Metabolic disorders are caused by defects in enzymes involved in metabolic processes. There are several categories of inborn errors of metabolism including disorders of amino acid, carbohydrate, lipid, protein, and organic acid metabolism. Symptoms vary depending on the specific enzyme deficiency but can include developmental delay, organomegaly, neurological symptoms, and in some cases death in infancy if left untreated. Many metabolic disorders are inherited in an autosomal recessive pattern and while individually rare, as a group they have a prevalence of around 1 in 5,000 live births.

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

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

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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)

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

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

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Genetic Basis
of
Inherited Disorders
Point mutations,
Insertions, Deletions,
Missense Mutations
and Rearrangements

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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

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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

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

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

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

16. Vitamin disorders
 Biotinidase deficiency

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

18. Wilson Disease (KF rings)

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

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

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

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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

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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.

26. 26
Phenylketonuria PKU

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

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Defect here causes
Type I Tyrosinemia
Defect here causes
alkaptonuria
Catabolic pathway for phenylalanine and
tyrosine
Homogentisate
dioxygenase
Fumarylacetoacetate
hydrolase

29. Tyrosinemia

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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

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Normal urine
Urine from patients
with alkaptonuria
Symptoms of alkaptonuria

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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.

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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

34. MSUD patient after liver transplant

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Homocystinuria
Defective activity of cystathionine synthase

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Major phenotypic expression
Ectopia lentis
Vascular occlusive disease
Malar flash
Osteoporosis
Accumulation of homocysteine and methionine

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A family of homocystinuria

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Albinism

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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

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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

43. Cystinosis

44. Cystiene deposits in cornea

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

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

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

48. © 2007 Thomson - Wadsworth

49. 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

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

51. Hypercholestrolemia

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

53. 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

57. 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

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

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

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

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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:

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

64. 64Zellweger

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

66. Farber Disease

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

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

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

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

71. Thankyou