Compound Heterozygous COQ4 Missense Mutations Cause Coenzyme Q10 Deficiency Associated with Severe Infantile Epileptic Encephalopathy and Cerebellar Cysts

Background/Purpose: Coenzyme Q10 (CoQ10) plays an important role in the mitochondrial respiratory chain by shuttling electrons. At least 15 proteins are known to be involved in CoQ10 biosynthesis. Until now, mutations in 8 of them have been associated with primary CoQ10 deficiency presenting with different clinical phenotypes. We report on a 5-months-old girl with severe infantile epileptic encephalopathy and cerebellar cysts caused by variants in COQ4.

Methods: Case report.

Results: After uneventful pregnancy and delivery first seizures were observed at the age of 2 months. Drug-resistant epileptic encephalopathy with multifocal seizures, severe developmental delay and secondary microcephaly evolved over the course of the disease. EEG demonstrated abnormalities similar to Malignant Migrating Partial Seizures of Infancy. Brain MRI revealed cortical atrophy and cerebellar cysts. Lactate concentrations were elevated in CSF and plasma. Biochemical analyses of a muscle biopsy showed slightly decreased activities for complex I and IV. Histological studies were suggestive of mitochondrial dysfunction (e.g., COX negative fibers). Using exome sequencing, we identified compound heterozygous missense variants in COQ4. The functional relevance of the previously undescribed variants was supported by decreased CoQ10 concentrations in muscle. Supplementation with high-dosed CoQ10 provided no positive effect.

Conclusion: Deficiency of CoQ10 biosynthesis due to biallelic COQ4 mutations represents a very rare cause of respiratory chain disease. The clinical manifestation includes infantile epileptic encephalopathy. A therapeutic approach with CoQ10 supplementation is limited by the blood-brain barrier. To our knowledge, cerebellar cysts have so far not been associated with mitochondrial dysfunction.