approach to Inborn Errors of Metabolism in neonates


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Detailed approach on IEM in newborn

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  • Neuro: Lethargy , coma, tone changes,involuntary movements, apnea, bradycardia & hypothermia
  • arginine: glycine amidinotransferase (AGAT) deficiency; OMIM 602360; and guanidinoacetate methyltransferase (GAMT) deficiency (OMIM 601240)) and one disorder of creatine transport (X-linked recessive SLC6A8 creatine transporter deficiency (OMIM 300036)).
  • Severe hypotonia is a common symptom of sick neonates..few iem present as predominant hypotonia in newborn period
  • when there is ingestion of fructose or sucrose, in the neonate usually a soy formula
  • GSD
  • Electrolytes and blood gases are required to determine whether an acidosis or alkalosis is present and, if so, whether the abnormality is associated with an increased anion gap. The organic acidemias and the primary lactic acidosis cause metabolic acidosis with a raised anion gap in early stages. Most metabolic conditions result in acidosis in late stages as encephalopathy and circulatory disturbances progress. A persistent metabolic acidosis with normal tissue perfusion may suggest an organic acidemia or a congenital lactic acidosis. A mild respiratory alkalosis in nonventilated babies suggests hyperammonemia. However, in late stages of hyperammonemia, vasomotor instability and collapse can cause metabolic acidosis.
  • HCS: holocarboxylase synthetase
  • Plasma citrulline 25-50μmol/L)
    THAN: transient hyperammonemia of newborn
    Ass: argino succinic acid synthetase
    ASL: arginosuccinate lyase
    HHH:hypornithinemia, hyperammonemia, homocitrullinuria
  • 4. Plasma uric acid test is a convenient screen for the few IEM that are associated with either hyperuricemia (type I glycogen storage disease) or hypouricemia (xanthine dehydrogenase deficiency).
  • , as may be falsely normal if the child is off feeds.
  • by measurement of abnormal metabolites in the amniotic fluid or by enzyme assay or DNA analysis of amniocytes by amniocentesis
  • .(CSF glucose level is equal to or less than 1/3rd of the blood glucose level.. responds to the ketogenic diet.)
  • , as IEM may present in different age groups in members of the same family.
  • The catalytic properties of many enzymes depend on
    the participation of non protein prosthetic groups, such as vitamins and minerals, as
    obligatory cofactors. The following co-factors may be beneficial in certain IEM
    Electron transport flavoprotein
  • Therefore when the diagnosis is known and confirmed in the index case, prenatal
    diagnosis can be offered, wherever available for the subsequent pregnancies.
  • approach to Inborn Errors of Metabolism in neonates

    1. 1. DR.GOKULDAS P K Junior resident in Pediatrics Govt.medical college, Kozhikkode
    2. 2. Introduction to IEM Differential diagnosis of any sick neonate IEM are individually rare Overall incidence upto 1 in 2000 High index of suspicion for diagnosis
    3. 3. Clinical pointers 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
    4. 4. Clinical pointers  Persistent vomiting  Peculiar odor  Acute fatty liver or HELLP (long-chain-3- hydroxyacyl-coenzyme dehydrogenase deficiency (LCHADD).
