Genetic pattern of common pediatric disorder

GENETIC PATTERN OF COMMON PEDIATRIC DISORDERHARSHITA

M. SC NURSING

GENETICS

Genetics is the study of genes, genetic variation,

and heredity in living organisms.

GENETIC DISORDER

A genetic disorder is a genetic problem caused by one or more

abnormalities in the genome, especially a condition that is

present from birth (congenital). Most genetic disorders are quite

rare and affect one person in every several thousands or millions.

HOW GENETIC DISORDER IS CAUSED

A genetic disorder is a disease caused in whole or in part by a

change in the DNA sequence away from the normal sequence.

Genetic disorders can be caused by a mutation in one gene

(monogenic disorder), by mutations in multiple genes

(multifactorial inheritance disorder), by a combination of gene

mutations and environmental factors, or by damage to

chromosomes (changes in the number or structure of entire

chromosomes, the structures that carry genes).

CLASSIFICATION OF GENETIC DISORDERS

A. Genetic disorders due to traditional modes of inheritance.

Mendelian disorders: (Single gene)

• Autosomal dominant (AD)

• Autosomal recessive (AR)

• X-linked recessive (XLR)

• X-linked dominant (XLD)


• Chromosomal disorders:

• Numerical abnormalities

• Structural abnormalities

• Multifactorial disorders

• Somatic cell mutations


B. Genetic disorders due to non-traditional modes of inheritance.

• Mosaicism

• Genomic imprinting

• Uniparental disomy (UPD)

• Inheritance of unstable mutations

• Cytoplasmic/mitochondrial inheritance

MENDELIAN (SINGLE GENE) DISORDERS

• When a certain gene is known to cause a disease, it is a single

gene disorder or a Mendelian disorder.

• Disorders caused by a defect in a single gene follow the

patterns of inheritance described by Mendel. Risks within an

affected family are usually high and are calculated by knowing

the mode of inheritance and details of the family pedigree

AUTOSOMAL DOMINANT DISORDERS

• Generally, the autosomal dominant mutations caused faults in

the synthesis of structural or non-enzyme proteins.

• These disorders manifest even if only one of the alleles of the

normal gene is affected

AUTOSOMAL RECESSIVE DISORDERS

• Autosomal recessive disorders manifest only in homozygous

states, i.e. both the alleles are mutant genes.

• Generally autosomal recessive mutation affect synthesis of

enzyme proteins, leading to inborn error of metabolism.

X-LINKED RECESSIVE DISORDERS

• Males have an X and shorter Y chromosome. There may be no

corresponding locus or mutant allele of the X chromosome on

the shorter Y chromosome. The mutant recessive gene on X

chromosome, therefore expresses as a clinical disorder in male

child.

• In X-linked recessive conditions only males are affected as

there is no corresponding allele. All his daughters will be

carriers as they receive abnormal X from father.

X-LINKED DOMINANT DISORDERS

These disorders manifest even in XX females as it is an

dominant gene. The gene is transmitted in families in the same

way as X-linked recessive genes, giving rise to an excess of

affected females.

• In some disorders the condition is lethal in hemizygous males.

In this case there will be fewer males than expected in the

family, all of whom will be healthy, and an excess of females,

half of whom will be affected.

• There is no male to male transmission in this pattern of

inheritance

CHROMOSOMAL DISORDERS

• Chromosomal abnormalities are generally sporadic and

therefore, the risk of their recurrence in the offspring is low.

There are two type of chromosomal abnormalities numerical

and structural

NUMERICAL DISORDERS

This is called aneuploidy (an abnormal number of chromosomes),

and occurs when an individual either is missing a chromosome

from a pair (monosomy) or has more than two chromosomes of a

pair (trisomy, tetrasomy, etc.).

