Transcript Inborn Errors Of Metabolism (IEM)

Introduction
• Metabolism: chemical or physical changes undergone
by substances in a biological system.
• Small molecule disease
Carbohydrate
Protein
Lipid
Nucleic Acids
• Organelle disease
Lysosomes
Mitochondria
Peroxisomes
Cytoplasm
How do you recognize a metabolic
disorder ?
• Laboratory tests
Glucose, Electrolytes, Gas, Ketones, BUN (blood
urea nitrogen), Creatinine.
Lactate, Ammonia, Bilirubin.
Amino acids, Organic acids, Reducing subst.
DNA analysis.
Definition of Inborn errors of metabolism
• IEM are a large group of hereditary biochemical
diseases in which specific gene mutation cause
abnormal or missing proteins that lead to alter function.
• Inborn errors of metabolism occur from a group of rare
genetic disorders in which the body cannot metabolize
food components normally.
• Food not broken down properly may produce chemicals
that build up in various parts of the body causing
medical problems and learning disorders.
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IEM are usually Autosomal recessive.
Some are x-linked recessive condition including:
 Agammaglobulinemia.
 Granulomatous disease.
 Hunter’s Syndrome.
A few inherited as Autosomal dominant trait
including: hyperlipedemia
Categories of IEMs
• Disorders of protein metabolism (eg, amino
acidopathies, organic acidopathies, and urea cycle
defects)
• Disorders of carbohydrate metabolism (eg,
carbohydrate intolerance disorders, glycogen storage
disorders, disorders of gluconeogenesis and
glycogenolysis)
• Lysosomal storage disorders
• Fatty acid oxidation defects
• Mitochondrial disorders
• Peroxisomal disorders
Pathophysiology
• Single gene defects result in abnormalities in the
synthesis or catabolism of proteins, carbohydrates, or
fats.
• Most are due to a defect in an enzyme or transport
protein, which results in a block in a metabolic
pathway.
• Effects are due to toxic accumulations of substrates
before the block, intermediates from alternative
metabolic pathways, and/or defects in energy
production and utilization caused by a deficiency of
products beyond the block.
• Every metabolic disease has several forms that
dependent on: age of onset, clinical severity and, mode
of inheritance.
The Type of Inborn Errors of Metabolism
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Type 1: Silent Disorders
Type 2: Acute Metabolic Crises
Type 3: Neurological
Type 1: Silent Disorders
Untreated could lead to brain damage and developmental
disabilities.
• Example: PKU (Phenylketonuria).
 First newborn screening test was developed in 1959
 Error of amino acids metabolism.
 Incidence of 1: 15,000
 No acute clinical symptoms
 Untreated leads to mental retardation
 Associated complications: behavior disorders, skin disorders,
and movement disorders
 Treatment: phenylalaine restricted diet (specialized formulas
available).
Clinical Features
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Hyperactivity, vomiting.
Blond
eczema skin.
Seizures.
Severe mental retardation.
Bad odor of phenyl acetic acid.
Diagnosis
• Screening : Guthrie Test.
o High Phenylalanine > 20 mg/dl.
o High Phenyl pyruvic acid.
Nutritional Treatment
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Restrict the food sources of phenylalanine
Supplement the tyrosine
Provide adequate calories, protein, fats and
carbohydrates, vitamins and minerals for meeting
energy needs, growth and development.
Type 2: Acute Metabolic Crisis
• Life threatening in infancy
• Children are protected in utero by maternal circulation
which provide missing product or remove toxic
substance
• Example: Urea Cycle Disorders: is a genetic disorder
caused by a deficiency of one of the enzymes in the
urea cycle which is responsible for removing ammonia
from the blood stream. In urea cycle disorders, the
nitrogen accumulates in the form of ammonia, a highly
toxic substance, and is not removed from the body.
Urea Cycle Disorders
• Appear to be unaffected at birth
• In a few days develop vomiting, respiratory distress,
and coma.
• Symptoms mimic other illnesses
• Untreated results in death
Type 3: Progressive Neurological
• Examples: Tay Sachs disease, Gaucher disease
• DNA analysis show: mutations
• Nonfunctioning enzyme results:
Early Childhood: progressive loss of motor and
cognitive skills.
Pre-School: non responsive state.
