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F Ahmadabadi Child Neurologist ARUMS 2014 INBORN ERRORS OF METABOLISM Every child with unexplained . . . Neurological deterioration Metabolic acidosis Hypoglycemia Inappropriate ketosis Hypotonia Cardiomyopathy Hepatocellular dysfunction Failure to thrive . . . should be suspected of having a metabolic disorder When to suspect an IEM? Clinical: Vomiting Lethargy FTT Seizure Respiratory Coma Cardiomyopathy Odor Abnormal hair Dysmorphology Labs: Metabolic acidosis Hypoglycemia Hyperammonemia Reducing substances in urine Ketonuria Pancytopenia Metabolic Disorders High Normal Urea cycle defect Normal HAG Acidosis Organic acidemia HAG Acidosis Organic acidemia Normal or N AG Aminoacidopathy or Galactosemia Organic Acidemia Ketosis No No skin\ manifestation No Odor 1)MMA 2)PPA Characteristic odor 1)MSUD 2)IVA Skin manifestation MCD No Ketosis 1)Glutaric A 2)Acyl CoA deficiency 3)HMG CoA deficiency Screening 1)Gutherie 2)MS/MS Perform before discharge or 7th day of birth Disease PKU MSUD Thyrosinemia Propionic acidemia Methyl mallonic Isovalleric Biotinidase deficiency Galactosemia Urea cycle defect Test Age of treatment Confirming Guthrie MS/MS MS/MS 1st weeks of life Phenylalanin(p) AA (p)AA (p) 1st week of life 1st weeks of life Organic acids(u) profile OAP (u)- AA (p) Enzyme assessment Biotinidase Enzyme assessment 1st days of life MS/MS 1st days of life GALT AA (p) profile DNA motations Treatment in hyprammonemia 1. D/C oral intake temporarily 2. Usually IVF’s with glucose to give 12-15 mg/kg/min glu and at least 60 kcal/kg to prevent catabolism (may worsen PDH) 3. Bicarb/citrate 4. Carnitine/glycine 5. Na benzoate/arginine/citrulline 6. Dialysis--not exchange transfusion 7. Vitamins--often given in cocktails after labs drawn before dx is known Biotin, B6, B12, riboflavin, thiamine, folate Metabolic Disorders Presenting as Severe Neonatal Disease 1. Disorders of Carbohydrate Metabolism • Galactosemia - presents with severe liver disease, gram negative sepsis, and/or cataracts Enz deficiency: Gal-1-phos uridyl transferase, UDP-gal-4epimerase • Glycogen storage disease type 1a & 1b - presents as hypoglycemia Enz deficiency: Glucose-6 phosphatase Lactic Acidosis - presents as lactic acidosis +/- hypoglycemia Enz deficiency: Pyruvate carboxylase, Pyr dehydrogenase, etc. • Fructose intolerance - Needs fructose exposure, hypoglycemia and acidosis Metabolic Disorders Presenting as Severe Neonatal Disease 2. Amino Acid Disorders • Maple syrup urine disease - presents with odor to urine and CNS problems • Nonketotic hyperglycinemia - presents with CNS problems • Enz deficiency: Branched chain ketoacid decarboxylase Enz deficiency: Glycine cleavage system Tyrosinemia - Severe liver disease, renal tubular dysfunction Enz deficiency: Fumaryl acetate Transient tyrosinemia of prematurity - progressive coma following respiratory distress Metabolic Disorders Presenting as Severe Neonatal Disease 3. Urea Cycle Defects and Hyperammonemia 4. All present with lethargy, seizures, ketoacidosis, neutroenia, and hyperammonemia Ornithine carbamyl transferase (OTC) deficiency Carbamyl phosphate synthetase deficiency Citrullinemia Arginosuccinic Aciduria Argininemia Transient tyrosinemia of prematurity Metabolic Disorders Presenting as Severe Neonatal Disease All present with lethargy, seizures, ketoacidosis, neutropenia, hyperammonemia, and/or hyperglycinemia 4. Organic Acid Defects • Methylmalonic acidemia • Proprionic acidemia • Isovaleric acidemia - odor of “sweaty feet” • Glutaric aciduria type II • Dicarboxylic aciduria 5. Miscellaneous • Peroxisomal disorders • Lysosomal storage disease • Pyridoxine dependent seizures Amino acids metabolism diorders Phenyl ketonuria AR Prevalence 1/10000 They are normal at birth. Inheritance normal carrier GSD “Baby” Phenylketonuria Phenylalanin Phenlketones Thyrosin Clinical manifestation Normal at birth Severe MR(IQ<30) Blound appearance Odor Microcephalia Seborroic dermatitis Dominant maxilla Diagnosis Ferric chloride test(urin phenyl ketones) Guthrie test Screening test MS/MS Phenylalanin>6mg/dlit(360 mic M) Thyrosin (low) Diagnostic test Treatment Low phenylalanin Regimen (Phenylalanin2-6mg/dlit) Treatment must start in first 10 days of life. It must be continued till 10-12 yrs old. In malignant PKU, Neurotransmitters are needed.(BH4) + Maternal hyperphenylallanenimiaMR-MicrocephalliaCHD Carbohydrate metabolism disorders 1)Galactosemia Lactose Glucose+Galactose Galactose -1_phosphate Glucose-1-Phosphate Clinical findings Feeding Hepatic failure (Bil –Coagulopathy -Glu) Tubulopathy (Acidosis-Glucosuria-A aciduria) Cataract E coli sepsis is more than others In older patients Learning disorders-Ovarian Failure Diagnosis: Screening Urin reducing substrare Diagnostic test RBCs Gal1-P U transferase Glycogen Storage Diseases Type 0 Type IV Type I Type VII Type II GSD Type III Type III 2)Glycogen storage diseases 1) liver involement &Hypoglycemia (1-6-8) 2) Muscle involvement (5-7) 3) Both of liver and Muscle (3) 4) Without any effect on Glucose & anearobic activities (2-4) Mucopolysaccharidosis Disease Onset Corneal involevment Retinal involvement Organomega ly CNS involvement B/M Hurler 1Yrs + _ ++ Severe Alder-reilly Hunter 1-2yrs _ + ++ Mild Alder-reilly Sanfilippo 2-6 yrs _ _ + Severe Alder-reilly Normal Alder-reilly Liver Morquo 2 yrs +- _ _ Hurler syndrome HURLER SYNDROME LIPIDOSIS Organome Cherry red galy spot Guacher disease Nimenpic + _ + + Taysachs _ + Fabry + Farber + Onset 1st month 3-6 month 1st 4 Treatment in hyprammonemia 1. D/C oral intake temporarily 2. Usually IVF’s with glucose to give 12-15 mg/kg/min glu and at least 60 kcal/kg to prevent catabolism (may worsen PDH) 3. Bicarb/citrate 4. Carnitine/glycine 5. Na benzoate/arginine/citrulline 6. Dialysis--not exchange transfusion 7. Vitamins--often given in cocktails after labs drawn before dx is known Biotin, B6, B12, riboflavin, thiamine, folate