Inborn errors of Metabolism(IEM) Romana Siddique

Inborn errors of metabolism Many autosomal recessive traits reflect mutations in key metabolic enzyme and result in a variety of disorders classified as inborn errors of metabolism. Garrod termed these disorders as “inborn errors of metabolism”. In these cases a single nucleotide substitution has produced a recessive allele(i.e., both parents must be carriers) that interferes with a metabolic pathway and causes death and illness of the homozygotes. Now also refered to as ‘congenital metabolic disorders’ or ‘ inherited metabolic disorder’.

What is genetic disorder? A genetic disorder is a disease that is caused by an abnormality in an individuals DNA. Abnormalities can range from a small mutation in a single gene to the addition or subtraction of an entire chromosome or set of chromosomes.

Cystinuria is an autosomal recessive defect in reabsorptive transport of cystine and the dibasic amino acids ornithine, arginine, and lysine from the luminal fluid of the renal proximal tubule and small intestine. Mutations in genes for transportation protein in kidney prevents reabsorption of cystein in blood from proximal convoluted tubules.

Lysinemia Caused by the lack of enzymes leading to inability to metabolize lysine. Characterized by muscular weakness and mental retardation.

Maple syrup urine disease Maple syrup urine disease is an inherited disorder in which the body is unable to process certain protein building blocks (amino acids) properly. The condition gets its name from the distinctive sweet odor of affected infants' urine. Beginning in early infancy, this condition is characterized by poor feeding, vomiting, lack of energy (lethargy), and developmental delay. If untreated, maple syrup urine disease can lead to seizures, coma, and death. What genes are related to maple syrup urine disease? Mutations in the BCKDHA, BCKDHB, DBT, and DLD genes can cause maple syrup urine disease. These four genes provide instructions for making proteins that work together as a complex. The protein complex is essential for breaking down the amino acids leucine, isoleucine, and valine, which are present in many kinds of food (particularly protein-rich foods such as milk, meat, and eggs).

How do people inherit maple syrup urine disease? This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Inborn errors leading to Nutritional disorder Numerous inherited metabolic disorders,respond to dietary treatment. Most of these relatively rare disorders are inherited as autosomal recessive traits and result in a specific enzyme or cofactor that that has reduced activity or is absent altogether Pernicious anemia-is a form of megaloblastic anemia due to vitamin B12 deficiency dependent on impaired absorption of vitamin B12 due to the absence of intrinsic factor.

Errors in Carbohydrate metabolism Pentosuria-a condition where xylulose ( a pentose) is present in the urine in unusually high concentrations. It is associated with a defiency of L-xylulose reductase. L-xylulose is a reducing sugar so it may give false diagnosis as it is found in high concentrations in urine.

Galactosemia is a disorder that affects how the body processes a simple sugar called galactose. A small amount of galactose is present in many foods.Seen shortly after birth.

Errors in lipid metabolism Niemann-Pick disease is an autosomal recessive disorder affecting lipid metabolism(the breakdown and use of fats and cholesterol in the body),in a way which causes harmful amounts of lipids to accumulate in the spleen, liver,lungs ,bone marrow, and brain. High level of fat compouds in the body as a result.

Errors in nucleic acid metabolism Gout:Deposition of Uric acid Drug:Allopurinol Gout ia a disease created by a build up of uric acid. In this condition ,mono sodium urate or uric acid crystals are deposited on the articular cartilage of joints, tendons and surrounding tissues due to elevated concentrations of uric acid in the blood stream. This provokes an inflammatory reaction of thiese tissues.

What is LNS? LNS is a genetic disorder first discovered in 1964 by Michael Lesch and William Nyhan. It is a recessive disease that is linked to the X chromosome It is caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT)

Symptoms of LNS All of the following are a result of an overproduction of Uric Acid Urate crystal formations, which look like orange sand, are deposited in diapers of the babies Kidney stones Blood in the urine Dysphagia (difficulty swallowing) Swelling of the joints Vomiting Athetosis (uncontrolled spastic muscle movements of the arms and legs) Involuntary writhing movements Chorea (purposeless repetitive movements) Moderate mental retardation Irritability

HPRT’s role in the body Hypoxanthine-guanine phosphoribosyltransferase is an enzyme that plays a key role in the recycling of the purine bases, hypoxanthine, and guanine into purine nucleotide pools Without HPRT the purine bases are broken down and excreted as uric acid Since these purine bases cannot be reused, the production of purine bases is increased Both of these together cause a significant overproduction of uric acid in all body fluids, and leads to problems such as severe gout , por muscle control, and moderate retardation, which apper in the first year of life.

Other genetic diseases Wilson diseases, in which death results from poisning by copper because of a blockage in the pathway of copper detoxification.

History of SLE 1948 – Malcolm Hargraves discovers the lupus erythematosus (LE) cell. 1957 – The first anti-DNA antibody is identified.

LE Cell The LE cell is a neutrophil that has engulfed the antibody-coated nucleus of another neutrophil. LE cells may appear in rosettes where there are several neutrophils vying for an individual complement covered protein.

Symptoms Non-specific: Fatigue Weight loss Malaise = generally feeling ill Fever Anorexia (over time) Arthritis 90% of patients experience arthritic symptoms Symmetrical Appears in hands, wrists, and knees mainly

Systemic Lupus Erythematosus Affects the Skin Joints Serous membranes Renal system Hematologic system Neurologic system

Systemic Lupus Erythematosus A variable disease Chronic Unpredictable Characterized by exacerbations & remissions