approach to inborn errors-seminar 13.08.10

Approach to patient with inborn errors of metabolism : 

Approach to patient with inborn errors of metabolism Dr. Hariharan 13.08.2010

History : 

History 1908- Garrod (1857–1936)– alkaptonuria, benign pentosuria, albinism, and cystinuria – which “. . . apparently result from failure of some step or other in the series of chemical changes which constitute metabolism”. present at birth, persisted throughout life Følling’s -phenylketonuria (PKU) in 1934, Harry Harris-1955-starch gel electrophoresis-demonstred of a large number of protein polymorphisms in humans discovery of PKU sparked the search for other clinically significant inborn errors of metabolism> 500 disorders

IEM’s in General : 

IEM’s in General Mostly due to defect in or absence of an enzyme, cofactor or transport protein resulting a block in a specific metabolic pathway Common defects on a biochemical level Transport defects Accumulation of substrate Deficiency of product Secondary inhibition

What can go wrong? : 

A A B C D negative E F Apoenzyme + cofactor What can go wrong? Molecule A needs to enter the cell via a transport protein. If A can’t enter cell because of defective transport protein then the rest of reactions are moot (transport defect) A goes to B, then B goes to C via enzymatic reactions. If the enzyme converting B to C is defective, B can back up and divert down alternate pathways to D. Also, if the apoenzyme and cofactors that form the enzyme converting B to C are defective, B backs up and diverts down alternate paths again to D (accumulation of substrate) Let’s suppose C has negative feedback inhibition of reaction A to B. If C is not present because the enzyme to make B to C is defective, B accumulates and further shunts down alternate pathways to D. (deficiency of product) Let’s consider secondary inhibition. Let’s look at the reaction of E to F. The primary defect is in the conversion of B to C, but as B backs up and diverts down the path to D, D acts as an inhibitor on the enzyme converting E to F. Let’s consider molecule A sitting outside a cell Modified from Clarke, 2002, Cambridge University Press, used with permission

Disease results from : 

Disease results from

Symptoms of disease are the result of substrate accumulation : 

Symptoms of disease are the result of substrate accumulation

Disease are the result of product deficiency : 

Disease are the result of product deficiency

Symptoms due to secondary metabolic defects : 

Symptoms due to secondary metabolic defects

PART I -Symptoms and signs : 

PART I -Symptoms and signs 1.Neurologic syndrome Chronic encephalopathy Acute encephalopathy Stroke Movement disorder Myopathy Autonomic dysfunction Psychiatric problems 4.Cardiac syndromes Cardiomyopathy Arrhythmias Coronary artery disease 5.Storage syndrome and dysmorphism Lysosomal disorders Peroxisomal disorders Mitochondrial disorders Biosynthetic defects 2.Metabolic acidosis Lactic acidosis Ketoacidosis Organic aciduria 3.Hepatic syndrome Jaundice Hepatomegaly Hypoglycemia Hepatocellular dysfunction

Chronic encephalopathy : 

Chronic encephalopathy Children- Developmental delay or psychomotor retardation is the commonest. The diagnosis of psychomotor retardation involves assessment of age appropriateness In a number of developmental spheres, including IQ in older patients, and grossmotor, fine motor, socio-adaptive, and linguistic milestones in young children and infants. In adults, chronic encephalopathy may take the form of progressive dementia.

Psychomotor retardation : 

Psychomotor retardation global, affecting all spheres of development to some extent severe irritability Impulsivity Aggressiveness hyperactivity Progressive

An approach through chronic encephalopathy : 

An approach through chronic encephalopathy

Initial investigation of chronic encephalopathy : 

Initial investigation of chronic encephalopathy Thorough developmental assessment and neurologic examination CT or MRI scan Electrophysiologic studies: auditory brain stem responses, visual evoked potentials, Somatosensory evoked potentials, nerve conduction studies, EMG X RAYS of the hands, chest, spine: for evidence of dysostosis multiplex URINE: organic acid analysis MPS oligosaccharide screening test Urinary amino acid TLC Plasma Ammonium Lactate quantitative amino acid analysis, if abnormalities are found

