This document provides an overview of various inborn errors of amino acid metabolism, including the underlying genetic defects, clinical manifestations, and treatment approaches. It describes conditions such as phenylketonuria (PKU), maple syrup urine disease, homocystinuria, cystinuria, alkaptonuria, tyrosinaemia, albinism, histidinaemia, and Hartnup disease. For each disorder, it discusses the affected enzyme, accumulated metabolites, symptoms, and dietary or supplement-based therapies aimed at preventing associated neurological or physical abnormalities.

1. R. C. Gupta
Professor and Head
Department of Biochemistry
National Institute of Medical Sciences
Jaipur, India
Inborn Errors
of
Amino Acid Metabolism

2. Inborn errors of metabolism occur when
some enzyme involved in metabolism is
abnormal
The abnormality occurs due to a mutation
in gene encoding the enzyme
The affected enzyme may be absent or
deficient

3. Inborn errors may occur in metabolism of
all nutrients including amino acids
When an enzyme is absent or deficient,
metabolism of the concerned amino acid
becomes abnormal

4. Over 50 inborn errors of metabolism of
amino acids have been discovered
The clinical abnormalities may occur
due to:
Decreased synthesis of products
Accumulation of intermediates
Formation of alternate metabolites

5. Many disorders result in neurological
abnormalities and mental retardation
Early diagnosis and treatment can
prevent neurological abnormalities
Generally, the treatment comprises
restricted intake or exclusion of the
affected amino acid from the diet

6. Some relatively common inborn errors are:
• Primary hyperoxaluria
• Maple syrup urine disease (MSUD)
• Cystinuria
• Homocystinuria
• Phenylketonuria (PKU)
• Alkaptonuria
• Tyrosinaemia
• Albinism
• Histidinaemia
• Hartnup disease

7. Primary hyperoxaluria is a disorder of
glyoxylate metabolism
Glyoxylate is formed from hydroxyproline
Normally, glyoxylate is transaminated to
glycine or is oxidised to formate
Primary hyperoxaluria

8. Glyoxylate is converted into oxalate when:
Glycine transaminase is deficient
This leads to hyperoxaluria and recurrent
formation of oxalate stones in urinary tract
Oxidation of glyoxylate is impaired

9. This is a disorder of the branched-chain
amino acids, valine, leucine and isoleucine
Enzymes catalyzing the first two reactions
in the catabolism these are common
Maple syrup urine disease (MSUD)

10. Branched-chain amino acids are first
transaminated to a-keto acids
The a-keto acids undergo oxidative
decarboxylation
Oxidative decarboxylation is catalysed by a-
ketoisovalerate dehydrogenase
This enzyme is absent or deficient in MSUD

12. The enzyme deficiency leads to accumu-
lation and increased urinary excretion of:
Branched chain amino acids
Their a-keto acid derivatives
This imparts a typical odour to urine similar
to that of maple syrup or burnt sugar

13. The clinical signs and symptoms appear
within one week of birth
Lethargy, vomiting and aversion to food
are early signs
These are followed by severe brain
damage and ultimately death

14. The treatment consists of exclusion of
branched-chain amino acids from diet
This is required until the plasma levels fall
to normal
Thereafter, the intake is restricted so as
to maintain the plasma levels

15. A milder variant of maple syrup urine disease
is intermittent branched-chain ketonuria
In this, the decrease in enzyme activity is only
moderate
The signs and symptoms are milder and
appear much later
The excretion of branched-chain a-keto acids
is intermittently increased

16. There is a defect in tubular reabsorption of
cystine
Urinary excretion of cystine is increased
Being sparingly soluble, cystine deposits in
the kidneys and forms cystine stones
The defect also involves reabsorption of
lysine, arginine and ornithine
Cystinuria

17. Cystathionine synthetase is severely
deficient in homocystinuria
This impairs the conversion of methionine
into cysteine
Homocysteine accumulates and is
converted into homocystine
Homocystinuria

18. Homocystine is made up of two homo-
cysteine molecules
Urinary excretion of homocystine is
increased
Plasma methionine and homocysteine
levels are increased

19. The clinical features of homocystinuria are:
Thrombotic phenomena
Osteoporosis
Dislocation of lenses in the eyes
Mental retardation
Ischaemic vascular disease

20. Accumulation of homocysteine causes:
Abnormal cross-linking of collagen
Abnormalities in the ground
substance of walls of blood vessels
Increased platelet adhesiveness

21. Dislocation of ocular lenses and osteo-
porosis occur due to abnormal collagen
Thrombotic phenomena occur because
of abnormalities in the walls of blood
vessels

22. Increased platelet adhesiveness and
abnormal vessel walls cause:
Ischaemic heart disease
Cerebral thrombosis
Peripheral vascular disease

23. Ischaemic vascular diseases occur at a
young age
Homocysteine has been described as the
new cholesterol because of its propensity to
cause ischaemic vascular diseases

24. Early diagnosis and treatment prevent most
of the clinical abnormalities
The treatment consists of a low-methionine,
high-cysteine diet
Pyridoxine supplements may be given to
activate the residual cystathionine synthetase

25. Hyperhomocysteinaemia may occur due
to deficiency of some vitamins also,
specially folic acid and vitamin B12
In such cases, vitamin supplements
correct the abnormality

26. Phenylketonuria is the commonest inborn
error of amino acid metabolism
It has an incidence of about 1 in 10,000
live births
It was the first inborn error of amino acid
metabolism to be treated successfully by
diet manipulation
Phenylketonuria (PKU)

27. There is a block in the conversion of
phenylalanine into tyrosine in PKU
Two-thirds of the patients suffer from PKU,
type I
Phenylalanine hydroxylase is deficient in
PKU, type I
Several mutations have been observed in
the phenylalanine hydroxylase gene

