INBORN ERROR

OF METABOLISM
Moretta Damayanti
Objectives
■ To know the definition of inborn error metabolism
(IEM)
■ To know when to suspect IEM
■ To know how to diagnose IEM
■ To know the management of emergency state of IEM
■ To know the principal management of IEM
■ Genetic counseling
Genetic disorders

■ … a disease caused by the abnormalities in an

individual’s genetic materials (genome)
■ Types of genetic disorders:
■ Chromosomal disorders
■ Single gene disorders
■ Complex disorders
Human genome
• By 2003 the DNA
sequence of the entire
human genome was
known.
• Approximately three
billion base pairs of
deoxyribonucleic acid
(DNA) that make up the
entire set
of chromosomes of the
human organism.
• The human genome
includes the coding
regions of DNA, which
encode all
the genes (between
20,000 and 25,000) of
the human organism, as
well as the noncoding
Single gene disorders
= Mendelian disorders
■ are caused by DNA changes in one particular gene, and often
have predictable inheritance patterns.
■ known as a mutation, the mutated version of the gene
responsible for the disorder is known as a mutant.
■ Individually, single gene disorders are each very rare, but as a
whole, they affect about one per cent of the population.
■ Since only a single gene is involved, these disorders can be easily
tracked through families and the risk of them occurring in later
generations can be predicted.
■ Single gene disorders can be divided into different
categories: dominant?, recessive? and X-linked.
Introduction
Sir Archibald Garrod (1857-1936)
■ proposed the term inborn error of
metabolism to describe a group of
disorders; alkaptonuria, pentosuria,
albinism and cystinuria (1908).
■ Garrod’s concept: IEM resulted from failure
of some step in the series of chemical
changes which constitute metabolism.
■ Typically present at birth, persisted
throughout life, was relatively benign and
not significantly affected by treatment.
■ IEM was transmitted as a recessive trait
by Mendel’s laws of inheritance.
Alkaptonuria (black urine
disease)
■ Mutation of the
homogentisate 1,2-
dioxygenase (HGD) gene 
encoding an enzyme known
as homogentisate 1,2-
dioxygenase which is
essential for the breakdown
of homogentisic acid.

■ Excess homogentisic acid

and related compounds are
deposited in connective
tissues, causes cartilage and
skin to darken (ochronosis). 
Homogentisic acid is also
excreted in urine, making the
urine turn dark when exposed to
air.
Ochronosis
Introduction
Dr. Asbjörn Fölling (1888-1973)
■ Fölling’s described an inherited
metabolic disorder characterized by
severe intellectual impairment, motor
problems, and skin abnormalities.
 Initially termed as imbecillitas
phenylpyrouvica, would later come to be
known as phenylketonuria or PKU by dr.
Lionel Penrose (geneticist).
 Fölling’s discovery made Garrod’s
concept underwent a major change.
Phenylketonu
ria
Egeland family
• They have 2 children who were
attractive but severely retarded
and irritable with destructive
behavior.
• The parents became aware that
both of the children had a
strange musty odor to their
urine.
• They began to think whatever
was causing this odor might
also be causing their children to
be mentally retarded.
• Mixing ferric chloride with the urine of the
Egeland children --> their urine immediately
turned dark green and then faded in color
after a few minutes. Fölling’s
• Phenylacetate mousy odor pada urine. discovery
Discovery of newborn screening
■ Følling continued to search for more
individuals with PKU.
■ Screening young infants with the ferric
chloride test on fairly recently wet diapers
began in California in the late 1950s but
could not consistently be accomplished until
the infant was a few weeks old. Thus, many
infants did not get tested.
■ What was needed was a blood test that
could be performed while the infant was in
the hospital newborn nursery. Such tests
were developed in the early 1960s.
Guthrie
card
• Developed by dr. Robert
Guthrie (1960).
• Spot of blood was put on
the surface of an agar
culture gel which
contained beta-2-
thienylalanine to inhibit
the growth of Bacillus
subtillis, but which was
reversed by
phenylalanine.
• If excess phenylalanine
was present in the blood,
it removed the growth
inhibition and bacteria
grew (hallo sign).
EARLY DETECTION AND SUCCESSFUL TREATMENT OF
PKU
■ A special diet food
had been developed
in mid 1950s and
were successfully
treated to prevent
the mental
retardation of PKU.
■ To be successful the
diet had to be
started in early
infancy before the
onset of mental
retardation.
 Formula Diet for
PKU

■ Phenyl-Free-1
■ Phenyl-Free-2
■ Phenyl-Free-2HP
 Definition:
IEM is a group of disorders in which a single gene defect causes a
clinically significant block in a metabolic pathway resulting either
in accumulation of substrate behind the block or deficiency of the
product.
■ Classified as a rare disease (1:2000 of live birth).
■ Onset: infantile, juvenile, adulthood.
■ In Indonesia, laboratory facility has not been developed yet
for screening or diagnosis IEM.
■ Suspicion of IEM must be made by anamnesis and clinical
findings.
Principal concept of IEM: normal vs mutation
Primary consequences of IEM
 IEM are inherited

