E-Book, Englisch, Band Volume 31-4, 286 Seiten
Reihe: The Clinics: Radiology
E-Book, Englisch, Band Volume 31-4, 286 Seiten
Reihe: The Clinics: Radiology
ISBN: 978-0-323-26109-8
Verlag: Elsevier Health Care - Major Reference Works
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)
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Clinical Neurogenetics
Recent Advances in the Genetics of Epilepsy
Rohini Coorg, MD, Judith L.Z. Weisenberg, MD and Michael Wong, MD, PhD*, Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, St Louis, MO 63110, USA. E-mail address: wong_m@wustl.edu *Corresponding author. Epilepsy represents a diverse group of disorders with primary and secondary genetic etiologies, as well as non-genetic causes. As more causative genes are identified, genetic testing is becoming increasingly important in the evaluation and management of epilepsy. This article outlines the clinical approach to epilepsy patients, with emphasis on genetic testing. Specific targeted tests are available for numerous individual genetic causes of epilepsy. Broader screening tests, such as chromosome microarray analysis and whole exome sequencing, have also been developed. As a standardized protocol for genetic testing has not been established, individualized diagnostic approaches to epilepsy patients should be used. Keywords Epilepsy Seizure Genetics Key points
• Epilepsy is not a single disease. It can result from many diseases, and may be classified into primary genetic, structural/metabolic, or unknown causes. • Electroclinical syndromes are specific types of epilepsy that have characteristic ages of onset, seizure types, electroencephalographic abnormalities, and other features. Many of these electroclinical syndromes are currently of unknown cause, but most are presumed to be genetic in origin and some have been found to have primary genetic causes. • Other epilepsies are secondary to other well-defined structural or metabolic diseases or entities, which may also have genetic causes. • Genetic testing is an increasingly useful way to establish a diagnosis and aid in treatment of epilepsy. An individualized approach to genetic testing should be adapted for each patient. • Although at present there are limitations and challenges to genetic testing, ongoing and future research may expand the utility and applications of genetics in epilepsy. Introduction
Definitions
A seizure is a transient, stereotyped change in behavior caused by abnormal neuronal activity in the brain.1 Epilepsy is traditionally defined by the occurrence of 2 or more unprovoked seizures. An updated definition of epilepsy includes the occurrence of a single seizure in the context of a brain disorder predisposing to future seizures.1 Epilepsy has a prevalence of 0.5% to 1% in the general population.2 Epilepsy may itself be a primary disorder, often with a known genetic origin, or may be part of a group of symptoms comprising another disease. It may also exist secondary to a metabolic cause, structural brain malformation, or acquired injury. Classification
The International League Against Epilepsy (ILAE) has recently revised the terminology and classification system for seizure types and epilepsy.3 This system describes seizures as involving networks within the brain, rather than single areas. Seizures can have a wide range of clinical manifestations, and may be classified as focal or generalized. Focal seizures originate within networks localized to one hemisphere, whereas generalized seizures involve initiation and rapid propagation within distributed networks involving both hemispheres (Box 1). Box 1 2010 ILAE classification of seizure types Generalized seizures Tonic-clonic Absence Typical Atypical With special features: myoclonic, eyelid myoclonia Myoclonic Myoclonic Myoclonic atonic Myoclonic tonic Clonic Tonic Atonic Focal seizures Unknown Epileptic spasms From an etiologic standpoint, ILAE reorganized epilepsy into having a “genetic,” “structural/metabolic,” or “unknown” cause.3 Electroclinical syndromes are specific types of epilepsy that share characteristic clinical features, seizure types, and patterns on an electroencephalogram (EEG). Electroclinical syndromes resulting from a known primary genetic abnormality are classified as epilepsies with a “genetic” cause (formerly known as “idiopathic” epilepsy). Most of the remaining electroclinical syndromes do not have an identified cause but are still presumed to have an underlying genetic cause, often polygenic in nature. In addition, epilepsy may be secondary to well-defined structural or metabolic abnormalities or diseases (formerly known as “symptomatic” epilepsy), some of which also have genetic causes. Finally, the remaining types of epilepsy without a known or presumed etiology are grouped as having an “unknown cause” (formerly known as “cryptogenic”). This article provides a brief overview of the different clinical presentations of epilepsy related to primary and secondary genetic etiology, and outlines the clinical approach to evaluation of patients with epilepsy, focusing on the role of genetic testing. Epilepsies attributable to nongenetic causes are outside the scope of this review. Clinical findings, genetics, and etiology
Primary Genetic Causes/Electroclinical Syndromes
Electroclinical syndromes with known genetic causes are summarized in Table 1. A few selected syndromes are discussed here, and are organized by age of onset: the neonatal period and infancy (the first 2 years of life), childhood (ages 2–11 years), and adolescence (ages 12–17 years). Table 1 Electroclinical syndromes with known genetic causes Syndromes with onset in the neonatal period and infancy Benign familial neonatal epilepsy is an autosomal dominant electroclinical syndrome with an 85% penetrance linked to a mutation in a voltage-gated potassium channel.4,5 This syndrome may occur in otherwise developmentally normal infants, with age of onset during the first 3 months of life. These seizures may be of multiple types but are usually characterized as tonic, and may occur up to 30 times daily.6 Resolution occurs 1 to 6 months after onset, but as many as 14% of neonates develop other seizure types later.6 Benign familial neonatal-infantile epilepsy is an autosomal dominant sodium channelopathy with onset in the first 7 months, usually resolving by 12 months.7 The seizures are brief, usually with focal features such as eye and head deviation, occur in clusters of 5 to 10 per day, and occur in the setting of normal development.8 Benign infantile epilepsy presents similarly with an onset between 3 and 20 months of age and is characterized by focal, brief seizures occurring in clusters during the day. These seizures may consist of behavioral arrest, head or eye deviation, or unilateral clonic activity.8 It has been linked to regions in chromosome 19.9 Of note, benign infantile epilepsy may occur with familial hemiplegic migraine owing to missense mutations in the ATP1A2 transporter gene,10 or with choreoathetosis caused by a mutation in PRRT2 in chromosome 16.11,12 In all 3 of these epilepsy syndromes, an interictal EEG obtained between seizures is normal and the long-term prognosis is relatively good. Early infantile epileptic encephalopathy with suppression-burst (EIEE or Ohtahara syndrome), on the other hand, is a severe epilepsy occurring during the first 3 months of life characterized by tonic spasms occurring during wakefulness and sleep. Affected infants have abnormal neurologic examinations and a high risk of mortality, and a corresponding EEG showing a suppression-burst pattern.6 This electroclinical syndrome has been linked to mutations in ARX,13,14 CDKL5,15 STXBP1,16–18 PLB1,19 and KCNQ2,20 and affected infants who survive may have seizures that evolve into infantile spams.6 Just as different genotypes may produce a shared epilepsy phenotype, mutations affecting a single gene may result in different phenotypes. SCN1A sodium channel–related disorders include generalized epilepsy with febrile seizures plus (GEFS+), severe myoclonic epilepsy of infancy (Dravet syndrome), and myoclonic-astatic epilepsy (myoclonic epilepsy of Doose). These syndromes may show incomplete penetrance or variable expressivity, and may also occur de novo.21–23 GEFS+ is a syndrome typically affecting multiple family members with different generalized seizure...
