Inborn errors of metabolism Definition:- Inborn errors of metabolism occur from 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 food components.

1. Tapeshwar Yadav
(Lecturer)
BMLT, DNHE,
M.Sc. Medical Biochemistry

2. Inborn errors of metabolism
Definition:- Inborn errors of metabolism occur
from a group of rare genetic disorders in which t
he body cannot metabolize food components nor
mally.
• These disorders are usually caused by defects
in the enzymes involved in the biochemical path
ways that break down food components.

3. Introduction:-
• Protein contains carbon, hydrogen, oxygen and nitrogen
as the major components while sulfur and phosphorus
are minor components.
• Nitrogen is characteristics of proteins. On an average,
the nitrogen content of ordinary proteins is 16% by
weight. All proteins are polymers of amino acids.
Amino acids are linked by protein.
• A moderately active man consuming about 300g
carbohydrates, 100g fats and 100g proteins daily must
excrete about 16.5g of nitrogen daily.
• 95% is eliminated by the kidneys and the remaining 5%
for the most part as nitrogen in the feces.

4. Normal values of urea:-
• The normal concentration in blood plasma is 20-
40mg.
• Indians take less proteins, hence normal level in
Indians varies from 15-40 mg/dl.

5. Inborn errors of urea cycle :- These are divided in to
five type.
1.Hyperammonemia type-I
2.Hyperammonemia type-II
3.Citrullinemia.
4.Argininosuccinic aciduria.
5.Hyper argininemia.

6. Hyperammonemia type-I :-
• A familiar disorder, enzyme deficiency
carbamoyl phosphate synthase 1, produces
Hyperammonemia and symptoms of ammonia
toxicity.
• CO2+ NH3 Carbamoyl-(P)

7. Hyperammonemia type-II :-
• X-linked inheritance.
• Enzyme deficiency ornithine
transcarbamoylase, produces Hyperammonemia
and symptoms of ammonia toxicity.
• Ornithine Citrulline

8. Citrullinemia :-
• It is an autosomal recessive disorder.
• Enzyme deficiency is Argininosuccinate
synthatase.
• Citrulline+Aspartate Arginosuccinate
• Clinically :- Presents with, produces
Hyperammonemia and symptoms of ammonia
toxicity, and mental retardation.
• Urine:- large quantities of citrulline are
excreted in urine (1-2g/dl).
• Feeding arginine in the patients enhance
citrulline excretion.

9. Argininosuccinic aciduria :-
• Autosomal recessive disorder.
• Enzyme deficiency Argininosuccinase.
• Argininosuccinate Arginine + Fumarate.
• Clinically :- Hyperammonemia, ammonia toxicity and
mental retardation.
• The enzyme deficiency has been identified in brain,
liver, kidney and RBC.

10. Hyper Argininemia :-
• Enzyme deficiency is Arginase.
• Arginine Ornithine + Urea
• Defect in liver and RBC.
• Clinically:- Hyperammonemia.
• Urine :- increased urinary excretion of lysine,
cystine, ornithine and Arginine.
• Low protein diet result in lowering of plasma
ammonia levels and disappearance of urinary
lysinecystinuria pattern.

11. Disorders of Aromatic amino acids { Phe, Tyr &
Trp } :-
1.Phenylketonuria.
2.Alkaptonuria.
3.Tyrosinemia.
4.Albinism.
5.Hartnup’s disease.

12. Phenylketonuria :-
• Deficiency of the enzyme phenylalanine
hydroxylase.
• In some patients dihydrobiopterin reductase
deficiency, neurological symptoms appear.
• Frequency is 1 in10,000 births.
• Introduction of better diagnostic facilities
showed that the incidence is as high as 1 in
1,500 births (WHO-2003).

13. Biochemical abnormalities :-
• Phenyl alanine could not be converted to tyrosine.
• So phenylalanine accumulates in blood.
• So alternate minor pathways are opened, phenyl
ketone, phenyl lactate, phenyl acetate are excreted in
urine.
• Clinical conditions :-
• Mental retardation
• Failure to walk/talk.
• Failure of growth.

14. • This maybe because phenyalanine interferes
with neurotransmitter synthesis.
• The child often has hypopigmentation
explained by the inhibition of tyrosinase.
• Phenyllactic acid in sweet may lead to moucy
body odur.

