Inborn error of metabloism

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

2. Inborn errors of metabolism
Definition:- These are a group of rare genetic
disorders in which the body cannot metabolize
food components normally.
 These disorders are usually caused by defects
in the enzymes involved in the biochemical
pathways that break down very essential
biochemical components.

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

4. What is a metabolic disease?
According to Garrod’s hypothesis A genetically
determined biochemical disorder in which a specific
enzyme defect produces a metabolic block that may have
pathologic consequences at birth (e.g. phenylketonuria)
or in later life (e.g. diabetes mellitus); also called
enzymopathy and genetotrophic disease.

5. Classification

6. Mitochondrial inheritance :-
 Leber’s hereditary optic neuropathy is caused by
complex-I defect in ETC, leads to blindness, cardiac
conduction defects.
 Leigh’s syndrome :- Complex I defect, leads
movement disorders.
 Mitochondrial myopathies :- Defects in
mitochondrial genome will lead to mitochondrial
myopathies such as myoclonic epilepsy and myopathy
dementia.
 Complex-I defect also causes lactic acidosis, strokes
and seizures.

12. Inborn errors of Carbohydrate
Metabolism

13. Categories
1) Hemolytic anemia’s caused by deficiencies of-
A. Hexokinase
B. Pyruvate kinase
C. Glucose-6-(P)-dehydrogenase
2) Pyruvate dehydrogenase deficiency.
3) Carbohydrate intolerance disorders-
A. Lactose intolerance.
B. Fructose intolerance.
4) Fructosuria.
5) Galactosemia.
6) Pentosuria.
7) Glycogen storage disorders.
8) Mucopolysaccharidoses.

14. 1) Hemolytic anemia caused by
different enzyme deficiencies:

15. A. Hexokinase deficiency:
 This is very rare among all the hemolytic disorders.
 Glycolysis in the RBC is linked with 2,3-BPG
production, essential for the oxygen transport.
 In the deficiency of the hexokinase, the synthesis and
concentration of 2,3-BPG are low in RBC, so the oxygen
unload to the tissues decreased, condition leads to
Hemolysis.

16. B. Pyruvate kinase deficiency:
 It is an autosomal recessive disorder and most
common red cell enzymopathy after G-6-PD
deficiency.
 PK catalyses the conversion of phosphoenolpyruvate
to pyruvate with the generation of ATP.
 Inadequate ATP generation leads to premature red
blood cell death (Prickle cells).
 On the other hand in the patients with pyruvate kinase
deficiency the level of 2,3-BPG in RBC is high,
resulting in low oxygen affinity of Hb observed.

17. Blood film: PK deficiency: Characteristic "prickle cells"
can be seen.

18. C. Glucose-6-phosphate dehydrogenase deficiency :
 G-6-PD deficiency is a X-linked recessive disorder.
 Frequency is 1 in 5,000 births.
 The deficiency occur in all the cells of affected
individuals.
 But it is more severe in RBCs.
 RBCs depend only on HMP shunt for their NADPH
requirement.
 G-6PD deficiency leads impaired NADPH production, so
oxidized glutathione is not converted to its reduced form.

19.  Low NADPH concentration also results the
accumulation of methemoglobin and peroxides in
RBC, causes loss of RBC membrane integrity.
 Till now it is mostly asymptomatic.

20.  But when the enzyme deficient subjects exposed to
severe infection, administered oxidant drugs such as
– Anti-malarial (Primaquine)
– Anti-biotic (Sulfamethoxazole)
– Acetanilide (Antipyretic)
 Favism :- Ingestion of FAVA beans.
 Leads to  Hemolytic anemia.

21. 2) Pyruvate dehydrogenase deficiency:-
 Frequency is 1 in 2,50,000 births.
 Main symptom is lactic acidosis.
 Neuronal loss in brain.
 Muscular hypotonia.

22. 3) Carbohydrate intolerance disorders

23. A. Hereditary Lactose intolerance :-
 It is a rare disorder, due to the deficiency of Lactase
(β-Galactosidase) enzyme.
 Symptoms - Diarrhea, inadequate nutrition and fluid
& electrolyte disturbances.
 Prominent feature is Lactosuria (Lactose in urine).
 Milk is not digested in the individuals so milk
products are preferred.

24. B. Hereditary Fructose intolerance :-
 It is an autosomal recessive disorder.
 Incidence is 1 in 20,000.
 1 in 70 persons are carriers of abnormal gene.
 The defect is Adolase-B (fructose-1-(P) aldolase)
 Fructose -1(P) cannot be metabolized.
 Fructose-1(P) Glyceraldehyde + DHAP.
×

25.  It leads to accumulation of fructose-1-(P),
severe hypoglycemia, vomiting, hepatic failure and jaundice.
 Fructose-1-(P) allosterically inhibits liver phosphorylase
and blocks glycogenolysis leading to hypoglycemia.
 Treatment :- Early detection and intake of diet free from
fructose and sucrose, are advised to overcome fructose
intolerance.

26. 4) Essential fructosuria :-
 Due to the deficiency of fructokinase, fructose is not
converted to fructose-1-(P).
 Fructose Fructose-1-(P).
 This is an asymptomatic condition with excretion of
fructose in urine.
×

27. 5) Galactosemia:-
 It is a serious serious autosomal recessive disorder
resulting from the deficiency of galactose-1-(P)
uridyltransferase, leads to accumulation of Galactose-
1-(P) in the liver and becomes toxic.
 Incidence is one in 35,000 births.
 Galactose -1-(P) UDP Galactose.
×

28. Symptoms:
 The build up of galactose and the other chemicals can
cause serious health problems like
Swollen and inflamed liver,
Kidney failure,
Stunted physical and mental growth, and
Cataracts in the eyes.
 If the condition is not treated there is a 70% chance
that the child could die.
 Treatment :- Galactose free diet is preferred i.e. milk
will be avoided.

