Mitochondrial Disorders

The mitochondrial genome is 16.6 kb in length and encodes 13 polypeptides that are components of mitochondrial respiratory chain complexes, 22 tRNAs, and 2 rRNAs. Each mitochondrion can contain 5 - 10 copies of the mitochondrial genome, and each somatic cell can contain hundreds of mitochondria. Mutations in polypeptides that are subunits of a respiratory chain enzyme are generally associated with a phenotype caused by deficiency of the enzyme in question, whereas mutations in a mitochondrial tRNA may be associated with a more extensive phenotype because of the more general impairment in protein synthesis.

Mitochondrial genetics show three features that differ from nuclear genetics. First, mitochondria are maternally transmitted. Each oocyte contains up to 100,000 mitochondria. Disease-causing mitochondrial mutations are therefore transmitted from mother to children but are not transmitted by fathers to their offspring. Second,
all mitochondria do not necessarily have the same genome. In the case of disease-causing mutations, any cell may have a mixture of normal mitochondria and mutant mitochondria. This phenomenon is known as heteroplasmy. Third, in the case of heteroplasmy, the expression of a disease phenotype depends on the ratio of normal to mutant mitochondria. Although a deleterious mutation may be present, it may not manifest as a disease phenotype until a critical threshold of impaired biochemical function is reached. This threshold may vary according to a cell’s energy requirements and the nature of the mutation itself. Most mitochondrial disorders manifest phenotypically principally in tissues that have a high metabolic activity including skeletal muscle, neurons, heart, and some endocrine tissues.

In addition to these differences in pattern of genetic inheritance between mitochondria and the nucleus, mitochondria also use a slightly different genetic code that is similar to that of prokaryotes. A commonly held theory of the origin of mitochondria is that these sub-cellular organelles are derived from a prokaryote. Of clinical importance in this regard is the association between aminoglycoside toxicity and a mutation, A1555G, in the mitochondrial 12S ribosomal subunit gene. Aminoglycosides exert their antibiotic effect by inhibiting prokaryotic ribosomes, and it is believed that the A1555G mutation renders cochlear mitochondria highly susceptible to aminoglycoside-induced toxicity.

It is also important to bear in mind that mitochondrial disorders may arise from mutations in nuclear genes that encode mitochondrial proteins. The majority of proteins that are present in mitochondria are encoded by nuclear genes. In the case of a mutation in a nuclear gene encoding a mitochondrial protein, the disease inheritance pattern is one of the classic mendelian patterns and heteroplasmy is not seen.


SOME EXAMPLES OF MITHOCHONDRIAL DISORDERS

KEARNS-SAYRE SYNDROME

 

Kearns-Sayre syndrome is characterized by progressive external ophthalmoplegia (weakness of the external muscles of the eye), pigmentary retinopathy, age of onset under 20 yr, and one of the following: high cerebrospinal fluid protein concentration, cardiac conduction block, or ataxia. Additional, variably present features include weakness of the skeletal muscles, deafness, short stature, and diabetes or other endocrine disorders such as diabetes, hypogonadism, hypoparathyroidism, and growth hormone deficiency. KSS has been found to be associated with both deletions and duplications of mtDNA .


FRIEDREICH’S ATAXIA

Friedreich’s ataxia is an autosomal recessive disease caused by mutations in FRDA. The disease, which has an incidence of 1 in 20,000, is characterized by a triad that includes pre-adolescent onset of symptoms, progressive cerebellar dysfunction, and hypoactive reflexes in the lower limbs. An axonal sensory neuropathy can be demonstrated by electrophysiological studies. Other symptoms may include cardiomyopathy, kyphoscoliosis, optic atrophy, hearing loss, and diabetes mellitus. The range and progression of symptoms can be variable, even between affected siblings.

FRDA is on chromosome 9q13. The gene is composed of seven exons spread over 95 kb and encodes a 1.3-kb transcript. The encoded protein is termed frataxin. Alternative splice products have been described, but their function is unknown. The most common mutation, found in approx 96 - 98% of mutant alleles, is an expansion of a GAA trinucleotide repeat in intron 1. Normal subjects have ≤40 repeats, and affected individuals have approx 66 - 1700 repeats. Other mutations have also been described. In general, longer trinucleotide expansions are associated with earlier age of onset and with more severe disease. This is related to lower levels of production of the protein.

Decreased frataxin levels appear to result in accumulation of iron in mitochondria. This excess iron may lead to production of free radicals with resulting oxidative damage to mitochondria.


MYOCLONIC EPILEPSY WITH RAGGED RED FIBERS

Myoclonic epilepsy with ragged red fibers is a mitochondrial encephalomyopathy characterized by a constellation of symptoms that includes myoclonic epilepsy, ataxia, deafness, and ragged red fibers. The latter are seen on muscle biopsies stained with Gomori’s modified trichrome stain and represent subsarcolemmal aggregates of mitochondria. In up to 90% of patients, MERRF is caused by a point mutation, A8344G, in the mitochondrial tRNALys gene.