STRUCTURAL ABNORMALITIES

When the chromosome's structure is altered, this can take several forms:

Deletions: A portion of the chromosome is missing or deleted. Known

disorders in humans include Wolf-Hirschhorn syndrome, which is caused by

partial deletion of the short arm of chromosome 4; and Jacobsen syndrome,

also called the terminal 11q deletion disorder.

Duplications: A portion of the chromosome is duplicated, resulting in extra

genetic material. Known human disorders include Charcot-Marie-Tooth

disease type 1A, which may be caused by duplication of the gene encoding

peripheral myelin protein 22 (PMP22) on chromosome 17.


• Translocations: A portion of one chromosome is transferred to

another chromosome. There are two main types of translocations:

• Reciprocal translocation: Segments from two different chromosomes

have been exchanged.

• Robertsonian translocation: An entire chromosome has attached to

another at the centromere - in humans these only occur with

chromosomes 13, 14, 15, 21, and 22.

• Inversions: A portion of the chromosome has broken off, turned

upside down, and reattached, therefore the genetic material is

inverted.


• Insertions: A portion of one chromosome has been deleted

from its normal place and inserted into another chromosome.

• Rings: A portion of a chromosome has broken off and formed a

circle or ring. This can happen with or without loss of genetic

material.

• Isochromosome: Formed by the mirror image copy of a

chromosome segment including the centromere

ABNORMALITIES

MULTIFACTORIAL DISORDERS

Inheritance and expression of a phenotype being

determined by multiple gene at different loci and

the effects of the genes are cumulative, with each

gene contributing a small amount to the final

expressed phenotype aided by certain

environmental factors.

SOMATIC CELL MUTATIONS

Some cancers can be inherited as simple Mendelian

traits, with clear patterns of transmission, this is the

exception rather than the rule. Even though most

cancers involve quite substantial changes in the

genetic material, such mutations are somatic and

there is no risk to further generations.

MOSAICISM

• Somatic mosaicism is the term used to describe the finding of

two different cell lines in one individual that are derived from a

single zygote (i.e. coming from a single egg and sperm). It

occurs as a postzygotic event (after fertilization).

• The mosaicism may be for (i) chromosomal abnormalities or (ii)

single gene mutations.

MOSAICISM

• Chromosomal Mosaicism

It has been recognized in cultured lymphocytes of patients with

chromosomal aneuploidy syndromes.

• Single Gene Mosaicism

Somatic mosaicism for single gene mutations.

MOSAICISM

• Germline Mosaicism

Germline mosaicism refers to the presence of mosaicism in the

germ cells found in the gonads. The mosaicism may be for

chromosomal abnormality or a single gene mutation. Germ line

mosaicism has been found in Duchenne muscular dystrophy,

chronic granulomatous disease and osteogenesis imperfecta.

GENOMIC IMPRINTING

During the last decade, several new mechanisms of genetic

inheritances have been recognized and one such is genomic

imprinting.

UNIPARENTAL DISOMY

An individual inherits a pair of homologous chromosomes, one

from the father and the other from the mother. Recent DNA

technology has revealed that an individual may inherit both

homologous chromosomes from only one of his parents and this

situation is called as uniparental disomy.

MITOCHONDRIAL INHERITANCE

Mitochondria are intracellular organelles which are ubiquitous in

eukaryotes and are essential for survival

DOWN SYNDROME

• Down syndrome, the most

common chromosomal

condition that results in

intellectual disabilities, is

associated with an extra

chromosome on

chromosome 21.

DOWN SYNDROME

EDWARD SYNDROME

• Edward syndrome also

known as trisomy 18, is a

rare but serious genetic

condition that causes a wide

range of severe medical

problems

SYMPTOMS

• low birthweight

• a small, abnormally shaped head

• a small jaw and mouth

• long fingers that overlap, with underdeveloped thumbs and clenched fists

• low-set ears

• smooth feet with rounded soles

• a cleft lip and palate

• an exomphalos (where the intestines are held in a sac outside the tummy)

PATAU SYNDROME

Patau syndrome is a syndrome

caused by a chromosomal

abnormality, in which some or

all of the cells of the body

contain extra genetic material

from chromosome 13. The

extra genetic material disrupts

normal development, causing

multiple and complex organ

defects.

