Genetic Basis & Clinical Features of Achondroplasia [Autosaved].pptx

important genetic diseases

1. Genetic Basis & Clinical Features of Achondroplasia Cystic Fibrosis Vitamin D Resistant Rickets Haemophilia, Duchenne Muscular Dystrophy Sickle cell Anemia Dr. Suresh Managutti MBBS MD Anatomy Associate Professor Department of Anatomy SDMCMSH, Dharwad

2. Achondroplasia Autosomal dominant inheritance Form of dwarfism Insufficient/disorderly formation of bone in epiphysial plate or cartilage/ growth plate Interferes with growth of long bones Individual does not grow in height & becomes dwarf transmit it to 50% of children who can become dwarf If both parents have defective gene then results are fatal

3. Achondroplasia Features Disproportionate head, trunk, and limbs Large head with prominent forehead (frontal bossing) Depressed nasal bridge Genetic basis- Mutation in Fibroblast Growth Factor Receptor 3 (FGFR3) gene on chromosome 4p

4. Achondroplasia (Dwarfism) Occurs due to abnormality in the development of cartilage at the ends of long bones Inherited as autosomal dominant disorder Incidence of about 1 in 25,000 births Increased paternal age (>35 years) is a high risk factor Inherited from parents if they had a sporadic mutation Mutation can be completely spontaneous in a child even when neither of his parents are affected If both parents have achondroplasia, then there are remote chances that a homozygous child may survive for more than a few months after birth

5. Achondroplasia (Dwarfism)- Genotype Mutation in FGFR3 (Fibroblast Growth Factor Receptor 3) This gene is located on short arm of chromosome 4p In 98% cases, G to A point mutation in FGFR3 gene causes glycine to arginine substitution This causes an abnormality in cartilage formation

6. Achondroplasia (Dwarfism)-Clinical Presentation Short stature Short arms Short legs Enlarged head , frontal bossing Breathing disorders Obesity Recurrent ear infections

7. Achondroplasia (Dwarfism)

8. Achondroplasia (Dwarfism)-Life Span Majority have normal intelligence Majority lead a healthy, independent and productive life Rarely intelligence may be affected secondary to hydrocephalus or other CNS disorders Mean life expectancy is approximately 10 years less than the general population Homozygous achondroplasia is a lethal condition and babies die soon after birth

9. Achondroplasia (Dwarfism)-Genetic Counselling If either of parents have achondroplasia- Amniocentesis or CVS for molecular diagnosis for the presence of FGFR3 gene on short arm of chromosome 4 USG- short limbs and excessive amniotic fluid If antenatal tests are diagnostic of achondroplasia then parents are made aware of clinical features after birth Then given a choice to terminate or not to terminate pregnancy

10. Cystic Fibrosis Autosomal Recessive Inheritance Mutation in Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene on chromosome 7 This affects the cells that produce mucus, sweat, and digestive juices Accumulation of thick sticky mucus in various ducts of the body especially lungs, pancreas It is seen only when both copies of gene inherited from each parent) are defective

11. Cystic Fibrosis Clinical features Breathing difficulties & respiratory infections Mucus obstructs the respiratory passages Formation of scar tissue(fibrosis) and cysts in the lungs Mucus blocking the digestive tract- malnutrition, cirrhosis of liver, meconium ileus in new born

12. Cystic Fibrosis(Mucoviscidosis) Affects entire body causing progressive disability and often early death Genotype Autosomal recessive disorder Mutation in CFTR Gene ( Cystic Fibrosis Transmembrane conductance Regulator ) This gene is located on chromosome 7 It regulates the components of mucus, digestive juices and sweat

13. Cystic Fibrosis(Mucoviscidosis) Clinical presentation Newborns- meconium ileus and bowel obstruction Poor growth and poor weight gain in newborn Accumulation of thick sticky mucus Frequent coughing and chest infections Shortness of breath Infertile males Infection of paranasal air sinuses- sinusitis Nasal polyps

14. Cystic Fibrosis- Genetic counselling Couples tested for CFTR gene to determine the degree of risk for newborn If both parents tested positive for mutated copy of CFTR gene then foetus can also be tested for CFTR gene- amniocentesis, CVS If there is personal or close family history- then couple should be tested If both parents carry mutated gene and foetus also carry mutated copy of CFTR gene on both the chromosomes 7, then give the chance to parents regarding termination of pregnancy There is no cure for cystic fibrosis

