The mitochondrial chromosome carries its genetic information in a very compact form, for example there are no introns in the genes. Therefore any mutation has a high chance of having an effect. However as every cell contains hundreds of mitochondria, a single altered mitochondrial genome will not be noticed. As mitochondria divide there is a statistical likelihood that there will be more mutated mitochondria and at some point this will give rise to a mitochondrial disease. Most mitochondrial diseases are myopathies and neuropathies with a maternal pattern of inheritance. Many syndromes have been described, including myoclonic epilepsy with ragged red fibres (MERRF) and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). Leber’s optic atrophy, with late onset bilateral loss of central vision and cardiac arrhythmias, is an example of a mitochondrial disease caused by a point mutation in one gene.
SINGLE GENE DEFECTS
Mendelian and sex-linked single gene disorders Monogenetic disorders involving single genes can be inherited as dominant, recessive or sex-linked characteristics. Inheritance occurs according to simple Mendelian laws making predictions of disease in offspring and therefore genetic counselling more straightforward.
Autosomal dominant disorders
Each diploid cell contains two copies of all the autosomes. An autosomal dominant disorder occurs when one of the two copies has a mutation and the protein produced by the normal form of the gene cannot compensate. In this case a ‘heterozygote’ individual who has two different forms (or ‘alleles’) of the same gene will manifest the disease. The offspring of a heterozygote have a 50% chance of inheriting the chromosome carrying the disease allele and therefore also having the disease. However estimation of risk to offspring for counselling families can be difficult because of three factors:
1 These disorders have a great variability in their manifestation. ‘Incomplete penetrance’ may occur if patients have a dominant disorder but it does not manifest itself clinically in them. This gives the appearance of the gene having ‘skipped’ a generation.
2 Dominant traits are extremely variable in severity (variable expression) and a mildly affected parent may have a severely affected child.
3 New cases in a previously unaffected family may be the result of a new mutation. If it is a mutation, the risk of a further affected child is negligible. Most cases of achondroplasia are due to new mutations. The overall incidence of autosomal dominant disorders is 7 per 1000 live births.