Genetic Disorder &Sex Chromosomal abnormalities

Prof. K.Punithalakshmi

Professor cum Principal

JIET College of Nursing, Jodhpur

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Introduction

• 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).
• Genetic disorders may be hereditary, passed down from the parents' genes. In other genetic disorders, defects may be caused by new mutations or changes to the DNA.

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• What is the Difference Between a Genetic Defect and a Chromosomal Abnormality?
• Genes are the instructions for building and maintaining an organism. Chromosomes are the orderly chains these genes form during cell division. A genome is the complete set of genes, arranged in chromosomes, for a particular species. Genetic defects and chromosomal abnormalities are both sometimes called "genetic conditions" or "genetic disorders," but the difference lies in how much of the DNA is actually affected.

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Human Chromosomes

• The chromosome is that portion of the chromatin material of the nucleus which carries the genetic information.
• Chromosomes are composed of deoxyribonucleic acid (DNA) on framework of protein .
• Segments of DNA molecules comprise the genes; the units of heredity.
• During cell division, the chromosome can be seen to consist of 2 parallel strands; the chromatids, held together at one point, the centromere.

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Mutation

• A mutation may be defined as a permanent change in the DNA. Mutations that affect the germ cells are transputted to the progeny ( descendant) and may give rise to inherited diseases. Mutations that arises in somatic cells are important in the genesis of cancers and some congenital malformations.

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• Mutations may be classified into three catagories:
• Genome mutations – involve loss or gain of whole chromosomes (giving rise to monosomy or trisomy)
• Chromosome mutations – result from rearrangement of genetic material and give rise to visible structural changes in the chromosome.
• Gene mutations – may result in partial or complete deletion of a gene or, more often, affect a single base. For example, a single nucleotide base may be substituted by a different base, resulting in a point mutation.
• GENE (in informal use) a unit of heredity that is transferred from a parent to offspring and is held to determine some characteristic of the offspring.
• "proteins coded directly by genes"

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Types of Genetic Disorders�

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• AUTOSOMAL RECESSIVE Genetic Disorders

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• AUTOSOMAL DOMINANT Genetic Disorders

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• NONDISJUNCTION Genetic Disorders
• SEX-LINKED NONDISJUNCTION Genetic Disorders
• Chromosomal abnormalities
• Single gene disorders
• Multifactorial (polygenic) inheritance
• Unusual patterns e.g. mitochondrial inheritance
• Due to Teratogens

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• Autosomal dominant disorders - Only one mutated copy of the gene will be necessary for a person to be affected by an autosomal dominant disorder. Each affected person usually has one affected parent.(e.g.,neurofibromatosis, tuberous sclerosis, polycystic kidney disease, familiar polyposis coli, hereditary spherocytosis, Marfan syndrome, osteogenesis imperfecta, achondroplasia, familiar hypercholesterolemia)
• Autosomal recessive disorders - Two copies of the gene must be mutated for a person to be affected by an autosomal recessive disorder. An affected person usually has unaffected parents who each carry a single copy of the mutated gene (and are referred to as carriers).(e.g., cystic fibrosis, phenylketonuria, homocystinuria, hemochromatosis, sickle cell anemia, thalassemias, alkaptonuria, neurogenic muscular atrophies)

• Nondisjunction
• When chromosomes don't separate properly during meiosis.
• results in gametes w/ too many or few chromosomes.
• X-linkeddisorders (glucose-6-phosphate dehydrogenase deficiency)

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• Mitochondrial - This type of inheritance, also known as maternal inheritance, applies to genes encoded by mitochondrial DNA. Because only egg cells contribute mitochondria to the developing embryo, only mothers can pass on mitochondrial DNA conditions to their children.

Karyotype

• It is the set of chromosomes of an individual.
• It is the systematized arrangement of the chromosomes of a single cell.
• Chromosomes are arranged in groups A to G according to their shape & size.

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• In the human cell, there are 46 chromosomes or 23 pairs (diploid number); of these 23 pairs, 22 are similar in both sexes and are called the autosomes. The remaining pair is called sex chromosomes : XX in the female cells and XY in the male cells .
• The genotype is the set of genes the individual carries.
• The phenotype is the external appearance of an individual as determined by his genotype.

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Karyotype of a normal male

Chromosomal Abnormalities

• Chromosomal abnormalities are either numerical or structural.
• They are a very common cause of early spontaneous miscarriage.
• Usually, but not always, cause multiple congenital anomalies and learning difficulties.

