Genetics of metabolic diseases
Hereditary inborn errors of metabolism are the results of an enzyme defect involving one or more metabolic pathways. An enzymatic block may act by inducing deficiency of metabolites normally produced beyond the block, by interfering with other metabolic pathways as a result of deviation from normal to accessory or normally unused pathways, by producing accumulation of substances that may interfere with the cell’s function and/or survival, or by interfering in various ways with other essential metabolic processes. Classic genetic disorders are caused by an abnormality in a single gene or may be multifactorial. In addition there are other more recently described categories, such as mitochondrial inheritance, fragile site, and genomic imprinting. Most metabolic diseases are inherited according to single-gene Mendelian mode of inheritance. The inheritance of the phenotypic set follows the Mendelian rules of inheritance: autosomal dominant, autosomal recessive, or X-linked. Canavan (17p), Krabbe (14q), Gaucher (1q), galactosemia (9p), Hallervorden–Spatz (20p), and Wilson (13q) diseases are examples of autosomal recessive single-gene disorders. Adrenoleukodystrophy (ALD), Aicardi syndrome, and Pelizaeus–Merzbacher disease (PMD) are examples of X-linked single-gene disorders. The incidence of single-gene disorders is between 2 and 3% by the age of 1 year, closer to 5% by the age of 25 years. Newborn screening programs are available for single-gene disorders that respond well to dietary therapy, such as phenylalanine hydroxylase deficiency (phenylketonuria [PKU]), galactosemia, and maple syrup urine disease (MSUD). The completion of the Human Genome Mapping Project will make it possible to screen the population for many other single-gene disorders. This novel possibility raises many ethical and legal questions that have yet to be addressed.
Chromosomes are the structures in which genes are packaged. Chromosome disorders are the result of either deficiency or excess of chromosomal material. It is estimated that approximately 5 in 1000 live newborns will have a chromosome abnormality. Deficiency or excess of chromosomal material can be the result of a change in chromosome number (polyploidy, aneuploidy) or in structure.