Clinical Trials 2008: Genotype/Phenotype

1. Clinical Trials 2008: Genotype/Phenotype Jeffrey L. Neul M.D., Ph.D. Assistant Professor Division of Neurology Department of Pediatrics Assistant Medical Director Blue Bird Circle Rett Center Baylor College of Medicine

2. missense missense truncating truncating Genotype/phenotype correlation in typical RTT 8 mutations account for 55-65% cases in typical RTT R306C T158M R106W R133C MECP2 R255X C terminal truncations account for 8-10% R270X R168X R294X Large deletions account for 7-10%

3. Genotype/Phenotype comparison • Goal: Determine if there is any clinical difference between specific mutations • Large cohort (285 cases) allows analysis between common specific mutations • Participants: Girls and Women with Rett Syndrome seen at UAB or TCH/BCM • Clinical Severity Score assessed • Complete mutation testing • Exon 1 • Large DNA rearrangements (deletions) • Neul et al., Neurology 2008; 70: 1313-1321.

4. Typical Rett Syndrome: Clinical Criteria • Normal pre/perinatal period • Postnatal deceleration of head growth • Loss of purposeful hand skills • Stereotypic hand movements • Communication dysfunction • Social withdrawal • Absence of other disease processes

5. Clinical Severity Score-Percy • Clinical scoring system • Rated from 0 (better) to 5 (worse) • Thirteen categories Regression Onset Somatic Growth Head Growth Sitting Ambulation Hand Use Scoliosis Language Nonverbal Respiratory Autonomic Stereotypies Epilepsy • Overall score is a sum of all categories

6. Clinical Severity Score-example • Regression Onset 0 – No regression 1 - > 30months old 2 – between 18 and 30 months 3 – between 12 and 18 months 4 – between 6 and 12 months 5 – less than 6 months old

7. Genotype/Phenotype comparison

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

10. Genotype/Phenotype • What categories of the clinical severity score are different? Regression Onset Somatic Growth Head Growth Sitting Ambulation Hand Use Scoliosis Language Nonverbal Respiratory Autonomic Stereotypies Epilepsy

11. Genotype/Phenotype • What categories of the clinical severity score are different? Regression Onset Somatic Growth Head Growth Sitting AmbulationHand Use Scoliosis Language Nonverbal Respiratory Autonomic Stereotypies Epilepsy p<0.0038 Kruskal Wallis Bonferroni corrected

14. Full/partially preserved Absent/lost

19. C terminal truncations R306C R294X R133C R255X R270X R168X R106W Genotype/PhenotypeMolecular Conclusions MILD-hypomorphic SEVERE-null Large Deletions

20. Genotype/PhenotypeImportance for clinical trials • Specific common mutations have different clinical severity. • Balanced study design • Intra-subject paired design • Compare pre- and post-treatment • Each participant functions as own control.

21. Acknowledgements Blue Bird Circle Rett Center Daniel Glaze Judy Barrish Gay Horelica O’Brian Smith UAB Rett Center Alan Percy Jane Lane

22. *, # pair-wise p<0.05

25. Severity of Mutations p=0.0007 */# p<0.05 Differences for R133C, R168X, and large deletions hold up when only random XCI cases considered.

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27. * * * * Preserved * Short phrases * Single words * * Vocalizations None

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