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Mitochondrial Causes of Epilepsy: Evaluation, Diagnosis, and Treatment 300 Mitochondrial Causes of Epilepsy: Evaluation, Diagnosis, and Treatment Hannah E. Steele, MBBS, MRCP1,2 Patrick F. Chinnery, PhD, FRCP, FRCPath1,2 1 Institute of Genetic Medicine, Newcastle University, Newcastle upon Address for correspondence Patrick F. Chinnery, PhD, FRCP, FRCPath, Tyne, United Kingdom Institute of Genetic Medicine, International Centre for Life, Newcastle upon 2 Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 3BZ, United Kingdom (e-mail: [email protected]). Tyne, United Kingdom Semin Neurol 2015;35:300–309. Abstract Mitochondrial disorders are frequently associated with seizures. In this review, the Keywords authors discuss the seizure patterns and distinguishing features of mitochondrial ► epilepsy epilepsy, alongside the indications for investigating, and how to investigate epilepsy ► mitochondrial disease from a mitochondrial perspective. Finally, they discuss management strategies for this ► investigation complex group of patients. ► diagnosis ► treatment Seizures are a common and highly heterogeneous feature of is faced with a considerable challenge in identifying, classify- mitochondrial disease. They can arise at any age, may be the ing, and treating epilepsy arising due to mitochondrial presenting feature of the underlying biochemical defect, and disease. can occur in the absence of a clear family history despite the The aim of this review is therefore to provide the nonspe- genetic etiology. Furthermore, they are frequently a second- cialist reader with: ary feature in a complex phenotype; thus, detailed semiology • An introduction to the etiology and clinical features of is often lacking,1 although increasingly this is being ad- – mitochondrial disorders dressed.2 7 The heterogeneous patient populations used in • An overview of epilepsy in the context of both syndromic many of the series describing seizures add a further challenge – and nonsyndromic mitochondrial disease to seizure interpretation.2,3,8 12 • A practical approach of when to consider a mitochondrial Ictal activity in mitochondrial disease may result from disorder in a patient with epilepsy metabolic disturbance, encephalopathy, or an acquired struc- • A schema to investigate epilepsy with a suspected mito- tural lesion such as a stroke-like episode. However, seizures chondrial basis may occur without these factors. Furthermore, the mecha- • An overview of mitochondrial seizure management nisms are not mutually exclusive. Accordingly, epilepsy in mitochondrial disease straddles the genetic and structural/ Mitochondrial Disease Overview metabolic categories in the 2010 International League Against Epilepsy (ILAE) classification of the epilepsies outlined Mitochondrial disorders are genetically determined metabol- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. in ►Table 1.13 ic diseases arising due to biochemical deficiency of the A large driver for the restructuring of this classification is respiratory chain. They affect around 1 in 5,000 of the the ongoing advance in genetic medicine and diagnostic population in the United Kingdom (UK).16 technologies,13 exemplified by increasing descriptions of The mitochondrial respiratory chain sits in the inner epilepsy causing gene variations14 and mirrored in the field mitochondrial membrane and is responsible for the efficient of mitochondrial disease.15 As a combined consequence of the generation of ATP through the process of oxidative phosphor- phenotypic diversity, the increasing genetic complexity and a ylation (OXPHOS). The chain comprises five complexes, each historical paucity of detailed seizure semiology, the clinician with multiple subunits, which are coded for by both Issue Theme Etiology of Epilepsy; Guest Copyright © 2015 by Thieme Medical DOI http://dx.doi.org/ Editors: Philip Smith, MD, FRCP, Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0035-1552624. FAcadMEd, and Rhys Thomas, BSc, MRCP, New York, NY 10001, USA. ISSN 0271-8235. MSc, PhD Tel: +1(212) 584-4662. Mitochondrial Causes of Epilepsy: Evaluation, Diagnosis, and Treatment Steele, Chinnery 301 Table 1 International League Against Epilepsy classification Category Discussion Genetic The epilepsy is a direct result of a known or presumed genetic defect(s) in which seizures are the core symptom of the disorder. Structural/metabolic There is a distinct structural or metabolic condition or disease that has a substantially increased risk of developing epilepsy. Structural lesions may be acquired or of genetic origin, e.g., tuberous sclerosis. In contrast to genetic epilepsies, here there is a separate disorder interposed between the genetic defect and the epilepsy. Unknown The nature of the underlying cause