Seizures : 

Seizures Tay-Sachs disease Sandhoff disease Multiple carboxylase deficiency MELAS -Lactic acidosis, small stature, seizures, stroke, cortical blindness, psychomotor retardation Late-onset galactosialidosis Krabbe Peroxisomal disorders

White matter disease (leukodystrophy) : 

White matter disease (leukodystrophy) In diseases predominantly affecting cerebral white matter, the clinical presentation tends to be dominated by motor difficulties, including gross motor delay, weakness and incoordination. White matter disease (leukodystrophy)is a common feature of many inherited metabolic disorders presenting with chronic encephalopathy, including many ‘small molecule’ diseases. Therefore, the investigation of any patient presenting with signs of leukodystrophy should routinely include analysis of plasma amino acids and urinary organic acids. Taysachs-demyeination

Causes of metabolic acute encephalopathy to be considered at various ages : 

Causes of metabolic acute encephalopathy to be considered at various ages

Initial investigation of acute encephalopathy : 

Initial investigation of acute encephalopathy Blood gases and electrolytes (calculate anion gap), blood glucose Urinalysis, including tests for ketones and reducing substances Liver function tests Blood ammonium Plasma lactate Urinary organic acids Plasma amino acid analysis, quantitative Plasma carnitine and acylcarnitines, including tandem MSMS

An approach to the diagnosis of hyperammonemia in older children. : 

An approach to the diagnosis of hyperammonemia in older children.

Leucine encephalopathy (maple syrup urine disease – MSUD) : 

Leucine encephalopathy (maple syrup urine disease – MSUD) Acute encephalopathy without hyperammonemia or significant metabolic acidosis, on a background of chronic failure to thrive and mild to moderate psychomotor retardation, is typical ofMSUD. drowsiness, anorexia, and vomiting. The odor aroma of maple syrup is more like the smell of burnt sugar. The urine typically tests positive for ketones. The course of subsequent deterioration is often highly irregular with periods of lucidity alternating with stupor, progressing to coma. Signs of intracranial hypertension are an indication that the situation is grave and the chances of recovery, even with aggressive treatment, are seriously compromised. Quantitative analysis of plasma amino acids. Marked elevations of leucine, isoleucine, and valine, and the presence of alloisoleucine, are diagnostic of MSUD.

Reye-like acute encephalopathy (fatty acid oxidation defects) : 

Reye-like acute encephalopathy (fatty acid oxidation defects) SEEN in disorders of fatty acid oxidation. The commonest of these is medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. usually in the first year or two of life, with what may appear initially as ‘stomach flu’, with anorexia, vomiting, drowsiness, and lethargy. Drowsiness and lethargy progress rapidly to stupor and coma, hepatomegaly with evidence of hepatocellular dysfunction, hypotonia, hypoketotic hypoglycemia Hypoglycemic recurrence of acute metabolic decompensation during trivial intercurrent illnesses or fasting, are features peculiar Urine-C-6 to C-10 dicarboxylic acids Systemic carni tine deficiency and long-chain acyl-CoA dehydrogenase(LCAD) deficiency may present with a Reye-like acute encephalopathy,

Strokes or stroke-like episodes : 

Strokes or stroke-like episodes

Movement disorder : 

Movement disorder

Myopathy & muscle weakness : 

Myopathy & muscle weakness

Autonomic dysfunction : 

Autonomic dysfunction

Psychiatric problems : 

Psychiatric problems

Symptoms and signs : 

Symptoms and signs 1.Neurologic syndrome Chronic encephalopathy Acute encephalopathy Stroke Movement disorder Myopathy Autonomic dysfunction Psychiatric problems 4.Cardiac syndromes Cardiomyopathy Arrhythmias Coronary artery disease 5.Storage syndrome and dysmorphism Lysosomal disorders Peroxisomal disorders Mitochondrial disorders Biosynthetic defects 2.Metabolic acidosis Lactic acidosis Ketoacidosis Organic aciduria 3.Hepatic syndrome Jaundice Hepatomegaly Hypoglycemia Hepatocellular dysfunction

