APPROACH TO A CHILD WITH IEM DR GRK.pptx

in born errors ofmetabolism

1. Dr G.Rajkumar MD Professor of Paediatrics CHRI APPROACH TO A CHILD WITH INBORN ERRORS OF METABOLISM

2. OBJECTIVES • What are IEMs? • Categories • When to suspect? • History and clinical pointers • Metabolic presentation • Differential diagnosis • Emergency and long term management • Expanded newborn screening

3. WHAT ARE IEMS? Monogenic disorders primarily Autosomal Recessive resulting from deficiency of: ‐ A critical enzyme in the intermediary pathways of carbohydrate, protein and lipid metabolism or ‐ A co‐factor which is responsible for activation of an apoenzyme in the same pathways

4. WHAT ARE IEMS? Clinical effects result from: Lack of the product Accumulation of immediate and remote precursors/ toxic byproducts Secondary metabolic consequences

5. IEMS: A FORMIDABLE CHALLENGE Number and Complexity Diverse clinical manifestations Mimic many common pediatric illnesses including sepsis, encephalopathy Limited availability of lab services Emergency and long term care Counseling

6. CATEGORIES OF IEM •Carbohydrate ‐ Oxidative phosphorylation (OXPHOS) disorders ‐ Glycogen storage disorders, Galactosemia •Protein ‐ Urea cycle disorders ‐ Organic acidemias ‐ Aminoacidopathies •Lipids ‐ Fatty acid oxidation disorders (FAOD) ‐ Disorders of carnitine transport

7. CATEGORIES OF IEM •Lysosomal storage disorders (LSD): ‐ Mucopolysaccharidosis (MPS), sphingolipidosis • Peroxisomal disorders •Mitochondrial disorders

8. WHEN TO SUSPECT IEM? CLINICAL POINTERS ‐ HISTORY • Developmental delay (DD), regression, mental retardation (MR) • Refractory seizures • Encephalopathy • Rapid breathing (Acidotic) • Failure to thrive, episodic vomiting • Unusual body odours • Life threatening illnesses following seemingly minor infections • Consanguinity, family history of sibling deaths, DD/MR, seizures

9. ABNORMAL URINARY ODOURS Disorder Odor Phenylketonuria Musty Musty Maple Syrup Urine Disease (MSUD) Maple syrup or burnt sugar Isovaleric acidemia, Glutaric acidemia type 2 Sweaty feet Multiple carboxylase deficiency Cat urine

10. IEM Abnormal odor Maple syrup urine disease (MSUD) Maple syrup Isovaleric acidemia or glutaric acidemia type II Sweaty feet Cystinuria and tyrosinemia type I Sulfur Tyrosinemia type I Boiled cabbage Trimethylaminuria or dimethylglycine dehydrogenase deficiency Old fishy Multiple carboxylase deficiency (MCD) Cat’s urine Phenylketonuria Mousy

11. WHEN TO SUSPECT IEM? CLINICAL POINTERS ‐ EXAMINATION •Cataract, corneal clouding, cherry red spot •Micro/ Macrocephaly, coarse facies •Alopecia, intertrigo •Hepatomegaly, liver dysfunction •Splenomegaly •Abnormal CNS examination •Skeletal deformities

12. 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. Clinical pointers towards an underlying IEM include Deterioration after a period of apparent normalcy Parental consanguinity Family history of unexplained neonatal deaths Rapidly progressive encephalopathy and seizures of unexplained cause Severe metabolic acidosis Persistent vomiting Peculiar odor (urine, cerumen) 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).

13. Encephalopathy with or without metabolic acidosis: Encephalopathy , seizures, and tone abnormalities are predominant presenting features of Organic acidemias, Urea cycle defects and Congenital lactic acidosis. Isolated intractable seizures are prominent in pyridoxine dependency, pyridoxal phosphate dependency, folinicacid responsive seizures, and glucose transporter 1 deficiency

14. Acute liver disease • 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: persistent and severe hypoglycemia may be an indicator of an underlying IEM. Hypoglycemia is a feature of galactosemia, fatty acid oxidation defects, organic acidemias, glycogen storage disorders and disorders of gluconeogenesis

15. Dysmorphic features: Peroxisomal disorders, Pyruvate dehydrogenase deficiency, Congenital disorders of glycosylation (CDG), and Lysosomal storage diseases. Some IEMs may present with non-immune hydrops fetalis; these include lysosomal storage disorders and CDG.

