1. An approach to Metabolic diseases in Children Dr V. Thrishi Sagna DNB Pediatrics Resident Indraprastha Apollo Hospital NewDelhiwww.dnbpediatrics.com

2. INTRODUCTION Archibald Garrod - concept of inborn errors of metabolism (IEM) (1908)IEM - heterogeneous group of disordersAbnormalities of the synthesis, transport, and turnover of dietary and cellular components.Significant cause of morbidity and mortality.www.dnbpediatrics.com 3. What is a metabolic disease? Garrods hypothesisABC product deficiencysubstrate excessD toxic metabolite www.dnbpediatrics.com 4. PATTERN OF INHERITANCE 90% of IEMs - autosomal recessive.Of the remaining 10%, - two thirds are X-linked and one third autosomal dominant traits.Autosomal dominant AIP, Familial hypercholestrolemiaX- linked traits Fabry`s disease, Lesch-Nyhan syndrome, OTC defMaternal inheritance Mitochondrialwww.dnbpediatrics.com 5. CLASSIFICATION 1. 2. 3. 4. 5. 6.OF IEM:Amino acid metabolism Carbohydrate metabolism Lipid metabolism Protein metabolism Pigment metabolism Unknown biochemical defectswww.dnbpediatrics.com 6. CLASSIFICATIONOF IEM:1. Amino acid metabolism -Phenylketonuria -Tyrosinosis -Albinism -Alkaptonuria -Cystinosis -Cystinuria -Homocysteinuria -Hartnup disease -Maple syrup disease www.dnbpediatrics.com 7. CLASSIFICATIONOF IEM:2. Carbohydrate synthesis: -Congenital lactose intolerance -Galatosemia -Glycogen storage disease -Diabetes mellituswww.dnbpediatrics.com 8. CLASSIFICATIONOF IEM:3. Lipid metabolism: -Abetalipoproteinemia -Progressive lipodystrophy -Lipid storage disorders * Gaucher * Neimann-Pick * Tay-sachs * Hyperlipoproteinemia www.dnbpediatrics.com 9. CLASSIFICATIONOF IEM:4. Protein Metabolism: -Immunoglobulin deficiencies -Absent clotting factors (Hemophilia, Christmas dis, Hypoprothrombinemia) -Metal binding protein deficiency (Wilson hepatolenticular degeneration) -Alpha-1 anti trypsin deficiency www.dnbpediatrics.com 10. CLASSIFICATION5.OF IEM:Pigment metabolism: -Porphyrias -Methemoglobinemias -Albinism -Crigler-Najjar dis -Dubin-Johnson dis -Gilbert dis -Rotor synd -Primary hemochromatosis www.dnbpediatrics.com 11. CLASSIFICATION6.OF IEM:Unknown biochemical defect: -Osteogenesis imperfecta -Marfan synd -Achondroplasia -Ehler danlos syndwww.dnbpediatrics.com 12. www.dnbpediatrics.com 13. When to Suspect IEM in a neonate Family history- undiagnosed neonatal deaths or unexplained severe illness in childhoodGroups of congenital anomalies or obvious dysmorphism: disorders of energy metabolism that are active in fetal lifeExtreme or exceptional presentation of common conditions: infant presents with unusually severe reaction to infection or metabolic stresswww.dnbpediatrics.com 14. When to Suspect IEM in a neonate Neurologic symptoms: unexplained encephalopathyExtreme or unusual pathology: infant with unusual smell of body or urineSurprising lab values: Finding a low blood urea in a neonate with respiratory alkalosis in a symptomatic neonate may offer a clue to the diagnosis of urea cycle defectwww.dnbpediatrics.com 15. Clues - History Positive family historySeizuresConsanguinityRespiratory distress/ apneaFailure to thriveJaundiceVomiting / DiarrhoeaDevelopmental delayUnusual odorwww.dnbpediatrics.com 16. Clues History cont. Frequent infectionsProgressive paraparesisProgressive HemiparesisBehavioral disturbanceDystoniawww.dnbpediatrics.com 17. CLINICALLY: IEM must be also considered in the differential diagnosis of Critically ill newborns Neuro - degeneration Mental retardation Coarse facies / dysmorphic features Parenchymal liver disease Cardiomyopathy Organomegaly Unexplained acidosis Corneal opacity, cataract or dislocation of lens Hyperammonemia Hypoglycemia www.dnbpediatrics.com 18. Inborn Errors of Amino Acid Metabolism Associated with Peculiar Odour:www.dnbpediatrics.com 19. Patterns of Presentation: 1. Encephalopathy with or without metabolic acidosis. 