01/03/2020

What is
(Inborn errors of metabolism)
• inborn error : an inherited (i.e. genetic)
Inborn Errors Of Metabolism disorder
(IEM) • metabolism : biochemical changes
undergone by substances in a biological
system

MODUL EMTK
FK-USAKTI

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Disorders of protein
What is a metabolic disease?
metabolism
• Small molecule disease • Organelle disease Aminoacidopathy:
– Carbohydrate – Lysosomes • tyrosinemia :
• a genetic inborn error of metabolism associated with severe liver
– Protein – Mitochondria disease in infancy
– Lipid – Peroxisomes • autosomal recessive

– Nucleic Acids
– Cytoplasm • absence of the enzyme fumarylacetoacetate hydrolase (FAH) which
is essential in the metabolism of tyrosine
• leads to an accumulation of toxic metabolic products
(succinylacetone) in various body tissues, which in turn results in
progressive damage to the liver and kidneys
• Affected patients usually develop cirrhosis and its complications.
These children also require liver transplantation
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CLINICAL FEATURES

• normal at birth.
• mental retardation develop gradually
• older untreated children are hyperactive with
purposeless movement, rhythmic rocking and
athetosis.
• unpleasant odor of phenylacetic acid
• microcephaly
• Fair skin
• Eczema and skin rash
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Maple syrup urine disease

CLASSIC MSUD

• severe form, normal at birth, develop poor

feeding ,vomiting,lethargy,hypertonicity
alternate with flaccidity, muscular rigidity ,
convlsion,hypoglycemia.
• maple odor of urine and sweat.
• Lab: metabolic acidosis.
• Dx: hi plasma level of valine ,leucine and
isoleucine.and in urine also.
• Teatment: in acute state peritoneal dialysis.
after recovery special diet devoid of
valine,leucine and isoleucine (only small
amount).
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Albinism
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Pyruvate kinase (PK) deficiency:

This is the next most common red cell enzymopathy after G6PD
deficiency, but is rare. It is inherited in a autosomal recessive pattern
and is the commonest cause of the so-called "congenital non-spherocytic
haemolytic anaemias" (CNSHA).
PK catalyses the conversion of phosphoenolpyruvate to pyruvate with
the generation of ATP. Inadequate ATP generation leads to premature
red cell death.
There is considerable variation in the severity of haemolysis. Most
patients are anaemic or jaundiced in childhood. Gallstones,
splenomegaly and skeletal deformities due to marrow expansion may
occur. Aplastic crises due to parvovirus have been described. Hereditary hemolytic anemia
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Blood film: PK deficiency:

Characteristic "prickle cells" may be seen.
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Glycogen storage disease

Drug induced hemolytic anemia 19 20

Glycogen Storage Diseases

Type 0
Glycogen Storage Disease
Type IV
Type IIIb

• Deficiency of debranching enzyme in the liver needed to

completely break down glycogen to glucose
• Hepatomegaly and hepatic symptoms
– Usually subside with age
Type I • Hypoglycemia, hyperlipidemia, and elevated liver transaminases
occur in children
Type VII

Type II
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GSD Type III

Debranching Enzyme
• Amylo-1,6-glucosidase
– Isoenzymes in liver, muscle and heart
– Transferase function
– Hydrolytic function
Type III

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Clinical Features Clinical Features

Common presentation Less Common

• Hepatomegaly and fibrosis in childhood • Splenomegaly

• Fasting hypoglycemia (40-50 mg/dl)
• Hyperlipidemia • Liver cirrhosis
• Growth retardation
• Elevated serum transaminase levels
(aspartate aminotransferase and alanine aminotransferase > 500 units/ml)

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Type Enzyme defect Onset Liver Muscle Comments

Type I (von Gierke) Glucose-6-phosphatase Infant +++ -

Enlarged liver and
kidneys Galactosemia is an inherited disorder that affects the way the body breaks down
certain sugars. Specifically, it affects the way the sugar called galactose is broken
Growth failure.
Hypoglycaemia

down. Galactose can be found in food by itself. A larger sugar called lactose,
Good prognosis

Type II (Pompe) Lysosomal α-glucosidase Infant ++ +++ Hypotonia and

cardiomegaly at several
sometimes called milk sugar, is broken down by the body into galactose and glucose.
months. Death from heart
failure The body uses glucose for energy. Because of the lack of the enzyme (galactose-1-
phosphate uridyl transferase) which helps the body break down the galactose, it then
Type III (Cori) Amylo-1,6-glucosidase Infant ++ + Milder features of type I,
but muscles may be
builds up and becomes toxic. In reaction to this build up of galactose the body makes
affected
Good prognosis
some abnormal chemicals. The build up of galactose and the other chemicals can cause
serious health problems like a swollen and inflamed liver, kidney failure, stunted
Type V (McArdle) Phosphorylase Child - ++ Temporary weakness and physical and mental growth, and cataracts in the eyes. If the condition is not treated
cramps muscles after
exercise
Myoglobinuria in later
there is a 70% chance that the child could die.
life

