Mitochondrial Mutations and Congenital Metabolic Errors

Mitochondrial Mutations

Mitochondrial mutations are responsible for various diseases due to alterations in mitochondrial DNA. These disorders feature exclusive maternal inheritance. There is an increased proportion of mutations in mitochondrial DNA compared to nuclear DNA for two main reasons:

• Mitochondria lack DNA repair enzymes.
• They are exposed to free radicals (from oxidation) with mutagenic effects.

The expression of the disease depends on the number of mutated mitochondria. It primarily involves organ systems with an increased requirement for ATP, such as the central nervous system (CNS) and the muscular system. Three types of mutations are known:

• Missense mutations (incorrect base pairing): Leber hereditary optic neuropathy (LHON) occurs when one base is replaced by another. The disease consists of a central visual field loss around age 30, leading to blindness.
• Mutations in the gene for tRNA: Examples include Myoclonic epilepsy with ragged-red fibers (MERRF) and mitochondrial encephalopathy.
• Mutations due to duplications and deletions: Examples include Kearns-Sayre disease, Pearson syndrome, and chronic progressive external ophthalmoplegia (CPEO).

Congenital Metabolic Errors

This is a very large group of disorders caused by defects in metabolic pathway enzymes. When an enzyme is lacking, the final product is not produced, and the initial substrate accumulates. These include:

• Errors in amino acid metabolism: Phenylketonuria, Albinism, and Cretinism.
• Errors in carbohydrate metabolism: Galactosemia.
• Errors in lipid metabolism: Gaucher disease, Niemann-Pick, and Tay-Sachs disease.
• Errors in mucopolysaccharide metabolism: Hurler syndrome (gargoylism).
• Errors in nucleic acid metabolism: These are X-linked recessive diseases, such as Lesch-Nyhan syndrome.

Hemoglobin Disorders

These are hereditary diseases characterized by an alteration in the synthesis and function of hemoglobin. Hemoglobin is a molecule with four polypeptide chains attached to a heme group. There are four main types of hemoglobin:

• Hemoglobin A: Represents 98% of the hemoglobin in adults.
• Hemoglobin A2: Represents 2% of adult hemoglobin. It possesses 2 alpha chains and 2 beta chains.
• Embryonic hemoglobin: It has 2 alpha chains and 2 epsilon chains.
• Fetal hemoglobin: It has 2 alpha chains and 2 gamma chains.

Another major hemoglobin disorder is Sickle cell anemia (Hb S).

Thalassemia

Thalassemia is a disease associated with the unequal production of globin chains (alpha or beta). The resulting erythrocytes are hypochromic and microcytic. There are two main types based on the genetic defect:

• Deletions in the chain: The globin chains are encoded by 2 genes on chromosome 16. If there is a loss or deletion of one gene, there are no symptoms (silent carrier). If you lose 2 genes, the erythrocytes will be small and hypochromic, resulting in mild anemia.
• Nonsense mutations in the chain: The globin chains are encoded by 1 gene on chromosome 11. Reduced synthesis leads to two types:
  • Thalassemia minor: Often overlooked as its diagnosis is usually incidental; it produces mild anemia.
  • Thalassemia major (Cooley's anemia): A very serious disease that usually appears between 4 and 6 months of life.