| Description |
Mitochondrial disorders present with a wide spectrum of neurological manifestations. Clinical syndromes are described largely by phenotypic indicators. Epilepsy is a common but not universal feature. Myoclonus epilepsy with ragged red fibers (MERRF) is a common clinical syndrome that presents with epilepsy and myopathy, while mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) rarely presents with epilepsy. Genetic mutations can be shared between these defined disorders, making prediction of phenotypes difficult. The objective of our research was to present a genetic explanation for the clinical features in a large pedigree with refractory status epilepticus and chronic kidney disease. Based upon the phenotype and maternal inheritance pattern, a mitochondrial disorder was anticipated. Nine individuals with refractory status epilepticus, intractable seizures, and/or chronic kidney disease were identified from a large pedigree with maternal inheritance. A variant (m.608A>G) was identified in the MT-TF gene in one family member with both chronic kidney disease and refractory status epilepticus by sequencing of the mitochondrial genome. After the identification of the variant in one case, we demonstrated segregation of the variant was among other affected members of the family as well. The DNA for affected and unaffected individuals in the pedigree was obtained from saliva samples or cheek swabs. Segregation analysis was performed by Sanger sequencing for the MT-TF variant in 32 individuals in the pedigree. Individuals positive for the MT-TF variant underwent pyrosequencing for allele quantification to determine the degree of heteroplasmy in each individual to assess for a correlation to severity of disease. Our results indicated that five family members had a history of refractory status epilepticus, one had intractable epilepsy without status epilepticus, and one had seizures controlled with medication. Seven individuals had chronic kidney disease of the which three received kidney transplants. Sanger sequencing showed the m.608A>G variant in MT-TF was present in all affected individuals and some unaffected individuals. Pyrosequencing indicated that all affected individuals had a heteroplasmy level of 96% or more. All unaffected individuals had a heteroplasmy level of 95% or less. MT-TF mutations have been associated with a variety of mitochondrial syndromes including MELAS, MERRF, tubulointerstitial nephritis, and epilepsy. We describe a family with both severe chronic kidney disease and epilepsy with refractory status epilepticus due to a mutation previously associated only with renal disease. |