KLIFENTER SYNDROME

Klinefelter syndrome is a genetic

disorder that affects males. Klinefelter

syndrome occurs when a boy is born

with one or more extra X

chromosomes.

TURNER SYNDROME

Turner syndrome is a

genetic disorder that

affects about 1 in every

2,000 baby girls and only

affects females. A girl with

Turner syndrome only has

one normal X sex

chromosome, rather than

the usual two (XX).

This chromosome variation

happens randomly when

the baby is conceived in

the womb. It is not linked

to the mother's age.

THALASSAEMIA

Thalassaemia is a blood

related genetic disorder which

involve the absence of or

errors in genes responsible for

production of haemoglobin, a

protein present in the red

blood cells.

SICKLE CELL ANEMIA

• Sickle-cell anemia is a blood

related disorder that affects the

haemoglobin molecule, and

causes the entire blood cell to

change shape under stressed

conditions. In sickle cell anaemia,

the haemoglobin molecule is

defective. After haemoglobin

molecules give up their oxygen,

some may cluster together and

form long, rod-like structures

which become stiff and assume

sickle shape.

HAEMOPHILIA

• Haemophilia is a hereditary bleeding disorder, in which there is

a partial or total lack of an essential blood clotting factor. It is a

lifelong disorder, that results in excessive bleeding, and many

times spontaneous bleeding, which, very often , is internal.

Haemophilia A is the most common form, referred to as

classical haemophilia. It is the result of a deficiency in clotting

factor 8, while haemophilia B (Christmas Disease) is a

deficiency in clotting factor 9. This illness is a sex-linked

recessive disorder.

CYSTIC FIBROSIS

Cystic Fibrosis is a genetic

disorder that affects the

respiratory, digestive and

reproductive systems

involving the production of

abnormally thick mucus

linings in the lungs and can

lead to fatal lung

infections. The disease can

also result in various

obstructions of the

pancreas, hindering

digestion.

TAY SACHS DISEASE

Tay-Sachs disease is a fatal genetic disorder in which harmful

quantities of a fatty substance called Ganglioside GM2

accumulate in the nerve cells in the brain. This is caused by a

decrease in the functioning of the Hexosaminidase A enzyme.

FRAGILE X SYNDROME

The Fragile X syndrome is

caused by a "fragile" site at

the end of the long arm of

the X-chromosome. It is a

genetic disorder that

manifests itself through a

complex range of

behavioural and cognitive

phenotypes.

HUNTINGTON'S DISEASE

Huntington’s disease is a degenerative brain disorder, in which

afflicted individuals lose their ability to walk, talk, think, and

reason. They easily become depressed, and lose their short-term

memory capacity. They may also experience a lack of

concentration and focus

CANCER

• Cell undergoes in the process of malignant transformation.

• This take over 20 years or more.

• The mutation of critical genes, including supressor genes, oncogenes

and genes involved in DNA repair, leads to genetic instability and to

progressive loss of differentiation.

• Tumours enlarge because cancer cells lack the ability to balance cell

division by cell death (apoptosis) and by forming their own vascular

system (angiogenesis) .

CANCER

• The transformed cells lose their ability to interact with each

other and exhibit uncontrolled growth, invade neighbouring

tissues and eventually spread through the blood stream or the

lymphatic system to distant organs.

DIABETES

Diabetes is a disease in which the body does not produce or

properly use insulin. Insulin is a hormone that is needed to

convert sugar, starches and other food into energy needed for

daily life. The cause of diabetes continues to be a mystery,

although both genetics and environmental factors such as

obesity and lack of exercise appear to play roles. There are three

major classes of diabetes

• Type 1 diabetes

• Type 2 diabetes

CARDIOVASCULAR DISEASE

Cardiovascular diseases (CVD) include coronary heart disease,

cerebrovascular disease, heart failure, rheumatic heart disease

and congenital heart disease.

