Mitochondrial diseases are usually presumed to be from maternal inheritance or de novo mutations but as 95% of mitochondrial proteins are actually produced from the nuclear DNA which are transported into the mitochondria from the cytoplasm then mitochondrial diseases may be autosomal dominant or even X-linked hereditary patterns. Lynn Margulis an American Biologist about 40 years ago suggested that Mitochondria are derived from a specialised bacterial organism which was somehow incorporated into eukaryotic cells
- It is wise to know something about mitochondrial genetics and physiology for the exams as they are interesting.
- Mitochondria have their own double-stranded circular mitochondrial DNA - mtDNA which is quite different and separate to the nuclear DNA which is inherited along the maternal line.
- Faulty mtDNA and disease follow the maternal line.
- It is thought that mitochondria were aerobic bacteria that developed a symbiotic relationship with cells
- Genetic mutations can occur as the checking procedures are not as good as for nuclear DNA
- Abnormal Oxidative-phosphorylation through faulty enzymes and disorders of general protein synthesis
- Prevalence of mitochondrial diseases equals 1:10000 of live-born infants.
- Mutations of mitochondrial DNA (mtDNA) are their most frequent cause.
- Mitochondrial Protein Complexes produce Over 90% of the bodies energy.
- Muscle, nerves and cerebrum are high energy consuming tissues and tend to be affected primarily.
- complex I (reduced nicotinamide adenine dinucleotide-coenzyme Q oxidoreductase)
- complex II (succinate dehydrogenase)
- complex III (coenzyme Q-cytochrome c oxidoreductase)
- complex IV (cytochrome c oxidase)
- complex V (ATPase synthetase)
Mitochondrial DNA encodes for
- 22 transfer RNAs (tRNAs)
- 2 ribosomal RNAs (rRNAs)
- 13 messenger RNAs (mRNAs): The 13 mRNAs are translated into polypeptide subunits of the respiratory chain complex. A mutation in a mitochondrial tRNA gene can impair proper translation of the 13 mitochondrial mRNAs. However, the 13 proteins encoded by the mitochondrial genome account for less than 5% of mitochondrial proteins; the majority are encoded by nuclear DNA and are translated in the cytoplasm and transported into mitochondria.
Clinical Clues to Mitochondrial Disease
- Sensorineural hearing loss, retinitis pigmentosa
- Muscle weakness, ataxia, recurrent stroke
- Cardiomyopathy, Insulin-dependent diabetes mellitus
- Complete heart block and lactic acidosis.
- MELAS - Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like syndrome varying degrees of cognitive impairment and dementia. H/o Migraine like headaches and stroke under the age of 40 lactic acidosis, strokes, transient ischaemic attacks, hearing loss, dysmotility, weight loss
- MERRF - Myoclonic epilepsy and ragged-red fibres - progressive myoclonic epilepsy clumps of diseased mitochondria accumulate in the subsarcolemmal region of the muscle fibre and appear as "ragged-red fibres" when the muscle is stained with modified Gomori trichrome stain short stature, cardiomyopathy, and cutaneous lipomas
- KSS - Kearns-Sayre syndrome - external ophthalmoplegia, cardiac conduction defects, sensory-neural hearing loss and retinitis pigmentosa. Usually a sporadic mutation with a single gene defect. May also have short stature and delayed secondary sexual characteristics, peripheral neuropathy, and impaired ventilatory drive.
- PEO - Progressive external ophthalmoplegia - progressive ophthalmoparesis with severe ptosis is the cardinal feature and symptomatic overlap with many other mitochondrial myopathies
- Accumulations of abnormal mitochondria within cells in the muscle fibres. These fibres appear "ragged-red fibres" with trichrome stain and may fail to react for cytochrome c oxidase
- Elevated serum lactic acid at rest or on exertion, Raised CK, Myopathic findings on EMG
- Cerebrospinal fluid protein is often elevated.
Features of Mitochondrial Syndromes
- Neuropathy; Ataxia; Retinitis Pigmentosa
- Mitochondrial Encephalomyopathy; Lactic Acidosis; Stroke
- Myoclonic Epilepsy; Ragged Red Fibres
- Myopathy and external ophthalmoplegia;
- Neuropathy; Gastro-Intestinal; Encephalopathy
- Leber's Hereditary Optic Neuropathy
- Kearns-Sayre Syndrome: caused both by deletions and duplications of mtDNA. The onset of disease symptoms is observed before 20 years of age. Short stature, pigmentary retinal degeneration, ophthalmoplegia, ptosis, ataxias, disturbances in conduction in heart muscle, diabetes, and hearing loss occur in the syndrome.
- Chronic Progressive External Ophthalmoplegia which may occasionally occur as a result of de novo mutation, may be maternally inherited (mt tRNA mutations) or can be of autosomally dominant inheritance. Symptoms of CPEO are ptosis, myopathy, depression, cataract and ketoacidosis.
- Leigh's Syndrome - Subacute sclerosing encephalopathy