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This document provides an overview of the approach and management of inborn errors of metabolism. It discusses the incidence, clinical presentation, investigations, and management of various metabolic disorders. Key points include: - Metabolic disorders are caused by enzyme deficiencies or abnormalities that disrupt normal metabolism. They are often inherited in an autosomal recessive pattern. - Clinical features can include encephalopathy, liver disease, dysmorphic features, cardiac issues, and more nonspecific signs like jaundice or hypoglycemia. Laboratory tests help evaluate for issues like metabolic acidosis, hyperammonemia, or abnormal organic acids. - Management involves stabilizing the patient, addressing acute issues like seizures or infections, implementing dietary modifications
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- 1. Approach & Management of Inborn Errors of Metabolism DR R PETER M.D.(PAED)., D.M.(NEO)., NEONATOLOGIST GOVT.MEDICAL COLLEGE PUDUKKOTTAI
- 2. Introduction Congenital Metabolic Disorders/ Inherited Metabolic Diseases • Absence or Abnormality of an enzyme or its cofactor, • Accumulation or deficiency of a specific metabolite • Most of these disorders are transmitted as autosomal recessive traits. • Germ line Mutation/ Sporadic Mutation ‘Metabolic distress’
- 3. Staged evaluation Treatment and prognostication of Index Case Genetic Counselling and Antenatal diagnosis in subsequent pregnancies
- 4. Incidence Disorder Type Incidence Galactosaemia Carbohydrate Disorder 1 in 23 000 to 1 in 44 000 Ornithine transcarbamylase deficiency Urea Cycle Disorder 1 in 14 000 Methylmalonic acidaemia Organic Acidemia 1 in 50 000 Glycogen storage disorder type 1 Carbohydrate Metabolism 1 in 100 000 Familial hypercholesterolaemia Lipid disorder 1 in 500 IEM 1in 800 to 2500 births
- 5. Basic Biochemistry Intoxication Type, Energy Deficiency Type Storage type. BA E E D1D C 1 2 3 Gene
- 9. Acute Episodic Insidious Mitochondrial Disorders With Lactic Acidosis. Organic acidurias Canavan’s disease.
- 10. IEM Vs Non IEM Poor feeding, Drowsiness, Lethargy, Hypotonia and failure to thrive o Sepsis, o Hypoxic-ischemic encephalopathy, o Duct-dependant cardiac lesions, o Congenital adrenal hyperplasia and congenital infections
- 11. Term/AGA Traumatic Accident Hypoxia Intracranial Injury Infection Hypo/Hyper Ca Hypo/hyper Na Hypo/hyper K Isolated/Multiple Malformations Syndromes Clinical Hx CXR Cranial USG Septic Screen Antibiotics Simple Metabolic Screen Hormonal Renal Radiologic Investigation ECHO Genetic advice Inherited Metabolic Disorder
- 12. Case Scenario 1 • G6A3P2L0 • USG Cranium & Abdomen / ECHO - Normal • Baby had Jaundice treated with Phototherapy • Presented with clinical sepsis / shock/Pustules • Severe Metabolic acidosis with Hyponatremia • IEM screening- TMS • Sepsis screen -
- 13. Case Scenario 2 • G4P3L1 • Admitted on D15 of life • Failure to thrive / Dehydration / Excessive Cry/Hyperpigmentation • Severe Hyponatremia / Hyperkalemia • Elevated 17 OHP • Treated with Hydrocortisone, Fludrocortisone and Salt supplementation • Genetic Study – Autosomal Recessive / Homozygos CAH
- 14. Case Scenario 3 • Primi • Admitted for Perinatal Asphyxia /MAS/Pulmonary Hemorrhage • Ventilator dependent – 15 days • Neurosonogram normal and ECHO showed –ASD/PPHN • Carnitine Uptake defect • L-Carnitine supplementation 100 mg
- 15. Deterioration after a period of apparent normalcy Parental consanguinity Family history of neonatal deaths Rapidly progressive encephalopathy and seizures of unexplained cause Severe metabolic acidosis Persistent vomiting Peculiar odor Acute fatty liver or HELLP
- 16. Clinical Findings Disorder Coarse Facies Lysosomal Disorder Cataract Galactosemia/ Zellweger Syndrome Retinitis Pigmentosa Mitochondrial Disorder Cherry Red Spot Lipidosis Hepatomegaly Storage disorder, Urea Cycle Defects Eczema/alopecia Biotidinase Defieciency Renal enlargement Zellweger syndrome Abnormal kinky hair Menke disease Decreased pigmentation phenylketonuria