    5. 5. Neurologic deterioration With metabolic acidosis •MSUD •organic acidurias •fatty acid oxidation defects •Primary lactic acidemias (defects of gluconeogenesis, glucogenolysis, pyruvate metabolism, Krebs cycle, and respiratory chain)
    6. 6. Neurologic deterioration With hypoglycemia •organic acidurias •fatty acid oxidation defects •defect of gluconeogenesis
    7. 7. Neurologic deterioration With hyperammonemia •Urea cycle defects •Propionic acidemia •Methyl malonyl acidemia
    8. 8. Seizures
    9. 9. Seizures Non-ketotic hyperglycinemia in utero Pyridoxine –responsive seizures, 1st day Pyridoxal phosphate responsive seizures 1t day Folinic-acid responsive seizures 1st day Sulfite oxidase/molybdenum co-factor defect Peroxisomal disorders Disorders of creatine biosynthesis & transport
    10. 10. Hypotonia Mitochondrial respiratory chain defects Peroxisomal disorders Non-ketotic hyperglycinemia Sulfite oxidase/molybdenu m co-factor defect
    11. 11. Liver dysfunction Hepatomegaly with hyoglycemia Gluconeogenesis defects(GSD) Liver failure Galactosemia Hereditary fructose intolerance tyrosinemia type I FAO defects Mitochondrial respiratory chain defects
    12. 12. Cholestatic jaundice with failure to thrive: alpha-1-antitrypsin deficiency Niemann-Pick disease type C Inborn error of bile acid metabolism Peroxisomal disorders Citrin deficiency
    13. 13. Cardiac dysfunction Fatty acid oxidation defects Carnitine uptake deficiency Carnitine-acyl Carnitine translocase deficiency Carnitine palmitoyl transferase ll deficiency LCHAD deficiency Trifunctional protein deficiency VLCAD deficiency
    14. 14. Cardiac dysfunction Glycogen storage diseases Pompe disease Phoshorylase b kinase deficiency Mitochondrial electron transport chain defects TCA cycle defects Alpha keto glutarate dehydrogenase deficiency Lysosomal storage disorder I -cell disease
    15. 15. Apnea Long Chain Fatty acid oxidation defects Non ketotic hyperglycinemia
    16. 16. Abnormal urine odor
    17. 17. Glutaric acidemia (type II):Sweaty feet Isovaleric acidemia: Sweaty feet
    18. 18. Multiple carboxylase deficiency: Tomcat urine
    19. 19. Maple syrup urine disease: Maple syrup odour of urine
    20. 20. Hypermethioninemia: Boiled cabbage urine odor
    21. 21. Miscellaneous Lens dislocation : Sulfite oxidase deficiency
    22. 22. Skin changes : Biotinidase deficiency HCS deficiency
    23. 23. Dysmorphic Features Peroxisomal disorders : Zellweger syndrome Large fontanelle  prominent forehead  flat nasal bridge  epicanthal folds  hypoplastic supraorbital ridges
    24. 24. Dysmorphic Features Pyruvate dehydrogenase deficiency Epicanthal folds  flat nasal bridge  small nose with anteverted flared alae nasi  long philtrum
    25. 25. Dysmorphic Features Glutaric aciduria type II Macrocephaly  high forehead  flat nasal bridge  short anteverted nose  ear anomalies  hypospadias  rocker-bottom feet
    26. 26. Dysmorphic Features Cholesterol biosynthetic defects  Smith-Lemli-Opitz syndrome: Epicanthal folds, flat nasal bridge, toe 2/3 syndactyly, genital abnormalities, cataracts
    27. 27. Dysmorphic Features Congenital disorders of glycosylation: Inverted nipples, lipodystrophy Lysosomal storage disorders: I-cell disease Hurler-like phenotype
    28. 28. Hydrops fetalis Lysosomal disorders MPS type I, IV A, & VII GM 1 gangliosidosis Gaucher disease Niemann Pick disease type C Sialidosis Galactosialidosis Farber disease
    29. 29. Hematologic disorders Glucose-6-phosphate dehydrogenase deficiency Pyruvate kinase deficiency Glucosphosphate isomerase deficiency Others Congenital disorders of glycosylation Neonatal hemochromatosis Respiratory chain disorders Glycogen storage disease type IV
    30. 30. Initial evaluation  Complete blood count  Arterial blood gases and electrolytes  Blood glucose  Plasma ammonia  Arterial blood lactate  Liver function tests
    31. 31. Initial evaluation  Urine ketones if acidosis or hypoglycemia present  Urine reducing substances.  Serum uric acid (low in molybdenum cofactor deficiency). Plasma amino acids, quantitative
    32. 32. Laboratory studies if seizures present Cerebrospinal fluid (CSF) amino acids CSF neurotransmitters Sulfocysteine in Urine VLCFA Lactate : pyruvate ratio: Respiratory chain defects
    33. 33.  Complete blood cell count : Neutropenia and thrombocytopenia : Isovaleric acidemia, methylmalonic acidemia , and propionic acidemia .  Neutropenia :Glycogen storage disease type 1b Barth syndrome and Pearson syndrome.
