Overview: Inborn Errors of

Metabolism (IEM)

Endy Paryanto Prawirohartono

Division of Pediatric Nutrition and Metabolic Disorder
Department of Pediatrics
Medical School GMU
Yogyakarta
Objectives
Definition
Pathogenesis
Incidence
History
Diagnosis
Treatment
Newborn screening
Definition
Definition: METABOLISM
(From the Greek word metabolos for change)

Sum of all the chemical reactions

that convert nutrients (fats,
carbohydrates and proteins we eat as
food) into energy and complex
molecules required for living systems,
by enzymatic reactions helped by
minerals and vitamins
What is metabolism ?
Pathogenesis
 Inborn Errors of Metabolism
Inherited gene mutation

Altered protein
(enzyme, receptor, transport vehicle, membrane, structural elements)

Change of metabolites
(urine, plasma, CSF) Non-toxic

Toxic Variation of normal

Most IEM exhibiting clinical

DISEASE (IEM) consequences manifest in the
newborn period or shortly thereafter
 General Metabolic Concept

Disease results from point defects in metabolism

Accumulation of substrate

Accumulation of normally minor metabolite

Deficiency of product

Secondary metabolic phenomenon

Inborn errors of metabolism are inherited

Autosomal recessive or dominant

Sex linked recessive

Mitochondrial inheritance
 Point defects in metabolism
5

Membrane

1 2
A outside A inside B C
Holoenzyme

4
3

Apoenzyme
D + cofactor

E F
6
Incidence
Incidence of IEM

IEM are individually rare but the

cumulative incidence of IEM is
about 1/5000 live births.

20% of infants presenting with a

"sepsis" picture in the absence of
risk factors (such as prematurity,
chorioamnionitis, etc.) have an IEM.
History
 History
1908 : Sir Archibald Garrod firstly coined
the expression inborn errors of metabolism
(IEM) to describe a group of disorders
(alkaptonuria, benign pentosuria, albinism, &
cystinuria)

caused by point defect in metabolism

life long condition,
not significantly affected by treatment
transmitted by recessive trait by
Mendels law of inheritance
relatively benign
Modes of Inheritance
(Mendelian)
History (cont)

1934 : Flling discovered PKU

associated with a severe form of mental
retardation
could be prevented by newborn screening
& dietary treatment

1995 : < 400 inborn errors of metabolism

disorders (Scriver et al., 1995)
Diagnosis
 History that may indicate IEM

Consanguinity
Siblings with unexplained diseases
(encephalopathy,sepsis,SIDS)
Familial disorders (progressive neurological
disease, maternal PKU, multiple miscarriage,
HELPP syndrome, etc.)
Malnutrition or failure to thrive
 Initial findings include 1 or more the following:
poor feeding, vomiting, lethargy, convulsion not
responsive to i.v. glucose or calcium, coma

Metabolic disorder Infection

obtain plasma ammonia

Plasma ammonia Plasma ammonia

high normal
obtain blood pH and CO2
calculate anion gap
NEWBORN
APPROACH
normal high normal

Urea cycle defect Organic acidemia Aminoacidopathies or galactosemia

The anion gap

The anion gap is the difference

between the sodium concentration and
the combined concentrations of chloride
and bicarbonate
The anion gap
Normal plasma Acidosis (no gap) Acidosis (gap)

UC UC UC
UA UA
UA

HCO3- HCO3-
HCO3-
Na+ Na+ Na+

Cl- Cl- Cl-

UC = unmeasured cations UA = unmeasured anions

Physical examination

Most signs related to central nervous

system
Hepatomegaly (common finding)
Unusual odor see table
IEM associated with abnormal odor

IEM Urine odor

Glutaric acidemia (type II) Sweaty feet, acric
Hawkinisuria Swimming pool
Isovaleric acidemia Sweaty feet, acric
Maple syrup urine disease Maple syrup
Hypermethioninemia Boiled cabbage
Multiple carboxylase deficiency Tomcat urine
Gasthouse urine disease Hops-like
Phenylketonuria Mousy or musty
Trimethylaminuria Rotting fish
Tyrosinemia Boiled cabbage, rancid butter
IEM after the neonatal period
Mental retardation
Motor deficits
Developmental regression
Convulsions
Myopathy
Recurrent emesis with coma and hepatic
dysfunction
Cardiomyopathy
IEM after the neonatal period
Episodic or intermittent pattern

Acute clinical manifestations

Seemingly disease-free state

Trigger: stress, infection

Acute clinical manifestations

 IEM should be considered in child with
one or more the following:

Unexplained mental retardation,

developmental delay or regression, motor
deficits, or convulsion
Unusual odor, particularly during the acute
illness
Intermittent episodes of unexplained
vomiting, acidosis, mental deterioration, or
coma
Hepatomegaly
Renal stones
Muscle weakness or cardiomyopathy
Diagnostic Steps

Clinical presentation

Routine clinical chemistry

Selective screening (chromatography)

Enzyme assays

DNA mutation analysis

 The symptoms and signs that should
make you think about an IEM

Neurologic syndrom
Hepatic syndrome
Cardiac syndrome
Dysmorphism
Storage syndrome
Acute metabolic illness in newborn
Metabolic acidosis
Neurologic syndrome
Chronic encephalopathy
Developmental delay or psychomotor
retardation/regression
Acute encephalopathy
Deterioration of conciousness in previously healthy infant
or child
Movement disorders
Extrapyramidal movement disorders

Myopathy
Progressive muscle weakness, exercise intolerance with
cramps & myoglobinuria
Psychiatric problem
Autism, hyperactivity
 Hepatic syndrome
Jaundice
Unconjugated hyperbilirubinemia
G6PD deficiency, Gilbert syndrome, Crigler Najjar syndr.
Conjugated hyperbilirubinemia
Rotor or Dubin Johnson syndrome
Hepatomegaly +/- splenomegaly :
glycogenosis, lysosomal storage diseases
Hypoglycemia :
glygogenosis, gluconeogenesis defect
Hepatocellular dysfunction
Galactosemia, tyrosinemia, 1-antitrypsin deficiency
 Cardiac syndromes
Cardiomyopathy
Systemic carnitine deficiency, GSD type 2
(Pompe disease), Fabry disease
Arrhytmias
Kearns-Sayre syndrome, Fabry disease, CAT,
propionic acidemia
Coronary artery disease
Familial hypercholesterolemia, Homocystinemia
 Dysmorphism
Characteristic
Generally disturbances of shape, rather
than fusion or cellular migration
abnormalities or abnormalities of number
Tend to become more pronounced with age
Microscopic and ultrastructural
abnormalities are often prominent
Storage syndrome

Characteristic facies
Bone changes (dysostosis multiplex)
and short stature
Organomegaly (megalencephaly,
hepatosplenomegaly)
 Initial laboratory
investigation

Blood Urine
Hematology Color and odor
(anemia,neutropenia,trombo- Reducing substance
cytopenia, vacuolated
lymphocytes, reticulocytosis) FeCl3 tests
Blood gases & electrolytes DNPH and Acetest
Glucose, lactate, pyruvate, Nitroprusside test
ketone bodies LCS
Ammonia, AST, ALT, CK,
ALP,LDH, TG, Cholesterol BMP
Creatinin, urea, uric acid X-ray, USG,
Ferritin Echocardiography,ECG
 Metabolic investigation

Screening Specific
Amino acid analysis Function tests
Organic acid analysis Enzyme measurements
Urinary mucopolysaccharide & Blood
oligosaccharide Fibroblasts (skin biopsy)
Plasma VLCFA & phytanic acid,
Liver, muscle
plasmalogens, pipecolic acids
Mutation analysis
Urine Purines & Pyrimidines
Treatment
 Principles of emergency treatment

Supportive care
Ventilatory and circulatory supports

Nutrition
Normal, a low/free protein, a carbohydrate restriction,
a high glucose +/- lipid restriction diet
Toxin-Removal procedures
Exchange transfusion, peritoneal dialysis,
hemofiltration, hemodialysis
Additional therapies
Carnitine, vitamin supplementation
 Principles of treatment
Reducing the load on the affected pathway
Substrate deprivation by diet
Removing toxic metabolites
Sodium benzoate in hyperammonemia
Replenishing depleted products
Tyrosine in PKU, arginine/citrulline in UCD
Giving increased substrate
L-Carnitine in carnitine transporter deficiency
Blocking production of toxic metabolites
Blocking the effects of toxic metabolites
NTBC in tyrosinemia
Stimulating any residual enzyme
Biotin in biotin deficiency
Enzyme replacement
Symptomatic treatment
Drugs and Chemicals Used To Manage
Congenital Errors of Metabolism
Newborn screening
 Principle of
newborn screening

Spesific reason for genetic screening should be clearly

define, for medical intervention, reproductive
planning, or research
Screening for medical intervention should be carried
out as a part of an integrated program with the
facilities, resource and personal to provide
High risk individuals should be detectable by a simple,
inexpensive test with high sensitivity, specificity, and
predictive efficiency
Conclusion
IEM affect growth and development
The number of IEM could be
screened by clinical findings and
routine laboratory investigations
Early diagnosis & prompt management
could affect the subsequent growth
and development