Inherited metabolic diseases with renal tubular acidosis (RTA)- HCO 3 losses : 

Inherited metabolic diseases with renal tubular acidosis (RTA)- HCO 3 losses Galactosemia Hereditary fructose intolerance Hepatorenal tyrosinemia Cystinosis Von-Gierke disease Fanconi-Bickel syndrome -Defect in glucose and galactose transport Wilson disease Vitamin D dependency -Cholecalciferol 1-hydroxylase deficiency Osteopetrosis with RTA-Carbonic anhydrase II deficiency Lowe syndrome -Phosphatidylinositol-4,5-bisphosphate 5-phosphatase deficiency

Lactic acidosis : 

Lactic acidosis Defects of pyruvate metabolism PDH deficiency Pyruvate carboxylase deficiency Defects of NADH oxidation Mitochondrial ETC defects Disorders of gluconeogenesis GSD, type I HFI PEPCK deficiency Fructose-1,6-diphosphatase deficiency Fatty acid oxidation defects Defects of biotin metabolism Biotinidase deficiency Holocarboxylase synthetase deficiency Defects of organic acid metabolism HMG-CoA lyase deficiency Propionic acidemia Methylmalonic acidemia Others

Ketoacidosis : 

Ketoacidosis MSUD, Organic acidopathies Methylmalonic acidemia Propionic acidemia Isovaleric acidemia Holocarboxylase synthetase deficiency Glycogen storage diseases GSD type III Hepatic phosphorylase deficiency Phosphorylase kinase deficiency glycogen synthase deficiency Disorders of gluconeogenesis Pyruvate carboxylase deficiency fructose -1,6-diphosphatase deficiency Phosphoenolpyruvate carboxykinase deficiency

Organic aciduria : 

Organic aciduria

Symptoms and signs : 

Symptoms and signs 1.Neurologic syndrome Chronic encephalopathy Acute encephalopathy Stroke Movement disorder Myopathy Autonomic dysfunction Psychiatric problems 2.Metabolic acidosis Lactic acidosis Ketoacidosis Organic aciduria 4.Cardiac syndromes Cardiomyopathy Arrhythmias Coronary artery disease 5.Storage syndrome and dysmorphism Lysosomal disorders Peroxisomal disorders Mitochondrial disorders Biosynthetic defects 3.Hepatic syndrome Jaundice Hepatomegaly Hypoglycemia Hepatocellular dysfunction

Hepatic syndrome-jaundice : 

Hepatic syndrome-jaundice

Hepatomegaly : 

Hepatomegaly

Hypoglycemia : 

Hypoglycemia

Hepatocellular dysfunction : 

Hepatocellular dysfunction Wilson-mito

Symptoms and signs : 

Symptoms and signs 1.Neurologic syndrome Chronic encephalopathy Acute encephalopathy Stroke Movement disorder Myopathy Autonomic dysfunction Psychiatric problems 2.Metabolic acidosis Lactic acidosis Ketoacidosis Organic aciduria 3.Hepatic syndrome Jaundice Hepatomegaly Hypoglycemia Hepatocellular dysfunction 4.Cardiac syndromes Cardiomyopathy Arrhythmias Coronary artery disease 5.Storage syndrome and dysmorphism Lysosomal disorders Peroxisomal disorders Mitochondrial disorders Biosynthetic defects

Cardiac syndromes-cardiomyopathy : 

Cardiac syndromes-cardiomyopathy Pompe’s

Arrhythmias : 

Arrhythmias

Coronary artery disease : 

Coronary artery disease Hypercholesterolemias I, Iia, IIb, III, IV, V Tuberous xanthoma