    34. 34. Serum electrolytes & Blood gases Acidosis/ alkalosis & types Anion gap ( organic acidemias & primary lactic acidosis
    35. 35. High lactate Euglycemia Hypoglycemia Euglycemia Hypoglycemia Normal lactate No ketosis Ketosis + Metabolic acidosis MSUD Organic aciduria PC deficiency, HCS deficiency GSD1, Gluconeogen esis defects, Respiratory chain defects
    36. 36. HypoglycemiaEuglycemia High lactate Normal lactate No ketosis FAO defectPDH deficiency Renal tubular acidosis
    37. 37. Hyperammonemia Metabolic acidosis Respiratory alkalosis Plasma citrulline Organic aciduria, FAO defects, Primary lactic acidosis Urea cycle defects
    38. 38. Plasma citrulline Low Normal High Urine orotic acid Elevated Plasma ASAPlasma arginine Normal Normal NormalElevated Elevated OTC deficiency CPS deficiency NAGS deficiency Arginase deficiency HHH ASL deficiency ASS deficiency
    39. 39. Liver function tests Galactosemia Tyrosinemia Alpha-1-antitrypsin deficiency  Neonatal hemochromatosis mitochondrial respiratory chain disorders Niemann-Pick disease type C.
    40. 40. Urine-reducing substances, ketones & pH Clinitest reaction :galactose and glucose, but not fructose Clinistix reaction (glucose oxidase) specific for glucose pH <5 indicate IEM Ketonuria is abnormal in neonates Dinitrophenylhydrazine :α-ketoacids in MSUD.
    41. 41. Plasma carnitine and acylcarnitine profile Elevation of carnitine esters Fatty acid oxidation defects Organic acidemias Ketosis low carnitine levels Disorders of carnitine biosynthesis Preterm infants and neonates receiving total parenteral nutrition without adequate carnitine supplementation. Secondary carnitine deficiency.
    42. 42. Second line investigations • To be performed in a targeted manner  Gas chromatography mass spectrometry of urine Organic acidemias.  Plasma amino acids and acyl carnitine profile: by tandem mass spectrometry Organic acidemias  Urea cycle defects Aminoacidopathies Fatty acid oxidation defects.
    43. 43.  High performance liquid chromatography : Quantitative analysis of amino acids in blood and urine Organic acidemias and aminoacidopathies Lactate/pyruvate ratio- in cases with elevated lactate.  Urinary orotic acid- in cases with hyperammonemia for classification of urea cycle defect.
    44. 44. Enzyme assay: This is required for definitive diagnosis, but not available for most IEM biotinidase assay- biotinidase deficiency (intractable seizures, seborrheic rash, alopecia) GALT (galactose 1-phosphate uridyl transferase ) assay- galactosemia (hypoglycemia, cataracts, reducing sugars in urine).
    45. 45. Neuroimaging: MRI IEM may be associated with structural malformations e.g. Zellweger syndrome has diffuse cortical migration and sulcation abnormalities.
    46. 46. Neuroimaging: MRI Agenesis of corpus callosum : Menke’s disease Pyruvate decarboxylase deficiency Nonketotic hyperglycinemia
    47. 47. Neuroimaging: MRI Glutaric aciduria type II: frontotemporal atrophy, subdural hematomas
    48. 48. Neuroimaging: MRI MSUD: brainstem and cerebellar edema  Propionic & methylmalonic acidemia: basal ganglia signal change
    49. 49.  Magnetic resonance spectroscopy : lactate peak elevated in mitochondrial disorders leucine peak elevated in MSUD.  Electroencephalography (EEG):  Comb-like rhythm suggests MSUD  Burst suppression in NKH and holocarboxylase synthetase deficiency
    50. 50. Other investigations  Plasma very long chain fatty acid (VLCFA) levels: elevated in peroxisomaldisorders. Mutation analysis when available.  CSF aminoacid analysis: CSF Glycine levels elevated in NKH.
    51. 51. Collecting samples Should be collected before specific treatment is started or feeds are stopped  Samples for blood ammonia and lactate should be transported in ice and immediately tested. Lactate sample should be arterial or central line and should be collected after 2 hrs fasting in a preheparinized syringe.