28. One third of the cases
are due to a defect in:
Dihydropteridine
reductase or
Conversion of GTP into
tetrahydrobiopterin

30. The degree of defect is variable but it is
severe in majority of the patients
Plasma phenylalanine concentration rises
after ingestion of phenylalanine
When the level exceeds 1 mmol/L, alternate
metabolites of phenylalanine are formed

31. The alternate metabolites include:
Phenylpyruvate
Phenyl-lactate
Phenylacetate
Phenylacetylglutamine

33. Plasma concentration of phenylalanine is
raised in PKU
Plasma concentration of its alternate
metabolites is also raised
All these are excreted in urine

34. Some other amino acids share their transport
system with phenylalanine
A high phenylalanine level may inhibit
their intestinal absorption and renal tubular
reabsorption
Uptake of these amino acids by brain may
also be inhibited

35. Synthesis of myelin sheath is decreased
Synthesis of norepinephrine in brain is
decreased
Decreased availability of tyrosine may
decrease the synthesis of melanin

36. Clinical manifestations appear a few days or
weeks after birth
Developmental milestones are delayed
Motor hyperactivity and seizures occur
Skin is hypopigmented
Later on, there is severe mental retardation

37. Early diagnosis (within 3 weeks of birth) and
treatment prevent the clinical abnormalities
Since phenylalanine is an essential amino
acid, it cannot be excluded from the diet
A low-phenylalanine diet is given to keep the
plasma phenylalanine level below 6 mg/dl

38. Hence, tyrosine becomes an essential
amino acid for patients with PKU
Their diet needs tyrosine supplements
Tyrosine cannot be synthesized endo-
genously in PKU

39. Dihydropteridine reductase is deficient in
PKU, type II
There is a block in the synthesis of tetra-
hydrobiopterin from GTP in PKU, type III
These two also result in decreased
conversion of phenylalanine into tyrosine

40. Tetrahydrobiopterin is also required for
hydroxylation of tyrosine and tryptophan
Deficiency of tetrahydrobiopterin results
in decreased synthesis of:
Dopamine, norepinephrine and
epinephrine from tyrosine
Serotonin and melatonin from
tryptophan

41. The clinical abnormalities in phenyl-
ketonuria, types II and III:
Are more severe
Appear early
Do not improve despite
diet manipulation

42. Alkaptonuria is an inborn error of tyrosine
metabolism
It is due to absence of homogentisate
oxidase
Homogentisate, an intermediate in cata-
bolism of tyrosine, cannot be metabolised
further
Alkaptonuria

44. Homogentisate is excreted in urine
Freshly voided urine is normal in colour
Urine becomes dark on exposure to air
due to oxidation of homogentisate by
oxygen

45. Homogentisate and its oxidation product
form polymers that bind to collagen
This leads to generalized pigmentation of
connective tissues (ochronosis)
Chemical irritation of collagen causes
degenerative changes in connective tissue
Defective cross-linking of collagen also
adds to the degeneration

46. Damage to joint cartilages causes arthritis
(ochronotic arthritis)
Arthritis usually occurs in hip, knee and
shoulder joints and vertebral column
Pigmented spots may be seen on sclera
and ears

47. Treatment of alkaptonuria is symptomatic
Ascorbic acid supplements have been
tried but without much success

48. This is another inborn error of tyrosine
metabolism
Plasma tyrosine level is increased in
tyrosinaemia
Tyrosine and its metabolites are excreted
in urine
Tyrosinaemia

49. Two distinct genetic defects can cause
tyrosinaemia
Deficiency of fumarylacetoacetate
hydrolase causes tyrosinaemia, type I
Deficiency of tyrosine transaminase
causes tyrosinaemia, type II

51. Tyrosinaemia, type I causes neurological
abnormalities, liver damage and renal
tubular dysfunction
Tyrosinaemia, type II affects eyes and
skin

52. This is another inborn error of tyrosine
metabolism
It is due to absence of tyrosinase from
melanocytes
This enzyme is required for synthesis of
melanin
Albinism

53. Melanin is not synthesized in patients
having albinism
Their skin, hair and iris become white
Such patients are called albinos

54. Photophobia and skin hypersensitivity are
common in albinos
The incidence of skin cancer is also high
Goggles and sunscreen lotions can
reduce the discomfort

55. This is an inborn error of histidine
metabolism in which histidase is deficient
Histidine cannot be converted into
urocanic acid
Histidine concentration in plasma is
increased
Histidinaemia

57. Histidine is converted into some alternate
metabolites:
Imidazole pyruvate
Imidazole lactate
Imidazole acetate
The alternate metabolites are excreted
in urine

59. Histidinaemia was believed in the past to
impair development of speech
This later turned out to be incorrect
Most of the subjects with histidinaemia
have no symptoms

60. 1% of the histidinaemic subjects develop
behavioural problems, learning disorders
and intellectual disability
This usually happens when histidinaemic
babies are exposed to perinatal hypoxia

61. This disease was first diagnosed in the
Hartnup family
It was believed to be a disorder of
tryptophan metabolism at first
Later evidence showed a transport defect
involving all neutral amino acids
Hartnup disease

62. Intestinal absorption of neutral amino
acids is impaired
Renal tubular reabsorption of neutral
amino acids is also impaired
This leads to massive loss of amino acids

63. Tryptophan present in gut is converted
into indole and indoxyl derivatives by
bacteria
These are absorbed and are excreted in
urine

64. Decreased availability of tryptophan
decreases endogenous synthesis of niacin
This may produce a pellagra-like picture
The treatment consists of a high-protein
diet and niacin supplements