2. Acute liver disease: - Jaundice alone - Hepatic failure - Neonatal cholestasis - Hypoglycemia 3. Dysmorphic features. 4. Cardiac disease. 5. Diarrhea 6. Hepatomegaly +/- Splenomegaly 7. Predominant Neurological symptoms www.dnbpediatrics.com 20. 1.Acute encephalopathy Without metabolic acidosis - Pyridoxine dependency (clinical & EEG response) - Urea cycle defect- MSUD - NKH( persistent hiccups, hypotonia, Sz) - Molybdenum cofactor defect ( low urate) - Sulfite Oxidase defects (raised urine S sulfocysteine) www.dnbpediatrics.com 21. - Pyridoxal phosphate dependency - Folinic acid responsive seizures - Neurotransmitter defects(Cobalamin deficiency) With metabolic acidosis- Organic acidopathies (Severe acidosis, organic acids inhibit UC enzymes, gluconeogenesis ) - Congenital lactic acidosis - FAOD www.dnbpediatrics.com 22. Acute Encephalopathy Acid base, lactate, ammonium, glucoseMetabolic acidosis Lactic NH3 acidosis Lactic AcidosisNH3No acidosisGlucoseNo acidosis No Hyperamm No hypoglyUrine metabolic screen, plasma amino acids, acylcarnitine profile etcOrganic acid FAODMitochondrial Lactic AcidUCD THAN LPIFAOD, GSD, HFI Galactosemia MSUD www.dnbpediatrics.comAminoacid -opathy 23. 2) Acute liver disease: could manifest as-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. Persistent and severe hypoglycemia: -Galactosemia, -fatty acid oxidation defects, -organic acidemias, -glycogen storage disorders and -disorders of gluconeogenesis. www.dnbpediatrics.com 24. 3) Dysmorphic features: seen in -Peroxisomal disorders, -Pyruvate dehydrogenase deficiency, -Congenital disorders of glycosylation -Lysosomal storage diseases. Some IEMs may present with non-immune hydrops fetalis -lysosomal storage disorders -Congenital disorders of www.dnbpediatrics.com 25. ZELLWEGERS SYNDROMEwww.dnbpediatrics.com 26. Hurler schei syndromeSanfillippowww.dnbpediatrics.com 27. 4) Cardiac disease: Cardiomyopathy is a prominent feature in some IEM like in: -Fatty acid oxidation defects, -Glycogen storage disease type II( Pompes disease) -Mitochondrial electron transport chain defectswww.dnbpediatrics.com 28. 5. Diarrhea : a. Severe watery diarrhea: - Congenital chloride diarrhea - Galactosemia - Primary lactase , sucrase , isomaltase deficiency. b. Chronic diarrhea: -Bile acid disorders -Infantile Refsum disease -Respiratory chain disorders asso with steatorrhea -Vitamin deficiency osteopenia -Hypocholesterolemia c. Diarrhea, Failure to thrive, hypotonia , hepatomegaly: -Glycogen storage dis 1 - Wolmans disease www.dnbpediatrics.com 29. 6. Hepatomegaly : -Tyrosinemia -Galactosemia -Fructosemia -Alpha 1 antitrypsin deficiency. 7 Hepatomegaly + Splenomegaly: -Mucolipidosis -Gauchers dis -Niemann-Pick type Awww.dnbpediatrics.com 30. 