An inherited enzyme deficiency leading to the disruption of normal bodily metabolism. Accumulation of a toxic substrate. Impaired formation of a product normally produced by the deficient enzyme.

1. Tapeshwar Yadav
(Lecturer)
BMLT, DNHE,
M.Sc. Medical Biochemistry
INBORN ERRORS OF
METABOLISM

2. Garrod coined the term `INBORN
ERRORS OF METABOLISM`

3. An inherited enzyme deficiency leading to the
disruption of normal bodily metabolism.
Accumulation of a toxic substrate.
Impaired formation of a product normally
produced by the deficient enzyme.
Garrod`s hypothesis :-
A B C
D
substrate excess product deficiency
toxic metabolite

4. Small molecule
disease
Carbohydrate
Protein
Lipid
Nucleic Acids
 Organelle
disease
Lysosomes
Mitochondria
Peroxisomes
Cytoplasm

5. Prenatal Diagnosis
Newborn Screening
Later life diagnosis

6. Prenatal Diagnosis

7. Index of suspicion
Family History
Have a child already affected by an inherited
disorder.
One of the parents affected by autosomal or X-
linked disorder.
 H/O Neonatal deaths, fetal losses
Maternal family history
males - X-linked disorders
all - mitochondrial DNA is maternally
inherited
A positive family history may be helpful!

8. Enzymatic assay of cultured amniocytes
Chorionic villi sampling to determine the
chromosomal,enzymatic or molecular genetic
status of the fetus.
Cytogenetics
Enzyme assay.

9. Newborn Screening

10. Reliable screen test and low false negative
results.
Test is simple and inexpensive
Available results soon to start effective
therapy
Definite follow up test
Outcome without treatment is very bad
Effective therapy is available

11.  Index of suspicion
“with any full-term infant who has no antecedent
maternal fever or PROM (premature rupture of
the membranes) and who is sick enough to
warrant a blood culture or LP, one should proceed
with a family history & few simple lab tests.

12. Family History
Most IEM’s are recessive - a negative family
history is not reassuring!
Consanguinity, ethnicity, inbreeding
neonatal deaths, fetal losses
maternal family history
males - X-linked disorders
all - mitochondrial DNA is maternally inherited
A positive family history may be helpful!

13. Simple laboratory tests
Glucose, Electrolytes, Gases, Ketones, BUN
Creatinine
Lactate, Ammonia, Bilirubin, LFT
Amino acids, Organic acids, Reducing subst.

14. Specialized biochemical testing
Amino acid analysis
Maple syrup urine disease with increase
leucine, valine and isoleucine
Hyperglycinemia: increase glycine
Organic acid : propionic acidemia
Carnitine level
Chromatography of glycolipid
Increased level of long chain fatty acid with
perioxisomal disorder

15. Carbohydrate metabolism

16. GalactosemiaGalactosemia
Enzyme deficiency:-
Galactose-1-p uridyl transferase
Galactokinase
Uridine diphosphate galactose 4 epimerase
Screening :-
Failure to thrive
Hypoglycemia
Urine demonstrates the presence of
reducing substance that does not react to glucose
oxidase.
Galactose can be identified by
chromatography.
Galactose & galactose-1-p in blood
Confirmed :-
Assaying red blood cell transferase activity.

18. Fructosuriaa
Enzyme deficiency:-
• Essential Fructosuria - Fructokinase
• Inherited Fructose Intolerance - Fructose-1-P aldolase
• Hereditary fructose-1,6-diphosphatase deficiency
Screening :-
• Fructosuria after eating fructose containing food
• Hypoglycemia
Confirmed :-
• Enzyme defect in liver biopsy.

19. Hemolytic diseases
Enzyme deficiency:-
Pyruvate kinase
Glucose-6-phosphate dehydrogenase
Screening :-
Lactic acidosis on glucose load
Hemolytic anemia
Confirmed :-
Specific enzyme activity.

20. Glycogen Storage DisordersGlycogen Storage Disorders
Type 1-Von Gierke’s
Enzyme deficiency:-
Glucose-6-phosphatase
Screening :-
Life threatening
Hypoglycemia
Lactic acidosis
Hyper-uricemia
Hyper lipidemia
Adverse response to Glucagon with worsening Lactic acidosis.
Confirmed :-
Glucose-6-phosphatase enzyme activity
assay in liver biopsy.

21. Enzyme deficiency:-
Type 2- Pompe’s disease- Acid α-glucosidase
Type 3- Deficency of Glycogen debranching enzyme
Type 4- Deficiency of Branching enzyme
Type 5- McArdle`s Syndrome- Muscle phosphorylase
Type 6- Liver phosphorylase or phosphorylase kinase
Screening :-
Almost same as type I
Confirmed :-
Respective enzyme activity assay in liver & muscle biopsy.

