Clinical Trials 2008: Genotype/Phenotype

Clinical Trials 2008: Clinical Trials 2008: Genotype/PhenotypeGenotype/Phenotype

Jeffrey L. Neul M.D., Ph.D.Jeffrey L. Neul M.D., Ph.D.Assistant ProfessorAssistant Professor

Division of NeurologyDivision of NeurologyDepartment of PediatricsDepartment of Pediatrics

Assistant Medical DirectorAssistant Medical DirectorBlue Bird Circle Rett CenterBlue Bird Circle Rett CenterBaylor College of MedicineBaylor College of Medicine

8 mutations account for 55-65% cases in typical RTT

MECP2

C terminal truncationsaccount for 8-10%

R106WR133C

T158M

R168X

R255X

R270X

R294X

R306Cmissensemissense

truncatingtruncating

Large deletions account for 7-10%

Genotype/phenotype correlation in typical RTTGenotype/phenotype correlation in typical RTT

Genotype/Phenotype Genotype/Phenotype comparisoncomparison

Goal: Determine if there is any clinical difference Goal: Determine if there is any clinical difference between specific mutationsbetween specific mutations

Large cohort (285 cases) allows analysis Large cohort (285 cases) allows analysis between common specific mutationsbetween common specific mutations

Participants: Girls and Women with Rett Participants: Girls and Women with Rett Syndrome seen at UAB or TCH/BCMSyndrome seen at UAB or TCH/BCM

Clinical Severity Score assessedClinical Severity Score assessed Complete mutation testing Complete mutation testing

Exon 1Exon 1 Large DNA rearrangements (deletions)Large DNA rearrangements (deletions)

Neul et al., Neurology 2008; 70: 1313-1321.Neul et al., Neurology 2008; 70: 1313-1321.

Typical Rett Syndrome: Typical Rett Syndrome: Clinical CriteriaClinical Criteria

Normal pre/perinatal periodNormal pre/perinatal period Postnatal deceleration of head growthPostnatal deceleration of head growth Loss of purposeful hand skillsLoss of purposeful hand skills Stereotypic hand movementsStereotypic hand movements Communication dysfunction Communication dysfunction Social withdrawalSocial withdrawal Absence of other disease processesAbsence of other disease processes

Clinical Severity Score-PercyClinical Severity Score-Percy Clinical scoring systemClinical scoring system Rated from 0 (better) to 5 (worse)Rated from 0 (better) to 5 (worse)

Thirteen categoriesThirteen categoriesRegression OnsetRegression Onset Somatic GrowthSomatic Growth

Head GrowthHead Growth SittingSitting

AmbulationAmbulation Hand UseHand Use

ScoliosisScoliosis LanguageLanguage

Nonverbal Nonverbal RespiratoryRespiratory

AutonomicAutonomic StereotypiesStereotypies

EpilepsyEpilepsy

Overall score is a sum of all categoriesOverall score is a sum of all categories

Clinical Severity Score-exampleClinical Severity Score-example

Regression OnsetRegression Onset0 – No regression0 – No regression

1 - > 30months old1 - > 30months old

2 – between 18 and 30 months2 – between 18 and 30 months



5 – less than 6 months old5 – less than 6 months old

Genotype/Phenotype Genotype/Phenotype comparisoncomparison

RTT TypeRTT Type MutationMutation No mutationNo mutation TotalTotal

TypicalTypical 237 (97%)237 (97%) 8 (3%)8 (3%) 245245

AtypicalAtypical 30 (75%)30 (75%) 10 (25%)10 (25%) 4040

Random XCI cases: R168X (n=12), R133C (n=7), R306C (n=8), Large Deletions (n=8)

Genotype/PhenotypeGenotype/Phenotype What categories of the clinical severity What categories of the clinical severity

score are different?score are different?Regression OnsetRegression Onset Somatic GrowthSomatic Growth






EpilepsyEpilepsy

Genotype/PhenotypeGenotype/Phenotype What categories of the clinical severity What categories of the clinical severity

score are different?score are different?Regression OnsetRegression Onset Somatic GrowthSomatic Growth






EpilepsyEpilepsy p<0.0038 Kruskal Wallisp<0.0038 Kruskal WallisBonferroni correctedBonferroni corrected

