Inborn Errors

of
Amino Acid
Metabolism
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
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
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
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
Some relatively common inborn errors are:
• Primary hyperoxaluria
• Maple syrup urine disease (MSUD)
• Cystinuria
• Homocystinuria
• Phenylketonuria (PKU)
• Alkaptonuria
• Tyrosinaemia
• Albinism
• Histidinaemia
• Hartnup Disease
 Primary hyperoxaluria

Primary hyperoxaluria is a disorder

of glyoxylate metabolism

Glyoxylate is formed from hydroxyproline

Normally, glyoxylate is transaminated

to glycine or is oxidised to formate
Glyoxylate is converted into oxalate when:

Glycine transaminase is deficient

Oxidation of glyoxylate is impaired

This leads to hyperoxaluria and recurrent

formation of oxalate stones in urinary tract
 Maple syrup urine disease (MSUD)

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
Branched-chain amino are
acids transaminated to -keto
acids first
oxidative
The -keto acids undergo
decarboxylation
Oxidative decarboxylation is catalysed by -
ketoisovalerate dehydrogenase

This enzyme is absent or deficient in MSUD

 Valine Leucine lsoleucine

Branched-chain amino acid transaminase

a-Ketoiso­ a-Ketoiso­ a-Keto-p-methyl

valeric acid caproic acid valeric acid

a-Ketoisovalermle: ehydrogenase
■
lsobutyryl lsovaleryl a-Methylbutyryl
CoA CoA CoA
The enzyme deficiency leads to
accumu- lation and increased urinary
excretion of:

Branched chain amino acids

Their -keto acid derivatives

This imparts a typical odour to urine similar

to that of maple syrup or burnt sugar
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
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
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 -keto acids

is intermittently increased
 Cystinuria

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
 Homocystinuria

Cystathionine synthetase is severely

deficient in homocystinuria

This impairs the conversion of methionine

into cysteine

Homocysteine accumulates and is

converted into homocystine
Homocystine is made up of two
homo- cysteine molecules

Urinary excretion of homocystine

is increased

Plasma methionine and

homocysteine levels are increased
The clinical features of homocystinuria are:

Thrombotic phenomena

Osteoporosis

Dislocation of lenses in the eyes

Mental retardation

Ischaemic vascular disease

Accumulation of homocysteine causes:

Abnormal cross-linking of collagen

Abnormalities in the ground

substance of walls of blood vessels

Increased platelet adhesiveness

Dislocation of ocular lenses and
osteo- porosis occur due to abnormal
collagen

Thrombotic phenomena occur because

of abnormalities in the walls of blood
vessels
Increased platelet adhesiveness and
abnormal vessel walls cause:

Ischaemic heart disease

Cerebral thrombosis

Peripheral vascular disease

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
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
Hyperhomocysteinaemia may occur due
to deficiency of some vitamins also,
specially folic acid and vitamin B12

In such cases, vitamin supplements

correct the abnormality
 Phenylketonuria (PKU)

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
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
One third of the cases
are due to a defect
in:

Dihydropteridine
reductase

or

Conversion of GTP into

tetrahydrobiopterin
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
The alternate metabolites include:

Phenylpyruvate

Phenyl-lactate

Phenylacetate

Phenylacetylglutamine
Plasma concentration of phenylalanine is
raised in PKU

Plasma concentration of its

alternate metabolites is also raised

All these are excreted in urine

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
Synthesis of myelin sheath is decreased

Synthesis of norepinephrine in brain

is decreased

Decreased availability of tyrosine

may decrease the synthesis of melanin
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
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
Tyrosine cannot be synthesized
endo- genously in PKU

Hence, tyrosine becomes an

essential amino acid for patients with
PKU

Their diet needs tyrosine supplements

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
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
The clinical abnormalities in phenyl-
ketonuria, types II and III:

Are more severe

Appear early

Do not improve despite

diet manipulation
 Alkaptonuria

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
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
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
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
Treatment of alkaptonuria is symptomatic

Ascorbic acid supplements have

been tried but without much success
 Tyrosinaemia

This is another inborn error of

tyrosine metabolism

Plasma tyrosine level is increased

in tyrosinaemia

Tyrosine and its metabolites are excreted

in urine
Two distinct genetic defects can
cause tyrosinaemia

Deficiency of
fumarylacetoacetate hydrolase causes
tyrosinaemia, type I

Deficiency of tyrosine transaminase

causes tyrosinaemia, type II
Tyrosinaemia, type I causes neurological
abnormalities, liver damage and renal
tubular dysfunction

Tyrosinaemia, type II affects eyes

and skin
 Albinism

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
Melanin is not synthesized in
patients having albinism

Their skin, hair and iris become white

Such patients are called albinos

Photophobia and skin hypersensitivity are
common in albinos

The incidence of skin cancer is also high

Goggles and sunscreen lotions

can reduce the discomfort
 Histidinaemia

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
Histidine is converted into some alternate
metabolites:

Imidazole pyruvate

Imidazole lactate

Imidazole acetate

The alternate metabolites are

excreted in urine
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
1% of the histidinaemic subjects develop
behavioural problems, learning disorders
and intellectual disability

This usually happens when histidinaemic

babies are exposed to perinatal hypoxia
 Hartnup Disease

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
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
Tryptophan present in gut is converted
into indole and indoxyl derivatives by
bacteria

These are absorbed and are excreted in

urine
 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