Clinical Presentation Inborn Errors of Metabolism (IEM) Click on the following: - Clinical Pearl - link to movie clip - link to picture Investigations Blood Work Urine No Acidosis NH 4 + Metabolic Acidosis No NH 4 + Hypoglycemia General Treatment
Inborn Errors of Metabolism Individually rare, collectively common ~1 : 800-1500 Inherent deficiency in a key metabolic pathway: Carbohydrate vs. Fat vs. Protein Pathophysiology : Build up of toxic products cellular intoxication Cellular energy deprivation Combination of the above
Clinical Presentation Infant Looks like sepsis! Lethargy Hypotonia Decreased level of consciousness (LOC) Seizures Poor feeding Vomiting Sudden deterioration Children Mental retardation Regression Failure to thrive Coarse facial features Skeletal abnormalities Hernias Dietary aversion (protein/carbs) Deterioration after: New foods introduced Fasting
Blood Work Blood Work CBC+ Diff Blood Culture Blood gas Rationale/Predicted Result -Rule out sepsis -Pancytopenia (finding in some types of IEM) -Metabolic Acidosis -Alkalosis (seen initially in urea cycle defects from high NH 4 + ) Electrolytes + Ca/Mg/Phos Blood glucose Serum ketones NH + 4 (ammonia) Lactate AST, ALT, AlkPhos, GGT, -Signs of dehydration -Electrolyte derangements can have similar presentation -Hypoglycemia -Hydroxybutyrate: should be present if patient hypoglycemic - *** NO tourniquet, send on ice and process immediately *** NO tourniquet, send on ice and process immediately -Elevated liver enzymes bili, albumin, coags Acyl-carnitine profile, (Pyruvate) *** NO tourniquet, send on ice and process immediately -Pyruvate: only done if lactate high (only needed for pyruvate/ lactate ratio), need Biochemical/genetics lab approval + need special collection tubes. Plasma amino acids Newborn screen Must call to unlock the results
Newborn Screen (BC) 22 disorders tested in British Columbia Other provinces test for a spectrum Pertinent to IEM: Amino acid disorders PKU MSUD Citrullinemia Agininosuccinic Aciduria Homocystinuria **Tyrosinemia Type 1 - (not yet included but possibly added soon!) Fatty acid oxidation defects VLCAD LCHAD (Not LCAD- Long-chain 3-hydroxyacyl-CoA dehydrogenase) ****TFP (trifunctional protein deficiency) severe form of LCHAD MCAD Organic Acid Defects PROP (Propionic acidemia) MUT (Methylmalonic Acidemia) Cobalamin Disorders Glutaric Aciduria, Type I Isovaleric Acidemia Galactosemia Galactosemia
PKU - Cause: phenylalanine hydroxylase enzyme deficiency - Ddx: rare forms of BH 4 Cofactor deficiency - mousy odour - Light complexion - Eczema - Mental retardation and hyperactivity
MSUD - 1 st week of life - Smells sweet - Periods of hypertonicity - Secondary hypoglycemia - Ketosis
Tyrosinemia Type 1 - Smells of boiled cabbage
MCAD - Encephalopathy - Hypoglycemia
Isovaleric Acidemia - Smells like sweaty feet
Glutaric Aciduria, Type 1 Subdural bleeds Needs to be included in the non-accidental injury work up
Galactosemia Mechanism: Deficiency of galactose-1-phosphate uridyl transferase Leads to galactose-1-phosphate Clinical presentation: Presents @ ~end of 1 st, start of 2 nd week of life Recurrent Escherichia coli sepsis Galactose-1-phosphate is toxic to the liver: **Jaundice Vomiting Diarrhea Poor weight gain Cataracts Investigations: Urine for reducing substances: looking for non-glucose reducing substances Treatment: Stop galactose containing feeds Only time an infant needs SOY formula Only ISOMIL will work!
Homocystinuria ***Increased risk of stroke Clinical Presentation: Marfanoid appearance Dislocated lens etc. Mental retardation Treatment: pyridoxine
Urine Urine Tests Urinalysis Rationale/Predicted Result - Rule out sepsis - Ketones - In infants, should only be present if hypoglycemic! Urine Culture - Rule out sepsis Urine organic acids Urine reducing substances -Useful in galactosemia (non-glucose reducing substances), fructose intolerance, tyrosinemia
General Treatment Treatment STOP protein intake Rationale -Urea cycle defects/organic acid/amino acid defect -Prophree formula (has no protein) IV glucose (D10@ infusion rate of 8-10 mmol/kg/min) - Treats hypoglycemia - Provides calories to prevent protein catabolism - May need insulin to control glucose levels **may add IV lipids if no signs of fatty acid oxidation defect IV arginine (6ml/kg 10% arginine HCl over 90 min) IV sodium benzoate -Essential amino acid -Helps to excrete the excess nitrogen waste products in Argininosuccinic Aciduria and Citrullinemia -Increases excretion of ammonia by activating alternate pathways IV phenylacetate IV carnitine -Fatty acid oxidation defects: treats possible carnitine deficiency -Organic acidurias: binds toxic organic acids for excretion in urine Cofactors/vitamin Specific treatments Hemodialysis -Organic acidemia: hydroxycobalamin, biotin -Please see individual disorders for specific treatments -Arrange with ICU/Neprhology -Recall reasons for dialysis (AEIOU) -Acid/Base disorders, Electrolyte disorders (including Ammonia!), Intoxication, Overload, Uremic encephalopathy
