Review Question - QID 107004

The boy is suffers from a mitochondrial disease called mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). MELAS has a mitochondrial inheritance pattern and is best described by the statement "transmission only occurs from females and may have variable expression."

Mitochondrial diseases are inherited only from females with affected mitochondria. The mother will pass it onto all of her offspring (both males and females affected at equal frequency) due to the fact that sperm do not contribute mitochondria to the zygote. Mitochondrial diseases result from defects in electron transport/oxidative phosphorylation processes. Typical symptoms include neuropathies, myopathies, and lactic acidosis. If a muscle biopsy is taken, ragged, red muscle fibers may be seen on a Gömöri trichrome stain (Figure A); this pathology can also be seen in myoclonic epilepsy with ragged, red muscle fibers (MERRF) and Leber hereditary optic neuropathy. The disease may present differently depending on the percentage of mitochondria affected and the cell type containing the diseased mitochondria. This variable expression is termed heteroplasmy. Representative mitochondrial diseases are MELAS, Leber hereditary optic neuropathy, and MERRF.

DiMauro and Hirano review MELAS and discuss the disease characteristics. Symptoms of MELAS typically present between the ages of 2-10 with "generalized tonic-clonic seizures, recurrent headaches, anorexia, and recurrent vomiting." Some individuals present with exercise intolerance and limb weakness. The recurring seizures are accompanied by stroke-like episodes which eventually lead to brain damage resulting in deficits of motor skills and vision.

DiMauro and Hirano review MELAS and discuss the testing for it. The diagnosis relies on clinical features and most importantly, molecular genetics. The mutation causing MELAS is in the mitochondrial gene encoding tRNA-Leu. Over 80% of individuals carry the A to G transition in nucleotide 3243 and can be diagnosed by sequencing mtDNA from white blood cells. Due to heteroplasmy, the mutation may not be detected in white blood cells, so other tissue samples may need to be sampled.

Figure A demonstrates a Gömöri trichrome stain of a muscle biopsy taken from an individual with MELAS. The arrows point to the red ragged fibers (accumulation of diseased mitochondria).

Incorrect answers:
Answer 1: The statement "females of affected fathers are always affected" best describes X-linked dominant mode of inheritance.
Answer 2: The statement "3/4 of the offspring are affected when both parents are affected and heterozygous for the diseased allele" best describes autosomal dominant mode of inheritance.
Answer 3: The statement "1/4 of the offspring are affected when both the parents are carriers" best describes autosomal recessive mode of inheritance.
Answer 4: In mitochondrial disorders, both genders are affected equally.