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Galactosemia Treatment

Autosomal recessive trait. Can be diagnosed by urine reducing substance

• Metabolism of galactose produce fuel for cellular metabolism with enzyme assay.
through its conversion to glucose-1-phosphate.
• Galactosemia due to defect of one of 3 enzymes: Treatment: by elimination of galactose from
• galactose-1-phosphate uridyl transferase(classic). diet
• galactokinase (type 2).
• uridine diphosphate galactose-4-epimerase(type3).
• Accumulation of galactose 1-phosphate in liver,kidney and brain.
• May begin prenatally by transplacental galactose from mother diet or
endogenous production of galactose in the fetus.

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Galactosemia

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THE LIPIDOSES
GAUCHER’S DISEASE
• Also know as Inborn Error of the lipid
metabolism • The most frequent of the lipidoses characterized by
storage CEREBROSIDES
• Manifested by increases in specific
lipids in the blood and tissues • The lipid involded is GLUCOSYLCERAMIDE
• (+) Foam cells thus, histiocyte containing
• The defect is due to the deficiency of a galactose
the accumulated lipid material
transferase
• Foam cells causes the enlargement of
the affected organ and impaired their • (+) Gaucher Cell – a large multinucleated cell with
fibrillar non-vacuolated cytoplasm
function
• Genetic transmission is usually
autosomal recessive
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GAUCHER’S DISEASE
• CLINICAL MANIFESTATION GAUCHER’S DISEASE
• A. Acute Type
• Early onset with abdominal enlargement due • C. Chronic Type
to splenomegaly followed by hepatomegaly
• May start in adolescence or even in
• Strabismus & Dysphagia indicate CNS adult life
involvement
• Slow development of hepatic & splenic
• B. Subacute type
enlargment
• Manifestations maybe shown during late
• Skin usually shows a yellow and brown
childhood
tinge
• Hepatosplenomegaly, dementia, changes in
• Hypersplenism leading to pancytopenia &
behavior & Seizure bleeding
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GAUCHER’S DISEASE NIEMANN-PICK DISEASE

• An autosomal recessive degenerative trait
• TREATMENT • Accumulation of sphingomyelin in foam cells of the RES
& other tissues
• No Specific Therapy • is a result of the deficiency of a lysosomal hydrolase
• Splecnectomy (sphingomyelinase)
• Cortico Steroids may control bone pains •CLINICAL MANIFESTATION
TYPE A
• the child appears normal within the 6 months of life
• digestive disturbances with slightly prolonged
jaundice
• Hepatomegaly & weight loss
•Enormous enlargement of the liver is
a prominent finding
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NIEMANN-PICK DISEASE
• Neuromuscular Manifestation; Convulsion,
NIEMANN-PICK DISEASE
myoclonia & spasticity
• Red spot in the retina • DIAGNOSIS
• Deterioration is progression until death with
comes before the age of 4 • Foam cell in the bone marrow
• Pancytopenia with bone changes
Type B • Moderate increased of serum lipids
• Only with visceral involvement without nervous
system disease
• Juvenile types with neurological symptoms at 5-7 • TREATMENT
yrs of age • No definite therapy
• Progressive deterioration until death between the • Splenomegaly to relieve hematologic
1st to the 3rd decade
disorders
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TAY-SACHS DISEASES TAY-SACH’S DISEASE

CLINICAL MANIFESTATIONS
•Most common of the group of
• Apathy in the 1st year of life followed by
GANGLIOSIDE storage diseases
motor function regression & visual
•Accumulation of normal & abnormal impairment
ganglioside • Infants are easily startled by noise
• Deficiency or absence of • Neurologic impairment – difficulty in
GALACTOSIDASES & HEXOSAMINIDASES sucking, spasticity, seizures & opisthotonus
• A cherry red spot in the fovea region of
•Deposition of the gangliosides in the neurons the retina
of both CNS & ANS
• Death in the 3d to 4th yr of life

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TAY-SACH’S DISEASE
DIAGNOSIS
• Deficiency in enzyme ( Hexosaminadse A)
in the serum & leuckocytes & in the
amniotic fluid obtained in amniocentesis
• CSF enzymes are elevated
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TREATMENT
• No specific therapy
• Supportive measures

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