A 12-year-old Caucasian male with history of seizure disorder experiences several stroke-like episodes with residual neurological deficit. He also suffers from muscle weakness. Blood tests show increased serum lactate levels both post-exercise and at rest. This patient's condition is known to be maternally inherited. This patient's sister is also affected by the same disorder, but she displays very few symptoms. Which of the following is the most likely explanation for the variability in clinical presentation between the patient and his sister?

Question

A 12-year-old Caucasian male with history of seizure disorder experiences several stroke-like episodes with residual neurological deficit.  He also suffers from muscle weakness.  Blood tests show increased serum lactate levels both post-exercise and at rest.  This patient's condition is known to be maternally inherited.  This patient's sister is also affected by the same disorder, but she displays very few symptoms.  Which of the following is the most likely explanation for the variability in clinical presentation between the patient and his sister?

Quizplus · Accepted Answer

Mitochondria have a small amount of their own DNA, called mitochondrial DNA (mtDNA), which can have deletions and point mutations just like regular DNA. Mitochondrial disorders (mutations in mtDNA) are unique in that they are exclusively inherited from one's mother. Recall that the ovum is relatively large and has many copies of mtDNA; whereas, the few copies of mtDNA present in sperm are lost during fertilization. Mitochondrial diseases affect both male and female offspring with equal frequency (100%), but there are variable degrees of severity. This variability occurs because, during mitosis, mitochondria are randomly distributed between daughter cells. As a result, some cells contain mitochondria with mostly damaged mtDNA, while some contain mostly normal mitochondrial genomes. This mixture of two types of genetic material is called heteroplasmy and is responsible for the clinical variability of mitochondrial diseases. The following mitochondrial syndromes are important: (Choice A) Genetic imprinting is a selective inactivation of paternal or maternal alleles. This phenomenon explains the differences in clinical presentation between Prader-Willi and Angelman syndromes. (Choice C) Anticipation refers to the increase in severity of genetic disorders in subsequent generations. Anticipation is often seen in diseases involving an increased number of trinucleotide repeats, such as Huntington disease and Fragile X syndrome. (Choice D) Variable expressivity refers to the differences in severity of autosomal dominant disorders. For example, a patient with Marfan syndrome may have only tall stature, while another patient with the same genetic defect will have tall stature, aortic root dilation, and lens dislocation. Variable expressivity is not a feature of mitochondrial diseases. (Choice E) Female sparing is not characteristic of mitochondrial disorders. Both males and females are equally affected in mitochondrial disorders. Educational Objective: Mitochondrial diseases are characterized by exclusively-maternal inheritance. The variable severity of these diseases is explained by the random distribution of normal and mutated mitochondria between daughter cells during mitosis; as a result, some cells may have completely healthy mitochondria, while other cells contain mitochondria affected by genetic mutation (heteroplasmy). MELAS is a mitochondrial syndrome.

A 12-Year-Old Caucasian Male with History of Seizure Disorder Experiences