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Inborn Errors of metabolism
- 1. 121 âA clinical approach of inborn errors of metabolismâ -NITHTHY- Post graduate trainee in Neonatology, PGIM ,Colombo.
- 2. 1st case reported in 1908 by Sir Archibald Garrod
- 3. In 1920 girl from China, aged 3 months, was adopted by an American mother ď USA Child unusual beauty, blue eyes Musty odor from child, Later developmental delay No one could tell what was wrong What has been, need not for ever be so - Pearl S. Buck Book âThe Child Who Never Grewâ ď PKU
- 4. Objective ⢠Simple classification ⢠Clinical presentation ⢠Investigations approach ⢠Management principle
- 5. Inborn errors of metabolism(IEM) classification Energy source problems ⢠Amino-acidopathies ⢠Organic acid ⢠Urea cycle disorder Protein ⢠Fatty acid oxidation disorder ⢠( LCFAOD,MCAD,SCAD) Lipid ⢠Galactosemia ⢠GSD/gly synthase deficiency ⢠Fructose intolerance CHO Dysfunctional pathway in cellular organelles ⢠Mucopolysaccharidosis ⢠Sphingolipidoses ⢠Oligosaccharides Lysosomal ⢠Adrenoleukodystrophy ⢠Zellweger Peroxisomal ⢠MELAS ⢠KSS, MERRF Mitochondrial
- 6. Suspecting IEM from history ⢠Parental consanguinity ⢠Recurrent vomiting, Feeding difficulty ⢠Unusual odor of urine ⢠Respiratory difficulty ⢠Intractable seizure ⢠Retardation or unexplained sudden deaths in first and second degree relatives ⢠Central and peripheral nervous system
- 7. Suspecting IEM from examinations ⢠Critically ill newborn ⢠Coarse facies/ dysmorphic face ⢠Respiratory ⢠Cardiovascular system ⢠Nervous system ⢠Skeletal ⢠Eye & ear ⢠Gastro intestinal ⢠Hematology ⢠skin
- 8. Clinical presentation CJ ELLAWAY, B WILCKEN and J CHRISTODOULOU Western Sydney Genetics Program, Royal Alexandra Hospital for Children and Department of Paediatrics and Child Health,University of Sydney, Sydney, New South Wales, Australia,inborn error of metabolism, J. Paediatric and Child Health(2002)38, 511â517
- 9. Acute encephalopathy ⢠Can occur from hours to days or weeks after birth ⢠Irritability, vomiting, poor feeding, lethargy, seizures, coma ⢠Commonly misdiagnosed as sepsis, clinical & investigations can mimic each others Metabolic acidosis hyperammonemia hypoglycemia MSUD Urea cycle defects Organic acidurias Organic acidurias Propionic acidemia FAOD Fatty acid oxidation defect Methyl malonyl acidemia Defect of gluconeogenesis Primary lactic acidemias defect of gluconeogenesis Glucogenolysis pyruvate metabolism krebs cycle& respiratory chain disorder FAOD
- 10. Neonatal Seizures ⢠Non- ketotic hyperglycinemia -in utero ⢠Pyridoxine-responsive seizures , ⢠Pyridoxal phosphate responsive seizure ⢠Folinic acid responsive seizures ⢠Sulfite oxidase deficiency ⢠Peroxisomal disorder
- 11. Hypotonia ⢠Mitochondrial respiratory chain disorder ⢠Peroxisomal disorder ⢠Non ketotic hyperglycinemia ⢠Sulfite oxidase defect
- 12. Liver dysfunction ⢠Hepatomegaly, jaundice, clotting dysfunction &hypoglycemia ⢠Liver dysfunction without dysmorphism Galactosemia ,Tyrosinemia Hereditary fructose intolerance Gluconeogenesis defect Fatty acid oxidation disorder ⢠Liver dysfunction with dysmorphism peroxisomal disorder, lysosomal disorders
- 13. Cardiac dysfunction ⢠Arrythmias, cardiac arrest & cardiomyopathy in neonatal period -long chain Fatty acid oxidation defect, defect of carnitine transporter ⢠Cardiomyopathy in neonates â less common GSD- Pompe disease Mitochondrial electron transport chain defect TCA cycle defect
