clinical trials 2008: genotype/phenotype jeffrey l. neul m.d., ph.d. assistant professor division of...
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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
3 – between 12 and 18 months3 – between 12 and 18 months
4 – between 6 and 12 months4 – between 6 and 12 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
Head GrowthHead Growth SittingSitting
AmbulationAmbulation Hand UseHand Use
ScoliosisScoliosis LanguageLanguage
Nonverbal Nonverbal RespiratoryRespiratory
AutonomicAutonomic StereotypiesStereotypies
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
Head GrowthHead Growth SittingSitting
AmbulationAmbulation Hand UseHand Use
ScoliosisScoliosis LanguageLanguage
Nonverbal Nonverbal RespiratoryRespiratory
AutonomicAutonomic StereotypiesStereotypies
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