F Ahmadabadi F Ahmadabadi Child Neurologist ARUMS 20 14

 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

Organic Acidemia Ketosis No \ Skin manifestation MCD No Ketosis 1)Glutaric A 2)Acyl CoA deficiency 3)HMG CoA deficiency No skin manifestation No Odor 1)MMA 2)PPA Characteristic odor 1)MSUD 2)IVA

Screening 1)Gutherie 2)MS/MS Perform before discharge or 7 th day of birth ConfirmingAge of treatmentTestDisease Phenylalanin(p) AA (p)- AA (p) 1 st weeks of life Guthrie MS/MS PKU MSUD Thyrosinemia Organic acids(u) profile OAP (u)- AA (p) Biotinidase 1 st week of life 1 st weeks of life MS/MS Enzyme assessment Propionic acidemia Methyl mallonic Isovalleric Biotinidase deficiency GALT 1 st days of lifeEnzyme assessmentGalactosemia AA (p) profile DNA motations 1 st days of life MS/MS Urea cycle defect

Treatment in hyprammonemia 1.D/C oral intake temporarily 2.Usually IVF’s with glucose to give 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-4- epimerase 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  Enz deficiency: Branched chain ketoacid decarboxylase Nonketotic hyperglycinemia - presents with CNS problems  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 Thyrosin Phenlketones

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)  Diagnostic test  Thyrosin (low)

Treatment  Low phenylalanin Regimen (Phenylalanin2-6mg/dlit) Low phenylalanin Regimen  Treatment must start in first 10 days of life.  It must be continued till yrs old.  In malignant PKU, Neurotransmitters are needed.(BH4)  Maternal hyperphenylallanenimia  MR-Microcephallia- CHD +

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

Type 0 Type I Type II Glycogen Storage Diseases Type IV Type VII

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 B/MCNS involvement Organomega ly Retinal involvement Corneal involevment OnsetDisease Alder-reilly Severe ++_+1Yrs Hurler Alder-reilly Mild +++_1-2yrs Hunter Alder-reilly Severe + Liver __2-6 yrs Sanfilippo Alder-reilly Normal __+-2 yrs Morquo

Hurler syndrome

HURLER SYNDROME

LIPIDOSIS Onset Cherry red spot Organome galy 1 st month_+ Guacher disease ++ Nimenpic 3-6 month +_ Taysachs + Fabry 1 st 4 month + Farber

Treatment in hyprammonemia 1.D/C oral intake temporarily 2.Usually IVF’s with glucose to give 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