- 14. Non-immune hydrops fetalis ⢠Lysosomal disorder ⢠Glycogen storage disease type IV ⢠Congenital defect of glycosylation
- 15. Defect in metabolism of Carbohydrates
- 18. â˘Type-1,3,4,6,9,11 Liver glycogenoses â˘Type-2,3,5,7,9 Musule glycogenoses â˘Type -9,3 Muscle and liver
- 19. Glycogen storage disorder type1 ⢠Shortly after birth present with hypoglycemia and lactic acidosis ⢠Severe life threatening hypoglycemia with seizures&hepatomegaly in 3 month
- 20. Glycogen storage disorder type1 ⢠Investigation ⢠Hypoglycemia, lactic acidosis ,Hyperuricemia, Hyperlipidemia ⢠Lactic acidosis- due to isolated glycolysis of glucose 6 phosphate ⢠Neutropenia in type1b ⢠Definitive Dx: liver biopsy, ⢠gene panel, single gene sequence
- 21. Glycogen storage disorder type1 ⢠Treatment ⢠Maintain normal glucose level by continuous NG infusion of glucose, uncooked cornstarch by oral ⢠Infancy : NG drip feeding ⢠Medium chain triglyceride supplementation ⢠Lactose , Sucrose, fructose & sorbitol should be avoided ⢠Orthotopic liver transplantation is a potential cure
- 22. Glycogen storage disorder type2- Pompe ⢠Deficiency of alpha 1,4 glucosidase enzyme deficiency ⢠Infantile- ⢠Within weeks ⢠Hypotonia, generalised Muscle weakness ⢠Floppy ⢠Macroglossia ⢠Hepatomegaly ⢠Hypertrophic cardiomyopathy
- 23. Glycogen storage disorder type2- Pompe ... ⢠Later onset :- presents cardiac rhythm abnormality to cardiomyopathy ⢠Proximal limb girdle muscle :- wheel chair bound ⢠diaphragm muscle weakness -respiratory insufficiency ⢠Investigation High CPK, LDH, ALT and AST Muscle Biopsy - vacuoles stain positively for glycogen ECG-High voltage QRS, WPW, short PR interval Definitive diagnosis-Enzyme assay ⢠Treatment-Enzyme replacement
- 24. Galactosemia ⢠Jaundice, hepatomegaly ,vomiting, irritability, seizure, lethargy, feeding difficulty, poor weight gain in few days or week after birth ⢠Escherichia coli sepsis ⢠Later; Cataracts, chronic liver cell disease & complication, Hypergonadotropic hypogonadism ⢠Ix; Clinitest: positive, clinistix test:negative, hypoglycemia enzyme assay Tx; removal of all galactose contain food ,non lactose containing formula milk ; soy bean based formula, casein hydrolysate
- 25. Energy source problems Deamination Protein Ammonia pH-H/N Ammino acidopathies (PKU,Tyrosinemia) pH-N Amminoacids Organic acids pH-L
- 27. Amino acidopathies- Phenylketonuria ⢠Phenylalanine hydroxylase or tetrahydrobiopterin deficiency ⢠Presentation - normal at birth, vomiting, eczematoid rash, fair complexion, seizure, spasticity, hyperreflexia , tremor, later-hyperactivity, autistic behaviour , low IQ ⢠Dx- serum AA profile ,ferric chloride test in urine â green, molecular analysis ⢠Mx- low phenyl alanine diet, BH4
- 28. Amino acidopathies: Tyrosinemia-I ⢠Precursor of neuro transmitters ,melanin, thyroxine ⢠Fumaryl acetoacetate hydrolase deficiency ⢠Hepatic crisis ⢠Fever, irritability, vomiting, jaundice, haemorrhage, hepatomegaly, cirrhosis, hepato cellular carcinoma ⢠Boiled cabbage odor ⢠Peripheral neuropathy ⢠(Acquired - hepatocellular dysfunction, scurvy, hyperthyroidism ) ⢠Ix- elevated urinary succinyl acetone , ALT/AST, alpha fetoprotein ⢠Rx - Nitisinone ,diet low in phenylalanine and tyrosine
- 29. Amino acidopathies: Albinism ⢠Deficiency of melanin in skin ,hair and eye ⢠Ocular - hypopigmentation of iris &retina with foveal hypoplasia, alternating strabismus, nystagmus, refractory error ⢠Rx- avoid UV light, sunscreen SPF >30, avoid ototoxic drug ⢠Associated syndrome ⢠Hermansky pudlak syndrome-bleeding manifestation, IBD, pulmonary fibrosis ⢠Chediak-higashi syndrome- bleeding, infection, giant lysosomal granules in granulocyte, HLH ⢠Waardenburg syndrome - heterochromia of irides, white forelock, sensory neural deafness