- 17. IEM ODOUR Isovaleric aciduria Sweaty feet Maple syrup urine diease Maple syrup Phenyl ketonuria Musty Tyrosinemia Cabbage Glutaric aciduria type II Sweaty feet Multiple carboxylase Male cat urine
- 18. Laboratory Persistent hypoglycaemia persistent acidosis Persistent abnormal hepatic and renal parameters Hyperammonemia Persistent abnormal coagulation profile Pancytopenia, leucopenia, thrombocytopenia. Ketosis Abnormal amino acid profile
- 19. Clinical Presentation Encephalopathy Acute liver disease Dysmorphic features Cardiac disease
- 20. Encephalopathy with or without metabolic acidosis • Encephalopathy, seizures, and tone abnormalities • Organic acidemias • Urea cycle defects • Congenital lactic acidosis • Intractable seizures • Pyridoxine dependency • Non-ketotic hyperglycinemia • Molybdenum co-factor defect • Folinic-acid responsive seizures
- 21. • Jaundice alone- Gilbert syndrome, Criggler-Najjar syndrome • Hepatic failure (jaundice, ascites, hypoglycemia, coagulopathy)- Tyrosinemia, galactosemia, neonatal hemochromatosis, glycogen storage disease type IV. • Neonatal cholestasis: alpha-1 antitrypsin deficiency, Niemann-Pick disease type C. • Hypoglycemia: galactosemia, fatty acid oxidation defects, organic acidemias, glycogen storage disorders and disorders of gluconeogenesis. Acute liver disease
- 22. Dysmorphic facies • Peroxisomal disorders, pyruvate dehydrogenase deficiency, congenital disorders of glycosylation (CDG), and lysosomal storage diseases. • Non-immune hydrops fetalis: lysosomal storage disorders and CDG
- 23. Cardiac disease • Cardiomyopathy: • Fatty acid oxidation defects, • Glycogen storage disease type II and mitochondrial electron transport chain defects
- 25. Specific test Specialised test Screening Test Investigations IEM
- 26. Investigations Complete blood count Arterial blood gases and electrolytes Blood glucose Plasma ammonia Arterial blood lactate Liver function tests Urine ketones Urine reducing substances. Serum uric acid
- 27. Hyperammonemia Premature Full term THAM PC Deficiency Organic acidemia UCD Citrulline Absent citrulline Moderate Markedly Urine orotic acid CPS deficiency OTC deficiency ASA citrullinemia Acidosis
- 28. Metabolic Acidosis with Increased Anion Gap Normal Lactate Elevated Lactate Abnormal Organic acids ORGANIC ACIDEMIA Abnormal Organic acids Dicarboxylase aciduria FAOD MMA,PA,MCD Normal Organic acids Elevated Pyruvate Normal L-P ratio Hypoglycemia No Hypoglycemia Normal or Low Pyruvate Elevated L-P ratio GSD Type 1, Fructose 1,6 DP Deficiency PEP Carboxy kinase deficiency Pyruvate Dehydrogenase deficicincy Pyruvate carboxylase deficiency Respiratory chain defects
- 29. Neonate in Coma Blood for NH3, pH Electrolytes Urine Ketones NH3 Metabolic Acidosis Classic organic aciduria Glutaric aciduria Urea Cycle Defects Transient Neonatal Hyperammonemia Maple Syrup urine disease Ketolysis Defects NKH Sulfite oxidase or Molybdenum cofactor efieciency Ketonuria
- 30. Hypoglycaemia Urine for non glucose reducing substance GALT FAOD Ketogenic Defects GSD Organic Acidemia Galactosemia Ketones
- 31. Normal NH3 No Metabolic Acidosis Refractory myoclonic seizure Opisthotonus Vomiting Hypoglycemia HSM Jaundice Sepsis Dysmorphic features Hypotonia Blindness Galactosemia Non Ketotic Hyperglycinemia Peroxisomal Disorder
- 32. General Aspects • Knowledge of the natural history of the diseases and a comprehensive understanding of the molecular basis and the pathophysiological consequences of gene defects. • Continuous sympathetic company and guidance of patients and their families are essential for optimal outcome. • Inherited metabolic diseases are chronic conditions that involve various different organ systems and often show progressive pathology.