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• Numerical Aberrations (abnormalities)
• Polyploidy: Multiple of the haploid (> Diploid)
• Aneuploidy: Abnormal number

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• Structural abnormalities
• Translocation
• Deletion
• Others

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Numerical Aberrations

• Autosomal

- Trisomies: 1 ch extra (e.g. trisomy 21-13-18)

- Monosomies: 1 ch is missing

• Sex chromosome

- Klinefilter syndrome (47, XXY male)

- Turner syndrome (45, XO female)

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�Numerical abnormalities�

Trisomy i.e. 47 chromosomes

- Trisomy 21 (the extrachromosome is No 21)

- Klinefelter syndrome ( 47, XXY male)

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Monosomy i.e. 45 chromosomes

- Monosomy 21

- Turner syndrome (the missing chromosome is X in female : 45, X or 45 XO )

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When to suspect chromosomal abnormalities?

• Abnormal features
• * coarse facies * Mongoloid eye
• * Low set ears * Micrognathia/cleft lip & palate
• * Simian crease * Clinodactyly
• Mental retardation Do chromosomal analysis
• Ambiguous genitalia Do chromosomal analysis
• Delayed puberty:
• Klinefelter syndrome and Turner syndrome

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Coarse Features�

Cardiofaciocutaneous Syndrome

Antimongoloid slant

Micrognathia�

Ambiguous Genitalia�

Clinodactyly

Nondisjunction Genetic Disorders��

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• Downs syndrome/Trisomy 21

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• Patau syndrome/Trisomy 13

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• Edwards syndrome/Trisomy 18

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Down Syndrome�(Mongolism) Trisomy 21

Incidence :

• The most common chromosomal aberration
• Incidence 1/700 live birth & 10 % of M.R.

Definition : It is trisomy 21 i.e. the cell contain an extra chromosome, number 21 i.e. the cell contains three 21 chromosomes instead of two .

Genetic types (Cytogenetics)

(1) Non-disjunction : “ 95 % of cases”

• It is due to failure of disjunction of the 2 chromosomes of the pair No 21 during division, the extra 21 chromosome is separate and so total no. in cell is 47.
• Incidence is higher with increasing maternal age & so it is age-dependent

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(2) Translocation : “ 4 % of cases”

• The extra 21 chromosome is translocated (attached) to another chromosome e.g. (15/21) so total no. of chromosomes is 46 but the genetic material is that of 47 chromosomes .
• Incidence is usually in young mothers & risk of recurrence is high & mother is called translocation carrier

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(3) Mosaicism : “ 1 % of cases”

• Some cells are normal (46 chromosomes) & others are trisomic (47 chromosomes)
• Clinical feature are less evident & M.R. is mild .

Down syndrome-Prenatal diagnosis

• Triple test ( low estriol, low maternal serum alpha-fetoprotein and elevated HCG) is often associated with chromosomal syndromes; 15-18 weeks
• Quad screen (quad test): Triple test + inhibin A (↑ )
• Ultrasonography: nuchal thickening; 11-14 weeks
• Amniocentesis: chromosomal analysis; 15-18 weeks
• Chorionic villous sampling: chromosomal analysis; 10-12 weeks

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Abnormal nuchal thickening

Clinical Features

1) Mental retardation

• Moderate - severe range except in mosaic
• Manifested by delayed smiling, laughing & recognition of mother .

2) Delayed motor development (Hypotonia)

• Delayed head support, sitting & standing

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3) Characteristic physical features

Head

• Flat occiput
• Upward slanting of palpebral fissure
• Epicanthal folds
• Flat nasal bridge
• Malformed ears
• Protruded tongue

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Hands

• Simian crease (transverse palmar crease)
• Clinodactly (incurved little finger)
• Short broad hand

Feet

• Big space between the first and second toes

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Down Syndrome

Down Syndrome

Trisomy 13 – Patau syndrome

• Symptoms
• defects of eye, nose, lip, and forebrain
• Polydactyly (more then 5 fingers or toes)
• hyperconvex fingernails (arches down)
• Only 18% survive the first year
• Survivors have severe mental defects
• seizures

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Patau syndrome

Patau syndrome

Trisomy 18- Edwards syndrome

• Clenched hand
• Distinct patterns on the fingertip
• Low Arch Dermal - the crease on tip the 5^th finger is missing.
• 80% die w/in first two months
• Only 10% survive the first year
• Usually feeble (weakness)
• Limited capacity for survival
• Resuscitation (artificial breathing) often performed at birth
• apneic episodes neonatally (stop breathing during sleep)

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Edwards syndrome

���Sex linked Nondisjunction Genetic Disorders����

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• Turner syndrome

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• Klinefelter syndrome

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• Fragile-X syndrome

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Turner Syndrome

• Females with only one X sex chromosomes
• Physical Characteristics
• Short stature
• Web neck
• Infertile
• Normal intelligence
• Low posterior hairline
• broad chest with widely spaced nipples
• elevated frequency of renal (kidney) and cardiovascular anomalies

