In Born Error of Metabolism (IEM) Dr Mohammad Khassawneh Assistant professor of pediatrics

When to consider it What to do quickly to determine it is present or not

Prospective approach for a healthy newborn Reactive approach to a clinically abnormal child

Rarely a cause of disease in neonates –Hyperphenylalaninemia 1:10,000 –Galactosemia 1:50,000 –Homocystinurea 1:200,000 –Estimated overall incidence 1:2000 Many of metabolic diseases are under diagnosed

Common conceptions It should only be considered with a family history –AR disease 2 sibs diseased 6%, 2 of 3 14%… –X-linked commonly a new mutation Hard to differentiate from sepsis –Galctosemia and e- coli –Many diseases present different from sepsis illness

Common Conception Biochemical pathway are impossible to remember –This is true for expert –Pathways are not the important part of the evaluation – general approach is more important It is difficult to conduct diagnostic study –Should progress from broad to specific

Continue Few metabolic diseases are treatable –Should give more consideration to treatable conditions –Genetic counseling sake –Gene therapy hold a promise

Newborn Screening Reliable screen test and low false negative Test is simple and inexpensive Available results soon to start effective therapy Definite follow up test Outcome without treatment is very bad Effective therapy is available

The “sick” newborn infant Cardiomegaly/cardiomyopathy Eye anomalies / Gastrointestinal abnormalities Hair and skin abnormalities Hematological / Hepatic dysfunction Sepsis Unusual odor –PKU mousy smell –Cystiurea sulfourus smell

Sick newborn Cardiorespiratory, central nervous system, poor feeding Present in1 st week of life Lethargy and coma low tone & Seizure Acidosis or hyperamonemia may lead to respiratory distress Causes: – include fatty acid, carbohydrate, organic acid, respiratory chain, ammonia metabolism

Example/hyperglycenemia AR disorder Profound hypotonia, poor feeding, hiccupping, lethargy Coma and Seizure with myoclonic jerk Elevated CSF/plasma glycine EEG findings

Cardiomegaly and cardiomyopathy Beta oxidation glycogen storage Most common is Pompe disease (acid maltase) generalize hypotonia and FTT Lysosomal (cytoplasmic organelles) –MPS, sphingolipid, glycoprotein mitochondria disorders

Hurler Syndrome and others AR, alfa L-idurinidase Coarsening of feature 6-12 monthes Cloud cornea Deafness Cardiomypathy Airway obstruction Death by early teenage Scheie, Hunter, Sanfilippo’s, Morquio

Eye abnormalities Cataract: galactosemia, adrenoleukodystrophy, mucopolysacharidosis Lens dislocation: homocystinurea, marfan Blue sclera in oseogenesis imperfecta Cherry red spot in lysosomal disorder (farber disease)

Gastrointestinal/Hair and skin Vomiting in acidosis and urea cycle defect Menkes disease: spares kinky scalp hair associated with hypotonia, intractable seizure and developmental delay PKU: Fair hair and skin Multiple carboxylase deficiency skin rash and partial allopecia

Hepatic dysfunction Enlargement (lysosomal storage disorder) Hypoglycemia –Galactosemia –Hereditary fructose intolerance Hepatocellular damage, like above and adrenoleukodystrophy, fatty acid oxidase def. Cholestatic disease –Alfa 1 antitrepsine, ZZgenotype

Initial laboratory screening Blood –Cell count, electrolytes, amonia, uric acid –Blood gas, lactate and pyrovate –Glucose and ketones Urine: –smell, pH, acetone, ketone –Reducing substances CSF: lactate pyrovate and glucose

Specialized biochemical testing Amino acid analysis –Maple syrup apple disease with increase leuocine, valine and isoleuocine –Hyperglycinemia: increase glycine Organic acid : propionic acidemia Carnitine level Chromatographic of glycolipid Increased level of long chain fatty acid with perioxysomal disorder

galactosemia Deficiency of galactose-1 phosphate uridyl transferase 1/50,000 Start early after feeding Autosomal recessive on chromosome 9p13 with male=female Affect brain, liver, kidny and overies

Galactosemia / clinical No enzyme …accumulation of galactose1 phosphate Liver; cirrhosis Kidney; fancony syndrome Brain; mental retardation Overy; amenorrhea Galactose to galactitol cause cataract

Hepatic and GI manifestation Lethargy irritability and vomiting Feeding difficulty and poor weight gain Jaundice, hypoglycemia, hepatomegally Ascites Hepatic cirrhosis

others Plydypsia, polyurea Rickets Mental retardation Seizure Cataract: perinuclear haziness to complete opacification Fulminant e-coli sepsis

investigation Positive clinitest and negative clinistix Urine galactose by chromatography Direct hyperbilirubinemia RBC’s galactose 1 phosphate uridyl transferase activity Increase galactose 1phosphate in RBC

management Lactose free formula Control seizure Consult ophthalmology Consult endocrinology Genetic counseling

Phenylketonurea (PKU) Phenylalanine hydroxylase deficiency Excess phenylalanine and its metabolites Normal at birth and months to diagnose Vomitting sever/ misdiagnosed pyloric stenosis. Fair skin and blue eyes Eczema and skin rash

PKU…continue Musty or mousey smell Microcephaly Growth retardation 50 point loss of IQ in the first year Clinical feature are rarely seen Neonatal screening

diagnosis Guthrie test; bacterial inhibition, positive in 4 hr old Preferable sample at >24-48 hr of life Positive test should be followed by Phenylalanine and tyrosine Increase PA, NL tyrosine, and increase PA metabolites in urine like phenylpyrovic

treatment Reduce phenylalanine and metabolites in blood. Formula low in phenylalanine Level between 3-15mg/dl Remember over treatment –Lethargy anorexia anemia rash diarrhea Treatment indefinitely Maternal PKU. Mental retarded/ microcphaly/ cardiac defect, keep level <10mg/dl