- 33. • Affected individual to achieve optimal development during childhood • Maximal independence, social integration, and self-esteem as an adolescent and adult. • Multidisciplinary approach
- 34. Management Airway , Breathing & Circulation Ventilate the baby If needed Omit all protein, fat and galactose and lactose including TPN Glucose infusion 6-8mg/kg/mt Start insulin if Hyperglycemic Correct hydration, acid base disorder and electrolyte disturbance Antibiotics Control seizure (avoid sodium valproate )
- 35. Specific Management Neonatal Hyperammonaemia Renal replacement therapy Sodium benzoate Sodium phenyl butyrate L-Arginine Organic Acidemia Reduce/stop protein intake l-carnitine Lactic acidosis Dichloroactate Biotin L-carnitine Thiamine Fatty acid oxidation defect Avoid prolonged fasting Galactosaemia Dietary exclusion of galactose
- 36. Disorder Management Methyl malonic acidemia Vit B12 1mg IM/day Biotinidase deficiency Biotin 10 to 60 mg/day oral Multiple carboxylase deficiency Biotin 10 to 60 mg /day oral Glutaric aciduria type II Riboflavin 100 to 300 mg/ day oral Thiamine 10 to 200 mg/day Homocystinuria Pyridoxine IM/IV 200 to 1000mg/24hrs Carnitine deficiency Carnitine 100 to 400 mg of L-carnitine/kg/day oral MSUD Thiamine 10mg to 200mg/24hrs Riboflavin 200 to 300 mg/oral TID Mevalonic acidemia Prednisone 2mg / kg / 24 hrs Hartnup disease Nicotinamide 50 to 300mg/day High protein
- 37. • Substrate reduction / removal • Provision of ‘ conditionally ’ essential or essential nutrients • Provision of alternative energy substrates • Avoidance of fasting / prolonged fasting to avoid accumulation of toxic metabolites or defi -ciency of substrate Dietary Modification
- 38. Others • Enzyme replacement therapy (ERT): Lysosomal storage disorders, Pompe’s disease • Hematopoietic Stem Cell Transplantation
- 39. Counselling 1. Food and food components 2. Chromosomes, genes and mutations 3. Inheritance 4. Productions and function of enzymes 5. Normal metabolism 6. Disease-specific disorders of metabolism 7. Diagnostic investigations for screening and confirmation of diagnosis 8. Principles of treatment 9. Measures for monitoring treatment and outcome 10. Principles of prognosis as a statistical and individual concept
- 40. Preventive aspects • Genetic Counselling and Prenatal Diagnosis • Chorionic Villus Sampling/Amniocentesis • The possibility of carrier detection, and prenatal or preimplantation diagnosis • Severe psychosocial burden for individuals and families as a whole. • Screening TMS
- 41. Metabolic Autopsy • Blood: 5-10 ml; frozen at -200c; both heparinized (for chromosomal studies) and EDTA (for DNA studies) samples to be taken • Urine: frozen at -200c • CSF: store at -200c • Skin biopsy: including dermis in culture medium or saline with glucose. Store at 4-80c. Do not freeze. • Liver, muscle, kidney and heart biopsy: as indicated. • Clinical photograph (in cases with dysmorphism) • Infantogram (in cases with skeletal abnormalities)
- 42. Prognosis • Biotin Dependent Holocarboxylase synthase Deficiency • Phenylketonuria • Tyrosinemia Type 1 • Maple Syrup Urine Disease • Urea cycle Disorder • Galactosemia
- 43. Conclusion • IEM are not uncommon • Do suspect IEMs in all babies with unexplained deterioration of clinical condition and suspected sepsis when sepsis screen is negative. • Start with a simple approach to hold on to a ‘thread of logic’ which will lead on to the diagnosis. • Stabilization is the key to management. • Sample for metabolic Autopsy if the child is very sick. • An attempt to make a diagnosis gives the choice to the parents in subsequent pregnancies. • Genetic counseling to the parents
