Title: Finding the gene for hereditary motor and sensory neuropathy with pyramidal signs
1Classification of hereditary spastic paraplegias
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8normals
affecteds
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10Gene sequencing
11mutation GTAgtGGA val 148gly
12Problem- too many HSP genes and they can be very
large.
Solution collaborators specialising in
different genes new methods rapid
screening chips with many mutations
13MANAGEMENT
- Symptomatic and presymptomatic counselling -
Support of physical and social environment - Maint
ain independence - Reproductive issues -
counselling - antenatal testing and
alternatives.
14Drug treatments
- Spasticity
- antispasmodics
- baclofen (Lioresal)
- Cramps
- heat massage magnesium
- quinidine
- For bladder urgency
- oxybutynin (Ditropan)
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16Genetic Counselling issues
- Determine need
- Check diagnosis
- Check family history
- Mode of inheritance or (availability of direct
test) - - DNA - Protein
- - Cytogenetic - Ultrasound
- Make test/prediction (write it down for family)
17DIFFICULT ISSUES
- Family disruption - Denial of access (i)
to at risk individuals (ii) to affected
individual for testing - Childrens rights -
Societys rights
18SPECIFIC TREATMENTS
- - Replace product. (e.g. factor VIII)
- - Block product
- - Pharmacological treatment.
- Gene therapy
- ?? Stem cell therapy
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20Aim To identify the defective gene causing HSP
HMN with pyramidal signs
- To map the CMT with pyramidal signs gene mutation
to a chromosomal locus - To fine map the critical region
- To locate and screen genes for mutations in
linked CMT with pyramidal signs families.
21Mapping a defective gene on the chromosome
- Family selection and clinical examination
- Exclusion of known HSP loci in the selected
families - Genome screen and linkage analysis.
22Family selection and clinical examination
- Family selection is based on the clinical
features, neurophysiology, pathology and mode of
inheritance - We have 30 families available for this study
- Two large families were selected for genetic
study.
23Family
24Family 105
25Exclusion of known HSP/HMN loci in the selected
families
26linkage analysis
- Linkage analysis is a statistical technique to
test the co-segregationof trait and marker. If a
particular form of a marker, called an allele, is
always associated with a high value of the trait
then this particular marker is located close to a
gene influencing this trait. - To perform a linkage analysis
- Identifying families which segregate a disease
trait - Multigeneration families segregating a particular
trait with multiple affected individuals. - Genotyping family with genetic markers
- the human genome project has produced genetic
maps containing markers that are spaced at 1 cM
intervals on average. - Performing linkage analysis to identify
chromosomal location of disease.
27Testing power to detect linkage
28Genome Screen
- A 5 cM genome screen was performed at Australian
Genome Research Facility (AGRF) - A total of 28 individuals were genotyped (12
individuals definitely affected) - Genome screen took 2 months to obtain genotype
data for analysis.
29Maximum 2-point LOD score generated from genome
screen for each chromosome
Maximum 2-point LOD score
Chromosome
30- L O D T A B L E R E P O R T
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- Order 0.0 0.01 0.05 0.1 0.2
0.3 0.4 - ----- ------- ------- ------- ------- -------
------- ------- - D1S468 -6.34 -1.42 -0.25 0.07 0.16
0.08 0.01 - D1S2660 2.76 2.73 2.61 2.41 1.89
1.27 0.61 - D1S214 -0.90 2.33 2.71 2.61 2.07
1.36 0.62 - D1S450 -2.39 -1.48 -0.09 0.47 0.80
0.70 0.37 - D1S2667 -3.17 -1.09 -0.44 -0.21 -0.07
-0.05 -0.04 - D1S434 0.49 0.50 0.53 0.52 0.42
0.27 0.12 - D1S507 -2.13 0.34 0.99 1.19 1.16
0.88 0.47 - D1S2697 -3.27 -1.04 -0.21 0.15 0.37
0.33 0.17 - D1S2644 -4.40 -1.77 -0.83 -0.35 0.06
0.16 0.11 - D1S199 -3.52 -0.48 0.26 0.53 0.62
0.48 0.25 - D1S2684 -1.90 0.00 0.62 0.79 0.74
0.53 0.27 - D1S234 -3.95 -1.56 -0.73 -0.33 0.01
0.11 0.09 - D1S233 -0.13 -0.06 0.12 0.24 0.28
0.21 0.09
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