1. Inborn Errors of Metabolism Dr. Mohamed Haseen Basha Assistant professor ( Pediatrics) Faculty of Medicine Al Maarefa College of Science and Technology

2. Major categories of Inherited Metabolic Diseases Disorders of carbohydrate metabolism Galactosemia Glycogen storage disease (types IA, IB, II, III, and IV) Hereditary fructose intolerance Disorders of amino acid metabolism Phenylketonuria Maple syrup urine disease Nonketotic hyperglycinemia Hereditary tyrosinemia

3. Disorders of organic acid metabolism Methylmalonic acidemia Propionic acidemia Isovaleric acidemia Disorders of pyruvate metabolism and the electron transport chain Pyruvate carboxylase deficiency Pyruvate dehydrogenase deficiency Electron transport chain defects

4. Disorders of the urea cycle Ornithine-transcarbamylase deficiency Carbamyl phosphate synthetase deficiency Transient hyperammonemia of the neonate Lysosomal storage disorders GM1 gangliosidosis type I (b-galactosidase deficiency) Gaucher's disease (glucocerebrosidase deficiency) Niemann-Pick disease types A and B (sphingomyelinase deficiency) Disorders of fatty acid oxidation Medium chain acyl dehydrogenase deficiency

5. Disorders of porphyrin metabolism Acute intermittent porphyria Disorders of purine or pyrimidine metabolism Lesch - Nyhan syndrome Disorders of steroid metabolism Congenital adrenal hyperplasia Disorders of mitochondrial function Kearns-Sayre syndrome Disorders of peroxisomal function Zellweger syndrome

6. Disorders of Carbohydrate Metabolism

7. Galactosemia Autosomal recessively inherited disorder results from deficiency of the enzyme galactose-1-phosphate uridyl transferase, which is essential for galactose or lactose metabolism Accumulation of galactose-1-phosphate results in damage to the Brain, Liver and Kidney. When lactose-containing milk feeds such as breast or infant formula are introduced, affected infants develop vomiting, hypoglycemia, feeding difficulties, seizures, irritability, jaundice, hepatomegaly, splenomegaly and hepatic failure. Sepsis due to E coli is typical.

8. Even if treated early, there are usually moderate learning difficulties (adult IQ 60-80). Chronic liver disease, cataracts and developmental delay are inevitable if the condition is untreated. Diagnosis is assisted by Non-glucose reducing substances in urine. Confirmation by Galactose-1-Phosphate uridyl transferase activity in RBCs. Management is with a lactose- and galactose-free diet for life.

9. Hereditary Fructose Intolerance Occurs after ingestion of Fructose or sucrose (Glucose + Fructose) It results from deficiency of enzyme aldolase B results in inability to metabolize Fructose or sucrose Severe and life threatening intoxication occurs with the accumulation of Fructose-1-Phosphate in hepatocytes. Presents with emesis, abdominal pain, seizures and profound illness after ingestion of fructose. May also present similar to Galactosemia. Diagnosis is by enzyme analysis. Life long avoidance of fructose.

10. Glycogen storage disease Glycogen storage disease is the result of defects in the processing of glycogen synthesis or breakdown within muscles, liver, and other cell types. GSD Type I( Von Gierke’s Disease) Enzyme deficiency: glucose-6-phosphatase Symptoms: Hypoglycemia, Hyperlipidemia, Hepatomegaly, Lactic acidosis, and Hyperuricemia. Progression: Growth failure This deficiency impairs the ability of the liver to produce free glucose from glycogen and from gluconeogenesis. Since these are the two principal metabolic mechanisms by which the liver supplies glucose to the rest of the body during periods of fasting, it causes severe hypoglycemia.

11. Treatment: The essential treatment goal is prevention of hypoglycemia and the secondary metabolic derangements by frequent feedings of foods high in glucose or starch. Two methods have been used to achieve this goal in young children: (1) Continuous nocturnal gastric infusion of glucose or starch; and (2) Night-time feedings of uncooked corn starch.