Adolescence: death
Tyrosinemia
• Hereditary tyrosinemia is a genetic inborn error of
metabolism associated with severe liver disease in
infancy.
• The disease is inherited in an autosomal recessive.
• In families where both parents are carriers of the gene
for the disease, there is a one in four risk that a child
will have tyrosinemia.
• About one person in 100 000 is affected with
tyrosinemia globally.
How Is Tyrosinemia Caused
• Tyrosine is an amino acid which is found in most
animal and plant proteins.
• The metabolism of tyrosine in humans takes place
primarily in the liver.
• Tyrosinemia is caused by an absence of the enzyme
fumarylacetoacetate hydrolase (FAH) which is
essential in the metabolism of tyrosine.
• The absence of FAH leads to an accumulation of
toxic metabolic products in various body tissues,
which in turn results in progressive damage to the
liver and kidneys.
symptoms Of Tyrosinemia
• The clinical features of the disease ten to fall into two
categories, acute and chronic.
• In the so-called acute form of the disease,
abnormalities appear in the first month of life.
• Babies may show poor weight gain, an enlarged liver
and spleen, a distended abdomen, swelling of the
legs, and an increased tendency to bleeding,
particularly nose bleeds. Jaundice may or may not be
prominent.
• Death from hepatic failure frequently occurs between
three and nine months of age unless a liver
transplantation is performed.
• Some children have a more chronic form of
tyrosinemia with a gradual onset and less severe
clinical features.
• In these children, enlargement of the liver and spleen
are prominent, the abdomen is distended with fluid,
weight gain may be poor, and vomiting and diarrhoea
occur frequently.
• Affected patients usually develop cirrhosis and its
complications.
• These children also require liver transplantation.
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 down. Galactose can be found in food by itself.
• Two types
 Galactokinase deficiency
 Galactose-1-phosphate uridyl transferase deficiency (GALT) –Classic
galactosemia
• Because of the lack of the enzyme (galactose-1-phosphate
uridyl transferase) which helps the body break down the
galactose, it then builds up and becomes toxic. In reaction to
this build up of galactose the body makes 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 physical and
mental growth.
• If the condition is not treated there is a 70% chance
that the child could die.
• Deficiency of galactose-1 phosphate uridy l transferase
1/50,000
• Start early after feeding
• Affect brain, liver, kidny and overies
Clinical
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No enzyme: accumulation of galactose1 phosphate
Liver: cirrhosis
Kidney: fancony syndrome
Brain: mental retardation
Ovary: amenorrhea
management
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Lactose free formula
Control seizure
Consult ophthalmology
Consult endocrinology
First line investigations (metabolic screen)
• The following tests should be obtained in ALL babies with
suspected IEM.
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Complete blood count
Arterial blood gases and electrolytes
Blood glucose
Plasma ammonia (Normal values in newborn: 90-150 mg/dl or
64-107 mmol/L).
5. Arterial blood lactate (Normal values: 0.5-1.6 mmol/L)
6. Liver function tests
7. Urine ketones
Second line investigations (confirmatory tests)
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Gas chromatography mass spectrometry (GCMS) of urine.
High performance liquid chromatography (HPLC): for
quantitative analysis of amino acids in blood and urine;
required for diagnosis of organic acidemias and
aminoacidopathies.
Lactate/pyruvate ratio: in cases with elevated lactate.
Enzyme assay: This is required for definitive diagnosis, but
not available for most IEM’s. Available enzyme assays
include: biotinidase assay- in cases with suspected
biotinidase deficiency.
Mutation analysis when available.
Precautions to be observed while collecting samples
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Should be collected before specific treatment is started or feeds
are stopped, as may be falsely normal if the child is off feeds.
Samples for blood ammonia and lactate should be transported
in ice and immediately tested.
Lactate sample should be arterial and should be collected after
2 hrs fasting in heparinized syringe. Ammonia sample is to be
collected approximately after 2 hours of fasting in EDTA
vacutainer.
Detailed history including drug details should be provided to
the lab.
Aims of treatment
1. To reduce the formation of toxic metabolites by
decreasing substrate availability (by stopping feeds
and preventing endogenous catabolism)
2. To provide adequate calories.
3. To enhance the excretion of toxic metabolites.
4. To institute co-factor therapy for specific disease
and also empirically if diagnosis not established.
5. Supportive care