    52. 52. Collecting samples Ammonia sample is to be collected approximately after 2 hours of fasting in EDTA vacutainer. Avoid air mixing. Sample should be free flowing. Detailed history including drug details should be provided to the lab. (sodium valproate therapy may increase ammonia levels).
    53. 53. Metabolic autopsy Samples to be obtained in infant with suspected IEM when diagnosis is uncertain and death seems inevitable Blood: 5-10 ml; frozen at -200C; both heparinized (for chromosomal studies) and EDTA (for DNA studies)  Urine: frozen at –20oC CSF: store at –20oC
    54. 54. 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)
    55. 55. MANAGEMENT OF INFANT AT RISK FOR A METABOLIC DISORDER When a sibling has had symptoms consistent with a metabolic disorder, or has died of a metabolic disorder: Before or during subsequent pregnancy Prenatal discussion of possible diagnoses, and the parents and relatives should be screened for possible clues.
    56. 56. Old hospital charts and postmortem material should be reviewed. When a diagnosis is known, intrauterine diagnosis to be tried.  The new baby should be delivered in a facility equipped to handle potential metabolic or other complications.
    57. 57. Initial evaluation includes a careful physical examination for the signs of IEM  All nonmetabolic causes of symptoms should be excluded. The newborn screening program should be contacted for the results of the screening and for a list of the disorders screened. Blood and urine tests before starting treatment for metabolic disease.
    58. 58. The specimens can be frozen (plasma, urine) and analysis performed later.  Enzyme assay of red blood cells, or enzyme and DNA analysis of white blood cells, fibroblasts, or liver tissue may be done for confirmation of diagnosis.  DNA analysis can sometimes be performed on a dried blood specimen (Guthrie blood spot).
    59. 59. In most cases, treatment needs to be instituted empirically without a specific diagnosis. The metabolic screen helps to broadly categorize the patient’s IEM (e.g. urea cycle defect, organic academia, congenital lactic acidosis etc).
    60. 60. Aims of treatment Decreasing substrate availability (by stopping feeds and 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.
    61. 61. 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.
    62. 62. Management of hyperammonemia Discontinue all feeds. Provide adequate calories by intravenous glucose and lipids. Maintain glucose infusion rate 6- 8mg/kg/min. Start intravenous lipid 0.5g/kg/day (up to 3g/kg/day).  After stabilization gradually add protein 0.25 g/kg till 1.5 g/kg/day.
    63. 63. 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. Sodium benzoate (IV or oral)- loading dose 250 mg/kg then 250-400 mg/kg/day in 4 divided doses. (not available in India). L-carnitine (oral or IV)- 200 mg/kg/day
    64. 64. Sodium phenylbutyrate (not available in India)-loading dose 250 mg/kg followed by 250-500 mg/kg/day. L-arginine (oral or IV)- 300 mg/kg/day (Intravenous preparation not available in India)
    65. 65. Suspected organic acidemia • Acute management  The patient is kept nil per orally and intravenous glucose is provided.  Supportive care: hydration, treatment of sepsis, seizures, ventilation.  Carnitine: 100 mg/kg/day IV or oral.  Treat acidosis: Sodium bicarbonate 0.35- 0.5mEq/kg/hr (max 1-2mEq/kg/hr)
    66. 66. Biotin 10 mg/day orally. Vitamin B12 1-2 mg/day I/M (useful in B12 responsive forms of methylmalonic acidemias) Thiamine 300 mg/day (useful in Thiamine- responsive variants of MSUD).  If hyperammonemia is present, treat as above.
    67. 67. Congenital lactic acidosis  Supportive care: hydration, treatment of sepsis, seizures, ventilation. Avoid sodium valproate.  Treat acidosis: sodium bicarbonate 0.35-0.5mEq/kg/hr (max 1-2mEq/kg/hr)  Thiamine: up to 300 mg/day in 4 divided doses.  Riboflavin: 100 mg/day in 4 divided doses.  co-enzyme Q: 5-15 mg/kg/day  L-carnitine: 50-100 mg/kg orally.
