In Born Error of Metabolism (IEM)

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

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

How to identify? • Prospective approach for a healthy newborn • Reactive approach to a clinically abnormal child

Common conception about IEM • 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

Clinical presentations • 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 in1st 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 • Fulminante-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

In Born Error of Metabolism (IEM)