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. Skeletal muscle biopsy of the patient shows ragged-appearing muscle fibers. After further evaluation, all the affected family members are found to suffer from the same inherited disease. Pedigree analysis is shown in the image below. Which of the following is the most likely explanation for the variability of clinical manifestations in the affected family members?

Question

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.  Skeletal muscle biopsy of the patient shows ragged-appearing muscle fibers.  After further evaluation, all the affected family members are found to suffer from the same inherited disease.  Pedigree analysis is shown in the image below.  Which of the following is the most likely explanation for the variability of clinical manifestations in the affected family members?

Quizplus · Accepted Answer

11ec160b_3789_9ede_9249_cbc9ad123e29_MD0001_00 The neuromuscular lesions, ragged skeletal muscle fibers, and lactic acidosis in these family members suggest mitochondrial encephalomyopathy. Mitochondrial disorders follow a maternal inheritance pattern because an embryo's mitochondria are inherited from the ovum only. Mitochondria are responsible for ATP production via oxidative phosphorylation, which is why mitochondrial defects tend to cause lactic acidosis and primarily affect tissues with the highest metabolic rates (eg, neural tissue, muscular tissue). Although many mitochondrial proteins are coded for in the nuclear genome, mitochondria also contain their own genome, which is vulnerable to mutations. Each cell has hundreds of mitochondria, and defects in their genome may occur in any number of the mitochondria within the cell. Heteroplasmy describes the condition of having different mitochondrial genomes within a single cell. The severity of mitochondrial diseases is often directly related to the proportion of abnormal to normal mitochondria within a patient's cells. (Choice A) Anticipation refers to increased severity or earlier onset of an inherited disease in successive generations. It is commonly seen in autosomal and X-linked trinucleotide repeat disorders due to trinucleotide amplification during gametogenesis. (Choice C) Penetrance is the probability that a person with a given genotype will express its associated phenotype. If all individuals with a given gene express its phenotype, that gene is said to have complete penetrance. (Choice D) Mosaicism refers to the presence of 2 or more cell lines, each with a unique nuclear genome, within the same individual. While patients with combined somatic and germline mosaicism can demonstrate disease traits and also pass the disease on to their offspring, mosaicism would not explain the pattern of female-only transmission. (Choice E) Uniparental disomy occurs when both members of a chromosomal pair are inherited from one parent, which can cause problems due to genomic imprinting. For instance, although most often due to chromosomal deletions, uniparental disomy can also cause Prader-Willi and Angelman syndromes due to loss of expression of maternal/paternal imprinted components of a critical region of chromosome 15. Educational objective: The presence of lactic acidosis and ragged skeletal muscle fibers histologically suggests a mitochondrial myopathy. Variable clinical expressions in affected family members can occur due to heteroplasmy, which is the coexistence of distinct versions of mitochondrial genomes in an individual cell. __________ References: Epigenetics, epidemiology and mitochondrial DNA diseases. (http://www.ncbi.nlm.nih.gov/pubmed/22287136) Mitochondrial disease in childhood: mtDNA encoded. (http://www.ncbi.nlm.nih.gov/pubmed/23224691)

A 26-Year-Old Woman Is Being Evaluated for a Possible Inherited