15. Laboratory diagnosis :-
• Blood phenyl alanine normal level is 1mg/dl.
• In PKU the level is >20mg/dl.
• This is identified by chromatography.
Ferric chloride test :-
• Urine of the patient contains phenyl ketones,
about 500-3000mg/dl.

16. ALKAPTONURIA :- Alkaptonuria is an
autosomal recessive condition with an
incidece of 1 in 2,50,000 births.
• The metabolic defect is the deficiency of
homogentisate oxidase. This results in
excretion of homogentisic acid in urine.
• Homogentisic acid 4-maleyl aceto
acetate
• The only abnormality is the blackening of
urine on standing.
• The homogensic acid is oxidised by
polypheyl oxidase to bezoquinine acetate.
×

17. Homogentisic acid Benzoquinone acetate
• It is then polymerized to black colored alkapton
bodies.
• Black pigments are depositd over the connective
tissue including joint cavities to produce arthrities.
• No specific treatment is required.
• But low protein with phenylalanine less than
500mg/day.

18. Diagnosis of alkaptonuria :-
• Ferric choloride test :- It is positive for urine
• Benedict’s test :- It is strongly positve.
• Therefore alkaptonuria comes under the differential
diagnosis of reducing substance in urine.

19. Albinism :-
• It is an autosomal recessive disease with an incidence
of 1 in 20,000 births.
• Defect is tyrosinase enzyme leads complete absence
of melanin synthesis.
• The ocular fundus is hypopigmented and iris may be
grey or red. They will be associated photophobia and
decreased visual acuity.
• The skin has low pigmentation and so skin is
sensitive to UV rays.
• The hair is also white.
• Tyrosine DOPA
×

20. Hypertyrosinemias :-
• It is due to deficiency of phenylacetoacetate
hydrolase.
• Symptoms :- the first six months of life and death
occurs rapidly.
• Cabbage like odor and hypoglycemia are seen.
• Urine contains tyrosine, p-hydroxy phenyl pyruvic
acid and phenyl latic acid; and serum shows tyrosine
and methionine.

21. Hypertyrosinemia-2 :-
• It is due to deficiency of tyrosine amino transferase.
• Symptoms :- Mental retardation, keratosis of palmar
surface and photophobia are seen.
• There is increased excretion of tyrosine, tyramine in
urine.

22. • Hartnup’s disease :- It is a hereditary disorder of
tryptophan metabolism the clinical symptoms include
dermatitis and ataxia.
• The pellagra like symptoms are due to the deficiency of
niacin derived from tryptophan.
• The diagnosis is based on aminoaciduria and increased
excretion of indole compounds detected by the
Obermeyer test.
• Hartnup’s is characterized by low plasma level of
tryptophan and other neutral amino acids and their
elevated urinary excretion.

23. Glycine
• Glycine is a non-essential optically inactive and
glycogenic amino acids.
• Glycine is actively involved in the synthesis of many
specialized products in the body(Heme, purins,
creatinine).

24. Metabolic disorders of Glycine :-
• Glycinuria :- This is rare disorder, due to defect in the
glycine cleavage system.
• Glycine level is increased in blood and CSF.
• Very high amount of it is excreted in urine.
• Glycinuria characterized by increased tendency for the
formation of oxalate stones.

25. • Primary hyperoxaluria :- Increased excretion of
oxalates observed upto 600mg/day compared to a
normal of 50mg/day.
• Primary hyperoxaluria is due to defect in glycine
transaminase coupled with impairment in glyoxalate
oxidation to formate.
• Glycine Glyoxalate
×

26. • In vit-B6 deficiency, urinary oxalate is elevated it can
be corrected by B6 supplementation.
• However B6 administration has no effect on
endogenous hyperoxaluria.

27. Sulphur containing Amino acids
• Sulfur containing amino acids :- Methionine, Cystein
and Cystine.
• The other sources of sulfur in the body are sulfur
containing vitamins are the thiamin, biotin and lipoic
acid.
• Disorders :- Cystinuria, Cystanosis,
Homocysteinurias(I, II, III), Hyper methioninemias.

