Inborn Errors of Metabolism

1. Inborn Errors of Metabolism Dr Maha Al-Sulaimani Department of Biochemistry College of Sciences

2. Inborn Errors of Metabolism • Inborn errors of metabolism comprise a large class of genetic diseases involving disorders of metabolism. • The majority are due to defects of single genes that code for enzymes.

3. Inborn Errors of Metabolism • In most of the disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or to the effects of reduced ability to synthesize essential compounds. Inborn errors of metabolism are now often referred to as congenital metabolic diseases or inherited metabolic diseases.

4. Categories of Inherited metabolic Disease • Traditionally the inherited metabolic diseases were categorized as disorders of carbohydrate metabolism, amino acid metabolism, organic acid metabolism, or lysosomal storage diseases. • In recent decades, hundreds of new inherited disorders of metabolism have been discovered and the categories have proliferated.

5. Categories of Inherited metabolic Disease • Disorders of carbohydrate metabolism: • E.g., glycogen storage disease. • Disorders of amino acid metabolism: • E.g., phenylketinuria , maple syrup urine disease, glutaricacidemia type 1. • Disorders of organic acid metabolism (organic acidurias): • E.g., alcaptonuria.

6. Categories of Inherited metabolic Disease • Disorders of fatty acid oxidation and mitochondrial metabolism: • E.g., Medium-chain acyl-coenzyme A dehydrogenase deficiency (often shortened to MCADD). • Disorders of porphyrin metabolism: • E.g., acute intermittent porphyria.

7. Categories of Inherited metabolic Disease • Disorders of purine or pyrimidine metabolism: • E.g., Lesch-Nyhan syndrome. • Disorders of steroid metabolism: • E.g., congenital adrenal hyperplasia. • Disorders of mitochondrial function: • E.g., Kearns-Sayre syndrome.

8. Categories of Inherited metabolic Disease • Disorders of peroxisomal function: • E.g., Zellweger syndrome. • Lysosomal storage disorders: • E.g., Gaucher's disease. • E.g., Niemann Pick disease.

9. Diagnostic Techniques • Dozens of congenital metabolic diseases are now detectable by newborn screening tests, especially the expanded testing using mass spectrometry (mass v. ionic charge). • This is an increasingly common way for the diagnosis to be made and sometimes results in earlier treatment and a better outcome.

10. Diagnostic Techniques • An abnormal result is often followed by a subsequent "definitive test" to confirm the suspected diagnosis. • Common screening tests used in the last sixty years include: • Ferric chloride test (turns colors in reaction to various abnormal metabolites in urine). • Ninhydrin paper chromatography (detects abnormal amino acid patterns).

11. Diagnostic Techniques 3. Quantitative measurement of amino acids in plasma and urine. 4. Urine organic acid analysis by Gas chromatography-mass spectrometry. 5. Plasma acylcarnitine analysis by mass spectrometry. 6. Urine purine and pyrimidine analysis by Gas chromatography-mass spectrometry.

12. Diagnostic Techniques 7. Specific diagnostic tests (or focused screening for a small set of disorders): • Tissue biopsy or necropsy: liver, muscle, brain, bone marrow. • Skin biopsy and fibroblast cultivation for specific enzyme testing. • Specific DNA testing.

13. Treatment • Dietary restriction: • E.g., reduction of dietary protein remains a mainstay of treatment for phenylketonuria and other amino acid disorders. • Dietary supplementation or replacement: • E.g., oral ingestion of cornstarch several times a day helps prevent people with glycogen storage diseases from becoming seriously hypoglycemic.

14. Treatment • Vitamins: • E.g., thiamine supplementation benefits several types of disorders that cause lactic acidosis. • Intermediary metabolites, compounds, or drugs that facilitate or retard specific metabolic pathways. • Dialysis.

15. Treatment • Enzyme replacement E.g. Acid-alpha glucosidase for Pompe disease. • Gene transfer. • Bone marrow or organ transplantation. • Treatment of symptoms and complications. • Prenatal diagnosis.

