metabolic disease
metabolic disease, any of the diseases or disorders that disrupt normal metabolism, the process of converting food to energy on a cellular level. Thousands of enzymes participating in numerous interdependent metabolic pathways carry out this process. Metabolic diseases affect the ability of the cell to perform critical biochemical reactions that involve the processing or transport of proteins (amino acids), carbohydrates (sugars and starches), or lipids (fatty acids).
Metabolic diseases are typically hereditary, yet most persons affected by them may appear healthy for days, months, or even years. The onset of symptoms usually occurs when the body’s metabolism comes under stress—for example, after prolonged fasting or during a febrile illness. For some metabolic disorders, it is possible to obtain prenatal diagnostic screening. Such analysis usually is offered to families who have previously had a child with a metabolic disease or who are in a defined ethnic group. For example, testing for Tay-Sachs disease is relatively common in the Ashkenazi Jewish population. Countries that perform screening for metabolic diseases at birth typically test for up to 10 different conditions. Tandem mass-spectrometry is a new technology that allows for the detection of multiple abnormal metabolites almost simultaneously, making it possible to add approximately 30 disorders to the list of conditions for which newborns may be tested. If an infant is known to have a metabolic disorder soon after birth, appropriate therapy can be started early, which may result in a better prognosis. Some metabolic disorders respond very well if treatment is introduced at an early age. However, others have no effective therapy and cause severe problems, despite early diagnosis. In the future, gene therapy may prove successful in the treatment of some of these diseases.
Metabolic diseases are quite rare individually, but they are relatively common when considered as a group. Specific metabolic disorders have incidences ranging from approximately 1 in 500 (or even higher in isolated populations) to fewer than 1 in 1,000,000. As a group, it has been estimated that metabolic disorders affect approximately 1 in 1,000 individuals.
The origins of metabolic disease
Metabolic pathways
In 1908 British physician Sir Archibald Garrod postulated that four inherited conditions of lifelong duration—alkaptonuria, pentosuria, albinism, and cystinuria—were caused by defects in specific biochemical pathways due to the diminished activity or complete lack of a given enzyme. He called these disorders “inborn errors of metabolism.” Although Garrod was incorrect in his categorization of cystinuria, his insights provided the field of biochemical genetics with a solid foundation, and the list of inherited inborn errors of metabolism has rapidly grown. This article is primarily concerned with these inherited metabolic diseases, although other disorders, including endocrine diseases (e.g., diabetes mellitus and hypothyroidism) and malnutrition (e.g., marasmus and kwashiorkor), also affect cellular metabolism.
Food is broken down in a series of steps by cellular enzymes (proteins that catalyze the conversion of compounds called substrates) into products with a different biochemical structure. These products then become the substrate for the next enzyme in a metabolic pathway. If an enzyme is missing or has diminished activity, the pathway becomes blocked, and the formation of the final product is deficient, resulting in disease. Low activity of an enzyme may result in the subsequent accumulation of the enzyme’s substrate, which may be toxic at high levels. In addition, minor metabolic pathways that usually lie dormant may be activated when a substrate accumulates, possibly forming atypical, potentially toxic, products. Each cell in the body contains thousands of metabolic pathways, all of which are interlinked to some extent, so that a single blockage may affect numerous biochemical processes.
The consequences of metabolic imbalance may be severe; intellectual disability, seizures, decreased muscle tone, organ failure, blindness, and deafness may occur, depending on which enzyme is dysfunctional. In recent years, it has become apparent that even some conditions associated with multiple congenital anomalies (e.g., Smith-Lemli-Opitz syndrome) have an underlying metabolic cause.
Genetic mutations
The molecular blueprint for nearly all enzymes, structural proteins, cellular transport proteins, and other constituents that are responsible for carrying out the complex reactions involved in metabolism is stored as deoxyribonucleic acid (DNA) in the nucleus of the cell. A small amount of DNA of critical importance to metabolism also is contained in cellular organelles called mitochondria. DNA is organized into smaller units, termed genes, which direct the production of specific proteins or enzymes. In 1945 American geneticists George Beadle and Edward Tatum proposed a central tenet of molecular biology, the “one gene-one enzyme” principle, which states that a single gene directs the synthesis of a single enzyme. This principle has been refined to account for the fact that not all gene products are enzymes and that some enzymes are composed of multiple structural units encoded by different genes. Nevertheless, the one gene-one enzyme theory had immediate implications when applied to Garrod’s initial theories regarding inborn errors of metabolism. Inherited metabolic diseases were postulated to occur when a gene is mutated in such a way as to produce a defective enzyme with diminished or absent function. In 1948 methemoglobinuria became the first human genetic disease to be identified as being caused by an enzyme defect. In 1949 American chemist Linus Pauling and colleagues demonstrated that a mutation causes a structural alteration in a protein; hemoglobin (the protein in red blood cells that carries oxygen to the tissues of the body) extracted from normal human red blood cells was shown to behave differently from hemoglobin taken from persons with the hereditary disease sickle-cell anemia. Thus, it was determined that mutant genes that direct the formation of abnormal proteins with altered function cause inborn errors of metabolism.