Autosomal recessive disorders

X-Linked recessive disorders
Autosomal dominant disorders
Classification of IEM
Human cell structure
When to suspect IEM ???
Circumstances suggesting the
Suspicion
possibility of IEM in newborn
 A metabolic disorder may present differently
depending on the age of the child:

Neonatal period:  Childhood: 

• Poor feeding/sucking • Recurrent unexplained

• Vomiting vomiting with severe
• Hypotonia dehydration
• Respiratory failure / • Stroke like episodes 
apnea • Acute liver or renal
• Progressive failure
encephalopathy • Cardiomyopathy
• Seizures • Failure to thrive
• Clinical picture often • Unexplained
mistaken for sepsis encephalopathy and
seizures
 Another prsentation may also be suspicion

• Developmental delay or regression

• Coarsening of features and skeletal changes
• Psychiatric disorders
• An acute metabolic disturbance following a recent
dietary change e.g. introduction of solids, fasting or
following excessive physical activity
 Mucopolysaccharidoses
tipe II

3 tahun

9 bulan

16 bulan
7 tahun
Bone survey examination

J-shaped sella
turcica

Presence of small irregular carpal bones,

broad and proximally pointed short
metacarpals
 Initial investigations when suspect IEM

• Complete blood count

• Arterial blood gases and electrolytes
• Blood glucose, plasma ammonia, plasma lactate
• Liver function tests, renal function tests, uric acid
• Urine ketones
• Lumbar puncture, Bone marrow puncture
• Radiology (X-Ray,CT-Scan, MRI, USG)
• Echocardiography, EKG
Advanced investigations

• Amino acid analysis

• Organic acid analysis
• Plasma Very long chain fatty acid (VLCFA)
• Plasma carnitine
• Urinary mucopolysaccharide and
oligosaccharide screening test
• Organ biopsy
• Enzyme assay
• DNA mutation analysis
Manifestations of IEM
■ Neurologic syndrome
■ Hepatic syndrome
■ Cardiac syndrome
■ Dysmorphism
■ Storage syndrome
■ Acute metabolic illness of newborn
■ Metabolic acidosis
 Neurologic syndromes

■ Chronic encephalopaty
■ Acute encephalopaty
■ Stroke
■ Movement disorder
■ Myopathy
■ Psychiatric and behavioral abnormalities
 Metachromatic
leukodystrophy
Lysosomal storage disease  Arylsulfatase A
Deficiency  accumulation of a fatty substance
known as sulfatide in the brain and other areas of
the body.

Symptoms:
Blindness, personality changes, and motor
disturbances such as clumsiness, hypotonia, rigidity,
inability to coordinate movement (ataxia), and/or
muscle spasms.
Loss of previously acquired intellectual skills.
 X-Linked
Adrenoleukodystrophy
• Attention deficit
disorder
• Progressive loss
of intellectual
function
• Vision, hearing
and motor
deterioration
• Onset 4-8 years
Acute encephalopathy
 Other neurologic
syndrome
■ Movement disorder
– Lesch-Nyhan syndrome, glutaric aciduria, Wilson
disease
■ Myopathy
– Pompe disease, GSD III, CPT II deficiency
■ Psychiatric or behavioral abnormalities
– Hunter syndrome, Sanfilippo syndrome, Lesch-Nyhan
syndrome, Wilson disease, X-Linked ALD,
 Wilson disease
Reduced
excretion of
copper into bile
 gradual
accumulation of
copper into liver

Onset 8-12 years

 Hepatic syndromes
■Jaundice
– Unconjugated hyperbilirubinemia: G6PD deficiency, Crigler-najjar
syndrome
– Conjugated hyperbilirubinemia: galactosemia, hepatorenal
tyrosinemia, HFI
– Mixed: rotor syndrome, Dubin-Johnson syndrome
■Hepatomegaly and or splenomegaly
– Asymptomatic hepatomegaly: glycogen storage disease
– Tyrosinemia, Gaucher disease
■Hypoglycemia
■Hepatocellular dysfunction
Glycogen storage disease

Manifestations :
- Failure to thrive
- Developmental
delay
- Rounded doll-like
face
- Protuberant
abdomen
(Hepatomegaly)

Laboratory
findings:
-
 Doll-like
face

hepatomegal
y
Pasien Rayyan
 Gaucher
■disease
Hepatosplenomegaly
■ Bisitopenia
■ Mutations in
the GBA gene
greatly reduce or
eliminate the activity
of beta-
glucocerebrosidase

Courtesy of RSUPN Cipto

Mangunkusumo
Gaucher cells in bone marrow
aspiration with characteristic
crinckled tissue paper
 Rounded
thinning of
the medial
cortex on the
left femur

Erlenmeyer
flask
deformity Pathologic
on distal fracture on
femur femoral
neck in
Gaucher
Cardiac syndromes

■ Cardiomyopathy
– Pompe disease, Niemann Pick disease, systemic
carnitine deficiency,
■ Arrhythmias
– Fabry disease, propionic acidemia
■ Coronary artery disease
– Familial hypercholesterolemia
 Familial hypercholesterolemia

• Very significantly elevated low-density lipoprotein (LDL)

cholesterol
• Early onset of coronary artery disease if not sufficiently
treated.

