Biochemical basis of systemic

and Inborn error of metabolism

Narayan Ghimire
M.Sc Medical Biochemistry
SHAS,PU
3rd batch
Inborn Error of Protein Metabolism
 Phenylketonuria
• Phenylketonuria (PKU) is the most common metabolic disorder in
amino acid metabolism.
• The incidence of PKU is 1 in 10,000 births.

• due to the deficiency of the hepatic enzyme, phenylalanine

hydroxylase, caused by an autosomal recessive gene.

• A variant of PKU—due to a defect in dihydrobiopterin reductase

(relatively less)—has been reported. This enzyme deficiency impairs
the synthesis of tetrahydrobiopterin required for the action of
phenylalanine hydroxylase

• The net outcome in PKU is that phenylalanine is not converted to

tyrosine.
 Clinical/biochemical manifestations of PKU
Effects on central nervous system
• Mental retardation, failure to walk or talk, failure of
growth, seizures and tremor are the characteristic
findings in PKU.
• If untreated, the patients show very low IQ (below
50)
• Defect in myelin formation
Effect on pigmentation
• Melanin is the pigment synthesized from tyrosine by
tyrosinase
• The result is hypopigmentation that causes light skin
colour, fair hair, blue eyes etc.
 Diagnosis of PKU
• Plasma levels of phenylalanine: PKU is mostly
detected by screening the newborn babies for
the increased plasma levels of phenylalanine
(PKU, 20–65 mg/dl; normal 1–2mg/dl).
• Guthrie test
• Ferric chloride test
Alkaptonuria
 Diagnosis of Alkaptonuria
• Urine becomes black on standing
• Ferric chloride test
• Benedict's test i
 Albinism
• Autosomal recessive disease with an incidence of 1 in 20,000
population
• Due to the lack of synthesis of the pigment melanin
Biochemical basis:
 Clinical manifestations
Hypopigmentation
• Oculocutaneous albinism
• Vitiligo and leukoderma
• Vitiligo is an acquired progressive disease with
loss of pigmentation around mouth, nose,
eyes and nipples. Leukoderma is comparable
with vitiligo, but lack of pigmentation usually
begins with hands and then spreads
 Hartnup’s disease
• hereditary disorder of tryptophan metabolism

• The clinical symptoms include dermatitis, ataxia,

mental retardation etc.
• Hartnup’s disease is characterized by low plasma
levels of tryptophan and other neutral amino acids
and their elevated urinary excretion

• Increased urinary output of indoleacetic acid and

indolepyruvic acid is also observed
 Cystinuria (cystine –lysinuria)
• Most common inherited disease (Prevalence=1/7000)
• One of the inborn errors of metabolism included in the
Garrod's tetrad.
• Increased excretion of cystine (25-40 times normal)
• Specific carrier system exists in kidney tubules for
reabsorbtion of AAs like COAL.

• Defect in the carrier system leads to increased urinary

output of cysteine, lysine, arginine and ornithine
(COAL)
 Homocysteinuria
 Group of metabolic disorder which are the latest in the series of
inborn errors of metabolism.

 All of them are autosomal recessive conditions.

 Accumulation & increased excretion of homocysteine and S-

adenosylmethionine (SAM)

 Plasma methionine also increased

• Homocystinuria type I
• Homocystinuria type II
• Homocystinuria type III
• Homocystinuria type IV
 Homocysteinuria type I
 Defect in enzyme cystathionine synthase

 Complications due to accumulation of homocysteine

• Thrombosis
• Osteoporosis
• Mental retardation

 Deficiency of cystathionine is associated with damage

to endothelial cells leading to atherosclerosis

 Type
• Vitamin B6 responsive
• Vitamin B6 not responsive
Homocystinuria type III
• Defect in N5-N10—methyl THF-homocysteine
methyltransferase
• Due to impairment in synthesis of
methylcobalamine

Homocystinuria type IV
• Defect in N5—methyl THF-homocysteine
methyltransferase
• Due to defect in intestinal absorption of vitamin
B12
 Cystathioninuria
• Due to cystathionase deficiency.

• Mental retardation, anemia, thrombocytopenia,

and endocrinopathies.

• Less severe forms may be seen in conditions

interfering with homocysteine remethylation, in
B12 deficiency and in impaired folate metabolism.

• Acquired cystathioninuria may be due to B6

deficiency.
 Maple Syrup Urine Disease (MSUD)

• Also called branched chain ketonuria.

• Defect in enzyme branched chain alpha keto acid
dehydrogenase .

• The incidence is 1 per 1 lakh births.

• The name originates from the characteristic smell of

urine (similar to burnt sugar or maple sugar) due to
excretion of branched chain keto acids in urine.
 Biochemical complications of MSUD

• Accumulation of branched chain AAs causes an

impairment in transport and function of other
amino acids.

• Protein biosynthesis is reduced.

• Branched chain AAs competitively inhibit glutamate

dehydrogenase.
Inborn error of Carbohydrate
Metabolism
 Classical Galactosemia
• Due to the deficiency of the enzyme galactose 1-
phosphate uridyltrans-ferase
• Incidence 1 : 30000
• It is a rare congenital disease in infants, inherited as
an autosomal recessive disorder.
• Salient features:
Galactosemia,galactoseuria,cataaract,hypoglycemia
 Hereditary fructose intolerance
 Due to the absence of the enzyme aldolase B.
Causes:
• Intracellular accumulation of fructose 1-phosphate
• severe hypoglycemia
• Vomiting
• hepatic failure
• jaundice

 Early detection and intake of diet free from

fructose and sucrose, are advised to overcome
fructose intolerance
Glycogen storage Disease
Inborn Error of Purine Metabolism
• Lesch-Nyhan disease is a genetic disorder associated with 3
major clinical elements: overproduction of uric acid,
neurologic disability, and behavioral problems.
• Due to deficiency of the hypoxanthine-guanine
phosphoribosyltransferase (HGPRT).
• Deficiency occurs due to mutations in the HPRT1 gene
located on X chromosome. 
• Affects about 1 in 380,000 live births