inborn errors of metabolism (iem) · inborn errors of metabolism ... carbohydrate, protein and...
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IAP UG Teaching slides 2015-16
INBORN ERRORS OF METABOLISM(IEM)
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OBJECTIVES
• What are IEMs?• Categories • When to suspect? • History and clinical pointers • Metabolic presentation• Differential diagnosis• Emergency and long term management• Expanded newborn screening
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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
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WHAT ARE IEMS?
• Lack of the product • Accumulation of immediate and remote precursors/ toxic byproducts
• Secondary metabolic consequences
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Clinical effects result from:
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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
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CATEGORIES OF IEM
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•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
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CATEGORIES OF IEM
•Lysosomal storage disorders (LSD): ‐ Mucopolysaccharidosis (MPS), sphingolipidosis
• Peroxisomal disorders
•Mitochondrial disorders
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CASE ILLUSTRATION
• A 6 month old male, 2nd order, born of non consanguinity, admitted for diarrhoea and dehydration
• H/O Sibling death with suspected Reye syndrome (encephalopathy)
• No developmental delay/ failure to thrive• O/E: Moderate dehydration, rapid breathing, drowsy• Hepatomegaly, firm, span 8cm
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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
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ABNORMAL URINARY ODOURS
Disorder Odor
Phenylketonuria Musty
Maple Syrup Urine Disease(MSUD)
Maple syrup or burnt sugar
Isovaleric acidemia, Glutaric acidemia type 2
Sweaty feet
Multiple carboxylase deficiency Cat urine
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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
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CLINICAL POINTERS TO DIAGNOSE IEM
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Feature disorder
EyeCataractCorneal clouding
Cherry red spot
GalactosemiaMPS: Hurler, Scheie, Morquio , Maroteaux‐Lamy syndromeTay‐Sachs, Niemann Pick
Skin ‐ Alopecia, intertrigoHair – Coarse, kinky
Biotinidase deficiencyMenkes kinky hair disease
Hepato ± splenomegaly LSD: MPS, sphingolipidosis, GSD
Hepatomegaly & liver dysfunction Galactosemia, tyrosinemia, GSD
Cardiomyopathy LSD, GSD, FAOD, mitochondrial disorders
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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 µg/dl (N: 25‐94) ‐ Hyperammonemia• Lactate 28.8 mg/dl (N:2.5‐20) – Lactic acidosis
• FINAL DIAGNOSIS – ORGANIC ACIDEMIA
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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
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Hyperammonemia
Lactic Acidosis
Hypoglycemia
No Ketonuria
Amino aciddisorders
present
Metabolic Acidosis
Absent
Absent
Ketosis
Absent
present
Urea Cycledisorders
Fatty AcidOxidation disorders
Organic Acidemias
GSD OXPHOS disorders
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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
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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 FAOD with hepatomegaly, hypoglycemia, hyperammonemia and hepatic dysfunction
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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
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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
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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
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Vitamin Dosage/ day IndicationsBiotin 10 ‐ 50 mg Holo carboxylase
deficiencyBiotinidase
Riboflavin 100 mg Glutaric aciduriaElectron Transport Chain defects
Thiamine 300 mg MSUD Pyruvate met defectsMitochondrial
Vit B12 1 ‐ 2 mg Methyl malonic acidemiaHomocystinuria
Pyridoxine 50 – 100 mg Dependent seizuresHomocystinuria
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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
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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
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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!
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THANK YOU
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