- 32. Amino acidopathies: Maple syrup urine disease ⢠Branch chain alpha ketoacid dehydrogenase deficiency ⢠Decarboxylation of leucine, isoleucine, valine ⢠Leucinosis; acute encephalopathy, cerebral edema, convulsion ⢠âBoxing and bicyclingââ -period of hypertonicity may alternate with bouts of flaccidity manifested as repetitive movement of extremities ⢠Peculiar odor of marble syrup in urine & sweat ⢠Hypoglycemia ⢠Rx - hydration, rapid removal of BCAA, haemodialysis, diet, neuroprotection
- 33. Amino acidopathies- Homocystinuria ⢠Cystathionine beta synthase deficiency ⢠Intellectual disability, down ward sub luxation of ocular lens, blue eye, skeletal abnormality resembling marfan Xn, fair complexion, psychiatric behaviour, ⢠Thromboembolic episodes ⢠Elevation of methionine and homocysteine in body fluids ⢠Rx - B6 100-500mg/day, betaine , diet low methionine with high cysteine ⢠Defect in methylcobalamin formation associated with methylmalonic acidemia- hyperpigmentation, bullâs eye maculopathy ,megaloblastic anemia ,
- 34. Organic acidemia
- 35. Organic acidemia- Isovaleric acidemia ⢠Isovaleryl-coenzyme A dehydrogenase deficiency ⢠Convulsion and coma ⢠Sweaty feet or rancid cheese odor ⢠Mimic diabetic ketoacidosis ⢠Rx- hydration, reversal of catabolic state ⢠L-carnitine 100mg/kg/day ⢠glysine supplement 250mg/kg/day ⢠temporary restriction of protein ⢠renal replacement therapy
- 36. Organic acidemia- Methylmalonic acidemias ⢠1st few days of life , sepsis like picture ⢠Encephalopathy , hypotonia, metabolic stroke, movement disorder ⢠Pancreatitis, bone marrow suppression ⢠Ix- elevated methylmalonic acid in urine, ⢠Rx - low protein diet, L-carnitine 50-100 mg/kg/day
- 37. Organic acidemia- Multiple carboxylase deficiency ⢠Holocarboxylase synthetase deficiency ⢠Breathing difficulty, hypotonia ⢠Generalised erythematous rash with exfoliation, alopecia ,seizure ⢠Tomcat urine ⢠Immunodeficiency ⢠Biotin 10-20 mg daily. ⢠Biotinidase deficiency - seizure , alopecia, dermatitis, optic nerve atrophy, hearing loss
- 38. Organic acidemia- Propionic acidemia ⢠Propinyl-coA carboxylase deficiency ⢠Seizure, intellectual disability, extrapyramidal & pyramidal dysfunction ⢠Metabolic stroke âdamage to basal ganglia ⢠Metronidazole( propiogenic gut microflora) ⢠L-carnitine 50-100 mg/kg/day
- 40. Urea Cycle Disorders Most disorders are AR inherited (OTC deficiency XLR / XL âSemidominant) Most disorders have similar type of presentations: ⢠Neonatal Presentation â Symptomatic after introduction of dietary protein Refusal to feed, vomiting, tachypnea, lethargy, coma Encephalopathy, seizures, hepatomegaly ⢠Infant/ Children Presentation â FTT, Chronic neurological symptoms, episodic encephalopathy
- 41. Hyperammonemia
- 42. Disorders of Mitochondrial Fatty Acid Oxidation 1. Defects in LCFA transport across Mitochondrial Membrane (Defects in Carnitine Transporter Mechanism) eg: CPT-1 deficiency 2. Deficiency of Enzymes for Beta-Oxidation 2.1 Short Chain Fatty Acid Oxidation Disorders eg: SCAD deficiency, 2.2 Medium Chain Fatty Acid Oxidation Disorders eg: MCAD deficiency 2.3 Long Chain Fatty Acid Oxidation Disorders eg: VLCAD deficiency, LCHAD Deficiency 3. Disorders of Electron Transport Chain eg: ETF deficiencies