8. Predominant Neurological Symptoms: a. Psychomotor delay: -Aminoacidopathies -Organic acidemias -CNS storage diseases b. Recurrent Reye : -Urea cycle defect -Systemic carnitine deficiency c. Ataxia: -Hartnup dis -Urea cycle disorders -Pyruvate decarboxylase deficiency d. Extrapyramidal signs: - Wilsons disease e. Hypotonia : - Zellweger synd -Mitochondrial myopathies -Muscle carnitine deficiency www.dnbpediatrics.com 31. Initial findings includePoor feeding Vomiting Lethargy Convulsion ComaMetabolic disorderinfectionObtainPlasma NH3 highnormalObtain ABGnormalAcidosisUrea cycle defectsOrganic acidemiasNormalAminoacidopathies/ galactosemiasClinical approach to a newborn with metabolic disorder www.dnbpediatrics.com 32. High Plasma Ammonia No Acidosis No KetosisUREA CYCLE DEFECTwww.dnbpediatrics.com 33. Normal or High Plasma AmmoniaAcidosis KetosisOrganic acidemias, Mitochondrial disorders www.dnbpediatrics.com 34. Normal or High Plasma AmmoniaAcidosis No KetosisFatty acid oxidation defectswww.dnbpediatrics.com 35. Clinical approach to infants with organic acidemia Refusal of feeds Vomitting Acidosis Dehydration Neutropenia HypoglycemiaKetosisNo skin manifestationsNo odorMethyl malonic acidemia Propionic acidemia Ketothiolase deficiencyNo KetosisSkin manifestationsCharacteristic odor3-Hydroxy-3methylglutaricaciduria Acyl CoA dehydrogenase deficiencyMultiple Carboxylase DeficiencyMSUD Isovaleric acidemia.www.dnbpediatrics.com 36. www.dnbpediatrics.com 37. www.dnbpediatrics.com 38. www.dnbpediatrics.com 39. INVESTIGATIONSwww.dnbpediatrics.com 40. First line investigations (metabolic screen): The following tests should be obtained in all babies with suspected IEM. 1) Complete blood count: (neutropenia and thrombocytopenia seen in propionic and methylmalonic academia) 2) Arterial blood gases and electrolytes 3) Blood glucose 4) Plasma ammonia (Normal values in newborn: 90150 mg/dl or 64-107 mmol/L) 5) Arterial blood lactate (Normal values: 0.5-1.6 mmol/L) 6) Liver function tests, 7) Urine ketones, 8) Urine reducing substances, 9) Serum uric acid (low in molybdenum cofactor www.dnbpediatrics.com deficiency). 41. Second line investigations (ancillary and confirmatory tests) These tests need to be performed in a targeted manner, based on presumptive diagnosis after first line investigations:1) Gas chromatography mass spectrometry (GCMS) of urine- for diagnosis of organic acidemias.2) Plasma amino acids and acyl carnitine profile: by Tandem mass spectrometry (TMS)- for diagnosis of organic acidemias, urea cycle defects, aminoacidopathies and fatty acid oxidation defects.3) High performance liquid chromatography (HPLC): for quantitative analysis of amino acids in blood and urine; required for diagnosis of organic acidemias and www.dnbpediatrics.com aminoacidopathies. 42. 4) Lactate/pyruvate ratio- in cases with elevated lactate.5) Urinary orotic acid- in cases with hyperammonemia for classification of urea cycle defect.6) Enzyme assay: This is required for definitive diagnosis, but not available for most IEMs. Available enzyme assays include: -Biotinidase assay- in cases with suspected biotinidase deficiency (intractable seizures, seborrheic rash, alopecia); -GALT (galactose 1-phosphate uridyl transferase ) assay- in cases with suspected galactosemia (hypoglycemia, cataracts, reducing www.dnbpediatrics.com sugars in urine). 43. 7) Neuroimaging: MRI Some IEM may be associated with structural malformations . Examples: Zellweger syndrome has diffuse cortical migration and sulcation abnormalities. Agenesis of corpus callosum has been reported in Menkes disease, pyruvate decarboxylase deficiency and nonketotic hyperglycinemia. Maple syrup urine disease (MSUD): brainstem and cerebellar edema. Propionic & methylmalonic acidemia: basal ganglia signal change. Glutaric aciduria: frontotemporal atrophy, subdural hematomas. www.dnbpediatrics.com 44. 