Classification of genetic disorders

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Genes

• Genes are the units of heredity. They contain the
  hereditary information encoded in their chemical
  structure for transmission from generation to
  generation. They affect development and function,
  both normal and abnormal.

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Genotypes

• Since genes are contained in the chromosomes,
  genes also occur in pairs. If the genes
  comprising a pair are alike (AA), the individual
  is described as homozygous for that gene.
• And if it is different (Aa) the individual is
  described as heterozygous.

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Mutation

• Genes are usually stable, but sometimes normal
  genes may be converted into abnormal ones - this
  change is called mutation. Mutation is a regular
  phenomenon in nature.
• The natural mutation rate is increased by
  exposure to mutagens such as ultraviolet rays,
  radiation or chemical carcinogens.

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Genotype

• The term genotype refers to the total genetic
  constitution of an individual But the genotype is
  relatively stable throughout the life of an
  individual. Thus there are two aspects of the
  genetic material -one fixed and the other plastic.

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Phenotype

• The term phenotype refers to the outward
  expression of the genetic constitution.
• Certain phenotype characteristics of an
  individual may change from infancy to adulthood
  such as height, weight, muscularity, body shape,
  The fixed characters are the genotype and the
  plastic ones are the phenotype.

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Chromosomal abnormalities

• Aneuploidy
• Translocation
• Deletion
• Duplication
• Inversion
• Isochrqmosomes
• Mosaicism

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Classification of genetic disorders

• These may be classified as
• a. Chromosomal abnormalitiesb. Unifactorial
  (single gene or Mendelian) diseasesc.
  Multifactorial disorders

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CHROMOSOMAL DISORDERS

• More than 300 numerical and structural types of
  chromosome aberrations have been described. A
  significant portion of embryonic and foetal
  wastage is due to chromosomal anomalies. The
  incidence of chromosomal abnormalities is 5.6 per
  1000 live births.

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Klinefelter's Syndrome

• This is a common sex -chromosome aneuploidy
  persons suffering from this syndrome are abnormal
  males having two or more X chromosomes in
  addition to one Y-chromosome (XXY, XXXY). They
  have a normal autosomal set of 22. The main
  features of this syndrome are that the affected
  persons are eunuchoid males with non-functional
  testis.

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XYY Syndrome

• The male with an extra Y chromosome has attracted
  much attention because of his reported tendency
  to anti-social, aggressive and often criminal
  behavior. However, the relationship is not yet
  clear. The principal features of this syndrome
  appear to be exceptional height (usually six feet
  and over) and a serious personality disorder
  leading to behavioural disturbances. The
  incidence of this syndrome is about 1 in 1000
  males at birth.

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Turner's Syndrome

• Persons suffering from this syndrome are apparent
  females with underdeveloped sex glands. They have
  45 chromosomes instead of the normal complement
  of 46.
• Clinically the patients are of short stature,
  infertile and have primary amenorrhoea. They
  often show other congenital defects such as
  coarctation of the aorta, pulmonary stenosis,
  renal malformations and mental retardation.

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• "Super Females" Females with 3 to 5
  X-chromosomes (XXX, XXXX, XXXXX) have beenfound.
  In general, the higher the number of
  X-chromosomes, the greater the degree of mental
  retardation and congenital abnormalities, e.g.,
  underdeveloped external genitalia, uterus and
  vagina.

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2. Relating to autosomes

• There are many syndromes associated with
  abnormalities of autosomes. mongolism is a public
  health problem in some countries,
• Most cases of mongolism are caused by an extra
  chromosome which occurs on the 21st pair.

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mongolism

• The anomaly is therefore sometimes described as
  "Trisomy 21". The syndrome is easily recognised
  in the older child and adult by the short stature
  and small round head, narrow, tilted eye-slits,
  mal-formed ears, short broad hands, lax limbs,
  mental retardation and quite a few other
  abnormalities especially internal congenital
  defects such as cardiac defects and atresia of
  the alimentary tract. In communities of European
  origin the incidence of mongolism at birth is
  reported to be one in 900 births.