30. 6) Essential pentosuria :
 It is a rare autosomal recessive disorder and benign
condition, asymptomatic.
 Individuals does not show any ill-effects.
 Incidence is one in 2,500 births.
 Primarily in Jewish population.

31.  Lack Xylitol dehydrogenase leads to excretion of larger
amounts of L-Xylulose in urine.
 L-Xylulose Xylitol
 It is also reported after administration of drugs such as,
Aminopyrine.
Antipyrine.
×

32. 7) Glycogen storage diseases :
 The metabolic defects concerned with the glycogen
synthesis and degradation are collectively called as
GSD.
 All Glycogen storage disorders are Autosomal recessive
disorders (except Type-VIII)
 Incidence estimated to be between 1 in 1 lack to 1
million births per year in all ethnic groups.

33. Disorder Enzyme Affected Tissue
Type I
(von Gierke’s
disease)
Glucose-6-phosphatase Liver, kidney,
intestine
Type II
(Pompe’s disease)
Lysosomal α 1,4- glucosidase
(Acid maltase)
All organs
Type III
(Cori’s disease)
Amylo α 1,6- glucosidase
(debranching enzyme)
Liver, muscle, heart,
leukocytes
Type IV
(Anderson’s disease)
Glucosyl 4,6-transferase Most tissues
Type V
(Mc Ardle’s disease)
Muscle glycogen
phosphorylase
Skeletal muscle
Type VI
(Her’s disease)
Liver glycogen phosphorylase Liver
Type VII
(Tauri’s disease)
Phosphofructokinase Skeletal muscle,
erythrocytes.

34. Disorder Incidence in births
(1 out of)
Chromosome
location
Type I
(von Gierke’s disease)
1,00,000 17
Type II
(Pompe’s disease)
1,75,000 17
Type III
(Cori’s disease)
1,25,000 1
Type IV
(Anderson’s disease)
1 million 3
Type V
(Mc Ardle’s disease)
1 million 11
Type VI
(Her’s disease)
1 million 14
Type VII
(Tauri’s disease)
1 million 1

35. Disorder Features
Type I
(von Gierke’s disease)
Hypoglycemia, Hepatomegaly,
Cirrhosis, Ketosis, Hyperuricemia.
Type II
(Pompe’s disease)
Generalized glycogen deposit;
lysosomal storage disease.
Type III
(Cori’s disease)
Hepatomegaly, Cirrhosis
Type IV
(Anderson’s disease)
Hepatomegaly, Cirrhosis
Type V
(Mc Ardle’s disease)
Exercise intolerance
Type VI
(Her’s disease)
Hepatomegaly, Hyperuricemia.
Type VII
(Tauri’s disease)

36. GSD Type-VIII :
 It is an X linked recessive disorder.
 Frequency is one in 1,25,000 births.
 Enzyme deficiency is Phosphorylase kinase.

37. Clinical Features
 Hepatomegaly and fibrosis in childhood, these symptoms
improve with age and usually disappear after puberty.
 Fasting hypoglycemia (40-50 mg/dl)
 Hyperlipidemia
 Growth retardation, Growth often normalizes by adulthood
as well.
 Elevated serum transaminase levels (Aspartate
aminotransferase and alanine aminotransferase > 500
units/ml)

38. 8) Mucopolysaccharidoses
Type I – Hurler’s syndrome – L-Iduronidase.
Type II – Hunter’s – Iduronate sulphatase.
Type III – Sanfilippo’s –N-Acetylglucosaminidase,
Heparin sulphatase.
Type IV – Morquio’s – Galactosamine sulphatase.
Type V – Scheie’s – L-Iduronidase.
Type VI – Maroteaux-Lamy’s – N-Acetyl-β-D-
galactosamino-4-sulphatase.
Type VII – Sly’s – β-Glucuronidase.

39.  Symptoms :- All mucopolysaccharidoses show skeletal
deformity, corneal clouding and corneal opacity.
 Mental retardation (except type V &VI).
 Urinary excretion of respective mucopolysaccharides
(C.S, D.S, H.S and K.S) observed.
– C.S = Chondroitin sulphate
– D.S = Dermatan sulphate
– H.S = Heparan sulphate
– K.S = Keartin sulphate.

40. Overview of Carbohydrate metabolism
Enzyme Deficiency Disease
Hexokinase
Pyruvate kinase
Glucose-6-(P) dehydrogenase
Hemolytic Anemia
Pyruvate dehydrogenase Muscular hypotonia,
Lactic acidosis.
Lactase
Aldolase B (fructose-1-(P) aldolase)
Hereditary Lactose intolerance
Hereditary fructose intolerance
Fructokinase Essential Fructosuria
Galactose-1-(P)-Uridyl transferase
Galactokinase
Uridine di-(P)-galactose-4-epimerase
Galactosemia
L-Xylitol dehydrogenase Essential Pentosuria
Glycogen storage disorders
And Mucopolysaccharidoses

41. Wernicke-Korsakoff syndrome :-
 This is a genetic disorder associated with HMP shunt.
 But it is not an inborn error.
 An alteration in transketolase activity that reduces
affinity with TPP(a Biochemical lesion).
 Symptoms are mental disorder, loss of memory and
partial paralysis.
 These symptoms manifested in chronic alcoholics,
whose diets are thiamin-deficient.

42. Thank U