1.
Metabolic Disorders
Prof. Imran Iqbal
Prof of Paediatrics (2003-2018)
Prof of Pediatrics Emeritus, CHICH
Multan, Pakistan

2.
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

3.
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)

4.
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What is a metabolic disease?
• Garrod’s hypothesis
product deficiency
substrate excess
toxic metabolite
A
D
B C

5.
Our Genetic background
• Total genes 25000 in pairs
• Genetic disorders 7000

6.
15 August 2019 Total slide. 132 7
Genetic Basis
of
Inherited Disorders
Point mutations,
Insertions, Deletions,
Missense Mutations
and Rearrangements

7.
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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

8.
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

9.
Metobolic Disorders
• Aminoacid Metabolim
• Lipid Metabolism
• Carbohydrate Metabolism
• Mitochondrial Energy Metabolism
• Vitamin Metabolism
• Metal Transport
• Nucleic acid and Heme Metabolism
• Organelles – lysosomes , peroxisomes

10.
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

11.
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

12.
Protein metabolism disorders
 Organic acidemias
 Aminoacidurias
 Urea cycle defects

13.
Carbohydrate metabolism
disorders
 Glycogen storage disease
 Galactosemia
 Fructose intolerance
 Glucose malabsorption

14.
Fat metabolism disorders
 Hypertriglyceridemia
 Hyperlipidemia
 Fatty acid oxidation defects

15.
Vitamin disorders
 Biotinidase deficiency

16.
Mineral disorders
 Wilson disease
 Menkes disease
 Cystinosis

17.
Wilson Disease (KF rings)

18.
Endocrine disorders
 Primary congenital hypothyroidism
 Congenital adrenal hyperplasia

19.
Hemoglobin disorders
 SS disease (sickle cell anemia)
 S, beta-thalassemia

20.
Common
amino acid metabolism disorders
 Phenylketonuria
 Tyrosinemia, type 1
 Maple syrup urine disease
 Homocystinuria

21.
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1. Hyperactivity, athetosis, vomiting.
2. Blond.
3. Seborric dermatitis or eczema skin.
4. Hypertonia.
5. Seizures.
6. Severe mental retardation.
7. Unpleasant odor of phenyl acetic acid.
PKU
CLINICAL FEATURES

22.
15 August 2019 Total slide. 132 24

23.
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.

24.
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Phenylketonuria PKU

25.
Child with PKU –
born before NBS
Full expression of
this genetic
disease
+ gene mutation
+ environmental
exposure

26.
Clinical Biochemistry Metabolic Disorders of Proteins
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Defect here causes
Type I Tyrosinemia
Defect here causes
alkaptonuria
Catabolic pathway for phenylalanine and
tyrosine
Homogentisate
dioxygenase
Fumarylacetoacetate
hydrolase

27.
Tyrosinemia

28.
Clinical Biochemistry Metabolic Disorders of Proteins
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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

29.
Clinical Biochemistry Metabolic Disorders of Proteins
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Normal urine
Urine from patients
with alkaptonuria
Symptoms of alkaptonuria

30.
Clinical Biochemistry Metabolic Disorders of Proteins
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Patients may display painless bluish darkening of the outer ears,
nose and whites of the eyes. Longer term arthritis often occurs.

31.
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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

32.
MSUD patient after liver transplant

33.
Clinical Biochemistry Metabolic Disorders of Proteins
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Homocystinuria
Defective activity of cystathionine synthase

34.
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

35.
Clinical Biochemistry Metabolic Disorders of Proteins
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36.
Clinical Biochemistry Metabolic Disorders of Proteins
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37.
Clinical Biochemistry Metabolic Disorders of Proteins
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A family of homocystinuria

38.
Clinical Biochemistry Metabolic Disorders of Proteins
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Albinism

39.
Clinical Biochemistry Metabolic Disorders of Proteins
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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

40.
Clinical Biochemistry Metabolic Disorders of Proteins
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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

41.
Cystinosis

42.
Cystiene deposits in cornea

43.
Organic acidemias
 Methylmalonic acidemia
 Propionic acidemia
 Isoveleric acidemia
 Glutaric acidemia
 3-Methylglutaconic aciduria
 2-Hydroxyglutaric aciduria

