A 19-year-old woman is evaluated for new onset generalized tonic-clonic seizures. For the past several years, she has also been having erratic jerks of her arms and legs, and intermittent muscle weakness. The girl has multiple family members with similar symptoms. Neurological examination reveals decreased sensation in the lower extremities and a broad-based gait. Skeletal muscle biopsy shows ragged, red-appearing muscle fibers. Further analysis reveals that the patient's symptoms are due to a mutation affecting extranuclear DNA. Which of the following pedigrees is most likely to represent this patient's family history? (The arrow points to the patient.)
This patient most likely has a form of mitochondrial myopathy. Without properly functioning mitochondria, cells are unable to use oxidative phosphorylation to efficiently produce adequate levels of ATP. Organ systems such as the brain and skeletal muscle will be affected first due to their high metabolic demand relative to other tissues. Affected patients often present with myopathy (eg, muscle weakness, myalgia), lactic acidosis due to impaired aerobic glycolysis, and nervous system dysfunction (eg, neuropathy, seizures). Muscle biopsy classically shows ragged red fibers.
Mitochondria are unique organelles because they contain their own DNA, known as mtDNA. Offspring inherit mtDNA in a maternal fashion with no paternal contribution (maternal inheritance). Only affected females transmit abnormal mitochondria to offspring; transmission never occurs through males (even if they are affected).
(Choice A) Autosomal dominant disorders affect 50% of all children (males and females) born to one affected parent. The disease will appear in consecutive generations, and father-to-son transmission can occur.
(Choice B) Autosomal recessive conditions affect about 25% of all children (males and females) with two carrier parents. Offspring of a single affected parent will be carriers for the disorder. As a result, the disease can skip generations, but consanguineous families will show increased incidence.
(Choice C) In X-linked dominant disorders, all female children of affected males will have the condition, but both female and male children of an affected female have a 50% chance of being affected. There is no father-to-son transmission.
(Choice D) In X-linked recessive conditions, male offspring of a carrier female have a 50% chance of being affected, whereas female offspring have a 50% chance of being carriers. Female children of an affected father are obligate carriers. The disease can skip generations, and there is no father-to-son transmission.
Educational objective:
Mitochondrial dysfunction frequently presents with myopathy, nervous system dysfunction, lactic acidosis, and ragged red fibers on muscle biopsy. Mitochondrial myopathies due to mtDNA mutations are inherited solely in a maternal fashion (ie, maternal inheritance). Therefore, transmission occurs only through affected females and never through males.