Metabolism I

PATHOPHYSIOLOGIC CLASSIFICATION OF INBORN METABOLIC DISEASES

Inborn errors of metabolism The diseases are rare individually, but they collectively contribute significantly to mortality and morbidity (up to 1-2% of population). A positive family history of unexplained child death could be obtained in most of the cases. Early diagnosis and treatment are essential for normal long-term neurologic development. Considerable amount of metabolic diseases could be treated effectively. Early diagnosis requires that the possibility of metabolic disease to be considered in every sick neonate or motor-mental retarded child. A positive family history of unexplained child death could be obtained in most of the cases.

Urine and/or body odor OdorSubstaceDisease Mouse Maple syrup Sweaty feet Cat urine Cabbage Rancid butter Acidic Rotten fish Sulphur Phenylacetate Sotolone Isovaleric acid ß-OH isovaleric acid 2-OH butyric acid 2-keto-4-methiolbutyrate Methylmalonic acid Trimethyamine Dimethyglycine Hydrogen sulphate Phenylketonuria (PKU) Maple syrup urine disease (MSUD) Isovaleric aciduria Glutaric aciduria ß-methylcrotonylglycinuria Multiple carboxylase def. Tyrosinemia type I Methionine malabsorption Tyrosinemia type I Methylmalonic aciduria Trimethyaminuria Dimethyglycinuria Cystinuria

Urine color ColorSubstaceDisorder Blue Blue-brown or black Brown Red-brown Indigo Homogentisic acid Methemoglobin Hemoglobin Hartnup disease Alkaptonuria Myoglobinuria Hemoglobinuria

Urine Ferric chloride test (phenylalanine, tyrosine, homogentisic acid, histidine, aspirin) Ketone Reducing substances (glucose, fructose, galactose, homogentisic acid) Ketoacids (DNPH) Sulfites (cyanide-nitroprusside test) Heparan and dermatan sulphate (CTAB test) pH, sediment (crystals), uric acid Blood Complete blood count, glucose, blood gases Electrolytes, ammonia, uric acid Beta-hydroxybutyric acid, acetoacetic acid, lactic acid, pyruvic acid

DIFFERENTIAL DIAGNOSIS OF NEONATAL METABOLIC DISEASES Sepsis Central nervous system diseases Cardiopulmonary diseases Perinatal asphxy (hypoxic ischemic encephalopathy) Gastrointestinal tract obstruction

Specific tests - Amino acid chromatography (urine, serum) - Oligosaccharide chromatography (urine, serum) - Mucopolysaccharide electrophoresis (urine) - Amino acids (quantitative) - Organic acids (gas chromatography-mass spectrophotometry) - Carnitine (plasma, urine, total, free) - Free fatty acids, very long chained fatty acids - Orotic acid (urine) - Galactose-1-phosphate uridyl transferase (Beutler test) Tissue enzymes, DNA investigations (leukocytes, liver, fibroblasts)

SIGNS AND SYMPTOMS OF NEONATAL METABOLIC DISEASE Central nervous system Poor suck Lethargy Irritability Hypo-or hypertonia Seizures Coma Gastrointestinal tract Poor feeding Vomiting Diarrhea Abdominal distention Cardiopulmonary system Apnea Tachypnea (compensation of metabolic acidosis) Respiratory distress Miscellaneous Abnormal skin or urine odor Cataracts Dysmorphic facies

I. Intoxication type small diffusible molecule disease Results from an acute or progressive intoxication from accumulation of toxic compounds proximal to the metabolic block. Aminoacidopathies (phenylketonuria, MSUD, homocystinuria, tyrosinemia) Organic acidopathies (pyruvic, isovaleric, methylmalonic acidemias) Urea cycle defects (OTC deficiency, sitrullinemia etc) Sugar intolerances (galactosemia, fructosemia etc)

There is a symptom free interval ranging from one day to several weeks or months. It depends on the residual enzyme activity, situations of increased catabolism (infections, stresses, operations, increased intake of proteins, stopping breast-feeding) Clinical signs and symptoms may be early- onset acute (neonatal), late-onset acute/recurrent, or chronic progressive. I. Intoxication type small diffusible molecule disease/Clinical presentation

Diagnosis Diagnosis is generally easy and relies mostly on amino acid and organic acid analyses. Treatment Treatment requires removal of the toxins by special diets, dialysis, drug and megavitamin therapy.

Energy-deficient type small diffusible molecule disease This group of diseases consists of intermediary metabolism with symptoms due at least partly to a deficiency in energy production or utilization resulting from a defect in liver myocardium, muscle or brain. Gluconeogenesis defects (G-6-Pase, PC, F-1, 6-diP, PEP carboxykinase) Glycogenolysis defects (GSD III, GSD V, and GSD VI) Glycogenesis defects (GSD 0, GSD IV) Lactic acidemias (PDH deficiency, electron transport chain diseases) Fatty acid oxidation defects (carnitine, MCAD, SCAD)

Energy-deficient type small diffusible molecule disease / Clinical presentation Hypotonia, myopathy, cardiomyopathy, failure to thrive, malformations, sudden infant death syndrome, hypoglycemia, hyperlactatemia

III. Diseases that disturb the synthesis or the catabolism of complex molecules Lysosomal diseases (Tay-Sachs, Gaucher, Neimann-Pick etc) Peroxisomal diseases (Zellweger, Refsum, adrenolekodystrophy) Synthesis defects (alpha-1-antitrypsin deficiency, carbohydrate deficient glycoprotein syndrome) Clinical presentation: Chronic progressive mental-motor retardation Diagnosis: Enzyme and DNA studies Therapy: Enzyme therapy (İf available)

Treatment-General principles 1. Removal of toxic metabolites a. Mechanical removal: (hemodialysis, peritoneal dialysis, hemofiltration and exchange transfusion). b. Diet therapy c. Drug therapy: carnitine, sodium benzoate, phenylacetic acid, NTBC 2. Addition of deficient product: glucose, arginine 3. Augmentation of residual enzyme activity (megavitamin therapy) 4. Enzyme therapy (Gaucher disease, MPS I, MPS II, MPS VI, alfa-1- antitripsin deficiency, ADA deficiency) 5. Correction of defective gene a. Organ, tissue or bone-marrow transplantation b. Somatic gene therapy (ADA deficiency)

EMERGENCY TREATMENT 1. Stop protein intake 2. Interrupt catabolic state High dose energy substitution: IV % glucose (10 mg/kg/min) (Check lactic acid and limit glucose intake when PDH deficiency suspected) b % intralipid solutions (exclude ß-oxidation defects) 3. Ensure adequate intake of fluid (150mL/kg/day) and electrolyte (0.2% Na Cl): Aim for a sodium concentration ≥140 mEq/L to reduce the risk of cerebral edema 4. Correct acidosis: Aim for a bicarbonate concentration ≥18 mEq/L 5. Removal of toxic metabolites a.Mechanical removal: (hemodialysis, peritoneal dialysis, hemofiltration and exchange transfusion). b.Carnitine: g/kg/day