- 44. THANK YOU
Editor's Notes
- Good morning to all Before starting my talk I would like to thank organizer for giving me the opportunity After two sessions about Investigating the error in metabolism I think everyone knows that IEM is TOO complicated I will try to explain the approach in simple way and proper management to reverse it to normal and to prevent the recurrence
- IEM is also called as congenital metabolic disorder/ Inherited metabolic disease even we can say it as metabolic distress as like respiratory distress IEM is due to Absence or Abnormality of an enzyme or its cofactor, leading to either accumulation or deficiency of a specific metabolite(s). Most of these disorders are transmitted as autosomal recessive traits or started as newer onset due to sporadic mutation. With few exceptions like ornithine transcarbamylase defieciency transmitted as X linked inheritance
- Step by step evaluation is important to diagnose IEM Diagnosis is important not only for treatment and prognostication but also for genetic counselling and antenatal diagnosis in subsequent pregnancies
- The number of diseases in humans known to be inherited point defects in metabolism now exceeds 500. While the diseases individually are rare, they collectively account for a significant proportion of neonatal and childhood morbidity and mortality
- When a precursor “A” in the body is to be converted to product “C” through product “B” with one helping enzyme in the pathway, the inadequacy or absence of that particular enzyme (E) results in one of three things Absence of product “C” Excess of substance “A” and “B” A new pathway taken by product “B” to produce new products “D” and “D1” Manifestations will be of these three types intoxication type like PKU, Energy defiecient like Mitochondrial Disorder and Storage type like LYSOSOMAL Storage disorder
- Some of maternal IEM Like PKU can affect fetus and cause dysmorphology in the fetus which results in congenital malformations (Fig.2). Vice versa, some disorders of the fetus can affect the mother too, eg. Very long chain hydroxy acyl CoA deficiency (VLCHAD) of fetus can manifest as acute fatty necrosis of maternal liver and hemolysis, elevated liver enymes, low platelets (HELLP) syndrome in the mother when she is
- The signs and symptoms can manifest at any age from neonatal period through infancy and childhood to adulthood. Age of onset has a significance since many IEM can have a typical age of onset. This is because the age of onset depends upon the developmental stage of a particular organ system,2 eg.cholesterol, peroxisomal biogenic disorders and lysosomal disorders can present at birth.4 The presentation may be insidious, eg.lysosomal storage disorders or acute, E.g. peroxisomal disorders.
- Intoxication type of disorders usually present one week….
- There are three types of onset Acute stormy onset with rapid life threatening deterioration over hours, eg. some of the mitochondrial disorders with lactic acidosis. Episodic with intermittent decompensation and asymptomatic intervals, eg. some of the organic acidurias. Insidious onset with slow degeneration over decades, eg.neurodegenerative disorders - Canavan’s disease.