8) Magnetic resonance spectroscopy (MRS): may be helpful in selected disorders E.g. lactate peak elevated in mitochondrial disorders, leucine peak elevated in MSUD. 9) Electroencephalography (EEG): Comb-like rhythm in MSUD, Burst suppression in Non Ketotic Hyperglycemia and holocarboxylase synthetase deficiency. 10) Plasma very long chain fatty acid (VLCFA) levels: elevated in peroxisomal disorders.11)Mutation analysis when available. 12) CSF aminoacid analysis: CSF Glycine levels elevated in NKH. www.dnbpediatrics.com 45. Precautions to be observed while collecting samples: 1. Should be collected before specific treatment is started or feeds are stopped, as may be falsely normal if the child is off feeds. 2. Samples for blood ammonia and lactate should be transported in ice and immediately tested. Lactate sample should be arterial and should be collected after 2 hrs fasting in a preheparinized syringe . Ammonia sample is to be collected approximately after 2 hours of fasting in EDTA vacutainer. Avoid air mixing. Sample should be free flowing. 3. Detailed history including drug details should be provided to the lab. (sodium valproate therapy may www.dnbpediatrics.com 46. Aims of treatment 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. www.dnbpediatrics.com 47. Management of hyperammonemia:1) Discontinue all feeds. Provide adequate calories by intravenous glucose and lipids. Maintain glucose infusion rate 8-10mg/kg/min. Start intravenous lipid 0.5 g/kg/day (up to 3 g/kg/day). After stabilization gradually add protein 0.25 g/kg till 1.5 g/kg/day.2) Dialysis is the only means for rapid removal of ammonia, and hemodialysis is more effective and faster than peritoneal dialysis. Exchange transfusion is not useful. 3) Alternative pathways for nitrogen excretion-: -Sodium benzoate (IV/oral)- loading dose 250 mg/kg then 250-400 mg/kg/day in 4 divided doses. -Sodium phenylbutyrate -loading dose 250 mg/kg followed by 250-500 mg/kg/day. -L-arginine (oral or IV)- 300 mg/kg/day -L-carnitine (oral or IV)- 200 mg/kg/day 4) Supportive care: Treatment of sepsis , seizures , ventilation. Avoid sodium valproate. www.dnbpediatrics.com 48. Acute management of newborn with suspected organic acidemia: 1) The patient is kept nil per orally and intravenous glucose is provided. 2) Supportive care: hydration, treatment of sepsis, seizures, ventilation. 3) Carnitine: 100 mg/kg/day IV or oral. 4) Treat acidosis: Sodium bicarbonate 0.35-0.5mEq/kg/hr (max 12mEq/kg/hr) 5) Start Biotin 10 mg/day orally. 6) Start Vitamin B12 1-2 mg/day I/M (useful in B12 responsive forms of methylmalonic acidemias) 7) Start Thiamine 300 mg/day (useful in Thiamine-responsive variants www.dnbpediatrics.com of MSUD). 49. Management of congenital lactic acidosis: 1) Supportive care: hydration, treatment of sepsis, seizures, ventilation. Avoid sodium valproate. 2) Treat acidosis: sodium bicarbonate 0.35-0.5mEq/kg/hr (max 1-2mEq/kg/hr)3) Thiamine: up to 300 mg/day in 4 divided doses. 4) Riboflavin: 100 mg/day in 4 divided doses.5) Add co-enzyme Q: 5-15 mg/kg/day 6) L-carnitine: 50-100 mg/kg orally. www.dnbpediatrics.com 50. Treatment of newborn with refractory seizures with no obvious etiology (suspected metabolic etiology): 1) If patient persists to have seizures despite 2 or 3 antiepileptic drugs in adequate doses, consider trial of pyridoxine 100 mg intravenously. If intravenous preparation not available, oral pyridoxine can be given (15 mg/kg/day). 2) If seizures persist despite pyridoxine, give trial of biotin 10 mg/day and folinic acid 15 mg/day (folinic acid responsive seizures). 