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 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

• 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