Inheritance
The inheritance of inborn errors of metabolism is most often autosomal recessive, meaning that two mutant genes are required to produce the signs and symptoms of disease. The parents of an affected child are most often asymptomatic carriers, because 50 percent of normal enzyme activity is adequate to maintain sufficient health. When two carriers of a deleterious trait produce offspring, however, there is a 25 percent chance of having an affected child, a 25 percent chance of having a child without the mutant allele, and a 50 percent chance of having a child who is also a carrier. In genetic terms, the carrier of an autosomal recessive condition has only one mutant gene (heterozygous), while an affected individual has two mutant genes (homozygous). All human beings have approximately six recessive mutant alleles in their genomes, but it is relatively rare for an individual to mate with someone who carries a mutation in the same gene. However, in cases of parental consanguinity, there is an increased risk of having a child with an autosomal recessive condition, because a common genetic background is shared.
Unlike autosomal recessive diseases, autosomal dominant diseases are expressed when only one mutant gene is present. These disorders show a strong family history, unless the condition arose from a new spontaneous mutation in an individual. A heterozygous individual has a 50 percent chance of passing the disorder to his offspring. Individuals with autosomal dominant disorders show a wide spectrum of disease severity, and carriers of a dominant trait may even appear asymptomatic.
Genetic material in the nucleus is found packed into DNA-protein complexes called chromosomes. Females have two X chromosomes, while males have an X and a Y chromosome. If a mutant gene is part of the X chromosome, the resulting disease is called X-linked. All male offspring who inherit an X-linked mutation are affected, because the Y chromosome of the XY pair does not have a compensating normal gene. Because the mutation is on the X chromosome and males transmit only the Y chromosome to their sons during fertilization, fathers do not transmit the disease to their sons. They can, however, transmit the carrier state (i.e., the mutant X chromosome) to their daughters. A heterozygous female carrier, meanwhile, has a 50 percent chance of producing a carrier daughter or affected son.
X-linked inheritance is complicated by the process of X chromosome inactivation (lyonization) in females. Although females carry two X chromosomes, early in embryonic development one of the X chromosomes is inactivated in each cell. The process of X chromosome inactivation is usually random, resulting in the formation of two cell lines in a given female who carries an X-linked disease mutation; one cell line has an inactivated normal X chromosome, and the other has an inactivated abnormal X chromosome. However, it is possible that a higher proportion of normal X chromosomes will be inactivated in a given individual, with the resultant appearance of symptoms of disease in various degrees. Such females are known as manifesting heterozygotes. Examples of X-linked disorders include ornithine transcarbamylase deficiency (an enzyme deficiency resulting in high blood levels of ammonia and impaired urea formation), X-linked adrenoleukodystrophy (a disorder that is characterized by progressive mental and physical deterioration and adrenal insufficiency), and Lesch-Nyhan syndrome (a disorder of purine metabolism that is characterized by the excretion of large amounts of uric acid in the urine, neurological disturbances, and self-mutilation).
The transmission of genes that are located in mitochondria (i.e., not contained in the nucleus of the cell) is termed maternal (mitochondrial) inheritance. Mitochondrial DNA (mtDNA), although much smaller than nuclear DNA, is critical in cellular metabolism. Most of the energy required by a cell to drive its metabolism is produced in mitochondria by proteins in a series of electron donor-acceptor reactions that make up the electron-transport, or respiratory, chain. Mitochondria are located in the cytoplasm of the ova and are inherited from the mother. Spermatozoa also have mitochondria, but these do not become incorporated into the developing embryo. When a cell divides, the mitochondria are randomly distributed to daughter cells. Each mitochondrion contains 2 to 10 copies of mtDNA, and each cell contains numerous mitochondria. In a given cell of a person with a mitochondrial disorder, the number of normal mitochondria may be greater than the number of abnormal mitochondria, and the cell may function well. On the other hand, if a cell contains a significant percentage of abnormal mitochondria, this cell and any tissue containing many such cells will exhibit impaired function. Affected children may demonstrate a spectrum of abnormalities, from appearing normal or mildly affected to being severely compromised, depending on the degree of mitochondrial dysfunction and the extent of tissue involvement.
