OBJECTIVES

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OBJECTIVES
Use Inborn Errors of Metabolism for clinical
correlation
Definition and history
Provide some examples
Treatments and/or prevention
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INBORN ERRORS OF METABOLISM
Humans are the only species that intentionally
modify our experience and thus modify natural
selection
We do this by
1. Curing some diseases
2. Controlling conditions and preventing
disease
3. Provide Care when first two fail
AS YET NO CURE FOR IEM gene therapy holds this
promise
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Sir Archibald Garrod (1857-1936)
From Mange a Mange, Basic Human Genetics1999
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METABOLISM
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IEMs ARE RARE EVENTS Almost without exception
they are inherited as Autosomal Recessive traits
1 per 5000 live births (all IEMs)
1 per 500 hypercholesterolemia
1 per 12,000 PKU
1 per 45,000 galactosemia
1 per 180,000 MSUD
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NEWBORN SCREENING CARD
Not ok
ok
ok
Blood sample
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Newborn Screening programs
Elevated plasma levels of
Phenylketones-PKU
Leucine-MSUD
Methionine-homocystinuria
Tyrosine-tyrosinemia
Galactose-galatosemia
T3/T4- Hypothyroidism
Sickle Cell disease
Steroid hormones-CAH
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In utero
Mainly transcription factors
Neonatal and beyond
Loss or gain of function for a protein
Percent of total
1y-puberty
Puberty-50
In utero
Birth-1yr
gt50
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Why would you suspect an IEM?
Lethargy
Poor Feeding
Apnea
Vomiting
Failure to thrive
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ODORS ATTRIBUTED TO IEMs
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Lab tests suggested if IEM suspected
1. CBC with differential 2. Urinalysis 3.Blood
gases 4. Serum electrolytes 5. Blood glucose 6.
Plasma ammonia 7. Urine reducing substances 8.
Urine ketones if acidosis or hypoglycemia
present 9. Plasma and urine amino acids 10. Urine
organic acids 11. Plasma lactate
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Flow chart for differential diagnosis
Hyperammonemia
gt24hr
1st 24 hr
premature
acidosis
No acidosis
Full-term
Organic acids
IEM Full workup
Urea cycle defects
transient
PLASMA AMINO ACIDS
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Treatments currently used for IEM
1. Supportive-- Antibiotics for infections, Pain
relievers, etc. TaySachs, Huntington,
Adrenoleukodystrophy
2. Reduce substrate intake-- PKU, MSUD,
Galactosemia, MCAD
3. Elimination (chelation) -- Wilsons disease,
Hemochromatosis
4. Supplying missing end product-- steroid
biosynthesis defects, Smith-Lemli-Opitz
(cholesterol)
5. Pharmacologic vitamins (cofactors)-- MMA,
Homocysteinuria
6. Enzyme replacement- Gaucher disease, SCID
7. Tissue/organ transplants-Crigler-Najjar,
MPS-I(Hurler)
8. Gene therapy- OTC, SCID, Lesch-Nyhan
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LYSOSOMAL STORAGE DISEASES
Muccopolysaccharidosis
I-H Hurler II Hunter III Sanfilippo IV Marquio VI
Maroteaux-Lamy VII Sly
Sphinolipidoses
Tay-Sachs Sandhoff Fabry Shindler Gaucher Nieman-p
ick Krabbe
I-Cell
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Hurlers Disease
from Metabolic Basis of Inherited Disease 7th ed
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Hunters Disease
from Metabolic Basis of Inherited Disease 7th ed
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I-Cell Disease
from Metabolic Basis of Inherited Disease 7th ed
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Comparison of TSD with Gaucher
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Test for Tay Sachs Disease
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TAY SACHS DISEASE
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TAY SACHS DISEASE
Data adapted fromKaback et al. 1993 JAMA 2702307
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GAUCHER DISEASE
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OTHER IEMs
Amino aciduria
Cystinuria Phenylketonuria Homocystinuria Maple
syrup urine disease Hyperglycinemia
Organic aciduria
Isovaleric acidemia Propionic acidemia Methylmalon
ic acidemia Glutaric acidemia
Carbohydrate defects
Galactosemia Hereditary fructose
intolerance Glycogen storage diseases
Urea Cycle Disorders
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Still more IEMs
Fatty Acid oxidation
MCAD LCAD SCAD Carnitine deficiencies
Peroxisomal disorders
Zellweger Adrenoleukodystrophy Refsum
disease Hyperoxaluria
Mitochondria disorders
Pyruvate dehydrogenase deficiency MERRF MELAS
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TAKE HOME LESSONS
What is an inborn error of metabolism?
What pathways can be affected?
What are the inheritance patterns of transmission?
What are the alerting signals if newborn
screening not done?
What are the treatment choices?