A mosaic activating mutation in AKT1 associated with the Proteus syndrome.

BACKGROUND: The Proteus syndrome is characterized by the overgrowth of skin, connective tissue, brain, and other tissues. It has been hypothesized that the syndrome is caused by somatic mosaicism for a mutation that is lethal in the nonmosaic state. METHODS: We performed exome sequencing of DNA from biopsy samples obtained from patients with the Proteus syndrome and compared the resultant DNA sequences with those of unaffected tissues obtained from the same patients. We confirmed and extended an observed association, using a custom restriction-enzyme assay to analyze the DNA in 158 samples from 29 patients with the Proteus syndrome. We then assayed activation of the AKT protein in affected tissues, using phosphorylation-specific antibodies on Western blots. RESULTS: Of 29 patients with the Proteus syndrome, 26 had a somatic activating mutation (c.49G→A, p.Glu17Lys) in the oncogene AKT1, encoding the AKT1 kinase, an enzyme known to mediate processes such as cell proliferation and apoptosis. Tissues and cell lines from patients with the Proteus syndrome harbored admixtures of mutant alleles that ranged from 1% to approximately 50%. Mutant cell lines showed greater AKT phosphorylation than did control cell lines. A pair of single-cell clones that were established from the same starting culture and differed with respect to their mutation status had different levels of AKT phosphorylation. CONCLUSIONS: The Proteus syndrome is caused by a somatic activating mutation in AKT1, proving the hypothesis of somatic mosaicism and implicating activation of the PI3K-AKT pathway in the characteristic clinical findings of overgrowth and tumor susceptibility in this disorder. (Funded by the Intramural Research Program of the National Human Genome Research Institute.).

Evaluating quality of life after endolymphatic sac surgery: The Ménière's Disease Outcomes Questionnaire.

OBJECTIVE: To develop a disease-specific instrument to measure the quality of life in patients with Ménière's disease and to assess quality-of-life outcomes after endolymphatic sac decompression. STUDY DESIGN: Retrospective survey. PATIENTS: Patients with Ménière's disease who underwent endolymphatic sac decompression from June 1996 to June 2001, after failing a course of medical management. Two hundred fifteen potential subjects were identified; completed questionnaires were returned by 159 patients. MAIN OUTCOME MEASURES: The Ménière's Disease Outcomes Questionnaire was developed, and consists of questions in three domains that determine quality of life: physical, emotional, and social well-being. The Ménière's Disease Outcomes Questionnaire consisted of 18 multiple-choice questions that were paired for pre- and postoperative conditions, and one global quality-of-life question. The preoperative quality-of-life score (total score for preoperative items) was compared with the postoperative quality-of-life score. The main outcomes measure was the change in quality-of-life score. RESULTS: Overall, the mean change in quality-of-life score was +25.6 points (range, -34 to 83) (p < 0.001). The change in Ménière's Disease Outcomes Questionnaire quality-of-life score was highly correlated with the change in the global question score (p < 0.01). Quality of life was improved in 87% of respondents, unchanged in 3% of patients, and poorer in 9% of patients after endolymphatic sac decompression. CONCLUSIONS: The Ménière's Disease Outcomes Questionnaire is a new disease-specific quality-of-life tool that is a valid measure of quality of life in patients with Ménière's disease, and is responsive to measuring change in quality of life after treatment. Significant improvement in quality of life was reported by 87% of patients after endolymphatic sac decompression.