A 26-year-old woman is being evaluated for a possible inherited disorder. She has a 6-year history of generalized tonic-clonic seizures and, a year ago, she had partial loss of vision due to an occipital infarction. Her mother has chronic intermittent muscle weakness and lactic acidosis, and her maternal uncle has hemiplegia. The patient's skeletal muscle biopsy shows muscle fibers with irregular contours when stained with Gomori trichrome. After further evaluation, all affected family members are found to have the same inherited disease. Pedigree analysis is shown in the image below.
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Which of the following is the most likely explanation for the variability of clinical manifestations in the affected family members?
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This patient with seizures and a cerebral infarction has muscle biopsy findings showing irregularly shaped fibers on Gomori trichome staining (ie, ragged red fibers), which represent the accumulation of abnormal mitochondria. These findings are diagnostic of mitochondrial encephalomyopathy.
Although most mitochondrial proteins are coded for in the nuclear genome, mitochondria also synthesize their own proteins from mitochondrial DNA (mtDNA). Because mtDNA is inherited almost exclusively from the mother, mitochondrial disorders frequently exhibit a maternal inheritance pattern, as seen in this pedigree in which all offspring of an affected mother have disease and all offspring of an affected father are unaffected.
Because each cell contains hundreds of mitochondria and each mitochondrion contains several copies of its own genome, mitochondria with normal and mutant genomes often coexist in the same cell, a condition known as heteroplasmy. In those with mitochondrial disorders, the degree of heteroplasmy varies randomly, leading to a range of phenotypes, even within the same family; the proportion of mutant to normal mitochondria correlates with symptom severity.
Due to the impairment in oxidative phosphorylation, mitochondrial defects tend to cause lactic acidosis and primarily affect tissues with the highest metabolic rates (eg, brain, muscle). In this case, the family likely has MELAS, or Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes.
(Choice A) Anticipation refers to the earlier onset and/or increased severity of an inherited disease over successive generations. It often occurs in autosomal and X-linked trinucleotide repeat disorders, not mitochondrial disease, due to trinucleotide amplification during gametogenesis.
(Choice C) Locus heterogeneity describes mutations that occur at different loci (ie, different genotypes) but cause similar phenotypes. In contrast, family members affected by a mitochondrial disease likely have the same genotype but a variable phenotype due to heteroplasmy.
(Choice D) Mosaicism refers to the presence of ≥2 cell lines, each with a unique nuclear genome, within an individual. Although patients with germline mosaicism can have affected offspring, a maternal inheritance pattern would not be expected.
(Choice E) Uniparental disomy occurs when both copies of a chromosome are inherited from one parent. For chromosomes containing genes in which an allele derived from a specific parent is normally imprinted (silenced), inheritance of 2 copies of this chromosome can result in absent gene expression, as in Prader-Willi or Angelman syndrome.
Educational objective:
Mitochondrial encephalomyopathy is characterized by ragged red fibers on muscle biopsy and a maternal inheritance pattern. Clinical presentation in affected family members varies due to the degree of heteroplasmy, or proportion of mitochondria with normal and mutant genomes in the same cell or tissue.