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Treatment of Cognitive Deficits in Genetic Disorders A Systematic Review of Clinical Trials of Diet and Drug Treatments

Thijs van der Vaart, MSc1,2,3; Iris E. Overwater, MSc3,4; Rianne Oostenbrink, MD, PhD2,3; Henriëtte A. Moll, MD, PhD2,3; Ype Elgersma, PhD1,3
[+] Author Affiliations
1Department of Neuroscience, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
2Department of Pediatrics, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
3ENCORE–Expertise Center for Neurodevelopmental Disorders, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
4Department of Neurology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
JAMA Neurol. 2015;72(9):1052-1060. doi:10.1001/jamaneurol.2015.0443.
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Importance  Knowing the underlying etiology of intellectual disability in genetic disorders holds great promise for developing targeted treatments. Although successful preclinical studies and many positive clinical studies have been reported, it is unclear how many purported therapies have become established treatments. The quality of the clinical trials may be an important determinant for achieving clinical impact.

Objective  To evaluate clinical impact, strengths, and weaknesses of clinical trials of diet or drug treatments to improve cognitive function in patients with a genetic disorder.

Evidence Review  MEDLINE, EMBASE, PsycINFO, and Cochrane databases were searched from inception date to January 26, 2014, for clinical trials with cognitive outcomes in patients with genetic disorders. Outcome measures of randomized clinical trials (RCTs) were compared between trial registries and reports, and trials were evaluated for the quality of design using the Jadad score and Consolidated Standards of Reporting Trials (CONSORT) criteria.

Findings  We identified 169 trial reports of 80 treatments for 32 genetic disorders. Seventy-five trials (44.4%) reported potential efficacy, of which only 2 therapies are now established treatments, namely, dietary restriction for phenylketonuria and miglustat for Niemann-Pick disease type C. The median sample size for RCTs was 25 (range, 2-537). Only 30 of 107 RCTs (28.0%) had acceptable Jadad scores exceeding 3. Reporting of key CONSORT items was poor. Reported outcome measures matched preregistered outcome measures in trial registries in only 5 of 107 RCTs (4.7%).

Conclusions and Relevance  The number of trials in the field of cognitive genetic disorders is rapidly growing, but clinical impact has been limited because few drugs have become established treatments and the benefit of most drugs remains unclear. Most trials have small sample sizes and low quality of design. Predefinition of outcome measures, improved trial reporting and design, and international collaboration to increase recruitment are needed to unequivocally determine efficacy of drugs identified in preclinical research.

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Figure 1.
Search Strategy and Results

In the first round, titles and abstracts were screened and excluded when articles were about nongenetic disorders, involved animal models, or did not describe a clinical trial with a biological intervention. In the second round, full texts were analyzed, and reviews, conference abstracts, and studies using only behavioral outcome measures or questionnaire-based outcomes were excluded. Articles written in English were selected. Four articles were follow-up reports, and these were excluded. RCTs indicates randomized clinical trials.

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Figure 2.
Clinical Trials Reporting Cognitive Outcomes in Genetic Disorders Over Time and Their Rationale

Studies based on animal models are increasingly published. Other rationales include empirical clinical data from human studies (eg, biomarkers and functional magnetic resonance imaging) or efficacy in a related disorder.

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