22. Mucopolysacccharidosis
Mutation in a gene encoding a lysosomal hydrolase
involved in the degradation of 1 or more GAGs
Defective lysosomal hydrolase
Accumulation of substates in various tissues including
Liver,spleen,skin,bone & CNS
Hurler syndrome – α l-iduronidase
Hunter syndrome - iduronate sulfatase
• Urinalysis for presence of ↑ GAGs
• Assay of suspected enzymes in WBC,fibroblast or serum
• Tissue biopsy with subsequent analysis of GAG by electrophoresis
• Use of specific gene test
• Prenatal diagnosis by amniotic fluid cells or chorionic villus sampling.

23. Amino acid metabolism

24. Aromatic Amino acid metabolism
Phenylketonuria
Enzyme deficiency:-
Phenylalanine hydroxylase
Dihydrobiopterine reductase
6-Pyruvoyl-tetrahydropterin synthase
GTP cyclohydrolase I
Pterin-4-carbinolamine dehydratase
Screening :- FeCl₃ to detect urinary phenyl pyruvate
Tandem mass spectrometry.
Prenatal Diagnosis :-
DNA probe
Confirmed :-
Elevated blood phenylalanine level.
Enzyme activity

26. Tyrosinemia
Enzyme deficiency:-
Type I- Fumarylacetoacetase
Type II-Tyrosine aminotransferase
Type III-4-hydroxyphenylpyruvate dioxygenase
Screening :-
FeCl₃
Tandem mass spectrometry.
Prenatal Diagnosis :-
RFLP
Confirmed :-
Elevated conc of tyrosine in plasma
Succinyllactone in urine,by product of fumaryl acetoacetic
acid in urine.

27. Maple syrup urine disease
Enzyme deficiency:-
Branched chain ketoacid dehydrogenase complex
Screening :-
Acidosis
Ketotic hypoglycemia
Pancreatitis
Odor of maple syrup
Mixing urine with DNPH
Prenatal Diagnosis :-
DNA analysis
Confirmed :-
Elevated plasma level of Branched chain amino-acids.
2hydroxy valeric acid in urine.

28. Enzyme deficiency:-
 Hypermethioninemia- Methionine adenosyl transferase
 Homocystenuria - Cysthionine β-synthase
 Cystathionuria - Cystathionase
Prenatal Diagnosis :-
DNA analysis
Confirmed :-
Elevated levels of the regarding substrates in
plasma.

29. Urea cycle disorders
 N-acetylglutamate synthase – Glutamine,Alanine & Citruline
 CPS - Glutamine,Alanine & Citruline ,Arginine
 OTC –Orotic acid(U) Glutamine,Alanine & Citruline ,Arginine
 Arginisuccinate synthase - Citrulline,Orotic acid(U)
 Arginisuccinate lyase- Arginisuccinic acid (B & U)
 HHH syndrome – Mytochondrial ornithin transporter.
Screening :-
Hyperamonimia
Prenatal Diagnosis :-
DNA analysis

30. Disorders of heme metabolism
Mutation in various genes
Abnormalities of the enzymes of the heme synthesis
Accumulation of ALA
& PBG
↓in heme in cell & body fluid
Nuropsychiatric
signs & symtoms
Accumulation of porphyrinogen
In skin & tissues
Sponteneous oxidation of
Porphyrinogen to porphyrin
photosensitivity
Prenatal diagnosis - Appropriate DNA probe
Diagnosis by ↑ corproporphyrin,uroporphyrin,ALA,PBG,protoporphyrin

31. Metabolism of Fatty acid

32. Impaired oxidation of Fatty acid
1) Transporter deficiency:-
CPT-I & CPT-II deficiency
Prenatal Diagnosis :-
Enzyme assay in aminocentesis
DNA analysis
Confirmed :-
Elevated levels of free carnitine & acyl
carnitine in plasma.
2) Dicarboxylic aciduria- medium chain acyl coa
dehydrogenase deficiency
3) Refsum disease- Accumulation of phytanic acid
4) Zellweger`s syndrome- Absence of peroxisomes

33. Lipid storage disease
Tay-Sachs disease – Hexosaminidase
Fabry`s disease – α-galactosidase
Metachromatic leucodystrophy- Arylsulfatase A
Krabbe`s disease- β- galactosidase
Goucher disease- β- glucosidase
Niemann-Pick disease- Sphingomyelinase
Farbe`s disease - Ceramidase
Diagnosis:-
Analysis of tissue sample
peripheral leucocyte
plasma
amniotic fluid
Culture fibroblast
for presence of enzymatic activity or accumulated lipid
Prenatal diagnosis – DNA probe

34. Disorder of nucleic acid metabolism
 Purine metabolism:-
Gout – Genetic defect in PRPP synthetase
Lesch-nyhan syndrome- hypoxanthine-guanine
phosphorybosyl transferase
Hypouricemia – Xanthine oxidase deficiency
ADA & purine nucleoside phosphorylase deficiency-
defective T & B cell function
 Pyrimidine metabolism:-
Hydroxy butyric aciduria- dihydropyrimidine
dehydrogenase
Orotic aciduria – Orotate phosphorybosyl transferase
& orotidyl decarboxylase
 Diagnosis :- Assay of respective enzyme activity

35. Thank you !