- 43. Clinical presentation of fatty acid disorder ⢠Encephalopathy with hypoglycaemia, provoked by infections, fasting or vomiting ⢠Sudden death- probably due to cardiac arrhythmias ⢠Cardiomyopathy ( not MCADD) ⢠Muscle weakness or rhabdomyolysis ⢠Acute fatty liver of pregnancy (AFLP) or HELLP syndrome in the mother
- 44. Disorders of Mitochondrial Fatty Acid Oxidation ⢠Hypoglycaemia ⢠Hypoketosis (Patients with SCFA disorders can produce KB, and patients with MCFA disorders can have mild ketosis) ⢠Elevated FFA level ⢠Lactic Acidosis (Can be severe) ⢠Hyperammonaemia (Usually Mild) ⢠Low level of Serum Carnitine and Elevated Specific Acylcarnitines ⢠Elevated CK, Myoglobin ⢠Elevated specific dicarboxylic Organic acids
- 45. Disorders of Mitochondrial Fatty Acid Oxidation General Principles of Management ⢠Management of Crisis ⢠IV Dextrose 12-15mg/kg/min (Can reduce to 7-10mg/kg/min depending on response) ⢠Use insulin to maintain normoglycaemia (Maintain Blood Glucose around 100mg/dL)-> Hyperglycaemia can aggrevate Lactic Acidosis ⢠Avoid Intravenous Lipid ⢠Monitor for Cardiac arrhythmias ⢠Detect and treat liver failure ⢠May need ammonia scavenging, if ammonia level is high and not responding to glucose ⢠Carnitine can be used in secondary carnitine deficiency
- 46. Disorders of Mitochondrial Fatty Acid Oxidation General Principles of Management ⢠Long term management â Avoidance of fasting ⢠Infants should be fed 3-4 hourly. Avoid fasting more than 6 hours during early infancy (Up to 4 months) ⢠Avoid fasting more than 8-10 hours during late infancy. ⢠Avoid fasting more than 10-12 hours rest of the life ⢠In milder illness and gastroenteritis, more frequent feeding is necessary ⢠Monitor CBS ⢠If enteral feeding is not tolerated or illness is moderate to severe or CBS is lowering, should receive IV Glucose immediately
- 48. Initial Investigation in a critically ill babies ⢠Full blood count ⢠Blood glucose ⢠Serum electrolytes and acid base status (check anion status) ⢠Glucose status with ketone bodies ⢠Ammonia and Lactate level ⢠Liver function test ⢠Urine ketones if acidosis or hypoglycemia present ⢠Urine reducing substance
- 49. Special investigationsâŚ. ⢠Plasma amino acids Elevated in aminoacidopathies, urea cycle defects ⢠Urine organic acids elevated in organic acidemias ,FAOD, some aminoacidopathies ⢠Plasma acylcarnitine profile useful in diagnosing FAOD, some organic acidemias
- 50. Special investigations ⢠Carnitine level markedly less in carnitine deficiency elevated in carnitine esters in FAOD & OA ⢠Enzyme assay of fibroblast/lymphocytes ⢠DNA testing ⢠Lactate : pyruvate ratio in respiratory chain defect
- 51. Ammonia, acid base, lactate, glucose, anion Met acidosis +/- hyperammonemia +/-lactic acidosis Hyperammonemia No acidosis hypoglycemia Lactic acidosis No acidosis No hyperammonemia No hypoglycemia Metabolic work up ;- plasma A .A profile, urine O.A profile ,acylcarnitine level, enzyme assay Organic acidosis FAOD(no ketosis) Mitochondrial Lactate disorder Urea cycle disorder THAN aminoacidopathies FAOD,GSD HFI,MSUD galactosemia seizure NKHG SO deficiency
- 52. Simplified Algorithms - Encephalopathy Mt.Diseases, AA, Other Suspected Metabolic Encephalopathy Plasma NH3 level OA, UCD, FAOD Mt.Diseases AA, Other Specific AA Neurotransmitter Diseases, Vitamin Responsive Diseases, Glut-1 Transporter deficiency, NKH, Menkeâs disease Plasma Lactate level AA profile High High Normal Normal Normal OA, FAOD UCD Blood Gas Metabolic Acidosis Respiratory Alkalosis Ketone Bodies OA FAOD High Low OA Profile, AA profile AcylCarnitine Profile, OA profile AA Profile, Urine OA profiled Mitochondrial Workup
