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8.Biochemical Genetics:

Disorders of Metabolism

VARIANTS OF METABOLISM

Inheritance of Metabolic Defects Most metabolic disorders are inherited in an autosomal recessive pattern: Only individuals having two mutant alleles are affected. Although a mutant allele produces reduced or no enzyme activity (loss of function), it usually does not alter the health of a heterozygous carrier. Because many of the genes encoding disease-related enzymes have been identified and their mutations characterized, carrier testing and prenatal diagnosis are available for many metabolic disorders. However, testing samples of dried blood for elevated levels of metabolites in the newborn period (e.g., for phenylketonuria and galactosemia) remains the most commonly used population-based screening test for metabolic disorders. Expanded newborn screening that tests for dozens of different disorders by checking for the presence of abnormal metabolites in blood is common. As the technology for rapid and efficient DNA testing of mutant alleles progresses, population-based screening for additional disorders is likely to be incorporated.

DEFECTS OF METABOLIC

PROCESSES

Almost all biochemical reactions in the human body are controlled by enzymes , which act as catalysts. The catalytic properties of enzymes typically increase reaction rates by more than a million-fold. These reactions mediate the synthesis, transfer, use, and degradation of biomolecules to build and maintain the internal structures of cells, tissues, and organs. Biomolecules can be categorized into four primary groups: nucleic acids, proteins, carbohydrates, and lipids. The major metabolic pathways that metabolize these molecules include glycolysis, citric acid cycle, pentose phosphate shunt, gluconeogenesis, glycogen and fatty acid synthesis and storage, degradative pathways, energy production, and transport systems. We now discuss how defects in each of these metabolic pathways can cause human disease.

Carbohydrate Metabolism

Carbohydrates function as substrates for energy production and storage, as intermediates of metabolic pathways, and as the structural framework of DNA and RNA. Consequently, carbohydrates account for a major portion of the human diet and are metabolized into three principal monosaccharides: glucose, galactose, and fructose. Galactose and fructose are converted to glucose before glycolysis. The failure to effectively use these sugars accounts for the majority of the inborn errors of human carbohydrate metabolism

GALACTOSE

Classic galactosemia typically manifests in the newborn period with poor sucking, failure to thrive, and jaundice. If galactosemia is left untreated, sepsis, hyperammonemia, and shock leading to death usually follow. Cataracts (opacification of the lens of the eye) are found in about 10% of infants. Newborn screening for galactosemia is widespread, and most affected persons are identified as they begin to develop symptoms. Early identification affords prompt treatment, which consists largely of eliminating dietary galactose. e thought to be caused by endogenous production of galactose. The effects of prospective dietary therapy on the prevalence of these long-term sequelae are less clear. Early studies suggested that there was no effect, but as more longitudinal data become available, it appears that patients treated early in life with dietary therapy may have a normal cognitive outcome.

FRUCTOSE

Three autosomal recessive defects of fructose metabolism have been described. The most common is caused by mutations in the gene encoding hepatic fructokinase. This enzyme catalyzes the first step in the metabolism of dietary fructose, the conversion to fructose-1- phosphate. Inactivation of hepatic fructokinase results in asymptomatic fructosuria (presence of fructose in the urine).

Enzymatic defects in this pathway cause hyperglycemia (1), Von Gierke disease (2), fructosuria (3), hereditary fructose intolerance (4), Cori disease (5), Anderson disease (6), Tarui disease (7), and fructose 1,6-bisphosphatase (FBPase) deficiency (8). UDP, Uridine diphosphate.

FRUCTOSE

Deficiency of hepatic fructose 1,6-bisphosphatase (FBPase) causes impaired gluconeogenesis, hypoglycemia (reduced level of circulating glucose), and severe metabolic acidemia (serum Ph <7.4) Affected infants commonly present for treatment shortly after birth, although cases diagnosed later in childhood have been reported. If patients are adequately supported beyond childhood, growth and development appear to be normal.A handful of mutations have been found in the gene encoding FBPase, some of which encode mutant proteins that are inactive in vitro.

Glucose

Abnormalities of glucose metabolism are the most common errors of carbohydrate metabolism. However, the causes of these disorders are heterogeneous and include both environmental and genetic factors. Historically, disorders associated with elevated levels of plasma glucose (hyperglycemia) have been classified into three categories: type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and maturity onset diabetes of the young (MODY), of which there are many subtypes. T1DM is associated with reduced or absent levels of plasma insulin and usually manifests in childhood. DM type 2 is characterized by insulin resistance and, most commonly, adult onset.

GLYCOGEN

Carbohydrates are most commonly stored as glycogen in humans. Consequently, enzyme deficiencies that lead to impaired synthesis or degradation of glycogen are also considered disorders of carbohydrate metabolism. Defects of each of the proteins involved in glycogen metabolism have been identified. These cause different forms of glycogen storage disorders and are classified numerically according to the chronological order in which their enzymatic basis was described. The two organs most severely affected by glycogen storage disorders are the liver and skeletal muscle. Glycogen storage disorders that affect the liver typically cause hepatomegaly (enlarged liver) and hypoglycemia (low plasma glucose level). Glycogen storage disorders that affect skeletal muscle cause exercise intolerance, progressive weakness, and cramping. Some glycogen storage disorders, such as Pompe disease, can also affect cardiac muscle, causing cardiomyopathy and early death. Treatment of some glycogen storage disorders by enzyme replacement (e.g., giving active forms of the enzyme intravenously) can improve, and in some cases prevent, symptoms and therefore preserve function and prevent early death

Phenylalanine

Defects in the metabolism of phenylalanine (an essential amino acid) cause the hyperphenylalaninemias, some of the most widely studied of all inborn errors of metabolism. These disorders are caused by mutations in genes that encode components of the phenylalanine hydroxylation pathway. Elevated levels of plasma phenylalanine disrupt essential cellular processes in the brain such as myelination and protein synthesis, eventually producing severe intellectual disability. Treatment of most hyperphenylalaninemias is aimed at restoring normal blood phenylalanine levels by restricting dietary intake of phenylalanine-containing foods. A complete lack of phenylalanine is fatal. Thus, a fine balance must be maintained between providing enough protein and phenylalanine for normal growth and preventing the serum phenylalanine level from rising too high.