Mitochondrial Causes of Epilepsy: Evaluation, Diagnosis, and Treatment

Hannah E. Steele, MBBS, MRCP; Patrick F. Chinnery, PhD, FRCP, FRCPath


Semin Neurol. 2015;35(3):300-309. 

In This Article

Epilepsy in Syndromic Mitochondrial Disease

Epilepsy is a major phenotypic feature of several syndromic mitochondrial disorders, including Leigh syndrome, Alpers–Huttenlocher syndrome, MELAS, and MERRF.

Leigh Syndrome

Leigh syndrome (LS) is a progressive, neurodegenerative syndrome characterized by impaired mitochondrial function (OMIM 256000). The genetic basis of LS is complex, but approximately 50% of cases arise due to mutations in SURF1, a complex IV assembly gene.[9]

A striking feature of LS is the characteristic bilateral, focal neuropathological change evident on magnetic resonance (MR) brain imaging. It is the most common manifestation of mitochondrial disease in children, and symptom onset usually occurs between 3 and 12 months. However, the diagnosis should be considered in older individuals, including adults, with suggestive clinical features.[17,18] Prognosis is poor, with death often occurring in early infancy.

Triad of Leigh syndrome:

  1. Progressive neurodegeneration

  2. Mitochondrial impairment

  3. Characteristic bilateral central nervous system (CNS) lesions

Seizures occur in at least 40% of those with LS,[7,19] though some smaller case series report a prevalence of up to twice that.[20,21] In a large natural history study of 130 patients with LS, epilepsy was the fourth most common clinical feature, after movement disorders, ocular involvement, and feeding difficulties, both at presentation and throughout the disease course.[7] Over half of individuals with epilepsy due to LS have a generalized seizure disorder, with both myoclonic and absence seizures reported.[7] This supports the findings of smaller series where myoclonic seizures are a frequent occurrence.[21,22] Focal seizures and infantile spasms are also recognized, but occur less often and may co-exist with generalized seizures.[7]

Treatment of seizures associated with LS is difficult: They are frequently refractory (31–75%) and a cause of death.[7,23] Genetic heterogeneity may contribute to seizure risk, and there is emerging evidence that the presence of seizures in LS indicates a poor prognosis.[7,23]

Key Points: Leigh syndrome

  • Triad of neurodegeneration, mitochondrial dysfunction, and characteristic symmetrical CNS imaging change

  • Generalized seizures > focal seizures

  • Mainly presents in children, but consider in adults with appropriate clinical features

Alpers–Huttenlocher Syndrome

Alpers–Huttenlocher syndrome (AHS) is a life-limiting condition arising due to recessive mutations in the nuclear gene encoding the mitochondrial polymerase gamma (OMIM 203700). It causes a classical triad of intractable seizures with intellectual decline and liver dysfunction. It has a bimodal distribution of onset, with a first peak occurring in the preschool years, and a second in the late teens/early twenties.[24]

Seizures, including status epilepticus, are the primary feature of AHS in about half of patients, but for others, nonspecific features such as failure to thrive, may predominate initially.[24] Seizure emergence heralds inexorable cognitive decline regardless of when in the disease course it occurs. The onset is often explosive, and in common with LS, multiple seizure types often co-exist. However, in contrast to LS, focal seizures and myoclonus are most frequent in AHS.[25–27] Progression to epilepsia partialis continua (EPC) and secondary generalized status epilepticus is characteristic and refractory seizures are a recognized cause of death.[24,25,28,29] There are no disease-modifying treatments available. Consequently, clinicians should anticipate the need for palliative care provision. The use of sodium valproate is contraindicated due to the occurrence of fatal hepatotoxicity.