Two types:
1. Heterozygous familial hypercholesterolemia (HeFH) 
xanthomas presenting later in life
2. Homozygous familial hypercholesterolemia (HoFH) 
more severe. Extremely high LDL-C levels (>400 mg/dl).
Xanthomas by early childhood. Planar xanthomas
affecting the skin on the hands, elbows, buttocks and
Storage syndrome
and dysmorphism
 Mucopolysaccharido
ses

■ Mucopolysaccharidoses is a group of heritable

lysosomal storage disorders caused by a
deficiency in glycosaminoglycan (GAG) -
degrading enzymes.
■ The resulting accumulation of unprocessed or
partly processed GAGs— dermatan sulphate,
heparan sulphate, keratan sulphate and
chondroitin sulphate—in lysosomes causes
progressive damage of affected tissues
■ Transmission occurs in an autosomal
recessive, except for MPS II, which is X-linked
An. D, 3
tahun

An. AS, 10
 Niemann-pick disease

• Affects many body systems.

• It has a wide range of symptoms that vary in severity. 
• Autosomal recessive pattern
• Divided into four main types: type A, type B, type C1, and type C2.
• Niemann-Pick disease types A and B  mutations in the SMPD1
 gene  Deficiency of sphingomyelinase.
• Niemann-Pick disease type C  Mutations in NPC1 or NPC2
 gene  shortage of functional protein, which prevents movement
of cholesterol and other lipids, leading to their accumulation in
cells. 
Manifestations:
• Enlarged liver and spleen
(hepatosplenomegaly) by age 3 months
• Thrombocytopenia
• Failure to thrive
• Psychomotor regression
• Neurological manifestation: ataxia,
vertical supranuclear gaze palsy,
dystonia.
• Severe liver disease
• Interstitial lung disease recurrent lung
infections and eventually lead to
respiratory failure.
• A cherry-red spot
• Increased LDL cholesterol,
triglycerides and decreased HDL
cholesterol 
Foam cell on BMP

Foamy cell on liver biopsy

Acute metabolic illness in newborn

■ Encephalopaty without metabolic acidosis

■ Encephalopaty with metabolic acidosis
■ Hepatic syndrome
■ Cardiac syndrome
■ Non-immune fetal drops
Metabolic acidosis
Maple syrup urine
disease
Baby born after a normal
pregnancy and delivery 
initial symptom after free
period  undergoes
deterioration with no
apparent cause and
unresponsive to
symptomatic therapy

First sign: poor feeding

and drowsiness, then
progressive coma
Infant and toddler products for MSUD
Principal emergency management of IEM

■ Supportive treatment : ABC  oxigen supplementation,

ventilator, hemodynamic monitoring.
■ Nutrition : diet restriction.
■ Toxin removal : exchange transfusion, (peritoneal)
dialysis
■ Supplementation of carnitine and vitamins.
First line management:

■ Stop all of toxic diet intakes such as fats, glucose and

fructose.
■ Insertion of IV access and blood samples. Laboratory
result should be finished in 30-60 minutes.
■ Start glucose 10%, 150 ml/kg/day or 10 mg/kg/minutes
(60 kkal/kg/hari) along with electrolytes.
■ Perform blood gas analysis and lactate periodically
 Specific Treatment of IEM

Control of substrate accumulation

■ Restricted dietary intake  special medical purpose formula
– PKU : Phenylalanine restriction
– Galactosemia : dietary galactose restriction
– Propionic aciduria : restriction of isoleucine, valine, threonin,
methionine
■ Control of endogenous production of substrate
– X-linked adrenoleukodystrophy  lorenzo oil
■ Acceleration of removal substrate
– Dyalisis
– UCED  sodium benzoate and sodium phenylacetate
– Homocystinuria  betaine
Propionic/ methylmalonic Glutaric
aciduria aciduria

Phenylketonu Phenylketonu
ria ria
 Specific Treatment of IEM

Replacement of product
■ Reaction product replacement
– Arginosuccinic aciduria : arginine
– Hyperammonemia –hyperornithinemia-
homocitrullinemia: ornithine
■ Gene product replacement (enzyme replacement
therapy
– Gaucher disease, Hunter syndrome, Morquio
syndrome
 Specific Treatment of IEM

Cofactor replacement therapy

• Pyridoxin responsive seizures
• Biotin responsive multiple carboxylase deficiency

Gene transfer therapy

• Organ tranplantation (Bone marrow)
• Single gene transfer therapy
Genetic counseling
Purposes of GC are:
■ IEM is an inherited disorder --> recurrent risk of
disease.
■ Explain to parents about the course of the disease
and prognosis.
■ Family planning : Preimplantation genetic diagnosis,
prenatal diagnosis and newborn screening.
Take home messages
■ IEMs are rare disorders which can be manifest as common
diseases.
■ Diagnosis of IEM starts with a suspicion based on signs,
symptoms and laboratory results.
■ Early detection and intervention can improve the history of
disease and optimize growth and development of patients.
■ Metabolic emergency such as sudden coma/seizures/lethargy
can appear after normal period of living on babies who were
born normal.
Thank you