NH 4 + Presentation <24 hours old ph N - (possible 1 o respiratory alkalosis) Normal lactate NH + 4 Acidosis Anion gap ± Lactate ±Ketosis Hypoglycemia No Ketosis LFTs NH + 4 ± Hypoglycemia NH 4 + Transient Hyperammonemia of the Newborn Urea Cycle Defect Organic Acidemia Fatty Acid Oxidation Defect (Most likely )
Transient Hyperammonemia Clinical Presentation: Extremely sick of the Newborn Usually large premature neonate (~36wks) Symptomatic pulmonary disease (respiratory distress) Caused by compensatory respiratory alkalosis Does not recur! Treatment: Follow treatment for NH 4 +
Urea Cycle Defect Ornithine Transcarbamylase Deficiency The only X-linked urea cycle defect All other urea cycle defects are autosomal recessive
Fatty Acid Oxidation Defect Two mechanisms: Impaired capacity to use stored fat as fuel in periods of fasting with depleted glycogen stores Defect in carnitine which transports fatty acids during oxidation Recall Defects lead to a decrease in Acetyl CoA and therefore ketone production Thus presentation is most often a non ketotic hypoglycemia Screening: Urine Organic Acids Plasma acyl-carnitine profile Examples Treatment: IV glucose Carnitine supplementation (except in LCHAD where carnitine can lead to accumulation of toxins that cause severe arrhythmias and cardiomyopathy)
Examples VLCAD = Very Long Chain Acyl-CoA Dehydrogenase Deficiency LCHAD = Long-chain 3-hydroxyacyl-CoA Dehydrogenase Deficiency MCAD = Medium Chain Acyl-CoA Dehydrogenase Deficiency Clinical presentation: Non ketotic hypoglycemia Reye like reaction ALTE/Sudden death May have family history of SIDS Fat accumulation in liver or muscle
Organic Acidemia 4 key examples: Organic Acid Defect Treatment (cofactor/vitamin to residual enzyme activity) Methylmalonic Acidemia Hydroxocobalamin(B12) Proprionic Acidemia Multiple carboxylase PO/NG Biotin PO/NG Biotin Glutaric acidemia type 1 Riboflavin
Metabolic Acidosis Normal Anion Gap NOT IEM!!! Increased Anion Gap (MUDPILES) (No ketosis, Normal Lactate) - RTA - Diarrhea Acidosis Anion gap ± Lactate ±Ketosis ± Hypoglycemia NH + 4 Lactate Normal Glucose Organic Acidemia Mitochondrial Disorders
Organic Acidemia 4 key examples: Organic Acid Defect Treatment (cofactor/vitamin to residual enzyme activity) Methylmalonic Acidemia Hydroxocobalamin(B12) Proprionic Acidemia Multiple carboxylase PO/NG Biotin PO/NG Biotin Glutaric acidemia type 1 Riboflavin
(MUDPILES) anion gap In IEM, hidden anions are lactate or organic acids M Methanol U D P I L E S Uremia DKA Peraldehyde Isoniazid, Iron Lactate Ethylene Glycol Salicylates
No Acidosis No NH 4 + Non Ketotic Hyperglycinemia Homocystinuria
Non-Ketotic Hyperglycinemia Clinical Presentation Severe and progressive encephalopathy Uncontrolled hiccups and apnea Myoclonic seizures Hypotonia Investigations: No urine/serum ketones Increased glycine in blood and CSF
Homocystinuria ***Increased risk of stroke Clinical Presentation: Marfanoid appearance Dislocated lens etc. Mental retardation Treatment: pyridoxine
Hypoglycemia Acidosis ± Lactate Hypoglycemia Anion gap Hepatomegaly Liver Failure ±Ketosis ± Lactate LFTs ±Ketosis NH 4 + ± Hypoglycemia NH 4 + Organic Acidemia Glycogen Storage Disorder (GSD) **Note: some exceptions! Tyrosinemias GSD IV Galactosemia Neimann Pick Fatty Acid Oxidation Defects Hyperinsulinemia (Type C)
Organic Acidemia 4 key examples: Organic Acid Defect Treatment (cofactor/vitamin to residual enzyme activity) Methylmalonic Acidemia Hydroxocobalamin(B12) Proprionic Acidemia Multiple carboxylase PO/NG Biotin PO/NG Biotin Glutaric acidemia type 1 Riboflavin
Fatty Acid Oxidation Defect Two mechanisms: Impaired capacity to use stored fat as fuel in periods of fasting with depleted glycogen stores Defect in carnitine which transports fatty acids during oxidation Recall Defects lead to a decrease in Acetyl CoA and therefore ketone production Thus presentation is most often a non ketotic hypoglycemia Screening: Urine Organic Acids Plasma acyl-carnitine profile Examples Treatment: IV glucose Carnitine supplementation (except in LCHAD where carnitine can lead to accumulation of toxins that cause severe arrhythmias and cardiomyopathy)
Glycogen Storage Disorder (GSD) Mechanism: Unable to release glucose from glycogen Several types assigned #s based on order of discovery Liver types: Type 0, I, III, VI, IX Hypoglycemia is presenting symptom Muscle types: Type II (Pompe), V, VII Presents with rhabdomyolysis and weakness
Galactosemia Mechanism: Deficiency of galactose-1-phosphate uridyl transferase Leads to galactose-1-phosphate Clinical presentation: Presents @ ~end of 1 st, start of 2 nd week of life Recurrent Escherichia coli sepsis Galactose-1-phosphate is toxic to the liver: **Jaundice Vomiting Diarrhea Poor weight gain Cataracts Investigations: Urine for reducing substances: looking for non-glucose reducing substances Treatment: Stop galactose containing feeds Only time an infant needs SOY formula Only ISOMIL will work!