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The Genetics of Mitochondrial Disease

Mitochondrial disease is actually a group of disorders that vary in their inheritance pattern.  The majority are caused by defects in nuclear-encoded genes, and follow an autosomal recessive pattern in which there may be history of affected siblings but (unrelated) parents are asymptomatic carriers.  Carrier parents have a 1 in 4 or 25% chance in every pregnancy of having a child with mitochondrial disease.  It should be noted that some carriers display mild symptoms (Haas, 2007).

A minority of mitochondrial disease cases are associated with mitochondrial or maternal inheritance, in which an abnormal lesion in the mitochondrial DNA is potentially passed on from mothers to all offspring.  Affected males do not pass on their genetic abnormality.  The phenotypic severity in affected individuals can be very broad, even within the same family.  Upon questioning, there may be a history of family members with suspicious symptoms (when the diagnosis has not yet been made), but there are many cases of patients with documented mtDNA mutations who have no notable family history.

A smaller subset of disorders are associated with x-linked or autosomal dominant inheritance.  There are also a group of disorders in which the mitochondrial disease has occurred sporadically with a negligible risk of recurrence.

As stated before, in many cases of mitochondrial disease, it may be difficult or impossible to determine whether or not the abnormality (e.g., a defect in one of the complexes within the respiratory chain) is primary or secondary to some other disease process.  This is a critical piece of information which has a direct bearing on the genetic counseling provided to a family.  The recurrence risk is only accurate if the diagnosis is clear.

When a molecular DNA diagnosis cannot be made and when there is no obvious family history of disease, autosomal recessive inheritance is statistically the most likely inheritance pattern.  However, a careful review of all clinical and laboratory information available is necessary in order to best determine an individual couple's recurrence risk for having another child with mitochondrial disease.

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