12. GSD Type II- Pompe’s disease Accumulation of glycogen in the lysosome due to deficiency of the lysosomal acid alpha-glucosidase enzyme that transforms glycogen in to glucose in lysosomes. Damages muscle and nerve cells throughout the body. The build-up of glycogen causes progressive muscle weakness (myopathy) throughout the body and affects various body tissues, particularly in the heart, skeletal muscles, and weakness facial and oral muscles. Pompe's disease is one of the infiltrative causes of restrictive cardiomyopathy, Skeletal myopathy, Macroglossia and hepatomegaly. Progression: Death by age - 2years.

13. Treatment: European Medicines Agency (EMEA) and the U.S. Food and Drug Administration (FDA) both granted marketing approval for the drug Myozyme (al glucosidase alfa) for treatment of Pompe's disease. Myozyme replaces the missing enzyme in the disease, which helps to break down the glucose. Early diagnosis and early treatment leads to much better out comes.

14. Disorders of Amino acid Metabolism

15. Phenylketonuria PKU is a metabolic disorder caused by a deficiency of the liver enzyme phenylalanine hydroxylase. The inability to metabolize PKU exists from the time the infant is in the womb.

16. Neurologic signs include seizures, spasticity, hyperreflexia, and tremors, Mental Retardation, severe developmental delay. Fair Skin and blue eyes, “Mousy Odor” & Eczema. It is recommended that the blood for screening be obtained in the first 24- 48 hr of life after feeding protein. For neonatal Screening, The method of choice is Tandem mass spectrometry, which identifies all forms of hyperphenyalaninemia with a low false-positive rate, and excellent accuracy and precision. The addition of the phenylalanine/tyrosine molar ratio has further reduced the number of false- positive results. Diagnosis must be confirmed by measurement of plasma phenylalanine concentration.

17. Meat, fish, eggs, cheese, milk products, legumes, and bread are all foods that have high levels of phenylalanine, should be avoided. The only treatment available for PKU is a low phenylalanine diet for life. It is recommended that women with PKU who are of child bearing age, closely adhere to the low-phenylalanine levels before conception and throughout pregnancy. The risk of miscarriage, mental retardation, microcephaly, and congenital heart disease in the child is high if the mother’s blood phenylalanine is poorly controlled.

18. Maple syrup urine Disease(MSUD) Valine, Ieucine & Isoleucine are the branched chain & essential amino acids. These amino acids serve as an alternate source of fuel for the brain especially under conditions of starvation. Maple Syrup Urine Disease is a genetic disease in which the amino acids leucine, isoleucine and valine cannot be broken down by branched-chain alpha-keto acid dehydrogenase. Clinical Manifestations TimeSymptom/Sign 12-24 hoursMaple syrup odor(Burnt sugar) to cerumen, Elevated BCAA 2-3 daysIrritability, poor feeding, Ketonuria 4-5 daysEncephalopathy (lethargy, apnea, atypical movements) 7-10 daysComa and respiratory failure

19. Diagnosis Peculiar odor of maple syrup found in urine, sweat, and cerumen. confirmed by amino acid analysis showing marked elevations in plasma levels of leucine, isoleucine, valine, and alloisoleucine (a stereoisomer of isoleucine not normally found in blood) Urine contains high levels of leucine, isoleucine, and valine and their respective ketoacids. These ketoacids may be detected qualitatively by adding a few drops of 2,4-dinitrophenylhydrazine reagent (0.1% in 0.1N HCl) to the urine; a yellow precipitate of 2,4-dinitrophenylhydrazone, is formed in a positive test. Neuroimaging during the acute state may show cerebral edema, with advancing age, hypo myelination and cerebral atrophy. The enzyme activity can be measured in leukocytes and cultured fibroblasts. Newborn screening is by Tandem mass spectrometry -based amino acid profiling of dried blood spots between 24 and 48 hours of life

20. Treatment Acute state is aimed at hydration and rapid removal of the branched-chain amino acids and their metabolites from the tissues and body fluids by Peritoneal dialysis or, preferably, hemodialysis is the most effective mode of therapy in critically ill infants. Sufficient calories and nutrients should be provided IV or orally. Cerebral edema, if present, may need to be treated with mannitol, diuretics (e.g. Furosemide), or hypertonic saline. After recovery from the acute state requires a diet low in branched-chain amino acids. Synthetic formulas devoid of leucine, isoleucine, and valine are available commercially. Because these amino acids cannot be synthesized endogenously, small amounts of them should be added to the diet;