The major risk factors associated with cardiovascular diseases

are cigarette smoking, unhealthy diet, physical inactivity,

hypertension, diabetes and high blood cholesterol.

CVD may also result from a variety of genetic causes, including

single-gene mutations, the interaction of multiple genes and

environmental factors.

ASTHMA

Asthma is a disease in which the airways become blocked or narrowed. These effects are usually temporary, but they cause shortness of breath, breathing trouble, and other symptoms. When encountering a triggering particle, there is an inflammation of the linings, a constriction of the airways and mucous production. This results in difficulty in breathing, and may even block the airways completely. If an asthma episode is severe, a person may need emergency treatment to restore normal breathing. An asthma episode is triggered by things in the environment. These triggers vary from person to person, but common ones include cold air; exercise; allergens such as dust mites, mould, pollen, Cigarette smoke, animal dander or cockroach debris; and some types of viral infections.

MANAGEMENT

(i) Restriction of potentially toxic environmental agents,

(ii) Replacement of missing gene product, deranged organ or

even gene itself

(iii)Removal of either toxic substances of organs

(iv)Metabolic manipulation

(v) Surgical management.

RESTRICTION

(a) Phenylketonuria – phenylalanine should be restricted in the

diet,

b) Galactosemia – galactose should be eliminated from the diet

early in life. If prenatal diagnosis is made, the mother should not

drink milk in pregnancy,

(c) G-6-PD deficiency – primaquine, sulpha drugs and fava

beans should be restricted,

REPLACEMENT

• Examples for the replacement mode of treatment are:

• a. Hemophilia A and B: The treatment aims at replacement of factor VIII and factor IX by transfusion respectively.

• b. Diabetes mellitus: Insulin is the agent replaced.

• c. Alpha-1 antitrypsin deficiency: Can be successfully treated by replacement with recombinant alpha-1 antitrypsin.

• d. Congenital adrenal hyperplasia: The agents replaced are cortisone and aldosterone.

• e. Cystinosis Kidney transplantation.

• f. Adenosine deaminase deficiency: Bone marrow transplantation or somatic cell gene therapy.

• g. Familial hypercholesterolemia: Liver transplantation

REMOVAL

• The examples are:

(a) Wilson’s disease: It is an autosomal recessive disorder characterized

by accumulation of copper in various organs like the liver, brain and

kidneys. The copper can be effectively chelated by oral administration

of penicillamine;

(b) Hemochromatosis: The excess iron stores are removed by repeated

phlebotomy;

(c) Familial Polyposis coli: Colectomy is advised to prevent carcinoma

of colon, which develops during the fourth decade of life.

METABOLIC MANUPULATION

• Metabolic manipulation can correct certain types of disorders which

are: (a) Neural tube defects: Periconceptional folic acid therapy has

shown to prevent neural tube defects

(b) Homocystinuria: Classic homocystinuria is due to deficiency of

cystathionine synthetase. Among these, 40 percent of patients respond

to high doses of vitamin B6.

(c) Crigler-Najjar syndrome type II: These patients benefit by oral

phenobarbitone administration which induces hepatic glucuronyl

transferase activity;

SURGICAL MANAGEMENT

• Surgical management can be considered in certain cases like:

• (a) Congenital adrenal hyperplasia: Clitoroplasty and vaginal

reconstruction surgery;

• (b) Marfan syndrome: Surgery for aortic dilatation;

• (c) Hydrocephalus: Shunt surgery;

• (d) Obstructive uropathy: Intrauterine shunt or correction;

• (e) Diaphragmatic hernia: Repair

GENE THERAPY

GENETIC ENGINEERING

Health & Medicine

Genetic pattern of common pediatric disorder