Key points: Alpers–Huttenlocher syndrome

  • Triad of intractable seizures, intellectual decline, and liver dysfunction

  • Focal seizures and myoclonus > generalized seizures

  • Avoid sodium valproate use

MELAS Due to mt.3243A > G Mutation

The mt.3243A > G mutation in the mitochondrial DNA (mtDNA) MTTL1 gene is the most frequently identified mutation causing MELAS. Other phenotypes may also arise due to this point mutation, such as CPEO (chronic progressive external ophthalmoplegia) and MIDD (maternally inherited diabetes and deafness). Conversely, MELAS may also be caused by other mtDNA mutations,[30] and has been described in association with nuclear DNA mutations such as POLG.[31,32]

In a cohort of individuals carrying the mt.3243A > G mutation, 24% of all symptomatic individuals manifested seizures.[1] There was a clear relationship between phenotype and seizure prevalence, with 50 to 62% of those with MELAS and MELAS overlap syndromes (MELAS with either MIDD or CPEO) experiencing seizures. In comparison, seizure prevalence was 25% in those with mixed neurologic features, 17% with MIDD/CPEO overlap, and just 8% with MIDD alone.[1]

For those with mt.3243A > G MELAS, focal seizures and prolonged focal status epilepticus encompassing occipital lobe status, EPC, hemiclonic status, nonconvulsive status, and spike-wave stupor dominate the clinical picture.[4,33] However, truly generalized seizures are reported in a minority.[4] Therefore, mt.3243A > G MELAS should be considered a disorder in which focal and primary generalized seizures can manifest, although there are few reports to date of this occurring in the same individual.[2–4]

Electroencephalogram (EEG) changes such as focal slowing or epileptiform changes are rather nonspecific, but tend to show a posterior predilection.[4] In contrast, it is reported that periodic lateralized epileptiform discharges (PLEDS) in children have a limited differential diagnosis, with MELAS being a possibility.[4]

It has been proposed that seizures in mt.3243A > G MELAS may occur in two distinct and predictable patterns.[4] In some individuals, seizures appear solely in the context of stroke-like episodes, and in others seizures also occur at other times. The implication of this observation for seizure management remains unclear—in particular whether select individuals require antiepileptic drugs only at times of metabolic crises. However, as the numbers reported to date are small, this observation requires substantiation in larger cohorts.

Key Points: mt.3243A > G MELAS

  • 50% individuals with mt.3243A > G MELAS have epilepsy

  • Focal seizures predominate and may be prolonged

  • Primary generalized seizures may also manifest

MERRF Due to mt.8344A > G Mutation

Myoclonic epilepsy with ragged-red fibers is characterized by myoclonic epilepsy, generalized seizures, particularly clonic, and ataxia.[3] It most frequently arises due to the mtDNA mt.8344A > G point mutation in MTTK, although there are also other pathogenic mutations.[34,35] Myoclonic epilepsy with ragged-red fibers is one of the progressive myoclonic epilepsies that are associated with progressive intellectual decline and refractory seizures.

In contrast to the seizure phenomenology in mt.3243A > G MELAS, generalized seizures predominate in MERRF. Indeed, in a large genotype–phenotype analysis of the mt.8344A > G mutation, focal seizures were not reported.[6] However, 25 to 35% of patients with mt.8344 MERRF experienced generalized seizures (not otherwise specified), and 35 to 45% experienced myoclonus. Furthermore, they are frequently the reason an individual comes to medical attention, again in contrast with mt.3243 MELAS, where other clinical features such as stroke-like episodes are more commonly the reason for medical attention. Around one in three people with MERRF present before the age of 16 years.[6] Additional systemic features co-exist in many patients with weakness (59%), hearing loss (35%), ataxia (23%), raised serum creatine kinase (44%), and lipomatosis (32%) being notably common.[6]

The interictal EEG may be normal, but often shows slow background activity in conjunction with generalized epileptiform discharges, such as spikes, polyspike, and irregular and slow wave complexes.[5] Hyperventilation is safe,[36] and photic stimulation may enhance generalized discharges.[3,5]

Key Points: mt.8344A > G MERRF

  • Generalized seizure disorder

  • Valproate can be a first-line treatment