Inherited metabolic disorders

What is metabolic disorder? Also called inborn errors of metabolism, these are heritable (genetic) disorders of biochemistry. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (Substrates) into others (products) In most disorders, problems arise due to: Accumulation of substances which are toxic or interfere with normal function the effects of reduced ability to synthesize essential compounds

Figure 16. 4 Effects of enzyme defects Figure 16.4 Effects of enzyme defects. (a) Product D is synthesized from A by a series of reactions catalysed by enzymes a, band c. Enzyme c' catalyses the formation of a small amount of product E in a minor pathway. (b) In the absence of the enzyme c, no D is synthesized. (c) If the conversion of C to D is blocked, the concentration of the intermediate C, and possibly other precursors, may increase. (d) Increased formation of E may occur if the concentration of C increases and conversion of C to D is blocked.

Types of inherited disorders Disorders of carbohydrate metabolism Disorders of amino acid metabolism Urea Cycle Disorder. Disorders of organic acid metabolism Disorders of fatty acid oxidation Disorders of porphyrin metabolism Disorders of purine or pyrimidine metabolism Disorders of steroid metabolism Disorders of mitochondrial function Disorders of peroxisomal function Lysosomal storage disorders

Examples of inherited metabolic disorders Glucose-6-phosphatase deficiency Galactosaemia Phenylketonuria Steroid 21-hydroxylase deficiency Cystic fibrosis

Glucose-6-phosphatase deficiency G6PD deficiency is an inherited condition in which the body doesn't have enough of the enzyme glucose-6-phosphate dehydrogenase, or G6PD, which helps red blood cells (RBCs) function normally. This deficiency can cause hemolytic anemia, usually after exposure to certain medications, foods, or even infections.

Functions of G6PD G6PD is one of many enzymes that help the body process carbohydrates and turn them into energy. G6PD also protects red blood cells from potentially harmful byproducts that can accumulate when a person takes certain medications or when the body is fighting an infection.

Figure 16. 5 Glucose productions by glycogenolysis and gluconeogenesis Figure 16.5 Glucose productions by glycogenolysis and gluconeogenesis. Glucose 6-phosphate is an essential intermediate in the production of glucose by either glycogenolysis or gluconeogenesis. In the absence of glucose 6-phosphatase, glucose cannot be formed from glucose 6-phosphate.

Causes of G6PD Deficiency G6PD deficiency is passed along in genes from one or both parents to a child. The gene responsible for this deficiency is on the X chromosome. G6PD deficiency is more likely to affect males than females. (Why?)

Children with this disorder are prone to severe fasting hypoglycaemia since . Acute hypoglycaemia is treated with intravenous glucose infusion. Maintenance treatment is with frequent daytime feeding and overnight constant intragastric infusion with a glucose/glucose polymer feed. Older children are given uncooked corn starch, from which glucose is released only slowly in the gut.

Genetics of G6PD

Hemolysis in G6pD patients

Galactosaemia is a rare autosomal recessive genetic disorder that affects an individual’s ability to metabolize galactose properly.

Causes In classic galactosaemia: Three enzyme defects can cause galactosaemia. In classic galactosaemia: the absence of the enzyme galactose 1-phosphate uridyl transferase, which: results in the accumulation of galactose 1-phosphate, and the clinical features of the condition are thought to be due directly to the toxicity of this metabolite. In addition, the plasma concentration of galactose is increased and galactose is excreted in the urine. There may also be hypoglycaemia and impairment of renal tubular function.

Deficiency of the enzyme UDP-galactose 4-epimerase causes a similar clinical syndrome, but is much less common. Deficiency of the enzyme galactokinase Prevents the phosphorylation of galactose Leads to an increase in the plasma concentration of galactose and thus to galactosuria.

Figure 16.6 metabolic pathways for the conversion of galactose to glucose. UDP (uridine diphosphate).

Phenylketonuria Phenylketonuria (PKU) is another condition in which the accumulation of the substrate of the missing enzyme gives rise to a clinical syndrome. The enzyme concerned is phenylalanine hydroxylase, which: Hydroxylates phenylalanine to form tyrosine Phenylalanine accumulates in the blood and if the condition is untreated it results in severe learning difficulties, Thought to be due directly to the effect of excess phenylalanine on the developing brain.

Figure 16.7 metabolic pathways for the conversion of phenylalanine to tyrosine. The site of action of phenylalanine hydroxylase, the enzyme deficient in Phenylketonuria (PKUI, is shown.

Tyrosine, is a precursor of this pigment. The name of the condition derives from the urinary excretion of phenylpyruvic acid, (a phenylketone). This is normally a minor metabolite of phenylalanine but is produced in excess when the normal, major metabolic pathway is blocked. Many children with PKU have fair hair and blue eyes, owing to defective melanin synthesis: Tyrosine, is a precursor of this pigment. The diagnosis depends on the demonstration of an abnormally high concentration of phenylalanine in the blood

Since phenylalanine is an essential amino acid, a certain amount must be provided in the diet, and while tyrosine is not normally an essential amino acid, It becomes so when the intake of phenylalanine is limited: adequate quantities must therefore be provided. Thus treated, children in whom a diagnosis of PKU is made shortly after birth will grow and develop normally. Untreated, they rarely achieve an IQ of above 70, and usually require life-long institutional care.

Steroid 21-hydroxylase deficiency refers to any of several autosomal recessive diseases resulting from mutations of genes for enzymes mediating the biochemical steps of production of cortisol from cholesterol by the adrenal glands.

Figure 16.8 Adrenal steroid hormone synthesis, showing the increased synthesis of androgens when cortisol synthesis is blocked. Decreased 21-hydroxylase activity (i) leads to decreased cortisol synthesis (ii). Negative feedback to the pituitary (iii) is decreased leading to increased secretion of ACTH (iv). The conversion of cholesterol to 17-hydroxyprogesterone is stimulated, leading to increased synthesis of androgens (v).

Cystic fibrosis Cystic fibrosis is a disease passed down through families that causes thick, sticky mucus to build up in the lungs, digestive tract, and other areas of the body. It is one of the most common chronic lung diseases in children and young adults. It is a life-threatening disorder.

Clubbed fingers is a symptom of disease

Diagnosis Diagnosis of an inherited metabolic disease requires either: Measurement of the activity of the relevant enzyme Detection of the defective gene.

DNA analysis DNA extraction kit

PCR and gel electrophoresis

Screening for mutation

DNA sequencer

Treatment Restriction of substrate intake Supply of missing product Addition of vitamin cofactors Increased excretion of toxic substances Replacement of missing protein Replacement of the defective gene

References Marshall, W. and Bangert, S. (2008). Clinical chemistry (6th ed.). Edinburgh, London: Mosby Elsevier. ISBN 0723434557 (chapter 16) Gaw, A. et al. (2004). Clinical Biochemistry (3rd ed.) Beckett, G. et al. (2008). Clinical Biochemistry (8th ed.) Bishop., et al. (2000). Clinical Chemistry (4th ed.)