is currently unknown. mitochondrial and nuclear genomes. A relevant mutation in or MERRF (myoclonic epilepsy and ragged-red fibers). How- either genome may therefore compromise respiratory chain ever, many individuals are oligo-symptomatic and conse- function with resultant cellular ATP deficiency. Consequently, quently do not fulfil requirements for a syndromic diagnosis. the clinical features of mitochondrial disorders are most evident in tissues with high-energy demands, with the Epilepsy in Syndromic Mitochondrial Disease central and peripheral nervous systems being particularly susceptible. Epilepsy is a major phenotypic feature of several syndromic Recognition of mitochondrial phenotypes may be com- mitochondrial disorders, including Leigh syndrome, Alpers– plex. However, there are certain features (►Fig. 1) that Huttenlocher syndrome, MELAS, and MERRF. suggest a bioenergetic deficit. Specific symptom combina- tions may enable a clinician to diagnose one of the canonical Leigh Syndrome mitochondrial disorders such as MELAS (mitochondrial en- Leigh syndrome (LS) is a progressive, neurodegenerative cephalomyopathy, lactic acidosis, and stroke-like episodes), syndrome characterized by impaired mitochondrial function This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Fig. 1 An illustration of the common systemic features of mitochondrial disease. CNS, central nervous system; CPEO, chronic progressive ophthalmoplegia; ENT, ear, nose, and throat; PNS, peripheral nervous system. Seminars in Neurology Vol. 35 No. 3/2015 302 Mitochondrial Causes of Epilepsy: Evaluation, Diagnosis, and Treatment Steele, Chinnery (OMIM 256000). The genetic basis of LS is complex, but The onset is often explosive, and in common with LS, multiple approximately 50% of cases arise due to mutations in seizure types often co-exist. However, in contrast to LS, focal – SURF1, a complex IV assembly gene.9 seizures and myoclonus are most frequent in AHS.25 27 A striking feature of LS is the characteristic bilateral, focal Progression to epilepsia partialis continua (EPC) and second- neuropathological change evident on magnetic resonance ary generalized status epilepticus is characteristic and refrac- (MR) brain imaging. It is the most common manifestation tory seizures are a recognized cause of death.24,25,28,29 There of mitochondrial disease in children, and symptom onset are no disease-modifying treatments available. Consequently, usually occurs between 3 and 12 months. However, the clinicians should anticipate the need for palliative care provi- diagnosis should be considered in older individuals, including sion. The use of sodium valproate is contraindicated due to adults, with suggestive clinical features.17,18 Prognosis is the occurrence of fatal hepatotoxicity. poor, with death often occurring in early infancy. Key points: Alpers–Huttenlocher syndrome Triad of Leigh syndrome: • Triad of intractable seizures, intellectual decline, and liver 1. Progressive neurodegeneration dysfunction 2. Mitochondrial impairment • Focal seizures and myoclonus > generalized seizures 3. Characteristic bilateral central nervous system (CNS) • Avoid sodium valproate use lesions MELAS Due to mt.3243A > G Mutation Seizures occur in at least 40% of those with LS,7,19 though The mt.3243A > G mutation in the mitochondrial DNA some smaller case series report a prevalence of up to twice (mtDNA) MTTL1 gene is the most frequently identified muta- that.20,21 In a large natural history study of 130 patients with tion causing MELAS. Other phenotypes may also arise due to LS, epilepsy was the fourth most common clinical feature, this point mutation, such as CPEO (chronic progressive exter- after movement disorders, ocular involvement, and feeding nal ophthalmoplegia) and MIDD (maternally inherited dia- difficulties, both at presentation and throughout the disease betes and deafness). Conversely, MELAS may also be caused course.7 Over half of individuals with epilepsy due to LS have by other mtDNA mutations,30 and has been described in a generalized seizure disorder, with both myoclonic and association with nuclear DNA mutations such as POLG.31,32 absence seizures reported.7 This supports the findings of In a cohort of individuals carrying the mt.3243A > G smaller series where myoclonic seizures are a frequent mutation, 24% of all symptomatic individuals manifested occurrence.21,22 Focal seizures and infantile spasms are also seizures.1 There was a clear relationship between phenotype recognized, but occur less often and may co-exist with and seizure prevalence, with 50 to 62% of those with MELAS generalized seizures.7 and MELAS overlap syndromes (MELAS with either MIDD or Treatment of seizures associated with LS is difficult: They CPEO) experiencing
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