17. Metabolic Diseases 2

Carbohydrates Overview

• Definition: Large biological molecules made of carbon (C), hydrogen (H), and oxygen (O).

• Chemical Groups:

  • Monosaccharides

  • Disaccharides

  • Oligosaccharides

  • Polysaccharides

• Functions in Organisms:

  • Energy storage (starch, glycogen)

  • Structural components (cell walls, RNA, DNA backbone)

  • Immunity, fertilization, blood clotting, development.

• Lactose:

  • Disaccharide formed from D-galactose and D-glucose.

  • Chemical formula: C12H22O11.

Galactose Metabolism

• Galactose metabolism: converts galactose to glucose.

  • Key enzymes:

    • Galactokinase (GALK)

    • Galactose-1-phosphate uridyltransferase (GALT)

    • UDP-galactose-4’-epimerase (GALE)

Galactosemia

• Prevalence: 1 in 30,000 newborns, caused primarily by GALT mutations.

• Gene Info: Located on chromosome 9 (9p13), consists of 11 exons, encodes a 379 aa protein.

• Symptoms: Toxic accumulation of galactose-1-phosphate leads to:

  • Hepatomegaly, renal failure, cataracts, severe developmental issues.

• Diagnostic Methods: Newborn screening to detect enzyme levels before galactose intake.

Treatment for Galactosemia

• Dietary Management: Eliminate lactose and galactose.

• Potential Therapies:

  • Gene Therapy: Use CRISPR to correct mutations.

  • mRNA Therapy: Systemically administered mRNA to restore enzyme activity.

  • Pharmacological Chaperones: Small molecules that aid in protein stability.

Fructose Metabolism

• Fructose Classification: Simple monosaccharide found with glucose in sucrose.

• Common Disorders:

  • Fructosuria: Caused by hepatic fructokinase deficiency; benign in symptoms.

Hereditary Fructose Intolerance (HFI)

• Prevalence: 1 in 20,000 births, caused by ALDOB gene mutations on chromosome 9.

• Genetic Basis: Mutations result in deficiencies in fructose aldolase.

• Symptoms: Include severe hypoglycemia, vomiting, jaundice, and renal dysfunction.

  • After infancy, symptoms only occur if fructose is ingested, so treated with diet restriction

Glucose Metabolism

• Metabolic Process: Glycolysis and citric acid cycle convert glucose to ATP.

• Regulation: Insulin and glucagon control blood sugar levels.

Insulin Function and Regulation

• Produced in beta cells of pancreas, responds to blood glucose levels.

• Mechanism: Binds to receptors on liver, muscle, fat cells, aiding in glucose uptake.

  Type 1 Diabetes: Autoimmune destruction of insulin-producing cells.

  • Type 2 Diabetes: Insulin resistance often tied to obesity and lifestyle factors.

Type 1 Diabetes

• Cause: autoimmune-mediated destruction of insulin-producing β-cells in the pancreas, resulting in absolute insulin deficiency

• Symptoms: polyuria (frequent urination), polydipsia (increased thirst), polyphagia (increased hunger), and weight loss

• Treatment: regular insulin injections or pumps to lower blood sugar to normal range, dietary monitoring.

Type 2 Diabetes

• Cause: insulin resistance in peripheral tissues combined with relative insulin deficiency, often associated with obesity and sedentary lifestyle

• Symptoms: fatigue, blurred vision, slow-healing wounds, and recurrent infections

• Treatment: lifestyle modifications including weight loss, exercise, and oral hypoglycemic agents to improve insulin sensitivity, with insulin therapy if necessary.

Heavy Metals in Metabolism

• Roles: Essential as cofactors for various enzymes, but excessive amounts can be toxic.

• Common Heavy Metals: Chromium, copper, zinc, iron.

Copper

• a key constituent of the respiratory enzyme complex cytochrome c oxidase.

• absorbed by epithelial cells of the small intestine and is then distributed by various chaperone proteins

• Genes:

  • ATP7A: expressed in the small intestine

    • mediates the transport if copper into the bloodstream

  • ATP7B: expressed in the liver and kidney

    • controls the excretion of copper into the biliary tree

• Diseases:

  • Menkes Disease: X-linked disorder caused by mutations in ATP7A

    • inability to export copper into the bloodstream

    • copper deficiency

  • Wilson Disease: autosomal disorder caused by mutation in ATP7B

    • copper accumulation in tissues

    • liver disease and neurological abnormalities

Zinc

• Critical in DNA/RNA synthesis and enzyme reactions.

• Absorption of dietary zinc occurs over the duodenal and jejunal regions of the gastrointestinal tract

• Acrodermatitis enteropathica: autosomal recessive disorder caused by mutations in genes encoding for zinc uptake protein

  • Zinc deficiency can lead to growth retardation, hair loss, and impaired immune function.

  • Severe dermatitis

Iron

• Key in oxygen transport, found in hemoglobin and myoglobin.

• Hemochromatosis: autosomal recessive disorder caused by mutations in gene that regulates the cell’s ability to sense iron levels.

  • Leading to excessive iron storage

  • fatigue, joint pain, diabetes, increased skin pigmentation, cardiomyopathy, liver enlargement, and cirrhosis

Gadolinium

• Rare earth metal used in MRI contrast agents.

• Free gadolinium can be harmful; symptoms include pain and cognitive dysfunction.

• Gadolinium Poisoning: mostly occur in small levels after MRI

  • pain, dermal changes, muscle issues, cognitive symptoms