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Turner Syndrome

Klinefelter Syndrome

• XXY
• First sex chromosome abnormality to be reported
• Tall, thin relatively long legs
• appear normal until puberty
• Hypogonadism (sex hormones are not released)
• Infertile due to undeveloped sex orgnas
• significantly reduced IQ

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Klinefelter Syndrome

Fragile X Syndrome

• In males the lower portion of the X chromosome appears constricted in a karyotype.
• Moderate mental retardation
• Fragile site - chromatin fails to condense during mitosis
• Females who carry the trait may also show symptoms
• long face with a prominent jaw, large prominent ears, high arched palate; flattened nasal bridge; Prominent forehead

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Fragile X Syndrome

Fragile x syndrome is like Autism

• Developmental delay, speech delay, short attention span or hyperactivity, mouthing of objects persisting at an age beyond expected, difficulty in disciplining the child, frequent temper tantrums, autistic-like behaviors such as rocking, talking to oneself, spinning, unusual hand movements, difficulty with transitions, preference for being alone, echolalia, poor eye contact; poor motor coordination; history of vomiting, spitting up or colic during infancy; history of self-abusive behavior; hand flapping; drooling persisting beyond expected; increase fighting with others; hand/thumb sucking.

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General Human Genetic Disorders�

• ACHONDROPLASIA
• Dwarfism- small stature
• Large head
• Skeletal disorders
• Narrow nasal passages
• Respiratory problems
• 90% of cases are fresh mutations
• Older paternal age is a contributing factor to mutation

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ACHONDROPLASIA

Marfan Syndrome

It is a genetic disorder that affects the connective tissue

• Tall stature with long slim limbs
• Low tone muscles
• Little subcutaneous or skin fat
• 60% scoliosis
• Heart disorders (thought that Abraham Lincoln had this disorder)

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Marfan Syndrome

Progeria Syndrome

• Hutchinson-Gilford Progeria Syndrome or premature aging disease.
• Noticeable 18-24 months of age.
• Life expectancy 8-21 years with an average of 14 years
• Research on these individuals are

done to help us understand

the aging process

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Progeria Syndrome

• Aged looking skin
• Growth failure
• Hip dislocation
• Arthritis, joint stiffness
• Cardiovascular atherosclerosis disease and stroke, eventually leading to death.
• Enlarged heart and high blood pressure
• Not specific to sex or ethnicity

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Progeria Syndrome

Multifactoral &Teratogens

• Maternal illness, DM, HTN, Epilepsy
• Maternal infections, TORCH
• Drugs and toxins
• Thalidomide, anticogulants, anticonvulsants, psychiatric drugs
• Alcohol and smoking.
• Fetal alcohol syndrome
• Ionizing radiation

FAS (Fetal Alcohol Syndrome)

• Maternal alcohol consumption
• Major cause of mental retardation
• Growth retardation
• Skeletal defects
• Heart defects
• enlarged head
• neurological disorders

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FAS (Fetal Alcohol Syndrome)

FAS (Fetal Alcohol Syndrome)

Metabolic Disorders

• These disorders are characteristic of a breakdown of a biochemical pathway which can cause minor problems or major problems.
• Several of these disorders

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Tay’sachs

• Lethal autosomal recessive disorder
• Blindness
• Severe mental and physical deterioration
• A missing enzyme causes progressive nerve cell damage.
• Leading to seizures and paralysis.
• Death in early childhood by 5 years of age.
• first disorder where large scaled screening was performed

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Tay’sachs

3-5 year old with advanced Taysachs

Goggle.com

Phenylketonuria (PKU)

• Autosomal recessive trait.
• Causes severe mental retardation, skin rashes, irritable behavior, musty body odor.
• Cannot degrade the amino acid phenylalanine which accumulates in body fluids preventing the brain from growing and developing normally.
• 1/10,000 live births

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Phenylketonuria (PKU)

• Autosomal recessive trait.
• Causes severe mental retardation, skin rashes, irritable behavior, musty body odor.
• Cannot degrade the amino acid phenylalanine which accumulates in body fluids preventing the brain from growing and developing normally.
• 1/10,000 live births

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Phenylketonuria (PKU)

Genomic Imprinting

• The expression of the disease phenotype depends on whether it has been inherited from the father or from the mother.
• Prader-Willi Syndrome vs. Angelman’s Syndrome

