely normal. is possible given practical constraints, for each by Louis Ptacek on 07/19/13. For personal use only. Episodes are often triggered by mundane stim- disorder we review the clinical presentation, Complex disorder: uli, such as hunger, fatigue, emotions, stress, genetics, and pathophysiology, with particular a disease that develops exercise, diet, temperature, or hormones. Why emphasis on new discoveries and unanswered primarily due to these commonplace stimuli trigger episodes of questions. Finally, in the concluding section we Annu. Rev. Neurosci. 2013.36:25-50. Downloaded from www.annualreviews.org environmental neurologic impairment in some patients but present our view of the field’s urgent challenges. influences, although polygenic inheritance not others is poorly understood. may increase Many episodic neurologic disorders ex- susceptibility ist, encompassing a protean range of symp- COMPLEX DISORDERS NMJ: neuromuscular toms. These may include weakness, stiffness, Complex episodic neurologic disorders de- junction paralysis, arrhythmias, pain, ataxia, migraine, velop primarily due to environmental factors, Episodic disorder: involuntary movements, and seizures. Most although in most disorders some evidence a disease in which episodic neurologic disorders exhibit complex indicates polygenic inheritance, which remains symptoms occur in inheritance—that is, disease seems to develop largely undeciphered (Poduri & Lowenstein discrete paroxysms; primarily owing to environmental influences 2011, Shyti et al. 2011, Della-Morte et al. between paroxysms, patients appear to be rather than genetic ones. In this review, we 2012). Complex episodic disorders are very normal or near normal briefly address the complex disorders that are common in aggregate. This group includes commonly encountered in clinical practice: a legion of causes that are each individually 26 Russell · Fu · Pta´cekˇ NE36CH02-Russell ARI 7 June 2013 15:4 rare, such as autoimmune episodic disorders Four Common Complex Disorders (see below). Also, four complex disorders are A transient ischemic attack (TIA) results from commonly encountered in clinical practice: diminished cerebral perfusion that causes transient ischemic attack, syncope, epilepsy, abrupt, focal neurological symptoms in a and migraine (Figure 1). pattern corresponding to the compromised −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−→ vascular distribution (reviewed by Della-Morte Figure 1 et al. 2012). Cerebral hypoperfusion usually The landscape of episodic neurologic disorders. arises from platelet emboli or thrombi that There are many episodic neurologic disorders, with transiently lodge in a cerebral artery but are a vast range in genetic contribution and prevalence. dislodged before permanent neurologic injury Prevalence is depicted in crude approximation by develops; by definition, TIA symptoms resolve the size of each ellipse. This fascinating group within 24 h. Despite prompt resolution, TIAs includes four common complex disorders (left), many rare complex disorders including autoimmune typically recur over the course of days to (lower left), and many rare Mendelian forms (right). weeks with a stereotypic symptom cluster. Some Mendelian phenotypes exhibit profound These patients should be promptly evaluated similarity to particular complex disorders, as and treated, usually by addressing the source depicted by identical coloration (e.g., light green for of emboli or by anticoagulation, to decrease idiopathic epilepsy and for Mendelian epilepsy syndromes). Often, Mendelian phenotypes share the risk of progression to ischemic stroke phenotypic and/or genetic characteristics, as (Della-Morte et al. 2012). depicted by overlap and/or similar coloration of Transient cerebral hypoperfusion also each corresponding ellipse. Some complex disorders results in syncope (i.e., fainting) (reviewed seem to have a substantial genetic contribution, particularly epilepsy, but most of the complex inheritance remains unexplained (middle). Genetic contribution Abbreviations: ADPEAF, autosomal dominant partial epilepsy with auditory features; AF, atrial Complex Mendelian fibrillation; ATS, Andersen-Tawil syndrome; AHC, alternating hemiplegia of childhood; CIP, FHM congenital insensitivity to pain; CMS, congenital myasthenic syndromes; CPVT, catecholaminergic AHC EA Migraine polymorphic ventricular tachycardia; EA, episodic PME ataxia; ES, Escobar syndrome; FADS, fetal akinesia JME deformation sequence; FCM, familial cortical by Louis Ptacek on 07/19/13. For personal use only. myoclonus; FHM, familial hemiplegic migraine; ADPEAF GEFS+ GEFS+, generalized epilepsy with febrile seizures Epilepsy SeSAME plus; HH, hereditary hyperekplexia; HyperKPP, PED PNKD hyperkalemic periodic paralysis; HypoKPP, PKD hypokalemic periodic paralysis; IEM, inherited Annu. Rev. Neurosci. 2013.36:25-50. Downloaded from www.annualreviews.org erythromelalgia; JME, juvenile myoclonic epilepsy; TIA MDS LE, Lambert-Eaton myasthenic syndrome; LQTS, HH long QT syndrome; MC, myotonia congenita; FCM IEM CIP MDS, myoclonus-dystonia
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