16. Disorders of Carbohydrate Metabolism • Are inherited as autosomal recessive traits. • Most of the known defects of carbohydrate metabolism appear to be due to point mutations.

17. Glycogen Storage Diseases • Glycogen storage diseases are caused by lack of an enzyme needed to change glucose into glycogen (glycogen synthase) and break down of glycogen into glucose (glycogen phosphorylase). • Typical symptoms include weakness, sweating, confusion, kidney stones, and stunted growth.

18. Glycogen Storage Diseases • There are many different glycogen storage diseases (also called glycogenoses), each identified by a roman numeral. • Prevalence: About 1 in 20,000 infants has some form of glycogen storage disease.

19. Glycogen Storage Diseases • Some of these diseases cause few symptoms. Others are fatal. • The specific symptoms, age at which symptoms start, and their severity vary considerably among these diseases. • For types II, V, and VII, the main symptom is usually weakness. For types I, III, and VI, symptoms are low levels of sugar in the blood and protrusion of the abdomen (because excess or abnormal glycogen may enlarge the liver).

20. Glycogen Storage Diseases • Low levels of sugar in the blood cause weakness, sweating, confusion, and sometimes seizures and coma. • Other consequences for children may include stunted growth, frequent infections, and sores in the mouth and intestines.

21. Glycogen Storage Diseases • Glycogen storage diseases tend to cause uric acid to accumulate in the joints, which can cause gout, and in the kidneys, which can cause kidney stones (ATP degradation/glucagon). • In type I glycogen storage disease, kidney failure is common in the second decade of life or later.

22. Glycogen Storage Diseases • The specific type of glycogen storage disease is diagnosed by examining a piece of muscle or liver tissue under a microscope (biopsy). • Treatment depends on the type of glycogen storage disease. For most types, eating many small carbohydrate-rich meals every day helps prevent blood sugar levels from dropping.

23. Glycogen Storage Diseases • For people who have glycogen storage diseases that cause low blood sugar levels, levels are maintained by giving uncooked cornstarch every 4 to 6 hours around the clock. • For others, it is sometimes necessary to give carbohydrate solutions through a stomach tube all night to prevent low blood sugar levels from occurring at night.

24. Types and Characteristics of Glycogen Storage Diseases

25. Types and Characteristics of Glycogen Storage Diseases

26. Diagnosis and Treatment • Definitive diagnosis can only be made through a biopsy of the affected organ. • A primary treatment for individuals with GSD is a well-controlled diet that ensures consistent levels of blood glucose. Symptoms, if properly treated, may subside by the time the patient reaches adulthood. • In severe cases, an organ transplant may be the only option for the patient

27. Disorders of Amino Acid Metabolism • Maple syrup urine disease: is an autosomal recessivemetabolic disorder affecting branched-chain amino acids. • It is one type of organic acidemia. • The condition gets its name from the distinctive sweet odor of affected infants`s urine

28. Cause and symptoms • MSUD is caused by a deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKDC), leading to a build up of the branched-chain amino acids (leucine, isoleucine, and valine) and their toxic by-products in the blood and urine.

29. Symptoms • The disease is characterized in an infant by the presence of sweet-smelling urine, with an odor similar to that of maple syrup. • Infants with this disease seem healthy at birth but if left untreated suffer severe brain damage and eventually die.

30. Diagnosis and symptoms • From early infancy, symptoms of the condition include poor feeding, vomiting, dehydration, lethargy, seizures, hypoglycaemia, ketoacidosis, coma and neurological decline. • A blood test for amino acids can be done. If alloisoleucine is detected, the diagnosis is confirmed.

31. Management • Keeping MSUD under control requires careful monitoring of blood chemistry and involves both a special diet and frequent testing. • A diet with minimal levels of the amino acids leucine, isoleucine, and valine must be maintained in order to prevent neurological damage.

32. Management • As these three amino acids are required for proper metabolic function in all people, specialized protein preparations containing substitutes and adjusted levels of the amino acids have been synthesized and tested, allowing MSUD patients to meet normal nutritional requirements without causing harm.

33. Prevalence • Maple syrup urine disease affects approximately 1 out of 180,000 infants.