Status epilepticus in mitochondrial diseases and the role of POLG1 variants in the valproic-acid induced hepatotoxicity

Thesis event information

Date and time of the thesis defence

Place of the thesis defence

Oulu University Hospital/Auditorium 12 of the Department of Paediatrics

Topic of the dissertation

Status epilepticus in mitochondrial diseases and the role of POLG1 variants in the valproic-acid induced hepatotoxicity

Doctoral candidate

Licentiate of Medicine Johanna Hynynen

Faculty and unit

University of Oulu Graduate School, Faculty of Medicine, PEDEGO Research Unit

Subject of study



Docent Eeva-Liisa Metsähonkala, University of Helsinki; Helsinki University Hospital


Professor Johanna Uusimaa, University of Oulu; Oulu University Hospital

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Mitochondrial diseases are a more common genetic cause of prolonged epileptic seizures than previously thought

The doctoral study found that mitochondrial diseases, together with ion channel diseases, chromosomal disorders and neurocutaneous syndromes, are a relatively common genetic cause of prolonged epileptic seizures, i.e. status epilepticus.

In mitochondrial diseases, medically resistant or highly resistant prolonged seizures were more common than in the other groups of patients studied, and mortality was also high in these patients. Epilepsy associated with mitochondrial disease is often difficult to treat, and certain antiepileptic drugs, such as sodium valproate, should be avoided in this patient group due to their particularly high risk of liver injury. The role of liver transplantation in the treatment of acute liver injury in patients with mitochondrial disorders has been controversial due to the progressive nature of the underlying disease. However, according to the findings of this doctoral study, some patients with severe liver injury caused by this drug appear to benefit from liver transplantation, which should be taken into consideration when making treatment decisions.

The study investigated the genetic causes of status epilepticus using patient data collected from four university hospitals, focusing on the genetic alterations in mitochondrial and nuclear genes involved in mitochondrial disease and epilepsy. The effect of these nuclear genetic alterations on post-transplant prognosis in patients with valproate-induced liver injury was examined. In addition, certain common non-disease-causing genetic variants previously associated with an increased risk of liver injury during valproate treatment were studied.

The incidence of mitochondrial disease is estimated to be at least 1/4300, and therefore, there should be about 1200 mitochondrial disease patients in Finland. Moreover, mitochondrial genetic alterations are estimated to affect up to 1/200 people worldwide, most of whom are healthy carriers. Early identification of individuals with mitochondrial disease and related epilepsy and of the underlying genetic causes is important not only for patient and family counselling but also for individual patient care planning. The increasing use of genetic research in the diagnosis of epilepsy is likely to be reflected not only in the increasing recognition of mitochondrial diseases but also in the understanding of the underlying disease mechanisms and, consequently, of the mechanisms of adverse drug actions on mitochondria.
Last updated: 1.3.2023