16. IEM Facial features Zellweger syndrome (absence of peroxisomes) Large fontanelle, prominent forehead, flattened nasal bridge, epicanthal folds and hypoplastic supraorbital ridge Pyruvate dehydrogenase deficiency Epicanthal folds, flattened nasal bridge, petite nose with anteverted alae nasi, long philtrum Glutaric aciduria type II Macrocephaly, high forehead, flattened nasal bridge, short anteverted nose; genitourinary abnormality of hypospadias in males, aural anomalies and rocker bottom feet Smith-Lemli-Opitz syndrome (cholesterol biosynthetic defect) Epicanthal folds, flat nasal bridge, syndactyly, cataracts and genital abnormalities Congenital glycosylation disorders Inverted nipples and lipodystrophy Lysosomal storage disorders, Mucopolysaccharidoses Coarse facies

17. Cardiac disease: Cardiomyopathy is a prominent feature in some IEM including Fatty acid oxidation defects, Glycogen storage disease type II and Mitochondrial electron transport chain defects.

18. CLINICAL POINTERS TO DIAGNOSE IEM Feature Disorder Eye Cataract Corneal clouding Cherry red spot Galactosemia MPS: Hurler, Scheie , Morquio , Maroteaux ‐Lamy syndrome Tay‐Sachs, Niemann Pick Skin ‐ Alopecia, intertrigo Hair – Coarse, kinky Biotinidase deficiency Menkes kinky hair disease Hepato ± splenomegaly LSD: MPS, sphingolipidosis, GSD Hepatomegaly & liver dysfunction Galactosemia, tyrosinemia, GSD Cardiomyopathy LSD, GSD, FAOD, mitochondrial disorders

19. WHEN TO SUSPECT IEM? LAB POINTERS • Metabolic acidosis • Wide anion gap • Hyperammonemia • Hypoglycemia: • Urine Ketones ( Ketotic / non ketotic ) • Urine Reducing substances (Positive/ Negative) • Lactic acidosis • Altered liver function

20. CASE ILLUSTRATION • A 6 month old male, 2nd order, born of non consanguinity, admitted for diarrhoea and dehydration • H/O Sibling death with suspected encephalopathy • No developmental delay/ failure to thrive • O/E: Moderate dehydration, rapid breathing, drowsy • Hepatomegaly, firm, span 8cm

21. CASE ILLUSTRATION: INVESTIGATIONS • GRBS: 45 mg/dl; Urine ketones: Positive • ABG: pH 7.09, pCO2 14.8,BE – 23.6, HCO3 4.5 • Metabolic acidosis • Anion gap 33 ‐ Wide • NH3 328 μ g/dl (N: 25‐94) ‐ Hyperammonemia • Lactate 28.8 mg/dl (N:2.5‐20) – Lactic acidosis • FINAL DIAGNOSIS – ORGANIC ACIDEMIA

22. Suspected Metabolic Disorder

23. DEFINITIVE DIAGNOSIS • Blood: Tandem mass spectrometry for acyl carnitine, organic acids • Plasma and urine amino acids (quantitative) • Urine organic acids by chromatography • Specific metabolite assays • DNA mutation analysis • Enzyme assays on skin fibroblasts or blood cells Diagnosis is important not only for treatment and prognostication but also for genetic counselling and antenatal diagnosis in subsequent pregnancies.

24. DIFFERENTIAL DIAGNOSIS •Sepsis: ‐ Can mimic, precipitate and complicate IEM ‐ Galactosemia – predilection for E coli sepsis ‐ Negative CRP and blood culture in a rapidly deteriorating infant should alert to possible IEM •Reye encephalopathy ‐ An important differential for Fatty Acid Oxidation Disorders with hepatomegaly, hypoglycemia, hyperammonemia and hepatic dysfunction

25. Investigations Metabolic investigations should be initiated as soon as the possibility is considered. The outcome of treatment of many IEM especially those associated with hyperammonemia is directly related to the rapidity with which problems are detected and appropriate management instituted.

26. 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: 90-150 µg/dl or 64-107 µmol/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 deficiency).

27. Acidosis Ketosis Lactate Ammonia Diagnosis -- + -- __ Maple syrup urine disease + +/- -- __ Organic aciduria + +/- + +/- Lactic acidosis -- -- -- + Urea cycle -- -- -- __ Non- ketotic hyperglycinemia , sulfite oxidase deficiency, peroxisomal, Phenylketonuria, galactosemia

28. Second line investigations (ancillary and confirmatory tests) These tests need to be performed in a targeted manner, based on presumptive diagnosis reached 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 aminoacidopathies. 4) Lactate/pyruvate ratio- in cases with elevated lactate.

