This document discusses genetic disorders and their patterns of inheritance. It covers chromosomal disorders, single gene disorders, multifactorial inheritance, and mitochondrial disorders. Specific genetic disorders discussed in detail include Huntington's disease, Marfan syndrome, cystic fibrosis, thalassemia, and their inheritance patterns (e.g. autosomal dominant, autosomal recessive). Clinical features, investigations, management, and treatment options are provided for each disorder.

1. - Dr. Gourav Thakre
Jr-3
Dept. Of Anatomy
Dr.S.C.G.M.C. Nanded

2. Genetic disorders classified into:
 Chromosomal disorders
 Single gene disorders
 Multifactorial inheritance
 Mitochondrial disorders
 Analysis of Genetic disorder

3. Terminology
 Allele or Allelomorph
 Homologous genes
 Homozygous
 Heterozygous
 Dominant
 Recessive
 Genotype
 Phenotype

4. 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.

5. Autosomal dominant (AD) inheritance
 An AD trait express in heterozygote state.
 Homozygotes of it are severly affected because of double
dose of abnormal gene.

6. Pedigree analysis

7. 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

8. Punnett Square
A a A a
a Aa aa A AA Aa
a Aa aa a Aa aa

9. Examples of AD trait are:
1) Huntington chorea
2) Marfan syndrome
3) Achondroplasia
4) Tuberous sclerosis
5) Treacher collin’s syndrome
6) Osteogenesis imperfecta
7) Neurofibromatosis
8) Myotonic dystrophy
9) Brachydactaly
10) Angioneurotic oedema
11) Familial hypercholesterolemia
12) Diabetes insipidus
13) Poliposis coli
14) True porphyria with port wine urine.

10. Huntington’s Disease or chorea
 1872- George Huntington
 Incidence: 1 in 20,000 in western europe.
 Rare in asians & africans
Cytogenetics:
 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

11. 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

13. Death usually due to complications
 Aspiration pneumonia
 Cardio respiratory failure
 Subdural haematoma
 Suicidal rate is higher

14. 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?

15. *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…

16. 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.

17. 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

18.  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

19. Investigations:
 Body measurements
 ECG
 Ophthalmic evaluation
 MRI
Management
 Regular ophthalmic evaluation
 Avoid heavy exercise
 Beta blocker
 Surgical replacement of aortic valve & Ascending aorta

20. 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.

22. Pedigree analysis

23. Punnett square

24. 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.

25. 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

26.  Incidence: 2-14%
 Sindhis & Kutchis
 2-5% in northan & eastern india
 Punnett square
 Heterozygotes carrying trait phenotypically normal or
mildly anaemic, low MCV & MCH

27.  Balanced polyomorphism: resistance to P.falciparum
infection
 Clinical Features
1. Fatigue (feeling tired) and weakness
2. Pale skin or jaundice (yellowing of the skin)
3. Protruding abdomen, with enlarged spleen and liver
4. Dark urine
5. Abnormal facial bones and poor growth

28. 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

29. 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

30. 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)

31. 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

32. 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.

33.  Clinical presentation:
- chronic lung disease
- recurrent respiratory tract infection.
- cardiac failure,
- chronic pancreatitis,
- malabsorption,
- meconium ileus,
- liver cirrhosis.

35. Mucous in the airways cannot be easily cleared from the
lungs.

36. Pancreas
Colon
Sticky mucus secretion
Ducts are filled with sticky mucus.
Scaring of tissue.

37.  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.

38. 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.

39. 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.