Symptoms and signs : 

Symptoms and signs 1.Neurologic syndrome Chronic encephalopathy Acute encephalopathy Stroke Movement disorder Myopathy Autonomic dysfunction Psychiatric problems 2.Metabolic acidosis Lactic acidosis Ketoacidosis Organic aciduria 3.Hepatic syndrome Jaundice Hepatomegaly Hypoglycemia Hepatocellular dysfunction 4.Cardiac syndromes Cardiomyopathy Arrhythmias Coronary artery disease 5.Storage syndrome and dysmorphism Lysosomal disorders Peroxisomal disorders Mitochondrial disorders Biosynthetic defects

Storage syndrome and dysmorphism : 

Storage syndrome and dysmorphism

Slide 49: 

Coarse Facies MR/ seizures Dysostosis multiplex Cataracts/ corneal opacities Hepatosplenomegaly Presenting as ‘storage syndrome Mucopolysaccharidoses Glycoproteinoses Sphingolipidoses Niemann picks

Slide 50: 

Zellweger syndrome Infantile Refsum disease 3-Ketoacyl-CoA thiolase deficiency X linked adrenoleukodystrophy Severe peroxisomal phenotype’--- peroxisomal disorders -facial dysmorphism, -corneal clouding, -cataracts, congenital heart disease, -death in months

Acute metabolic illness in the newborn : 

Acute metabolic illness in the newborn

Encephalopathy : 

Encephalopathy Maple syrup urine disease Urea cycle enzyme defects Nonketotic hyperglycinemia Peroxisomal disorders without metabolic acidosis with metabolic acidosis Organic acidopathies Propionic acidemia Methylmalonic acidemia Isovaleric acidemia HMG-CoA lyase deficiency Glutaric aciduria, type II

Neonatal hepatic syndrome : 

Neonatal hepatic syndrome Hepatorenal tyrosinemia Hereditary fructose intolerance GSD, type IV MCAD deficiency LCAD deficiency CPT II deficiency Niemann-Pick disease Nonimmune fetal hydrops G6PD deficiency Pyruvate kinase deficiency Lysosomal storage diseases(many) Zellweger disease GSD, type IV Cardiac syndrome

PART II -Laboratory investigation : 

PART II -Laboratory investigation

Investigation of ‘small molecule disease’ : 

Investigation of ‘small molecule disease’ Plasma ammonium Plasma lactate and pyruvate Plasma ketones and free fatty acids Amino acid analysis colored reactions, TLC, HPLC for amino acid Quantitation, (GC-MS, MSMS Neurotransmitters Organic acid analysis Acylcarnitines and acylglycines Porphyrins

Slide 57: 

Ferric chloride TEST-phenyl pyruvate DNPH test-ketoacids Cyanide nitroprusside -S- Benedict’s reagent-Reducing substances Acetest-ketone bodies Chemical screening tests for amino acids and amino acid metabolites in urine

Investigation of Lysosomal disorders : 

Investigation of Lysosomal disorders -The laboratory investigation of diseases caused by hereditary deficiency of lysosomal enzymes involves morphologic studies; demonstration of a specific enzyme deficiency

Investigation of mitochondrial energy metabolism : 

Investigation of mitochondrial energy metabolism Morphologic studies Biochemical studies investigation of fatty acid -oxidation defects. oxygen utilization of intact lymphocytes, fibroblasts, or isolated muscle mitochondria is assessed polarographically using various energy substrates and specific ETC inhibitors. ETC activity of the individual complexes is then measured spectrophotometrically. Cytochrome c oxidase (COX, Complex IV) is measured directly by spectrophotometry Molecular genetic studies

Diagnosis of peroxisomal disorders : 

Diagnosis of peroxisomal disorders

References : 

References A Clinical Guide to Inherited Metabolic Diseases-Third Edition- Joe T. R. Clarke, MD, PhD, FRCPC Division of Clinical & Metabolic Genetics, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8 CANADA Thank you