21. Tyrosinemia (Type 1) Hepatorenal Tyrosinemia Tyrosinemia type 1 is a Severe disease of the liver, kidney, and peripheral nerves is caused by a deficiency of the enzyme fumaryl acetoacetate hydrolase. Organ damage result from accumulation of metabolites of tyrosine degradation, especially fumaryl acetoacetate and succinyl acetone. In the common form, symptoms develop within the first few months of life and may include diarrhea, bloody stools, failure to thrive, vomiting, lethargy, irritability, and a “cabbage-like” odor to the skin or urine. If untreated, liver problems such as hepatomegaly, jaundice, easy bleeding/bruising, and swelling of the legs/abdomen are common. Kidney problems can cause rickets and delays in walking. Without treatment, liver and kidney problems usually lead to death.

22. Periodic episodes of pain/weakness (particularly in the legs), tachycardia, breathing problems, seizures, and coma may occur. Diagnosis Reduced fumarylacetoacetase enzyme in cultured fibroblasts, Increased tyrosine levels in blood, Increased urinary succinylacetone and tyrosine metabolites, Increased serum alpha feto protein, Liver biopsy shows features of cirrhosis. Management Diet low in tyrosine and phenylalanine formula The treatment of choice is nitisinone(NTBC), which inhibits tyrosine degradation and prevents acute hepatic and neurologic crises. In early-treated patients, nitisinone has greatly reduced the need for liver transplantation.

23. Disorders of Organic acid Metabolism ( Organic Acidaemias)

24. Organic Acidaemias These presents with the elevation of one or more organic acids and often patient presents in the first few days of life severely unwell neonate with acidosis, vomiting and neurological features. Patient may have intermittent acute attacks triggered by stress. Clinical features Vomiting, lethargy, seizures, coma, hypertonia, opisthotonus, hypoglycemia and metabolic acidosis. DiseaseEnzyme defectSpecific treatment Methylmalonic acidemiaCobalamin defectB12 Propionic acidemiaPropionyl Co A CarboxylaseMetronidazole Isovaleric acidemiaIsovaleryl CoA dehydrogenaseGlycine

25. Investigations Metabolic acidosis, Hypoglycemia, ketosis, Hyperammonemia(more than 200) Management Acute attacks are treated with rehydration and calories, Correction of acidosis and hemofiltration if necessary. Benzoate helpful to remove ammonia. Carnitine may be beneficial. Long term features due to organic acidemia are mental retardation, seizures and movement disorders. Failure to thrive, anorexia, osteoporosis and renal impairment may occur.

26. Lysosomal storage disorders

27. Gaucher's disease It is one of the most common lysosomal storage diseases and the most prevalent genetic defect among Ashkenazi Jews. Gaucher disease results from the deficient activity of the lysosomal hydrolase, acid β-glucosidase. The enzymatic defect results in the accumulation of glucosylceramide, in cells of the reticuloendothelial system. This progressive deposition results in infiltration of the bone marrow, progressive hepatosplenomegaly, and skeletal complications.

28. Patient presents with epistaxis or bruising from thrombocytopenia, chronic fatigue secondary to anemia, hepatomegaly with or without elevated liver function test results, splenomegaly, and bone pain. Patients presenting in the 1st decade frequently have growth retardation and a more malignant course. In symptomatic patients, splenomegaly is progressive and can become massive. Most patients develop radiologic evidence of skeletal involvement, including an Erlenmeyer flask deformity of the distal femur. Clinically apparent bony involvement, which occurs in most patients, can present as bone pain, a pseudoosteomyelitis pattern or pathologic fractures. The pathologic hallmark of Gaucher disease is the Gaucher cell in the reticuloendothelial system, particularly in the bone marrow

29. Treatment Enzyme replacement therapy. Most symptoms (organomegaly, hematologic indices, bone pain) are reversed by enzyme replacement therapy. Enzyme preparations are approved by the FDA for the treatment of type 1 Gaucher disease, including vela glucerase alfa and Tali glucerase alfa. Alternative treatment includes, the use of oral substrate reduction agents designed to decrease the synthesis of glucosylceramide by chemical inhibition of glucosylceramide synthase (e.g., miglustat). Bone marrow transplantation (BMT), which is curative.

