Inborn errors of metabolism:

Inborn errors of metabolism are rare genetic (inherited) disorders due

to defects of single genes that code for enzymes that facilitate
conversion of various substances into others products.

IEM are present in all ethnic groups and across every age, most
common in newborns and may manifest at any stage of life, from
infancy to adulthood.

Also referred to as congenital metabolic diseases or inherited

metabolic diseases.
 In most of the disorders, problems arise due to accumulation of
substances which are toxic or interfere with normal function, or to the
effects of reduced ability to synthesize essential compounds.

-Garrod’s hypothesis-
 How are they caused:
 Most inherited disorders of metabolism are caused by mutations in
genes that code for enzymes.

 Mutation causes a gene to not function at all or not to function as

well as it should.

 Most often these altered genes are inherited from parent(s) (germ
line mutation), but they may also occur spontaneously or
environmental factors (aquired mutation). Every inborn error of
metabolism encountered may represent fresh mutations.
 How are they transmitted?
An abnormal gene is transmitted from one generation to other by
three modes,

 Autosomal

Dominant inheritance
A- one normal-other

abnormal-heterozygote

affected.

B- both affected-

homozygote individual-

death.
Autosomal Recessive inheritance
Sex linked inheritance
Occurrence of IEM can be of,
 Disturbances in molecular structures – eg sickle cell
anaemia

 Disturbances in protein and amino acid metabolism –

eg Phenylketonuria, alkaptonuria.
 Disturbance in carbohydrate metabolism – eg
Galactosemia.

 Disturbances in endocrine metabolism – eg Crieinism.

 Disturbances in pigment metabolism – eg Albinism.
 Disturbances in enzyme metabolism – eg, Cystic
fibrosis.
 Disturbances in lipid metabolism – eg Gaucher’s
disease.

 Muscular dystrophy
 Phenylketonuria
 Autosomal recessive disorder caused by mutation in the phenylalanine
hydroxylase gene (PAH gene)(recessive allels pp)

 Mutation in this gene fails to produce phenylalanine hydroxylase enzyme,

which is necessary to convert phenylalanine into thyrosine.

 As a result phenylalanine concentration increases in the blood serum.

 This amino acid is then partly converted into phenylpyruvate, phenylacetate,

phenyllactate. These are excreated through urine, mousy in odour.
 There are three other metabolic disorders associated with this amino acid
pathway ( alkaptonuria, albinism, tyrosinosis).
Symptoms
 Mental retardation
 Seizures and tremors
 Psychological issues
 Irritability and eczema.

Screening and treatment:

 Neonatal screening program : The baby’s heel is pricked
and a few drops of blood are taken. The blood is sent to
the state laboratory to find out if it has more than a normal
amount of phenylalanine. The purpose of these detection
programs is to treat the babies before they start exhibiting
symptoms of the disease.

 Treatment : Treatment involves a diet that is extremely low

in phenylalanine, particularly when the child is growing
 Phenylalanine occurs in significant amounts in milk, eggs, and other common
foods. The artificial sweetener NutraSweet (aspartame) also contains
phenylalanine. Any products containing aspartame should be avoided.

 A special infant formula called Lofenalac is made for infants with PKU.
 An enzyme assay can determine if parents carry the gene for PKU. Chorionic villus
sampling can be done during pregnancy to screen maternal PKU.

Alkaptonuria
 The person with autosomal homozygous recessive genes hh (mutation in HGD
gene) fail to produce the enzyme homogentisic acid oxidase which catalysis the
oxydation of 2,5,dihydrophenylacetic acid (alkapton).

 Therefore, in them, normal oxidation of alkapton into acetoacetic acid and

ultimately into H2O & CO2 does not take place. So alkaptone is accumulated in
blood and excreted in urine, which turns black upon expose to air.
 These patients have manifested by the darkening of cartilaginous
regions (pinna) and proneness to arthritis(ochronosis).

 Dark spots in the sclera eyes.

 Blue speckled discoloration of your skin, particularly around sweat glands.

 Kidney stones and prostate stones.

