3. Inborn errors of metabolism
A group of diseases caused by
a defect in the activity of an enzyme
that affect a wide variety of
metabolic processes;
defective processing or transport of
amino acids, fatty acids, sugars or metals
4. 15 August 2019 Total slide. 132 4
Inborn Errors of Metabolism
• An inherited enzyme deficiency leading to
the disruption of normal bodily
metabolism
• Impaired formation of a product normally
produced by the deficient enzyme
• Accumulation of a toxic substrate
(compound acted upon by an enzyme in a
chemical reaction)
5. 15 August 2019 Total slide. 132 5
What is a metabolic disease?
• Garrod’s hypothesis
product deficiency
substrate excess
toxic metabolite
A
D
B C
7. 15 August 2019 Total slide. 132 7
Genetic Basis
of
Inherited Disorders
Point mutations,
Insertions, Deletions,
Missense Mutations
and Rearrangements
8. 15 August 2019 Total slide. 132 8
Epidemiology and Inheritance
• Although each
individual IEM is rare,
cumulatively they occur
~ 1:5000 live births
• Majority of IEM follow
an autosomal recessive
mode of inheritance
9. 15 August 2019 Total slide. 132 9
Classification of Metabolic Diseases
Small molecule disease
– Carbohydrate
– Protein
– Lipid
– Nucleic Acids
– Minerals
– Vitamins
Organelle disease
– Lysosomes
– Mitochondria
– Peroxisomes
– Cytoplasm
10. Metobolic Disorders
• Aminoacid Metabolim
• Lipid Metabolism
• Carbohydrate Metabolism
• Mitochondrial Energy Metabolism
• Vitamin Metabolism
• Metal Transport
• Nucleic acid and Heme Metabolism
• Organelles – lysosomes , peroxisomes
11. Defects in Amino and Organic Acid Metabolism
Defects in Carbohydrate Metabolism
Errors in Fatty Acid Metabolism
Defects in Cholesterol and Lipoprotein Metabolism
Mucopolysaccharide and Glycolipid Disorders
Defects in Nucleotide Metabolism
Disorders in Metal Metabolism and Transport
Porphyrias and Bilirubinemias
Diseases Associated with Defective DNA Repair
Metobolic Disorders
12. Categories of IEMs
Disorders of protein metabolism
(amino acidopathies, organic acidopathies,
and urea cycle defects)
Disorders of carbohydrate metabolism (eg,
carbohydrate intolerance disorders, glycogen
storage disorders, disorders of gluconeogenesis
and glycogenolysis)
Fatty acid oxidation defects
Lysosomal storage disorders
Mitochondrial disorders
Peroxisomal disorders
25. 25
AMINO ACID DISORDERS
Phenyl Ketonuria (PKU)
Phenylalanine Tyrosine
Hydroxylase
Phenylalanine
Phenyl ethylamine Phenyl pyruvic acid
Phenyl pyruvic acid is what gives the urine its smell because its ketonic and acidic.
27. Child with PKU –
born before NBS
Full expression of
this genetic
disease
+ gene mutation
+ environmental
exposure
28. Clinical Biochemistry Metabolic Disorders of Proteins
15 August 2019 Total slide. 132 28
Defect here causes
Type I Tyrosinemia
Defect here causes
alkaptonuria
Catabolic pathway for phenylalanine and
tyrosine
Homogentisate
dioxygenase
Fumarylacetoacetate
hydrolase
30. Clinical Biochemistry Metabolic Disorders of Proteins
15 August 2019 Total slide. 132 30
abnormalities appear in the
first month of life
poor weight gain
enlarged liver and spleen
distended abdomen
swelling of the legs
increased tendency to
bleeding, particularly nose bleeds
Jaundice
death from hepatic failure
frequently occurs between three
and nine months of age unless a
liver transplantation is
performed.
Acute tyrosinemia
31. Clinical Biochemistry Metabolic Disorders of Proteins
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Normal urine
Urine from patients
with alkaptonuria
Symptoms of alkaptonuria
32. Clinical Biochemistry Metabolic Disorders of Proteins
15 August 2019 Total slide. 132 32
Patients may display painless bluish darkening of the outer ears,
nose and whites of the eyes. Longer term arthritis often occurs.
33. 15 August 2019 Total slide. 132 33
MSUD Clinical Manifestations
Time Symptom/Sign
12-24 hours Maple syrup odor to cerumen
Elevated BCAA
2-3 days Irritability, poor feeding
Ketonuria
4-5 days Encephalopathy (lethargy,
apnea, atypical movements
7-10 days Coma and respiratory failure
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Homocystinuria
Defective activity of cystathionine synthase
36. Clinical Biochemistry Metabolic Disorders of Proteins
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Major phenotypic expression
Ectopia lentis
Vascular occlusive disease
Malar flash
Osteoporosis
Accumulation of homocysteine and methionine
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15 August 2019 Total slide. 132 41
Characteristics of albinism:
Low Vision (20/50 to
20/800)
Sensitivity to bright light
and glare
Rhythmic, involuntary
eye movements
Absent or decreased
pigment in the skin and
eye and sensitivity to
sunburn that could lead to
skin cancers or cataracts
in later life
"Slowness to see" in
infancy
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15 August 2019 Total slide. 132 42
Characteristics of albinism:
Farsighted, nearsighted,
often with astigmatism
Underdevelopment of the
central retina
Decreased pigment in the
retina
Inability of the eyes to
work together
Light colored eyes ranging
from lavender to hazel,
with the majority being
blue
47. Disorders of Fat Metabolism
Defect in enzymes which allows transport of
fatty acids into the mitochondria; specific
to short-, medium- or long-chain fatty acids
Fatty acids not utilized resulting in
hypoglycemia, hyperammonemia, death
MCADD most common
Deficiencies of carnitine metabolism
61. Peroxisomal disorders
Zellweger syndrome
Adrenoleukodystrophy
Hyperoxaluria type I (alanine glyoxylate
aminotransferase deficiency)
Refsum disease (phytanyoyl CoA
hydroxylase deficiency)
62. 62
Hypotonia.
Dysmorphia.
Psychomotor delay and seizures.
Hepatomegaly.
Abnormal eye findings such as retinitis
pigmentosa or cataract.
Hearing impairment.
PEROXISOMAL DISORDERS
Clinical Manifestations:
63. Peroxisomal Disorders
• Zellweger Syndrome
(Cerebro-hepato-renal
syndrome)
• Dysmorphic facies.
• Progressive
degeneration of
Brain/Liver/Kidney,
• Death ~6 mo after onset.
• When screening for PDs. obtain
serum Very Long Chain Fatty Acids-
VLCFAs
67. Mucopolysaccharidoses (MPS)
MPS I (Hurler, Hurler-Scheie, Scheie)
MPS II (Hunter)
MPS III (Sanfillippo)
MPS IV (Morquio)
MPS VII (Sly)
MPS IX (Natowicz)
68. 68
Hurler’s
In hurler :
Nasal bridge is depressed , increase distance of philthrum , epicanthal
folds, bossing of the head , thick eyebrows , upturn nostrils
70. Mucolipidosis
Mucolipidoses type I (Sialidosis)
Mucolipidoses type II (I-cell)
Mucolipidoses type III (pseudo-Hurler)
Mucolipidoses type V (Sialolipidosis)