Mendelian Disorders

Mendelian disorders are caused by an alteration or mutation in a single gene, and — unlike chromosomal disorders — they follow the ordinary Mendelian pattern of inheritance from parent to offspring, and can be dominant or recessive, autosomal or sex-linked. This chapter's four worked examples between them cover every one of those combinations.

Thalassemia is an autosomal recessive disorder in which a gene mutation leads to abnormal haemoglobin production and excessive destruction of red blood cells. Normal haemoglobin is built from four polypeptide chains — two alpha-globin and two beta-globin — and thalassemia is classified as alpha or beta depending on which chain is defective. Alpha thalassemia results from mutation or deletion of one or more of the four alpha-globin gene copies (genes HBA1 and HBA2, on chromosome 16). Beta thalassemia — the more common form, also known as Cooley's anaemia — is controlled by a single gene, HBB, on chromosome 11; here beta-chain production is impaired while alpha-chain production continues at its normal (now relatively excessive) rate, and the resulting imbalance damages red blood cell membranes, causing anaemia.

Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism, caused by mutation of the PAH gene (chromosome 12) that normally encodes the liver enzyme phenylalanine hydroxylase — the enzyme responsible for converting the amino acid phenylalanine into tyrosine. Affected individuals lack this enzyme, so phenylalanine accumulates and is instead converted into phenylpyruvic acid and related compounds; PKU is characterised by severe mental retardation and light pigmentation of skin and hair, and phenylpyruvic acid is detectably excreted in the urine.

Albinism is likewise an autosomal recessive inborn error of metabolism, in which the affected person's melanocytes lack the tyrosinase enzyme system needed to convert DOPA (3,4-dihydroxyphenylalanine) into the pigment melanin. Because melanocytes are still present in normal numbers — only the enzyme is missing — an albino's skin, hair and iris simply lack pigment rather than lacking pigment-producing cells altogether. …