Diagnosis and treatment :
 If the diagnosis of alkaptonuria is suspected, this can
be confirmed or excluded by collecting urine for
twenty-four hours and determining the amount of
homogentisic acid by means of chromatography.
There is no validated assay of HGA in blood.

 Pain control and certain types of exercise can reduce

pain and improve mobility. Patients often need surgery
such as joint replacements.

 Several recent studies have suggested

nitisinone may be effective in the treatment of

alkaptonuria. Nitisinone inhibits the
enzyme, hydroxyphenylpyruviate dioxygenase,
responsible for converting tyrosine to homogentisic
acid, thereby blocking the production and
accumulation of HGA.
 Albinism
 The person with recessive aa genes do not produce tyrosinase enzyme
which is needed by melenocytes for converting DOPA into melanine.

 A mutation in the human TRP-1 gene (tyrosinase-related protein 1) may

result in the deregulation of melanocyte tyrosinase enzymes.

 So they lack the melanin pigmentation.

 Albinism is associated with vision defects like photophobia,

nystagmus, amblyopia, strabismus.

 This disorders are generally divided into two types.
Oculocutaneous Albinism or OCA and Ocular
Albinism.

 OCA involves decreased pigment in the eyes, hair,

and skin. There are 4 types of OCA that have been
described depending on the type of genetic defect.
These types are tyrosinase-related albinism, results
from a genetic defect in an enzyme called
tyrosinase. This enzyme helps the body to change
the amino acid, tyrosine, into pigment.

 Ocular albinism is caused by a change in the

GPR143 gene that plays a role that is especially
important for pigmentation in the eye. It is xlinked
and mostly affects male, female becomes carriers.
 There is no cure for albinism. Treatment is aimed to ease the symptoms and it
depends on the extent of the disorder. Treatment of the eye conditions consists
of visual rehabilitation.

 It is vital that people with albinism, use sunscreen when exposed to sunlight to
prevent premature skin aging or skin cancer. Special UV-proof clothing and
swimsuits are available and are a good alternative to excessive use of
sunscreen.

Muscular dystrophies:
 Muscular dystrophy was first described in the 1830s by ”Charles Bell”.
Greek –dys, meaning "difficult" and troph meaning "nourish“.

 Inherited disorders characterised by progressive muscle weakness.

 There are nine main categories of muscular dystrophy that contain more
than thirty specific types.
 They are due to mutations in genes that are involved in making muscle
proteins. This can occur due to either inheriting the defects from parents or the
mutation occurring during early development.

 The most common type is Duchenne muscular dystrophy(DMD) which typically

affects males beginning around the age of four.

 Clinical features include muscle pain, seizures, respiratory failure,

cardialmyopathy, Scoliosis (curvature of the spine and the back),
Progressive inability to walk, Waddling gait, Calf deformation, Limited
range of movement, Gowers’s sign.
Duchenne muscular dystrophy:
 Duchenne muscular dystrophy is the most common fatal genetic disorder diagnosed
in childhood, affecting approximately 1 in every 3,500 live male births.

 Because the Duchenne gene is found on the X-chromosome, it primarily affects boys;
however, it occurs across all races and cultures.

 Duchenne results in progressive loss of strength and is caused by a mutation in the

DMD gene that encodes for dystrophin. Because dystrophin is absent, the muscle
cells are easily damaged.

 Diagnosis often involves blood test and genetical screening.

 There is no cure for muscular dystrophy. Physiotherapy exercises and braces may
help with some symptoms. Assisted ventilation may be required in those with
weakness of breathing muscles. Medications used include steroids to slow muscle
degeneration, anticonvulsants to control seizures and some muscle activity, and
immunosuppressant to delay damage to dying muscle cells. Outcomes depend on
the specific type of disorder.
Precaution:
 Knowing the family history of genetic
defects.

 A genetic screening for parents.

 Attending genetic counselling before
pregnancy to know about the risk of
genetic disorders to the child.

 Creating awareness on congenital

abnormalities
THANKYOU

14BZO041
M. SREE VARSHINI