Classification of hereditary spastic paraplegias

NucleusRetrograde Transport

Anterograde Transport

Cell Body Distal Axon

NEURONOPATHIES AXONOPATHIES

normals affecteds

Gene sequencing

*mutationGTA>GGGA

val 148gly

*

Problem- too many HSP genes and they can be very large.

Solution:

collaborators specialising in different genes

new methodsrapid screeningchips with many mutations

- Symptomatic and presymptomatic counselling

- Support of physical and social environment

- Maintain independence

- Reproductive issues

- counselling

- antenatal testing and alternatives.

MANAGEMENT

Drug treatments

Spasticity:antispasmodics:

baclofen (Lioresal)

Crampsheat massage magnesiumquinidine

For bladder urgencyoxybutynin (Ditropan)

Determine needCheck diagnosisCheck family historyMode of inheritance or (availability of direct test)

- DNA - Protein- Cytogenetic - Ultrasound

Make test/prediction (write it down for family)

Genetic Counselling issues

DIFFICULT ISSUES

- Family disruption

- Denial of access

(i) to at risk individuals

(ii) to affected individual for testing

- Children’s rights

- Society’s rights

- Replace product. (e.g. factor VIII)

- Block product

- Pharmacological treatment.

- Gene therapy

- ?? Stem cell therapy

SPECIFIC TREATMENTS

Aim: To identify the Aim: To identify the defective gene causing HSP defective gene causing HSP & HMN with pyramidal signs& 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.

Mapping a Mapping a defective genedefective gene on the chromosomeon the chromosome

• Family selection and clinical examination;Family selection and clinical examination;

• Exclusion of known HSP loci in the Exclusion of known HSP loci in the selected families;selected families;

• Genome screen and linkage analysis.Genome screen and linkage analysis.

Family selection and clinical Family selection and clinical examinationexamination

• 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.

FamilyFamily1 2

3 4 5 6 7 8

9 10 11 12

?13 14 15 16 17 18

19 20 21

?22 23 24 25 26 27 28 29 30 31 32 33 34 35

36 44

?38 39

?40 41

?42

?4337

45 46

47

?48

?49

5051

?52

?53

?54

?55

?56

59

?57

?58

Family 105

2

4

14 15 16 17

6

18

8

19 20 21 22

11

23 24

13

28 26

?3031 32

?35 36

?

Exclusion of known Exclusion of known HSP/HMN loci in the HSP/HMN loci in the

selected familiesselected families

• Linkage analysis is a statistical technique to Linkage analysis is a statistical technique to test the co-test the co-segregationsegregationof trait and marker. If a particular form of a marker, called an of trait and marker. If a particular form of a marker, called an allele, is always associated with a high value of the trait then allele, is always associated with a high value of the trait then this particular marker is located close to a gene influencingthis particular marker is located close to a gene influencing this traitthis trait..

• To perform a linkage analysis:To perform a linkage analysis:– Identifying families which segregate a disease trait;Identifying families which segregate a disease trait;

• Multigeneration families segregating a particular trait Multigeneration families segregating a particular trait with multiple affected individuals.with multiple affected individuals.

– Genotyping family with genetic markers;Genotyping family with genetic markers;• the human genome project has produced genetic maps the human genome project has produced genetic maps

containing markers that are spaced at 1 cM intervals on containing markers that are spaced at 1 cM intervals on average.average.

– Performing linkage analysis to identify chromosomal Performing linkage analysis to identify chromosomal location of disease.location of disease.

linkage analysislinkage analysis

Family Recombination Fraction Zmax

0.00 0.05 0.10 0.20

Family 66 3.53 + 0.05 2.42 + 0.06 1.72 + 0.05 0.87 + 0.04 5.50

Family 105 3.02 + 0.04 2.18 + 0.06 1.55 + 0.05 0.74 + 0.04 4.86

Testing power to Testing power to detect linkagedetect linkage

Genome ScreenGenome Screen

• A 5 cM genome screen was performed at A 5 cM genome screen was performed at Australian Genome Research Facility Australian Genome Research Facility (AGRF);(AGRF);

• A total of 28 individuals were genotyped A total of 28 individuals were genotyped (12 individuals definitely affected);(12 individuals definitely affected);

• Genome screen took 2 months to obtain Genome screen took 2 months to obtain genotype data for analysis.genotype data for analysis.

Maximum 2-point LOD score Maximum 2-point LOD score generated from genome screen for generated from genome screen for

each chromosomeeach chromosome

0

0.5

1

1.5

2

2.5

3

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Series1

Chromosome

Max

imu

m 2

-poi

nt

LO

D s

core

L O D T A B L E R E P O R T

•

• 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

26

1 2

3 4 5 6 7 8

9 10 11 12

?13

?14 15 16 17 18

19 20 21

?22 23 24 25 27 28 29 30 31 32 33 34 35

36 44

?38 39

?40 41

?42

?4337

45 46

47

?48

?49

5051

?52

?53

?54

?55

?56

59

?57

?58

I

II

III

IV

V