3) Rule out glucose transporter defect: measure CSF and blood glucose. This disorder responds to the ketogenic diet. www.dnbpediatrics.com 51. Management of asymptomatic newborn with a history of sibling death with suspected IEM: 1) After baseline metabolic screen, start oral dextrose feeds (10% dextrose). 2) After 24 hours, repeat screen. If normal, start breast feeds. Monitor sugar, blood gases and urine ketones, blood ammonia Q6 hourly. 3) Some recommend starting medium chain triglycerides (MCT oil) before starting breast feeds, 4) After 48 hours, repeat metabolic screen. Obtain samples for urine organic acid tests. 5) The infant will need careful observation and follow-up for the first few months, as IEM may present in different age groups in members of the same family. www.dnbpediatrics.com 52. Long term treatment of IEM 1) Dietary treatment: This is the mainstay of treatment in phenylketonuria, maple syrup urine disease, homocystinuria, galactosemia, and glycogen storage disease Type I & III. Some disorders like urea cycle disorders and organic acidurias require dietary modification (protein restriction) in addition to other modalities. 2) Enzyme replacement therapy (ERT): ERT is available for some lysosomal storage disorders. However, these disorders do not manifest in the newborn period, except Pompes disease (Glycogen storage disorder Type II) which may present in the newborn www.dnbpediatrics.comfor which period and 53. 3) Cofactor replacement therapy: The catalytic properties of many enzymes depend on the participation of non protein prosthetic groups, such as vitamins and minerals,as obligatory cofactors.www.dnbpediatrics.com 54. PREVENTIONwww.dnbpediatrics.com 55. 1.Genetic counselling and prenatal diagnosis: 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 Villous tissue or Amniotic fluid.Modalities available are: -Substrate or metabolite detection: useful in phenylketonuria, peroxisomal defects .-Enzyme assay: useful in lysosomal storage disorders like NiemannPick disease, Gaucher disease. www.dnbpediatrics.com -DNA based (molecular) diagnosis: Detection of mutation in proband/ 56. 2) Neonatal screening: Tandem mass spectrometry is used for neonatal screening for IEM. Disorders which can be detected by TMS include -Aminoacidopathies ( phenylketonuria, MSUD, Homocystinuria, Citrullinemia , Argininosuccinic aciduria, hepatorenal tyrosinemia), -Fatty acid oxidation defects. -Organic acidemias (glutaric aciduria, propionic acidemia, methylmalonic acidemia, isovaleric acidemia). Samples should be collected between Day 1 and 3 day of life. www.dnbpediatrics.com 57. IEM collectively represent an important cause of morbidity and death in the neonatal period. The most important step in the diagnosis of IEM is clinical suspicion. Screening investigations such as arterial blood gases, blood ammonia, lactate, sugar and urine ketones help to categorize the possible IEM and guide immediate management. Appropriate immediate treatment not only improves survival but also reduces the chances of neurodevelopmental sequelae. www.dnbpediatrics.com 58. Dos and Donts 1) Dont think of IEM as rare, exotic and untreatable disorders. 2) Think of IEM in sick newborns in parallel with other common conditions such as sepsis. The signs and symptoms are usually non specific such a lethargy, poor feeding and vomiting. 3) Observe the precautions as explained while collecting and storing samples 4) Even if the chances of survival appear bleak, every attempt must be made to reach a diagnosis so that parents can be guided for future pregnancy. www.dnbpediatrics.com 59. www.dnbpediatrics.com