- Severe illness in the newborn, regardless of the underlying cause, tends to manifest with nonspecific findings, such as poor feeding, drowsiness, lethargy, hypotonia and failure to thrive. IEM should be considered in the differential diagnosis of any sick neonate along with common acquired causes such as sepsis, hypoxic-ischemic encephalopathy, duct- dependant cardiac lesions, congenital adrenal hyperplasia and congenital infections
- We use to think of IEM in sick term neonate rather in preterm neonate because premeturity itself will cause lethargy, poor feeding and hypoglycaemia and some of the lab use to ask whether baby is term or preterm Whenever we come across sick infant or neonate we use to think about these four groups of diseases with IEM
- when to suspect IEM Deterioration after a period of apparent normalcy Parental consanguinity Family history of neonatal deaths Rapidly progressive encephalopathy and seizures of unexplained cause Severe metabolic acidosis Persistent vomiting Peculiar odor Acute fatty liver or HELLP (hemolysis, elevated liver enzymes & low platelet counts) during pregnancy: seen in women carrying fetuses with long-chain-3-hydroxyacyl-coenzyme dehydrogenase deficiency (LCHADD)
- Here some of the clinical clues for specific disorders to look for
- List of IEM with unusual odours
- If metabolic disease is not considered within the differential diagnosis, it is unlikely to be identified through standard blood, urine, or cerebral spinal fluid investigations Early discussion with a specialist centre is vital. If a diagnosis is clear, then specific diagnostic investigations can be performed, including genetic testing.
- Investigations are often staged
- Complete blood count: (neutropenia and thrombocytopenia - propionic and methylmalonic academia) Arterial blood gases and electrolytes Blood glucose Plasma ammonia (Normal values in newborn: 90-150 g/dl or 64-107 mol/L) Arterial blood lactate (Normal values: 0.5-1.6 mmol/L) Liver function tests Urine ketones Urine reducing substances. Serum uric acid (low in molybdenum cofactor deficiency)
- Metabolic acidosis. E3, lipoamido oxido reductase; FBP, fructose bisphosphatase; G6P, glucose-6-phosphatase; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; IVA, isovaleric acidemia; KGDH, alpha-ketoglutarate dehydrogenase; MCD, multiple carboxylase deficiency;MCT1, monocarboxylate transporter1; MMA, methylmalonic aciduria; MSUD, maple syrup urine disease; OATD, oxoacid CoA transferase; PA, propionic acidemia; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; SCAD, short chain acyl-CoA dehydrogenase; bold face, treatable disorders
- Transient Hyper Ammonemia Carbomyl Phosphate synthase defieciency Ornithine Transcarbomylase deficiency Argino succinic aciduria
- Phosphoenol pyruvate carboxy kinase defieciency
- Some time will get basic investigations normal but clinically baby will be sick In that situation we have to keep these conditions in mind
- Care and treatment of patients with an inherited metabolic disease require both a detailed knowledge of the natural history of the diseases and a comprehensive understanding of the molecular basis and the pathophysiological consequences of gene defects. Continuous sympathetic company and guidance of patients and their families are essential for optimal outcome. Inherited metabolic diseases are chronic conditions that involve various different organ systems and often show progressive pathology.
- The aim is to help the affected individual to achieve optimal development during childhood and maximal independence, social integration, and self-esteem as an adolescent and adult. This goal can only be achieved by a multidisciplinary approach
- 1) To reduce the formation of toxic metabolites by decreasing substrate availability (by stopping feeds and preventing endogenous catabolism) 2) To provide adequate calories 3) To enhance the excretion of toxic metabolites. 4) To institute co-factor therapy for specific disease and also empirically if diagnosis not established. 5) Supportive care- treatment of seizures (avoid sodium valproate – may increase ammonia levels), maintain euglycemia and normothermia, fluid, electrolyte & acid-base balance, treatment of infection, mechanical ventilation if required.
