Clinical mitochondrial genetics

The last decade has been an age of enlightenment as far as mitochondrial pa thology is concerned. Well established nuclear genetic diseases, such as Fr iedreich's ataxia,(1 2) Wilson disease,(3) and autosomal recessive heredita ry spastic paraplegia,(4) have been shown to have a mitochondrial basis, an d we are just starting to unravel the complex nuclear genetic disorders whi ch directly cause mitochondrial dysfunction (table 1). However, in addition to the 3 billion base pair nuclear genome, each human cell typically conta ins thousands of copies of a small, 16.5 kb circular molecule of double str anded DNA (fig I). Mitochondrial DNA (mtDNA) accounts for only 1% of the to tal cellular nucleic acid content. It encodes for 13 polypeptides which are essential for aerobic metabolism and defects of the mitochondrial genome a re an important cause of human disease.(92 93) Since the characterisation o f the first pathogenic mtDNA defects in 1988,(5 13) over 50 point mutations and well over 100 rearrangements of the mitochondrial genome have been ass ociated with human disease(94 95) (http://www.gen.emory.edu/mitomap.html). These disorders form the focus of this article.