44.
Urea Cycle disorders
 Ornithin transcarbnamylase deficiency
 Carbamyl phosphate synthetase
deficiency
 Argininosuccinicaciduria
 Citrullinemia
 N-acetyl glutamate synthtase deficiency
 Arginase deficiency

45.
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

46.
© 2007 Thomson - Wadsworth

47.
Disorders of fatty acid oxidation
 Carnitine uptake defect(carnitine transport
defect)
 Carnitine Palmitoyl Transferase I deficiency
 Short-chain acyl-CoA dehydrogenase deficiency
 Medium-chain acyl-CoA dehydrogenase
deficiency
 Very long-chain acyl-CoA dehydrogenase
deficiency
 Long-chain-L-3- hydroxyacyl-CoA
dehydrogenase deficiency
 Trifunctional protein deficiency

48.
Disorders of Cholestrol
metabolism
 Hypercholestrolemia
 Hyperlipidemia
 Smith-Lemli-Opitz syndrome

49.
Hypercholestrolemia

50.
Disorders of carbohydrate intolerance
 Galactosemia
 Galactokinase deficiency
 Hereditary fructose intolerance
 UPD galactose epimerase deficeincy

51.
Glycogenolysis (Glycogen Storage
Diseases, GSD)
 Liver glycogen synthase deficiency (GSD 0)
 GSD I: von Gierke disease
 GSD II: Pompe disease
 GSD III: Cori/ Forbes disease
 GSD IV: Anderson disease
 GSD V: McArdle disease
 GSD VI: Hers disease
 GSD VII: Tarui disease
Phosphorylase b kinases deficiency

52.
Glycogen Storage Diseases
 GSD1 most commonly diagnosed
 Deficiency of enzyme glucose 6 phosphatase
resulting in hypoglycemia
 Low blood glucose results in short periods of
fasting (2-4 hours)
 Elevations in lipids, lactate, uric acid
 Hepatomegaly
 Chronic lactic acidosis, poor growth
 Osteoporotic bones, delayed bone age

53.
Gluconeogenesis disorders
 Fructose 1,6-biphosphatase
deficiency
 Pyruvate carboxylase deficiency
 Phosphoenolpyruvate
carboxykinase deficiency
 Pyruvate dehydrogenase deficiency

54.
Mitochondrial disorders
 Pyruvate carboxylase deficiency
 MELAS,
 MERRF,
 NARP
 K – S syndrome
 Pearson syndrome

55.
Peroxisomal disorders
 Zellweger syndrome
 Adrenoleukodystrophy
 Hyperoxaluria type I (alanine glyoxylate
aminotransferase deficiency)
 Refsum disease (phytanyoyl CoA
hydroxylase deficiency)

56.
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 Hypotonia.
 Dysmorphia.
 Psychomotor delay and seizures.
 Hepatomegaly.
 Abnormal eye findings such as retinitis
pigmentosa or cataract.
 Hearing impairment.
PEROXISOMAL DISORDERS
Clinical Manifestations:

57.
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

58.
64Zellweger

59.
 Lipid storage disorders
 Mucopolysacchridosis
 Mucolipidosis
 Farber disease
 Fabry disease
Lysosomal storage diseases

60.
Farber Disease

61.
Mucopolysaccharidoses (MPS)
 MPS I (Hurler, Hurler-Scheie, Scheie)
 MPS II (Hunter)
 MPS III (Sanfillippo)
 MPS IV (Morquio)
 MPS VII (Sly)
 MPS IX (Natowicz)

62.
68
Hurler’s
In hurler :
Nasal bridge is depressed , increase distance of philthrum , epicanthal
folds, bossing of the head , thick eyebrows , upturn nostrils

63.
Sphingolipidoses
 Gaucher disease
 Niemann-Pick disease
 Tay-Sachs
 Fabry disease
 Farber disease

64.
Mucolipidosis
 Mucolipidoses type I (Sialidosis)
 Mucolipidoses type II (I-cell)
 Mucolipidoses type III (pseudo-Hurler)
 Mucolipidoses type V (Sialolipidosis)

65.
Thankyou