Review Question - QID 106546

Heteroplasmy accounts for the variability in severity of diseases in mitochondrial diseases.

This patient is presenting with myoclonic epilepsy with red ragged fibers (MERRF), a mitochrondrial disease. MERRF presents with myoclonic seizures and neurologic deficits. It is caused by a point mutation in mitochondrial DNA, which disrupts the synthesis of proteins necessary for oxidative phosphorylation. Because all mitochondria are inherited from the offspring's mother, mitochondrial diseases such as MERRF demonstrate a maternal or mitochondrial pattern of inheritance with every offspring of the mother having the disease. Due to heteroplasmy, mitochondrial diseases are characterized by strong degrees of variable expression between generations and siblings. In fact, some siblings or the mother may not show significant symptoms at all, as is the case in this vignette.

Lorenzoni et al. review the clinical and laboratory manifestations, brain images, electrophysiological patterns, histology and molecular findings in MERFF. The clinical diagnostic criteria for MERRF include typical manifestations of the disease: myoclonus, generalized epilepsy, cerebellar ataxia, and ragged red fibers (RRF) on muscle biopsy.

Chinnery describes heteroplasmy as it relates to mitochondrial disease. He states a female harboring a heteroplasmic mtDNA single nucleotide variant may transmit a variable amount of mutant mtDNA to her offspring, resulting in considerable clinical variability among siblings within the same family. Furthermore, prenatal genetic testing and interpretation of test results for mtDNA disorders are difficult because of mtDNA heteroplasmy.

Illustration A is a pedigree demonstrating the maternal mode of inheritance seen in mitochondrial disorders such as MERRF.

Incorrect Answers:
Answer 1: Allelic heterogeneity refers to different mutations in the same genetic locus producing similar symptoms.
Answer 2: Phenotypic heterogeneity refers to mutations at the same gene producing different phenotypes and symptoms.
Answer 3: Genetic heterogeneity refers to mutation at different genes producing similar phenotypes and symptoms.
Answer 5: Locus heterogeneity refers to mutations at different loci producing the same phenotype (ex: Marfan's syndrome, MEN2B, and homocystinuria all cause marfanoid habitus).