Rett syndrome: Controlled study of an oral opiate antagonist, naltrexone

Percy, Alan K.; Glaze, Daniel G.; Schultz, Rebecca; Zoghbi, Huda Y.; Williamson, Dominic J.; Frost, James D.; Jankovic, Joseph; Junco, Deborah del; Skender, Martha L.; Waring, Stephen C.; Myer, Edwin C.

doi:10.1002/ana.410350415

Cited by 65 publications

(30 citation statements)

References 23 publications

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“…As such, they should include an assessment of the major clinical features as outlined in Table 1 and outcome measures such as those displayed in Table 2 as modified from Fitzgerald et al [FitzGerald et al, 1990]. Similar measures have been employed previously in our evaluation of the effect of the opiate antagonists, naltrexone and naloxone, [Percy et al, 1994] and a clinical trial of L-carnitine conducted by Ellaway et al [1999], and are currently being used in our folate-betaine trial in RS (see below). In addition, assessment of physiologic determinants including EEG characteristics, respiratory and sleep patterns, stereotypic movements, and EKG parameters is also important.…”

Section: Evaluation Of Therapeutic Efficacymentioning

confidence: 96%

“…These behaviors were reversible with the parenteral opiate antagonist, naloxone [Brase et al, 1989]. The availability of the oral analogue, naltrexone, provided the opportunity to evaluate the efficacy of this agent in ameliorating the clinical features of RS [Percy et al, 1994].…”

Section: Naltrexone Clinical Trialmentioning

confidence: 98%

“…The only other reported controlled clinical trial in females with RS involved the oral opiate antagonist, naltrexone [Percy et al, 1994]. This trial was based on the reported elevation of ␤-endorphin levels in cerebrospinal fluid from girls with RS [Brase et al, 1989;Myer et al, 1992] and increased ␤-endorphin content in thalamus and cerebellum from post-mortem tissue from one female with RS [Jellinger et al, 1988].…”

Section: Naltrexone Clinical Trialmentioning

confidence: 99%

“…The opiate antagonist, naltrexone (as described above in the treatment trial), may provide some benefit. Beneficial responses are not uniform and may be due, at least in part, to the sedating properties of this drug [Percy et al, 1994]. Dosing differences may also be responsible.…”

Section: Breathing Irregularitiesmentioning

confidence: 99%

“…Based on the hypothesis that naltrexone would be beneficial, 25 females fulfilling the clinical criteria for RS, were randomized into a double-blind, placebocontrolled crossover trial [Percy et al, 1994]. The study consisted of two treatment periods of four months each with either placebo or naltrexone and an intervening washout period of one month.…”

Section: Naltrexone Clinical Trialmentioning

confidence: 99%

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Clinical trials and treatment prospects

Percy

2002

Ment. Retard. Dev. Disabil. Res. Rev.

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Prospects for definitive therapeutic intervention for Rett syndrome (RS) have been elevated by the discovery of mutations in the methyl-CpG-binding protein 2 gene (MECP2) in more than 80% of females meeting clinical criteria for this disorder. As such, a review of previous clinical trials, descriptions of the status of clinical management for the prominent medical problems of RS, and a preview of an ongoing clinical trial conducted jointly at the Baylor College of Medicine and the University of Alabama at Birmingham are presented. The conduct of controlled clinical trials requires adherence to diagnostic criteria for RS; stratification by age, stage, and presence of MECP2 mutations; and use of clearly defined outcome measures. Previous clinical trials in RS have been conducted with L-carnitine, the ketogenic diet, and the opiate antagonist, naltrexone. The L-carnitine and naltrexone trials were double blind, placebo-controlled and us ed the motor behavioral analysis described in this review. All failed to provide evidence of dramatic improvements in the clinical features of RS. Specific recommendations are presented for clinical management of growth failure, breathing irregularities, seizures, ambulation, scoliosis, gastrointestinal function, self abuse, and habilitation/education although systematic evaluations of each in the context of RS have not been conducted. The only ongoing trial involves dietary supplementation with folate and betaine and is based on the finding that gene expression of some alleles of the agouti gene could be altered by dietary methyl supplementation. The availability of animal models expressing mutations in MECP2 should enhance the evaluation of innovative therapies for RS.

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Section: Evaluation Of Therapeutic Efficacymentioning

confidence: 96%

Section: Naltrexone Clinical Trialmentioning

confidence: 98%

Section: Naltrexone Clinical Trialmentioning

confidence: 99%

Section: Breathing Irregularitiesmentioning

confidence: 99%

Section: Naltrexone Clinical Trialmentioning

confidence: 99%

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Clinical trials and treatment prospects

Percy

2002

Ment. Retard. Dev. Disabil. Res. Rev.

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Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes

et al. 2000

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We screened 71 sporadic and 7 familial Rett syndrome (RTT) patients for MECP2 mutations by direct sequencing and determined the pattern of X chromosome inactivation (XCI) in 39 RTT patients. We identified 23 different disease‐causing MECP2 mutations in 54 of 71 (76%) sporadic patients and in 2 of 7 (29%) familial cases. We compared electrophysiological findings, cerebrospinal fluid neurochemistry, and 13 clinical characteristics between patients carrying missense mutations and those carrying truncating mutations. Thirty‐one of 34 patients (91%) with classic RTT had random XCI. Nonrandom XCI was associated with milder phenotypes, including a mitigated classic RTT caused by a rare early truncating mutation. Patients with truncating mutations have a higher incidence of awake respiratory dysfunction and lower levels of cerebrospinal fluid homovanillic acid. Scoliosis is more common in patients with missense mutations. These data indicate that different MECP2 mutations have similar phenotypic consequences, and random XCI plays an important role in producing the full phenotypic spectrum of classic RTT. The association of early truncating mutations with nonrandom XCI, along with the fact that chimeric mice lacking methyl‐CpG‐binding protein 2 (MeCP2) function die during embryogenesis, supports the notion that RTT is caused by partial loss of MeCP2 function. Ann Neurol 2000;47:670–679

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