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Prader-Willi Syndrome

• It is a genetic disorder due to loss of function of specific genes.
• Obesity
• Small hands and feet
• Short stature
• Mental retardation
• Do not produce the chemical that tells them they are full
• Severely over weight
• Their crave for food can be so server that parents have to lock their refrigerators
• Inherited from the mother

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Prader-Willi Syndrome

Angelman’s Syndrome

• It is a rare neuro genetic disorder.
• “Happy Puppets” disorder
• Mental Retardation
• Can understand only simple commands
• Inappropriate laughter

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• A dominant gene expresses itself whether homozygous or heterozygous while recessive gene expresses itself only when homozygous .
• Family pedigree means summarizing genetic data that is collected by observing the patterns of transmission of traits within the family

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�Autosomal dominant inheritance �

Characteristics :

1 - Every affected person has an affected parent.

2 - Unaffected persons are normal, do not transmit the

trait, no carrier state

3 - The trait appears in every generation, no skipping

4 - The trait is transmitted by an affected person to 1/2 of his children at least.

5 - Transmission of trait is not influenced by sex or consanguinity; male to male transmission occurs

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Autosomal recessive inheritance

Characteristics:

1- Affected persons are only homozygous(2 abnormal genes)

2- Unaffected persons can be normal or carriers

(1 abnormal gene)

3- The parents of the affected child may be consanguineous

(strong relation to consanguineous marriage)

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4- Both parents of affected child have affected gene.

5- On the average1/4 of sibs (recurrence risk is 25%) of affected child are also affected.

Males & females are equally affected.

6-The trait appears mainly in sibs of patient not

his parents or off springs.

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Multifactorial (polygenic) inheritance

• It results from interaction between genetic predisposition and environmental factors

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• Such disorders are much common than single gene disorders with much lower recurrence risk

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• Examples are cleft lip, congenital heart disease, spina bifida, pyloric stenosis; and in later life diabetes, hypertension and asthma

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Mitochondrial inheritance

• Mitochondria are cytoplasmic organelles that function as major energy producers for the cell and contain their own DNA (mt DNA).
• Sperm do not contain mitochondria, so a father with a disorder due to a mitochondrial DNA mutation will not have affected children.
• Mitochondrial DNA mutations show only maternal transmission.

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Dysmorphology

• The term 'dysmorphology' literally means 'the study of abnormal form' and refers to the assessment of birth defects and unusual physical features that have their origin during embryogenesis.

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Pathogenic mechanisms

Malformation

A primary structural defect occurring during the development of a tissue or organ, e.g. spina bifida and cleft lip and palate.

Deformation

Implies an abnormal intrauterine mechanical force that distorts a normally formed structure, e.g. clubfoot, congenital hip dislocation

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Pathogenic mechanisms

Disruption

Involves destruction of a fetal part which initially formed normally; e.g. amniotic membrane rupture may lead to amniotic bands which may cause limb reduction defects.

Dysplasia

Refers to abnormal cellular organization or function of specific tissue types, e.g. skeletal dysplasias and dysplastic kidney disease.

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Disruption

Pathogenic mechanisms

Sequence

Refers to a pattern of multiple abnormalities occurring after one initiating defect. Potter's syndrome (fetal compression and pulmonary hypoplasia) is an example of a sequence in which all abnormalities may be traced to one original malformation, renal agenesis.

Association

A group of malformations that occur together more often than expected by chance, but in different combinations from case to case, e.g. VACTERL association (Vertebral anomalies, Anal atresia, Cardiac defects, Tracheo-Esophageal fistula, Renal anomalies, Limb defects).

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Early diagnosis of single gene disorders

• Prenatal diagnosis

for thalassemia and Duchenne myopathy

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• Presymptomatic diagnosis for some autosomal disorders with onset in later life

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• Carrier detection for x-linked disorders as hemophilia and Duchenne myopathy by testing factor VIII and creatine kinase in suspected females. DNA markers are more accurate.

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Genetic counselling

• It is providing information about hereditary disorders i.e. its meaning, risk, and prevention or treatment if any
• Components:

1) Correct diagnosis by history, examination and investigations including DNA testing

2) Risk estimation

3) Communication with family

4) Discussion of options for prevention and treatment if any

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Genetic counseling, indications

1. Advanced maternal age
2. Consanguinity
3. Child with congenital anomalies or dysmorphic
4. Maternal history of stillborn with congenital anomaly

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Gene therapy

• It is the artificial introduction of genes into disease tissue in order to cure the diseases

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• Steps 🡪 Integration of the introduced gene into the chromosomal DNA of recipient cells by transferring the gene into suitable cells and then inserting the transfected cells into the patient

• One example is cystic fibrosis

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Gene therapy�

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THANK YOU