Inborn errors of protein metabolism occur from genetic disorders that cause defects in enzymes involved in biochemical pathways that break down food components normally. Some key points: 1. Genetic disorders are categorized as chromosomal, monogenic, or complex/multifactorial disorders. Inborn errors of metabolism fall under monogenic disorders caused by single gene defects. 2. Examples of inborn errors include disorders of the urea cycle like ornithine transcarbamylase deficiency and disorders of amino acid metabolism like phenylketonuria, alkaptonuria, and maple syrup urine disease. 3. Symptoms of newborns with urea cycle defects include lethargy, coma, seizures,

1. Inborn errors of protein
metabolism
Presenting by
T.hemanth

2. Genetic disorder fall into mainly three categories
1. Chromosomal disorders e.g. down syndrome and Klinefelter`s syndrome.
2. Monogenic disorders, “ inborn errors of metabolism (IEM) comes under this
group .
3. Complex disorders (multifactorial disorders): here, genetic factors and others
factors are involved in the pathogenesis.
4. Charaka the father of Indian medicine wrote that “diseases are three types;
inborn, exogenous and psychological.( charaka Samhita).
Background

3. • Sir Archibald Garrod (1857- 1936) coined the term of “inborn errors of metabolism”
in 1909. Garrod’s tetrad are alkaptonuria, albinism, pentosuria and cystinuria.
• Some inborn errors are completely, or almost completely harmless. They are
important because they produce effects that may lead misdiagnosis or alarm the
patient. example are glycosuria, alkaptonuria, and gilbert’s disease.

4. 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.

5. INTRODUCTION:-
• Moderately an active man consuming about 300g of carbohydrates, 100g fats
and 100g proteins.
• Protein contains carbon, hydrogen, oxygen and nitrogen as the major compo
nents while sulfur and phosphorus are minor components.
• Nitrogen is characteristics of proteins. On an average, the nitrogen content of
ordinary proteins is 16% of weight. All proteins are polymers of amino acids.
• 95% of nitrogen is eliminated by the kidneys and the remaining 5% excrete
through the feces.

6. INBORN ERRORS OF UREA CYCLE
Normal values of urea:-
• The normal level in blood plasma is 20- 40mg/dl .
• Indians take less proteins, hence normal level in Indians varies from 15-40 mg/dl.
• Deficiency of any of the urea cycle enzymes would result in hyperammonemia.
• Deficiencies of later enzymes results accumulation of other intermediates which
are less toxic. Disorders of urea cycle characterized by encephalopathy and respir
atory alkalosis.

7. SYMPTOMS OF NEWBORNS WITH UREA CYCLE DEFECTS
• Normal appearance at birth
• Somnolence progressing to lethargy then coma
• Loss of thermoregulation (hypothermia)
• Feeding disruption (increases catabolism)
• Neurologic posturing (from cerebral edema)
• Seizures
• Hyperventilation and then hypoventilation

8. BASED ON THE ENZYME DEFICIENCY DIVIDED INTO FIVE TYPES
1. Hyperammonemia type-I
2. Hyperammonemia type-II
3. Citrullinemia.
4. Argininosuccinic aciduria.
5. Hyper argininemia.

9. HYPERAMMONEMIA TYPE-I
• A familiar disorder, enzyme deficiency carbamoyl phosphate synthase 1,
produces Hyperammonemia and symptoms of ammonia toxicity.
• CO2 + NH3 +2 ATP Carbamoyl phosphate.
• A variant of the condition is seen in N- acetylglutamate synthetase.

10. HYPERAMMONEMIA TYPE-II
• X-linked inheritance.
• Ornithine Citrulline
• Enzyme deficiency ornithine transcarbamoylase,
• Increased ammonia in blood
• Increased glutamine in blood, CSF, and urine.
• Orotic aciduria due to channelling of carbamoyl phosphate into
pyrimidine synthesis.

11. CITRULLINEMIA
• It is an autosomal recessive disorder.
• Enzyme deficiency is Argininosuccinate synthatase.
• Citrulline + Aspartate Arginosuccinate
• Clinically :- Deficiency is characterized by hyperammonemia, cirullinemia
and cirullinuria (1-2 g/day).
• CSF citrulline levels are also elevated.
• Feeding arginine in the patients enhance citrulline excretion.