28. • Cystinuria :- It is one of the most inhereted disease with
a frequency of 1 in 7,000 births.
• It is primarily characterized by increased excretion of
cystine in urine.
• Defect :- it is considered to be due to a renal transport
defect in that re-absorption of the four amino acids,
lysine, arginine, and ornithine and diabasic amino acids
donot occur.
• A single re-absorptive site is involved.
• Complications :- Cystine is relatively insoluble amino
acids which may precipitate in renal tubules uterus and
bladder to form “cystine calculi”.

29. • Cystine stones account for 1-2 % of all urinary tract
calculi.
• It forms a major complication of the disease.
• Cyanide nitroprusside test :- It is a screening test
urine is made alkaline with ammonium hydroxide and
sodium cyanide is added cystine if present reduced to
cysteine. Then added sodium nitroprusside to get a
megenta red colored complex.
• Specific amino aciduria may be conformed by
chromatography.

30. Cystinosis:-
• Defect in the enzyme cystine reductase.
• It is a familial disorder characterised by the wide
spread deposition of cystine crystals in the lysomes.
• Cystine accumulates in liver,spleen,bone marrow,
WBCs, kidneys and lymphnodes.
• Microscopy of blood shows cystine crystals in
WBC’s.
• Treatment policies are to give adquate fluid intake so
as to increased urine output,alkalinasation of urine by
sodium-bi-carbonate as well as administration of D-
penicillamine.
Cystinosis:-
• Defect in the enzyme cystine reductase.
• It is a familial disorder characterised by the wide
spread deposition of cystine crystals in the lysomes.
• Cystine accumulates in liver,spleen,bone marrow,
WBCs, kidneys and lymphnodes.
• Microscopy of blood shows cystine crystals in
WBC’s.
• Treatment policies are to give adquate fluid intake so
as to increased urine output,alkalinasation of urine by
sodium-bi-carbonate as well as administration of D-
penicillamine.

31. Hypermethioninemias :
CAUSES
• Impaired utilization
• Excessive remethylation of homocysteine
• Oasthous syndrome is due to malabsorption of
methionine, in such children excrete methionin,
aromatic aminoacids and branched amino acids in
urine.

32. Homocystinuria Type-I
• These are a group of metabolic disorders due
to a defect in the enzyme cystathionine
synthase.
• Accumulation of homocystine results in the
various complications like thrombosis, mental
retardation etc.
• The deficiency of cystathionine is associated
with damage to endothelial cells.

33. TYPE-II
• N5
N10
METHYLENE THF reductase
TYPE-III
• N5
N10
METHYL THF HOMOCYSTEINE METHYL
transferase.
• This is mostly due to impairment in the synthesis of
methylcobalamin.
TYPE-IV
• N5
METHYL THF HOMOCYSTEINE METHYL
transferase, due to defect in intestinal absorption of
vit-B12.

34. Branched chain Amino acids
• VALINE
• LEUCINE
• ISOLEUCINE

35. MAPLE SYRUP URINE DISEASE:
• The urine of effected individuals smells like maple
syrup or burnt sugar.
• Enzyme defect is α-keto acid dehydrogenase, which
causes a blockade in conversion of α-keto acid to the
respective acyl CoA thioesters.
• Elevated levels of branched aa & their ketoacids in
plasma & urine, so known as branched chain
ketonuria

36. Biochemical complications & symptoms
• Impairment in transport of other aa
• Protein biosynthesis is reduced
• The disease results in acidosis, mental retardation,
coma & finally leads to death within one year of
birth.

37. Isovaleric Acidemia
• Specific inborn error of LEUCINE
metabolism.
• Due to defect in enzyme isovaleryl CoA
dehydrogenase.
Isovaleryl CoA  methylcrotonyl is impaired.
• Symptoms- acidosis & mild mental
retardation.

38. • Hypervalinemia
• Increased plasma concentration of valine
while leucine and isoleucine remain normal.
• The transamination of valine alone is
selectively impaired

39. Histidine
• Histidinemia :- defect in enzyme histidase
• Increased excretion of imidazole pyruvate &
histidine in urine.
• Symptoms – Defect in speech & mental
retardation.

40. Proline
• Hyperprolinemia type I:
• Defect in enzyme proline oxidase
Arginine :
• Hyperargininemia is due to defect in enzyme
arginase

41. Thank you