Mendelian Inheritance Caused by single mutanat gene. Follow one of the following four pattern of inheritance. - Autosomal Dominant. - Autosomal Recessive - Sex/ X- linked Dominant - X- linked Recessive inheritance.
Autosomal dominant (AD) inheritance An AD trait express in heterozygote state. Homozygotes of it are severly affected because of double dose of abnormal gene.
Unaffected parent in dominant trait A normal parent can be expected under 3 condition. 1) If the trait occurs because of mutant gene. 2) Gene though present in the parent has low expressivity. 3) Another reason could be extramarital paternity. Two features associated with AD are: Delayed onset Variable clinical expression
Punnett Square A a A a a Aa aa A AA Aa a Aa aa a Aa aa
Huntington’s Disease or chorea 1872- George Huntington Incidence: 1 in 20,000 in western europe. Rare in asians & africansCytogenetics: 4p16 80% early onset show paternal inheritance Similar expression in homozygous & heterozygous C-A-G nucleotide repeats > 36 Huntingtin Protein produced. Affects brain and spinal cord, especially the basal ganglia
Clinical features: Appears at 30-50 yrs Progressive dementia Several neurological & mental illness Psychiatric disorders Uncontrolled choreic movements Substantial degeneration of neurons Several parts affected Max. damage in corpus striatum
Death usually due to complications Aspiration pneumonia Cardio respiratory failure Subdural haematoma Suicidal rate is higher
Diagnosis & Treatment Diagnosis Family history, physical exam, cognitive/emotional assessment (Autosomal dominant: 50% chance for offspring) CT or MRI scan to show brain changes Blood test - HD defective gene presence?
*Treatment None Medications and drug treatment may relieve some symptoms (Depression or Psychosis) Benzodiazepenes to control chorea. Speech, physical, and occupational, therapy may help Ultimately, HD has no cure…
Marfan syndrome Disorder of fibrous connective tissue 1 in 10,000 Defect in type 1 fibrillin FBN1 gene 15q21 Fibrillin is imp. Component in connective tissue of aorta, periostium & ligaments of lens.
Clinical Features Eye: superior lens dislocation (ectopia lentis) Oropharynx: high palate and crowded dentition Cardiac: Mitral valve prolapse Aortic root dilation Pulmonary: Spontaneous pneumothorax Neurologic: Dural ectasia Skin: Stretch marks
Musculoskeletal: Tall stature Long digits Thumb sign (distal phalanx protrudes beyond border of clenched fist) Wrist sign (thumb and fifth digit overlap when around the wrist) Sternal deformity (prominent pectus) Scoliosis > 20 degrees Joint hypermobility Arm span exceeding height (ratio >1.05) Reduced elbow extension (<170 degrees) Medial displacement of medial malleolus
Investigations: Body measurements ECG Ophthalmic evaluation MRIManagement Regular ophthalmic evaluation Avoid heavy exercise Beta blocker Surgical replacement of aortic valve & Ascending aorta
Autosomal recessive inheritance Recessive trait is expressed only in homozygote state. The homozygote receives one abnormal gene from each parent. The trait typically appears only in siblings. A heterozygote for an autosomal recessive trait is called carrier.
Examples of AR inheritance: Many inborn error of metabolism. - Albinism - Galactosemia - Phenylketonuria. - Mucopolysaccharide disorders (Hurler’s Syndrome, Tay-Sachs disease) Haemoglobinopathies - Sickle cell anaemia. - Thalassemia Immunoglobinopathies Cystic fibrosis.
Thalassemia Syndrome Thalassa / Sea Mediterranean sea Mediterranean or Cooley’s Anaemia Normally 4 globin chains 2 alpha: chromosome 16 2 beta: chromosome 11 Two types - alpha thalassemia - beta thalassemia beta thalassemia common in india
Incidence: 2-14% Sindhis & Kutchis 2-5% in northan & eastern india Punnett square Heterozygotes carrying trait phenotypically normal or mildly anaemic, low MCV & MCH
Balanced polyomorphism: resistance to P.falciparum infection Clinical Features1. Fatigue (feeling tired) and weakness2. Pale skin or jaundice (yellowing of the skin)3. Protruding abdomen, with enlarged spleen and liver4. Dark urine5. Abnormal facial bones and poor growth
Beta Thalassemia Trait slight lack of beta globin smaller red blood cells that are lighter in colour due to lack of hemoglobin no major symptoms except slight anemia
Beta Thalassemia Intermedia lack of beta globin is more significant bony deformities due to bone marrow trying to make more blood cells to replace defective ones causes late development, exercise intolerance, and high levels of iron in blood due to reabsorption in the GI tract if unable to maintain hemoglobin levels between 6 gm/dl – 7 gm/dl, transfusion or splenectomy is recommended
Beta Thalassemia Major complete absence of beta globin enlarged spleen, lightly coloured blood cells severe anemia chronic transfusions required, in conjunction with chelation therapy to reduce iron (desferoxamine)
More Permanent Options Bone Marrow Transplants Replacing patient’s marrow with donor marrow First performed on thalassemia patient in 1981 Difficult, because donor must be exact match for recipient Even a sibling would only have a 1 in 4 chance of being a donor Cord Blood Transplants Rich in stem cells Also needs to be an exact match
Cystic fibrosis AR disorder. mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Incidence : in caucasians 1 in 2000/ 3000. in general population 1 in 17000. CFTR controls chloride ion movement in and out of the cell.
Mucous in the airways cannot be easily cleared from the lungs.
Pancreas ColonSticky mucus secretion Ducts are filled with sticky mucus. Scaring of tissue.
Locus: 7q31.2 - The CFTR gene is found in region q31.2 on the long (q) arm of human chromosome 7. Gene Structure: The normal allelic variant for this gene is about 250,000 bp long and contains 27 exons.
Diagnosis : - Elevated level of sodium and chloride in sweat, - Trypsin in blood elevated, - gene mapping of CF locus.Treatment: replace the defective gene clear the abnormal and excess secretions and control infections in the lungs, and to prevent obstruction in the intestines.
Gene Therapy Gene therapy is the use of normal DNA to "correct" for the damaged genes that cause disease. In the case of CF, gene therapy involves inhaling a spray that delivers normal DNA to the lungs. The goal is to replace the defective CF gene in the lungs to cure CF or slow the progression of the disease.