29. 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 IEM’s. Available enzyme assays include: biotinidase assay- in cases with suspected biotinidase deficiency (intractable seizures, seborrheic rash, alopecia); and . GALT (galactose 1-phosphate uridyl transferase) assay- in cases with suspected galactosemia (hypoglycemia, cataracts, reducing sugars in urine).

30. 7) Neuroimaging: MRI – Zellweger syndrome has diffuse cortical migration and sulcation abnormalities. Agenesis of corpus callosum has been reported in Menke’s 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 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) Urine for alpha-aminoadipic semialdehyde, - elevated in pyridoxine dependent seizures. (test not available in India yet).

31. 10)Electroencephalography (EEG): some EEG abnormalities may be suggestive of particular IEM; e.g. comb-like rhythm in MSUD, burst suppression in NKH and holocarboxylase synthetase deficiency.6 11) Plasma very long chain fatty acid (VLCFA) levels: elevated in peroxisomal disorders. 12) Mutation analysis when available. 13) CSF aminoacid analysis: CSF Glycine levels elevated in NKH

32. 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 increase ammonia levels).

33. 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.

34. MANAGEMENT GOALS • Prevention of formation of toxic metabolites • Removal of toxic metabolites • Increase activity of deficient enzyme by co‐factor therapy (Mega vitamins) • Addition of deficient substrate • Supply essential nutrients/ disease specific diet

35. MANAGEMENT: EMERGENCY • ABC • Correction of hypoglycemia and maintenance of blood sugars to suppress gluconeogenesis • Correction of acidosis: IV Sodium bicarbonate with serial ABGs • Carnitine supplementation • Broad spectrum antibiotics including anaerobic cover

36. HYPERAMMONEMIA – MANAGEMENT • Hemodialysis for rapid reduction • Decrease production: I.V. Arginine HCl • Promote excretion: I.V. sodium benzoate and sodium phenyl acetate • Calories: carbohydrate/ lipid; reintroduction of protein after 48 hours restricted to 1 g/kg with 50% essential amino acids • Avoid valproate, steroids

37. Vitamin Dosage/ day Indications Biotin 10 ‐ 50 mg Holo-carboxylase deficiency Biotinidase Riboflavin 100 mg Glutaric aciduria Electron Transport Chain defects Thiamine 300 mg MSUD Pyruvate met defects Mitochondrial Vit B12 1 ‐ 2 mg Methyl malonic acidemia Homocystinuria Pyridoxine 50 – 100 mg Pyridoxine Dependent seizures Homocystinuria

38. DIET MANAGEMENT •Restriction of proteins: 6% of total energy •Restriction of substrates which accumulate ‐ Homocystinuria: Methionine ‐ PKU: phenylalanine •Special diets: ‐ PKU, MSUD, galactosemia •Replacement of deficient nutrients ‐ Homocystinuria: cystein

39. 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.chorionic villus tissue or amniotic fluid. Modalities available are:17 • Substrate or metabolite detection: useful in phenylketonuria, peroxisomal defects. • Enzyme assay: useful in lysosomal storage disorders like Niemann-Pick disease, Gaucher disease. • DNA based (molecular) diagnosis: Detection of mutation in proband/ carrier parents is a prerequisite.

40. 2) Neonatal screening: Tandem mass spectrometry is used in some countries 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). The appropriate time for collection of samples is between 1 and 3 days of life.

41. EXPANDED NEWBORN SCREENING • Pre‐symptomatic detection of newborns that includes several IEM • Originated with the development of the ‘‘Guthrie test’’ for detecting phenylketonuria • Dried Blood Spots: Heel prick blood at 48‐72 hours of age on absorbent paper (Guthrie card) and analyzed by tandem mass spectrometry

42. IEMS ARE: • Individually rare but collectively have an incidence of 1 in 5000 • Presentation can occur at any age, even in adulthood • Increasingly a primary/ differential diagnosis especially in infancy • “Index of suspicion” ‐ The most difficult step in diagnosis is considering the possibility!

43. Do’s and Don’t’s 1) Don’t think of IEM as rare, exotic and untreatable disorders. 2) Think of IEM in sick newborns in parallel with other common conditionssuch as sepsis. The signs and symptoms are usually non specific such as 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.