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

Mixed Syndromic and Nonsyndromic Disorders

Recessive Polymerase Gamma- (POLG-) Related Disorders

Polymerase gamma is a DNA polymerase responsible for mtDNA repair and replication. Although POLG is encoded by nuclear DNA, it is the only DNA polymerase found in mitochondria; hence, POLG disorders are characterized by multiple mtDNA deletions that accumulate over time. Consequently, highly variable clinical features may arise due to either dominant or recessive mutations.[37]

Although CPEO characterizes the dominant disorders, the recessive disorders are more complex. There are several syndromes including mitochondrial recessive ataxia syndrome (MIRAS); myoclonic epilepsy myopathy sensory ataxia (MEMSA); spinocerebellar ataxia with epilepsy (SCAE); sensory ataxia with neuropathy, dysarthria, and ophthalmoplegia (SANDO); as well as AHS, described earlier. However, as many patients do not fulfill requirements for a syndromic diagnosis, particularly early in the disease course,[38,39] much of the literature pertaining to recessive POLG seizure manifestations considers these syndromes together. Consequently, our discussion reflects this.

Seizures are a common manifestation of the recessive POLG mutations, occurring in approximately 40% of those presenting in adulthood, and up to 85% of those presenting under the age of 5 years.[38] Although pathogenic mutations throughout the gene are reported,[38,40] two particular mutations are common in the European population: 1399G > A (p. A467T) and 2243G > C (p.W748S).[41] Individuals with compound heterozygous or homozygous changes in these variants have a mean age of symptom onset of 18 years. In over half of these people (63%), seizures are the presenting feature of the disorder.[42]

The hallmark of POLG-related seizures is progressive focal motor seizures, particularly affecting the upper limb, neck, or proximal trunk. Myoclonus is common, as are episodes of convulsive and nonconvulsive status epilepticus, including epilepsia partialis continua. Epilepsia partialis continua may remain focal for many years, but invariably progresses to refractory epileptic encephalopathy. Status epilepticus is almost ubiquitous.[39,42] Seizure onset is frequently explosive and progression fulminant.[39]

One clinical feature suggestive of POLG-related seizures is the occipital predilection in the early stages, characterized by visual disturbances including colored lights, scotoma, or visual blurring.[39,42] Many patients develop additional neurologic features as their condition progresses.[39] These include migraine, neuropathy, ataxia, and chronic progressive external ophthalmoplegia, clear indicators of a complicated epilepsy and ultimately of the underlying molecular diagnosis.

In addition to the clinical features, there are specific features in the EEG that suggest POLG mutations. These include rhythmic high amplitude delta with superimposed spikes and polyspikes (RHADS)[27] and asymmetric occipital lobe or central polyspikes/polysharp complexes with associated slowing.[26] Electroencephalogram changes correlate with magnetic resonance imaging (MRI) changes as well as the clinical epileptiform features.[39,42] The posterior predominance of seizure semiology, as seen in the EEG and MRI, reflects high metabolic activity in the occipital lobes rendering them vulnerable to the effects of bioenergetic dysfunction.[43]

Disease mortality in recessive POLG disorders is correlated with seizure severity and progression, and as with the other disorders mentioned above, status epilepticus is a common end-of-life event.[39] There is evidence that the genotype has an impact on survival, as those with compound heterozygous changes have a poorer prognosis than those with homozygous changes at either of the common European mutation sites described above.[39,40]

Key Points: Recessive POLG mutations

  • Seizures affect 40% of people presenting in adulthood and up to 85% of those presenting in childhood

  • Occipital predilection early in disease course

  • Prolonged focal motor seizures characteristic

  • Avoid sodium valproate due to risk of liver failure

Twinkle (C10orf2) Mutations

Twinkle (C10orf2) is a nuclear-encoded mitochondrial replicase. Mutations in twinkle result in the accumulation of mitochondrial DNA depletion, and consequently, the clinical features associated with these mutations mimic those seen with POLG. Chronic progressive external ophthalmoplegia arises due to dominant mutations in twinkle, whereas infantile-onset spinocerebellar ataxia (IOSCA) occurs with recessive mutations.

Seizures are seen in most of those with IOSCA (18/21 patients).[44] Typically, focal seizures and myoclonic jerks occur initially and then progress to epilepsia partialis continua and generalized status. Seizures are often triggered by infection or surgery, and are a common cause of death. Again, in common with POLG seizure disorders, PLEDs were identified on the EEG and progression of EEG findings was noted with disease progression.[44]