12. ARGININOSUCCINIC ACIDURIA
• Autosomal recessive disorder.
• Enzyme deficiency Argininosuccinate lyase
• Argininosuccinate Arginine + Fumarate
• Clinically :- enzyme deficiency leads to Argininosuccinic aciduria and
therefore metabolic acidosis.
• The enzyme deficiency has been identified in brain, liver, kidney and
RBC

13. HYPER ARGININEMIA
• Enzyme deficiency is Arginase.
• Arginine Ornithine + Urea
• Clinically:- Hyperammonemia, developmental delay and progressive spa
sticity
• Urine :- increased urinary excretion of lysine, cystine, ornithine and Argini
ne.
• Low protein diet result in lowering of plasma ammonia levels and disappe
arance of urinary lysinecystinuria pattern.

14. DISORDERS OF AROMATIC AMINO ACIDS { PHE, TYR & TRP }
1. Phenylketonuria
2. Alkaptonuria
3. Tyrosinemia
4. Albinism
5. Hartnup’s disease

15. PHENYLKETONURIA
• Autosomal recessive metabolic genetic disorder
• Mutation in the gene for phenylalanine hydroxylases (PAH)
• Gene located on 12th chromosome.
• A carrier does not have symptoms of the disease, but can pass on the
defective gene to his or her children.
• Deficiency of the enzyme phenylalanine hydroxylase.

17. 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, p
henyl acetate are excreted in urine.
• Type 1 due to phenylalanine hydroxylase deficiency
• Type II and III due to dihydrobiopterin reductase.
• Type IV and V due to enzyme synthesizing biopterin

18. CLINICAL CONDITIONS :
• Mental retardation
• Failure to walk/talk.
• Failure of growth.
• This maybe because phenylalanine interferes with neurotransmitter
synthesis.
• The child often has hypopigmentation explained by the inhibition of
tyrosinase.
• Phenyllactic acid in sweet may lead to mousy body odor.

19. SCREENING
• Every state now screens the blood phenylalanine level of all newborns
at about 3 days of age.
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.

20. ALKAPTONURIA
• Alkaptonuria is an autosomal recessive condition with an incidece of 1 in 2,
50,000 births.
• Black urine disease or black bone disease is an inborn error of amino acid
metabolism.

21. CAUSE
• Mutation or defect in HGD gene which caus
es lack of the enzyme homogentisate dioxy
genase (HGD).
• This causes a build up of homogentisic acid
(HGA) in the bones, cartilage and urine.
• HGA is an intermediate in the degradation p
athway of the amino acids (Phe & Tyr ) to th
e Krebs cycle.

22. SYMPTOMS
• Urine becomes black when exposed to air.
• Osteoarthritis (mainly spine, hips, shoulders and knees).
• Black spots in the sclera of the eye (Ochronosis).
• Discolored ear and dark earwax.
• Heart valves are affected by the accumulation of HGA.
• Blue-black speckled discoloration of the skin.
• Kidney, prostate and bladder stones due to the buildup of HGA in the gen
ito-urinary tract, during urine production.

23. DIAGNOSIS
• Urine test - addition of ferric chloride to the urine will change it’s color
to black. Gas chromatography to look for traces of HGA in urine.
• DNA testing - to check for mutated HGD gene. It is generally done by
analyzing blood sample.
• Prenatal tests (amniocentesis or chorionic villus sampling) can be do
ne to screen a developing baby for this condition if the genetic chang
e has been identified.

24. ALBINISM
• It is an autosomal recessive disease with an incidence of 1 in 20,000 birth.
• 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.

25. • The skin has low pigmentation and so skin is sensitive to UV rays.
• The hair is also white

26. 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.

27. 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.

28. HARTNUP’S DISEASE
• It is a hereditary disorder of tryptophan metabolism the clinical symptom
s 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

29. Obermeyer test
• Hartnup’s is characterized by low plasma level of tryptophan and other
neutral amino acids and their elevated urinary excretion.

30. 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, purines, creatinine).

31. 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.

32. 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 wit
h impairment in Glyoxalate oxidation to formate.
• Glycine Glyoxalate
• In vit-B6 deficiency, urinary oxalate is elevated it can be corrected by B6 s
upplementation.

33. 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.

34. • Cystinuria :-
• It is one of the most inherited disease with a frequency of 1 in 7,000 births.
• Defect :- it is considered to be due to a renal transport defect in that re-abs
orption of the four amino acids, lysine, arginine, and ornithine
• A single re-absorptive site is involved.

