Mitochondria are very complex organelles located in virtually all cells of the body. A large degree of the complexity is due to the fact that among the over 1000 proteins located in the mitochondria, 13 are encoded by the mitochondrial DNA (mtDNA), while the remainder are nuclear-encoded (on the chromosomes) and imported into mitochondria. Before launching into the inheritance of mitochondrial disease, I will define what this author defines as "mitochondrial disease". Herein, mitochondrial disease refers to any illness resulting from deficiency of any mitochondria-located protein which is involved in energy metabolism. Thus, deficiencies of the respiratory (electron transport) chain, either resulting from deficiency in one or more mitochondrial or nuclear-encoded proteins, are mitochondrial disorders. Also, by this definition, disorders of fatty acid (beta) oxidation, Krebs cycle and pyruvate dehydrogenase complex deficiency are mitochondrial disorders. Although the proteins involved are nuclear-encoded, they are located in the mitochondria and are involved in energy metabolism. Although genetically dissimilar, all of these disorders share clinical similarities in that they result in an energy deficient state.
Autosomal recessive inheritance may be familiar to some readers in that several non-mitochondrial disorders are inherited in this manner, including cystic fibrosis and albinism. Autosomal recessive inheritance is possibly the most common model in mitochondrial disorders, including disorders of fatty acid oxidation, Krebs cycle, nuclear-encoded subunits of the respiratory chain, assembly factors and transporters. Remember that we all have two copies of virtually every (nuclear-encoded) gene; one each from our mother and father. Only one of these two genes randomly enters an egg or sperm as they are formed. One gene from both egg and sperm results in the baby having two copies of that gene. With autosomal recessive inheritance, both parents are carriers in that they have one copy of the gene that is defective. They are not affected because they also have a normal copy of the same gene. If both the egg and sperm carried the defective (bad, mutant) gene, then the child will have no working (good, normal) copies, and will manifest the disorder.
Autosomal recessive inheritance was the "easy one"; maternal inheritance (also known as mitochondrial or cytoplasmic inheritance) is the most complicated of all. Maternally inherited mitochondrial disorders are not rare, and possibly are as common as autosomal recessive mitochondrial disorders. All maternally inherited diseases are mitochondrial disorders. Examples include MELAS, MERRF, NARP and LHON.
X-Linked Recessive Inheritance
X-linked recessive inheritance may be familiar to some readers in that many well-publicized non-mitochondrial disorders are inherited in this manner, including the most common forms of muscular dystrophy, hemophilia and color blindness. Among mitochondrial disorders, the most common type of pyruvate dehydrogenase complex deficiency (E1 alpha) is X-linked.
Autosomal Dominant Inheritance
Autosomal dominant inheritance may be familiar to some readers as the inheritance pattern in the non-mitochondrial disorders of Huntington disease and familial hypercholestrolemia. Among mitochondrial disorders, a rare form of Kearns-Sayre syndrome is autosomal dominant in inheritance.
Sporadic Cases — Where There Are No Affected Relatives
In the "real world", in the majority (perhaps about 75%) of cases the patient is the only family member affected with mitochondrial disease. These cases are called "sporadic", and present much difficulty in answering the questions posed about regarding inheritance.
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