- These are cofactor supplementations needed in treating IEM
- Substrate reduction / removal reducing the intake of nutrients/substrates that produce toxic metabolites, e.g. phenylalanine in phenylketonuria (PKU), branched-chain amino acids in maple syrup urine disease (MSUD), galactose in galactosaemia and long-chain fat in long chain hydroxyacyl-CoA dehydrogenase defi -ciency (LCHADD). Provision of ‘ conditionally ’ essential or essential nutrients : This is necessary as a consequence of the enzyme block, e.g. tyrosine in PKU, arginine/citrulline in urea cycle disorders and phenylalanine in tyrosinaemias Provision of alternative energy substrates , e.g. use of medium-chain triglycerides (MCT) in long-chain fatty acid oxidation disorders (LCFAODs), or provision of glucose and uncooked cornstarch (UCCS) in glycogen storage disease (GSD). Avoidance of fasting / prolonged fasting to avoid accumulation of toxic metabolites or defi - ciency of substrate , e.g. increased acylcarnitines/ free fatty acids in LC-FAOD, increased odd-chain fatty acids in propionic acidaemia (PA) and lack of glucose in GSD.
- There are four key strategies: – sup a defi product, e.g. supply of glucose in hepatic gsd Type I by regular daytime feeds and continuous overnight feed – preventing accumulation of a toxic substrate e.g. phenylalanine restriction in phenylketonuria to reduce harmful metabolites. To prevent malnutrition, protein substitutes and vitamin and mineral supplementation is required, guided by a specialist dietician – prevention of catabolism. Metabolic demands are increased when ill;, e.g. hyperammonaemia in urea cycle disorders. Oral glucose in the form of a glucose polymer, e.g. Polycal, is preferred during minor illnesses as it can be given at home. – ketogenic diet. Ketones can be used by the brain as an alternative fuel. Patients with GLUT1 (glucose transporter 1) deficiency are unable to transport glucose in to the central nervous system and thus rely on ketones as an alternative energy source for the brain and so require a ketogenic diet.
- Thiamine: mitochondrial disorders, thiamine responsive variants of MSUD, PDH deficiency & complex I deficiency) Riboflavin: Glutaric aciduria Type I, Type II, mild variants of ETF, ETF-DH, complex I deficiency Pyridoxine: 50% of cases of homocystinuria due to cystathionine β-synthetase deficiency, pyridoxine dependency with seizures, xanthurenic aciduria, primary hyperoxaluria type I, Hyperornithemia with gyrate atrophy Cobalamin: Methylmalonic academia (cblA, cblB), Homocystinuria and methylmalonic academia (cblC, cblD, cblF) Folinic acid: Hereditary orotic aciduria, Methionine synthase deficiency, Cerebral folate transporter deficiency, hereditary folate malabsorption, Kearns-Sayre syndrome Biotin: Biotinidase deficiency, holocarboxylase synthetase deficiency
- Its very difficult for doctors to make care givers to understand about IEM We have to keep these ten steps in mind while counselling parents
- Most of the IEM are single gene defects, inherited in an autosomal recessive manner, with a 25% recurrence risk. Therefore when the diagnosis is known and confirmed in the index case, prenatal diagnosis can be offered, wherever available for the subsequent pregnancies. The samples required are chorionic villus tissue or amniotic fluid. Modalities available are 1Substrate or metabolite detection: useful in phenylketonuria, peroxisomal defects. 2Enzyme assay: useful in lysosomal storage disorders like Niemann-Pick disease, Gaucher disease. 3 DNA based (molecular) diagnosis: Detection of mutation in proband/ carrier parents is a prerequisite.
- These are the Samples to be obtained in infant with suspected IEM when diagnosis is uncertain and death seems inevitable. Collectively Called as metabolic autopsy
- Generally IEM disorders will have guarded prognosis but few conditions have good prognosis too
- • IEM are not uncommon • Do suspect IEMs in all babies with unexplained deterioration of clinical condition and suspected sepsis when sepsis screen is negative. • Start with a simple approach to hold on to a ‘thread of logic’ which will lead on to the diagnosis. • Stabilization is the key to management. • If a diagnosis is not made when the child is alive, do collect blood samples and freeze to send for subsequent analysis. • An attempt to make a diagnosis gives the choice to the parents in subsequent pregnancies. • We have a long way to go in effective treatment and in the current scenario genetic counseling to the parents is the crux