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.
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.
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
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
12.
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
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.
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.
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.
Editor's Notes
Dural ectasia: enlargement of dural sac – seen in 60-80%