Ambulation Hand Use Language

0 Acquired<18mo Acquired and conserved

preserved

1 18mo<walks alone<30mo

Acquired on time, partially conserved

Short phrases

2 >30mo walks alone

Acquired late, partially conserved

Single words

3 >50mo or walks with help

Acquired and lost Vocalization/babbling

4 lost Never acquired Screaming/none

5 Never acquired

Ambulation Hand Use Language

0 Acquired<18mo Acquired and conserved

preserved

1 18mo<walks alone<30mo

Acquired on time, partially conserved

Short phrases

2 >30mo walks alone

Acquired late, partially conserved

Single words

3 >50mo or walks with help

Acquired and lost Vocalization/babbling

4 lost Never acquired Screaming/none

5 Never acquired

Absent/lost

Full/partially preserved

Clinical category Retained function or mildly affected

Regression Regression after 18 mo of life

Somatic growth weight decrease less than 2SD

Head growth OFC greater than the 10th% > 24 mo of life

Motor/sitting sitting maintained

Ambulation walks independently

Hand Use at least partially conserved

Scoliosis less than 20%

Language skills at least single words

Nonverbal communication maintains eye contact > 5 seconds

Respiratory dysfunction minimal respiratory dysfunction (<10%)

Autonomic symptoms no autonomic abnormality

Stereotypy stereotypy onset after 36 mo of life

Seizures absent or less than monthly

Genotype/PhenotypeGenotype/PhenotypeMolecular ConclusionsMolecular Conclusions

R106W

R133C

R168X

R255X

R270X

R294X

R306C C terminal truncations

MILD-hypomorphic

SEVERE-null

Large Deletions

Genotype/PhenotypeGenotype/PhenotypeImportance for clinical trialsImportance for clinical trials

Specific common mutations have different Specific common mutations have different clinical severity.clinical severity.

Balanced study designBalanced study design Intra-subject paired design Intra-subject paired design

Compare pre- and post-treatment Compare pre- and post-treatment Each participant functions as own control.Each participant functions as own control.

AcknowledgementsAcknowledgementsBlue Bird Circle Rett Blue Bird Circle Rett

CenterCenter

Daniel GlazeDaniel Glaze

Judy BarrishJudy Barrish

Gay HorelicaGay Horelica

O’Brian SmithO’Brian Smith

UAB Rett CenterUAB Rett Center

Alan PercyAlan Percy

Jane LaneJane Lane

Walks alone(%)

Uses words(%)

At least partially

conserved hand use (%)

R133C 75 50* 92*

R294X 86* 50* 86*

C-term 78* 67*# 83

Del 41 12 # 53

R168X 28* 3* 38*

*, # pair-wise p<0.05

Mutation group n %Age of Exam (mo)

Mean (SD)

R106W 9 3.7 173.5 (97.9)

R133C 12 4.9 124.8 (71.0)

T158M 29 12.2 104.9 (66.2)

R168X 29 11.8 132.5 (101.5)

R255X 32 13.1 99.5 (76.7)

R270X 18 7.4 146.3 (167.2)

R294X 14 5.7 183.8 (79.3)

R306C 21 8.6 141.6 (122.1)

Large rearrangements 18 6.9 101.1 (61.0)

C-term truncations 18 7.3 136.7 (101.3)

Other mutations 38 15.1 105.1 (70.0)

no mutation 8 3.3 158.3 (97.9)

Total 245 100 125.5 (95.9)

Severity of MutationsSeverity of Mutations

p=0.0007

*/# p<0.05

Classic Rett Syndrome CSS per mutation

05

1015202530

R13

3C

R29

4X

Cte

rm

R30

6C

T15

8M

Oth

erM

ut

no m

ut

R27

0X

R25

5X

R10

6W

Larg

eD

el

R16

8X

CS

S

**

*

#

# #

Differences for R133C, R168X, and large deletions hold up when only random XCI cases considered.

0

1

2

3

4

5

0

25

50

75

100

%

Ambulation

*

**

*

**

*

0

1

2

3

4

0

25

50

75

100

Language

*

*

**

Prese

rved

Short

phra

ses

None

Singl

e wor

dsVoc

aliz

atio

ns

0

1

2

3

4

0

25

50

75

100

Hand Use

*

**

*

genotype nwalks alone

(%)uses hands

(%)uses words

(%)

R106W 9 33 56 33

R133C 12 75 92* 50 *

T158M 30 60 50 27

R168X 29 28 * 38* 3 *

R255X 32 38 59 28

R270X 18 44 67 22

R294X 14 86 * 86 50 *

R306C 21 67 52 10 #

c-term. trunc. 17 82 * 88* 71 *#

large del. 17 41 53 12 #

other 37 43 78* 41 *

no mutation 9 33 78 33

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Clinical Trials 2008: Genotype/Phenotype