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mongolism

• One observation which is important is that the
  frequency of mongolism increases with rising
  maternal age but is un-affected by the age of the
  father. The risk for a woman of 20 is estimated
  at about \ in 3,000 and that for a woman of 45, 1
  in 50.

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"point" mutation

• Mendelian diseases are individually rare since
  there is strong selection against them and gene
  mutations are rare events. Mutation usually
  occurs at random. If mutation is confined to a
  single gene it is called "point" mutation, which
  is responsible for many human diseases and
  defects.

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• Blood groups
• ABO SYSTEM
• RHESUS SYSTEM
• Erythroblastosis foetalis
• Blood groups and disease

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Sickle cell anemia

• Sickle cell anaemia is an autosomal recessive
  disorder in which an abnormal haemoglobin leads
  to chronic haemolytic anaemia with a variety of
  severe clinical consequences. The disorder is a
  classic example of disease caused by a point
  mutation in DNA. Individuals with one gene of
  this disease are clinically healthy, but their
  RBC look abnormal under the microscope..

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Thalassemias

• The thalassemias are hereditary disorders
  characterized by reduction in the synthesis of
  globin chain (alpha or beta). Reduced globin
  chain synthesis causes reduced haemoglobin
  synthesis and eventually produces a hypo chromic
  microcytic anaemia because of defective
  haemoglobinization of red cells. Thalassemias can
  be considered among hypo-proliferate anemia's,
  the hemolytic anemia's, and the anaemias related
  to abnormal haemoglobin, since all of these
  factors may play a role.

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• Haemophilia
• Cystic fibrosis
• Phenylketonuria

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MULTIFACTORIAL DISORDERS

• Role of genetic predisposition in common
  disorders
• Cancer
• Coronary heart disease
• Diabetes
• Mental Disorders

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Advances in molecular genetics

• DNA technology
• Gene Therapy
• The Human Genome Project
• The Human Genome Diversity Project

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PREVENTIVE AND SOCIAL MEASURES

• EUGENICS Galton proposed the term eugenics for
  the science which aims to improve the genetic
  endowment of human population. Eugenics has both
  negative and positive aspects.
• EuTHENICS
• Mere improvement of the genotype is of no use
  unless the improved genotype is given access to a
  suitable environment, an environment which will
  enable the genes to express themselves readily.

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• (c ) GENETIC COUNSELLING
• (i) Prospective genetic counseling
• (ii) Retrospective genetic counseling
• OTHERGENETIC PREVENTIVE MEASURES
• Consanguinous marriages
• Late marriages

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Specific protection

• Increasing attention is now being paid to the
  protection of individuals and whole communities
  against mutagens such as X-rays and other
  ionizing radiations and also chemical mutagens.
  Patients undergoing X-ray examination should be
  protected against unnecessary exposure of the
  gonads to radiation. X-ray examination of the
  pregnant uterus to determine the presence of
  twins or the lie of the foetus is to be strongly
  deprecated. Rh haemolytic disease of the newborn
  which is a genetically determined immunological
  disorder is now preventable by immunization by
  anti- D globulin.

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Early diagnosis and treatment

• Detection of genetic carriers
• Prenatal diagnosis

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Amniocentesis

• Amniocentesis is called for in the following
  circumstances ifthe parents are prepared to
  consider abortion.
• 1. A mother aged 35 years or more (because of
  high risk of Down's syndrome with advanced
  maternal age).
• 2. Patients who have had a child with Down's
  syndrome or other chromosomal anomalies.
• 3. Parents who are known to have chromosomal
  translocation.

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• 4. Parents who have had a child with a
  metabolic defect -detectable by amniocentesis.
  The most common are defects of the neural tube,
  anencephaly and spina bifida which can be
  detected by an elevation of alpha fetoprotein in
  the amniotic fluid.
• 5. When determination of the sex is warranted,
  given a family history of a sex-linked genetic
  disease e.g., certain muscular dystrophies.
• c) Screening of newborn infants
• Recognizing preclinical cases

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Rehabilitation

• Finally, rehabilitation. With many genetic or
  partially genetic conditions causing physical or
  mental disability, much can be done for the
  patient and for his family in helping him to lead
  a better and more useful life.