15. Vitamin D Resistant Rickets Hereditary hypophosphatemic rickets – low levels of phosphate in blood X linked dominant trait On Xp22 Prevalence 1 in 20,000 Signs & symptoms begin in early childhood Clinical features- - limb bone abnormalities- bowed legs or knock knees - craniosynostosis – premature fusion of skull bones dental abnormalities enthesopathy - abnormal bone growth with attachments of ligaments and tendons to the joints

16. Vitamin D Resistant Rickets Hereditary hypophosphatemic rickets

17. Vitamin D Resistant Rickets Hereditary hypophosphatemic rickets

18. Haemophilia Group of hereditary genetic disorders that impair the body’s ability to control blood clotting Haemophilia A and Haemophilia B Haemophilia A Deficiency of clotting factor VIII It is most common variety X linked recessive disorder ( more likely to occur in males than in females) Incidence- 1 in 5000 to 10,000 male births Haemophilia B Deficiency of factor IX Females are generally asymptomatic carriers Incidence- 1 in 40000 male births

19. Only under rare circumstances it affects females Haemophilia as a whole incidence - 1 in 20,000- 34,000 male births Characteristically seen in European royalty- “ The Royal Disease ” Genotype- X linked recessive disorder Haemophilia

20. Haemophilia- Clinical Presentation Internal/external bleeding episodes Prolonged bleeding and rebleeding after injury/surgery Spontaneous bleeding without trauma Bleeding in soft tissues- muscles, joints, subcutaneous tissues Normal bleeding time but prolonged Clotting time Treatment- replacement therapy with plasma derive factor VIII or IX Life expectancy- varies with severity of the disease QOL – with proper treatment- lead a near normal life Average life span- 10 years lesser than unaffected person

21. Haemophilia-Genetic Counselling Prenatal diagnosis- amniocentesis, chorionic villi sampling Sample subjected to molecular diagnosis for the presence of antihaemophilic factor A and/or B on long arm of X chromosome near the distal end If antihaemophilic factor is low or absent then parents are versed with clinical picture of the disease and given choice to decide for termination of pregnancy

22. Duchenne Muscular Dystrophy ( DMD) X linked recessive disorder Both males and females are affected, but females are more often carriers Incidence is 1 in 3000 births Genotype Mutation in Dystrophin gene located on short arm of X chromosome

23. Duchenne Muscular Dystrophy ( DMD) Clinical presentation Symptoms appear in male children before 5 years Patient C/O Progressive proximal muscles weakness of legs and pelvis Loss of muscle mass Weakness spreading to arms, neck and other areas Difficulty in standing without support Inability to ascend staircase Using braces for walking Using a wheel chair

24. Duchenne Muscular Dystrophy ( DMD) Diagnosis Biochemical- elevated creatine kinase level Histopathology- muscle biopsy- muscle tissue replaced with fat and connective tissue Chromosomal analysis- Xp21 microdeletion Life Span – late teens to mid 20’s QOL- Lower Quality of Life

25. Duchenne Muscular Dystrophy ( DMD) Genetic Counselling X linked recessive disorder Males have only 1 X chromosome So 1 copy of mutated gene is enough to cause DMD in males Fathers cannot pass X linked traits to their sons, so a mutation is transmitted to son by mother Prenatal tests are done – to see the mutated dystrophin gene If Mutated dystrophin gene is found then parents may choose to have medical termination of pregnancy There is no cure for DMD

26. Sickle cell anemia Hemoglobinopathy due to change in the structure of hemoglobin chain Autosomal recessive inheritance Affected person is homozygous for mutant gene Sickling of RBCs leads to hemolytic anemia Obstruction of small arteries due to clumping of defective RBCs resulting in thrombosis, ischemia and infarction Genotype- mutation in gene responsible for coding beta polypeptide chain- hemoglobin beta gene on short arm of chromosome 11

27. Sickle Cell Disease-mutant gene on short arm of chromosome 11 – 11p15.4

28. Sickle cell anaemia Clinical features Splenomegaly Anaemia Severe fatigue/ tiredness Bone marrow hypertrophy Frequent infections Frequent episodes of pain in different parts of body – chest pain, abdominal pain

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