    68. 68. Refractory seizures with suspected metabolic etiology Seizures despite 2 or 3 antiepileptic drugs Pyridoxine 100 mg intravenously. oral 15 mg/kg/day. Despite pyridoxine.. give trial of biotin 10 mg/day and folinic acid 15 mg/day (folinic acid responsive seizures). Rule out glucose transporter defect: measure CSF and blood glucose
    69. 69. Asymptomatic newborn with a History of sibling death with suspected IEM:  After baseline metabolic screen, start oral dextrose feeds (10% dextrose).  After 24 hours, repeat screen. If normal, start breast feeds. Monitor sugar, blood gases and urine ketones, blood ammonia 6 hourly. Medium chain triglycerides (MCT oil) before starting breast feeds
    70. 70. After 48 hours, repeat metabolic screen. Obtain samples for TMS and urine organic acid tests. Follow-up for the first few months
    71. 71. Long term treatment of IEM Dietary treatment: phenylketonuria, maple syrup urine disease, homocystinuria, galactosemia, and glycogen storage disease Type I & III. Special diets for PKU and MSUD are commercially available in the west can be imported.
    72. 72. Based on the amino acid content of some common food products available in India, a low phenylalanine diet for PKU and diet low in branched chain amino acids for MSUDcanbe made. urea cycle disorders and organic acidurias require dietary modification (protein restriction)
    73. 73. Enzyme replacement therapy ERT is now commercially available for some lysosomal storage disorders. Pompe’s disease (Glycogen storage disorder Type II).
    74. 74. Cofactor replacement therapy Thiamine:  mitochondrial disorders  thiamine responsive variants of MSUD  PDH deficiency & complex I deficiency  Riboflavin:  Glutaric aciduria Type I, Type II  mild variants of ETF  ETFDH complex I deficiency
    75. 75.  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 Biotin:  Biotinidase deficiency  Holocarboxylase synthetase deficiency
    76. 76.  Cobalamin: Methylmalonic academia Homocystinuria  Folinic acid:  Hereditary orotic aciduria  Methionine synthase deficiency Cerebral folate transporter deficiency  hereditary folate malabsorption Kearns-Sayre syndrome
    77. 77. Prevention • Genetic counselling and prenatal diagnosis: • Most of the IEM are single gene defects, inherited in an autosomal recessive manner, with a 25% recurrence risk. • The samples required are chorionic villus tissue or amniotic fluid.
    78. 78. Substrate or metabolite detection: Phenylketonuria Peroxisomal defects.  Enzyme assay: lysosomal storage disorders like Niemann-Pick disease , Gaucher disease. DNA based (molecular) diagnosis:  Detection of mutation in proband/carrier parents
    79. 79. Neonatal screening  Tandem mass spectrometry is used in some countries for neonatal screening for IEM Aminoacidopathies ( phenylketonuria, MSUD, Homocystinuria, Citrullinemia, Argininosuccinic aciduria, hepatorenal tyrosinemia) fatty acid oxidation defects, Organic acidemias (glutaric aciduria, propionic acidemia, methylmalonic acidemia, isovaleric acidemia).
    80. 80. The cost of this procedure is high Test is highly sensitive, the specificity is relatively low; and there are difficulties in interpretation of abnormal test results in apparently healthy infants.
    81. 81. Commercially available formulations used in IEM Pyridoxine Tab Benadon (40mg) (Nicholas Piramal), Inj Vitneurin (1 ampoule contains 50 mg pyridoxine), Tab B-long 100mg Hydroxycobalamin (Vitamin B12) Inj Trineurosol (1000mcg/ml) (Tridoss Laboratories) Thiamine :Tab Benalgis (75 mg) (Franco India) Riboflavin :Tab Riboflavin (5 mg) (Shreya)
    82. 82.  Biotin Tab Essvit (5mg, 10mg) (Ecopharma)  Carnitine Syrup L-Carnitor (5ml=500 mg), Tab L- Carnitor (500 mg), Inj carnitor (1g/5ml) (Elder)  Folinic acid Tab Leukorin (15 mg) (Samrath)  Sodium Benzoate Satchet 20g (Hesh Co.)  Arginine ARG-9 Satchet (3g) (Noveau Medicament)  Coenzyme Q Tab CoQ 30 mg, 50 mg. (Universal Medicare)