35. • Complications :- Cystine is relatively insoluble amino acids which may
precipitate in renal tubules uterus and bladder to form “cystine calculi”.
• Cystine stones account for 1-2 % of all urinary tract calculi.
• It forms a major complication of the disease.

36. • Cyanide nitroprusside test :- It is a screening test urine is made alk
aline 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.

37. CYSTINOSIS
• Defective enzyme is cystine reductase.
• It is familial disorder characterized by the wide spread deposition of
cystine crystals in the lysosomes.
• Cystine accumulates in the liver, spleen, bone marrow and lymph nodes.

38. • Microscopy of blood shows cystine crystals in WBC.
• Treatment policies are to give adequate fluid intake so as to measured
output, alkalization of urine by sodium bicarbonate as well as
administration of D- Penicillamine.

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

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

41. TYPE-II
• N5N10 methylene THF reductase
TYPE-III
• N5N10 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.

42. BRANCHED CHAIN AMINO ACIDS
• VALINE
• LEUCINE
• ISOLEUCINE

43. 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

44. 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.

45. ISOVALERIC ACIDEMIA
• Specific inborn error of leucine metabolism.
• Due to defect in enzyme CoA isovaleryl dehydrogenase
• Isovaleryl CoA methylcrotonyl is impaired.
• Symptoms- acidosis & mild mental retardation.

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

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

48. PROLINE.
• Hyperprolinemia type I
• Defect in enzyme proline oxidase.
ARGININE :
• Hyperargininaemia is due to defect in enzyme arginase

49. TESTS FOR METABOLIC DISORDERS IN NEW-BORN
• These diseases may be demonstrated indirectly by detecting high
concertation of the substrate normally metabolized by the enzyme or
low concentration of the product.
• The ultimate specific diagnosis of inherited metabolic disease generally
requires the demonstration of primary biochemical abnormality, such as
a specific enzyme deficiency or mutation that have been shown to
cause disease

50. • A useful first step in helping to focus the laboratory investigation of possi
ble inherited metabolic diseases is to try to determine whether the disea
se is due to a defect in the metabolism of water soluble intermediates s
uch as amino acids, organic acids or likely due to an inherited defect in l
ysosomal, mitochondrial, or peroxisomal metabolism.

51. PRENATAL DIAGNOSIS
About 2 % life births associate with a genetic defect in addition, genetic disor
ders are also a major cause of pregnancy loss as well as perinatal mortality a
nd morbidity.
1. Genetic counselling: this process involves an attempt by the trained p
ersons to help the individual or family to.
2. Amniocentesis: prenatal diagnosis of IEM can be made by enzymatic a
ssays of cultured aminocytes. E.g. if the couple already had a child affec
ted by inherited disorder, if one of the parents is affected an autosomal or
X- linked.

52. 3. Chorionic villi sampling : the most common indications for CVS or ad
vanced maternal age, or biochemical or genetic disorders indicated by mo
lecular markers.
4. Cordocentesis : fetal blood sampling can be performed at 20 weeks
gestation.
5. Cytogenetics and molecular genetics: cytogenetics analysis may be
done with fluorescence in situ hybridization (fish), for common chromoso
mal aneuploidies involve in chromosomes 13,18,21,X,and Y.

53. PRENATAL SCREENING
• Prenatal screening of high-risk groups can be done to plan place and m
ethod of delivery or even to offer termination of pregnancy.
• Termination is commonly done by demonstrating metabolic defect in cul
tured fetal fibroblasts obtained by amniocentesis.

54. • Maternal serum screening : prenatal screening has become standard
obstetric practice in all pregnancies having a risk factor or abnormal
ultrasonographic (USG) findings.
• Five analytes namely alpha fetoprotein (AFP), human chorionic gona
dotropin (hCG), unconjugated estriol (uE3), inhibin, and pregnancy a
ssociated plasm protein A (PAPPA) are estimated.
• NTD’s, trisomy 21 and trisomy 18 are detected prenatally by these m
easurements.

55. Screening during the first trimester:
• double marker test: consists of PAPPA and hCG. These are measured
in maternal serum between 10 weeks, it is an indicator early pregnancy
failure and complications.
• Persistently lower level of PAPPA in second trimester is indicative of
trisomy 18.

56. THE TRIPLE TEST AND QUADRUPLE TEST
• The test is done at 18 weeks along with a detailed USG for any fetal an
omalies.
• Triple test include AFP, uE3, and hCG. While the quadruple marker
contains inhibin.