30. Niemann-Pick disease Niemann-pick is an autosomal recessive genetic disorder resulting in abnormal lipid metabolism. It can result from a deficiency of the acid sphingomyelinase enzyme, Types of Niemann-pick diseases Type A Most severe form, occurs in early infancy. It is characterized by an enlarged liver and spleen, swollen lymph nodes, and profound brain damage by six months of age. Type B involves an enlarged liver and spleen, which usually occurs in the pre-teen years. The brain is not affected. Type C May appear early in life or develop in the teen or adult years. Individuals have only moderate enlargement of the spleen and liver, and brain damage

31. Treatment Currently there is no specific treatment for NPD. Orthotopic liver transplantation in an infant with type A disease and cord blood transplantation in several type B NPD patients. Bone Marrow Transplantation in a small number of type B NPD patients has been successful in reducing the spleen and liver volumes, the sphingomyelin content of the liver, the number of Niemann-Pick cells in the marrow. A phase I trial of enzyme replacement therapy for type B NPD has been completed. Clinical trials of miglustat have been performed and the drug has been approved in Europe for the treatment of type C disease.

32. Disorders of Fatty acid oxidation

33. Fatty acid oxidation disorders Fatty acids are oxidized CO 2 and water in skeletal muscle and heart and to ketones in the liver. Fats are the main source of energy during starvation. All these disorders are AR. Clinical features Vomiting, hypoglycemia, lethargy, and coma induced by fasting. Cardiomyopathy, Muscle weakness, Acute rhabdomyolysis, Reye like syndrome. Disorders of fatty acid oxidation are MCAD- Medium chain acyl dehydrogenase deficiency VLCAD- Very long chain acyl dehydrogenase deficiency LCHAD- Long chain L-3-hydroxyacyl-CoA dehydrogenase deficiency CPT1 - Carnitine palmitoyl transferase1 deficiency

34. Investigations During acute attack- hypoglycemia with low urinary ketones ie, hypo ketotic hypoglycemia. Urinary organic acids Total and free carnitine levels may be low Acyl carnitine profile of blood spot by TMS is usually diagnostic. Confirmation by fibroblast FAOD studies, molecular genetics ex: MCAD mutation. Management Prevention of fasting stress Carnitine may be beneficial.

35. Disorders of Urea cycle

36. Urea cycle disorder The urea cycle is the pathway by which waste nitrogen is converted to urea for disposal. UCDs are inherited as AR except OTC deficiency, which is X-linked recessive. They often presents with neonatal illness with hyperammonemia( lethargy, poor feeding, vomiting, convulsions, coma, respiratory failure) sometimes presents with progressive spastic diplegia and developmental delay in arginase deficiency. Diagnosis Increased Serum ammonia Raised plasma amino acid glutamine Plasma AA and urine Orotic acid usually enables to make an initial diagnosis. Enzyme assay is required to confirm the diagnosis

37. Urea cycle defectEnzyme deficiencyAmino acidOrotic acid N-Acetyl glutamate synthase deficiency N-Acetyl glutamate synthase Glu ↑, Arg ↓, Cit↓Normal Carbamoyl phosphate synthase deficiency Carbamoyl phosphate synthase Glu ↑, Arg ↓, Cit↓Normal Ornithine transcarbamylase deficiency Ornithine transcarbamylaseGlu ↑, Arg ↓, Cit↓↑↑↑ CitrullinemiaArgininosuccinic synthaseGlu ↑, Arg ↓, Cit↑↑↑↑ Argininosuccinic aciduriaArgininosuccinic lyaseGlu ↑, Arg ↓, Cit↑ Argininosuccinate ↑ ↑ ArgininaemiaArginaseGlu ↑, Arg ↑↑↑↑ Arg: Arginine, Cit: Citrulline, Glu: Glutamine

38. Treatment Acute Remove ammonia Increase waste nitrogen excretion using iv sodium benzoate, sodium phenyl butyrate and arginine or dialysis if above ineffective Increase calories to prevent protein breakdown IV 10% glucose, lipids. Nil orally, No protein. Low protein feed after 24-48 hrs IV hydration and electrolyte balance Long term Dietary protein restriction Supplements of benzoate, Phenyl butyrate and arginine Avoid catabolic state

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