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

How Should I Investigate?

The ultimate aim of investigation is to reach a molecular genetic diagnosis. This obviates the need for ongoing investigation, aids management and follow-up, and enables individuals and their families to access appropriate genetic counselling. Although genetic testing of symptomatic individuals can be undertaken by general pediatricians or neurologists, the detection and interpretation of mtDNA mutations is particularly challenging due to the effects of heteroplasmy. Heteroplasmy describes a cardinal feature of mitochondrial disorders, whereby mtDNA mutation loads are carried at different levels in different tissues. This contributes to the highly variable phenotypic features of mitochondrial disorders, even within families. Consequently, if the diagnostic tissue has a low mutant mtDNA heteroplasmy level, the mutation may not be identified. Furthermore, the identification of a mtDNA mutation has particularly complex implications for relatives, and genetic counseling for family members is usually best undertaken by those with specific expertise.[62]

Syndromic Presentations

The approach to the investigation of a person with a syndromic presentation is relatively straightforward: appropriate targeted genetic testing.

Nonsyndromic Presentations

Many patients have nonsyndromic presentations, however, and for them the diagnostic process is often longer (Fig. 2). Many will undergo muscle or skin biopsy looking for biochemical evidence of mitochondrial dysfunction, and to help target genetic testing. Although invasive, it is well tolerated, has a low complication rate, and can be done under local anesthesia as a day case procedure (in adult patients). Samples provide invaluable information regarding the structure (histochemistry) and function (respiratory chain enzyme analysis) of muscle. Furthermore, muscle tissue can be used for further genetic analysis, as determined by the clinical features.

Figure 2.

A schematic of the investigative approach to suspected mitochondrial disorders. mtDNA, mitochondrial DNA; PCR, polymerase chain reaction; RFLP, restriction fragment length polymorphism; WES, whole exome sequencing; WGS, whole genome sequencing.

Future Direction

The impact of next-generation sequencing techniques on diagnosis will be determined as this becomes increasingly available at academic centers.[15] In addition, diagnostic biomarkers, as well as markers of disease progression are an area of active research. This is particularly salient as disease-modifying treatments are developed, and established markers of respiratory chain dysfunction such as lactate and pyruvate are neither sensitive nor specific.[63] Although fibroblast growth factor-21 (FGF-21) has shown some promise as a diagnostic tool, its use is not embedded in clinical practice.[64,65]