- 59. Aims of treatment ⢠Decreasing substrate availability(by stopping feed,& preventing endogenous catabolism) ⢠To provide adequate calories ⢠To enhance the excretion of toxic metabolites ⢠To institute co-factor therapy for specific disease and also empirically if diagnosis not established
- 60. Aims of treatmentâŚ.. ⢠Supportive care â treatment of seizure avoid sodium valproate ⢠Maintain euglycemia and normothermia ⢠Fluid and electrolyte & acid base balance ⢠Treatment of infection ⢠Mechanical ventilation if required
- 61. Management of hyperammonemia ⢠Discontinue all feeds ⢠Provide adequate calories by intravenous glucose and lipids ⢠Maintain glucose infusion rate 6-8 mg/kg/min, start intravenous lipid 0.5mg/kg/day(up to 3g/kg/day) ⢠After stabilization gradually add protein 0.25g/kg till 1.5 g/kg/day
- 62. Management of hyperammonemia⌠⢠Sodium benzoate & sodium phenylbutyrate (iv or oral) loading dose 250 mg/kg then 250-400mg/kg/day in 4 divided dose ⢠L-carnitine 200mg/kg/day ⢠L- arginine 300mg/kg/day ⢠Dialysis is the only means for rapid removal of ammonia, and hemodialysis is more effective and faster than peritoneal dialysis, exchange transfusion is not effective ⢠Reference: Das AM, Illsinger S, Hartmann H, Oehler K, Bohnhorst B, Kuehn-Velten N, Luecke T. Prenatal Benzoate Treatment in Urea Cycle Defects. Arch Dis Child Fetal Neonatal Ed. 2008 Nov 13. [Epub ahead of print
- 63. Urea Cycle Disorders No specific medical managements Main stay of treatment is scavenging ammonia and protein restriction Maintain anabolic state with high calory diet Limit Proteins (50% should contain essential aminoacids) Regular arginine therapy in CPS/OTC deficiency (Avoid in arginase deficiency) Ammonia scavenging agents (Na-benzoate, Na-phenylbutrate) daily Lactulose to reduce gut absorption Multivitamin supplementation Liver transplantation is curative if diagnosed early
- 64. â˘Suspected organic acidemia Acute management ⢠The baby kept nil per orally and intravenous glucose is provided ⢠Supportive care : hydration, treatment of sepsis, seizure ,ventilation ⢠Carnitine; 100mg/kg/day ⢠Treat acidosis 0.35-0.5 mEq/kg/hr(max 1-2mEq/kg/hr ⢠Treat hyperammonemia ⢠Biotin 10mg/day (biotinidase deficiency) ⢠Vitamin B12; 1-2mg/day (MMA) ⢠Thiamine 300mg/day (MSUD) ⢠Nelson text book pediatrics 21 st edition, page 709
- 65. Prevention ⢠Genetic counselling and prenatal diagnosis ⢠Most of the IEM are single gene mutation ⢠Inherited in an autosomal recessive manner with 25 % recurrence ⢠Sample- chorionic villus tissue or amniotic fluid substrate or metabolite detection enzyme assay DNA based diagnosis
- 70. Reference ⢠COMMITTEE, JOINT FORMULARY. British National Formulary for Children (BNFc). 2019 [cited 2019 7th November]; Available from: https://bnfc.nice.org.uk. ⢠. SAUDUBRAY, JEAN-MARIE, BAUMGARTNER, MATTHIAS R., and WALTER, JOHN HUGH, Inborn metabolic diseases : diagnosis and treatment. 2016. ⢠CJ ELLAWAY, B WILCKEN and J CHRISTODOULOU Western Sydney Genetics Program, Royal Alexandra Hospital for Children and Department of Paediatrics and Child Health,University of Sydney, Sydney, New South Wales, Australia,inborn error of metabolism, J. Paediatric and Child Health(2002)38, 511â517 ⢠nelson text book paediatric , 21st edition ⢠https://bimdg.org.uk/site/index.asp ⢠PARIKH, SUMIT, et al., A modern approach to the treatment of mitochondrial disease. Current treatment options in neurology, 2009. 11(6): p. 414-430.