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Cited by 17Genetics and Neurodevelopmental DisordersDown syndrome and intellectual disability researchLysosomal Storage Disorders Research

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

van der Vaart, Thijs, Overwater, Iris E., Oostenbrink, Rianne, Moll, Henriëtte A., Elgersma, Ype·2015·JAMA Neurology
DOI 10.1001/jamaneurol.2015.0443
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Abstract

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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  • In 44% of those studies, authors reported potential efficacy, but this led to only two approved treatments: dietary restriction for phenylketonuria and miglustat for Niemann-Pick disease type C.

    “In 44% of these studies, authors reported potential efficacy, but this led to only two approved treatments: dietary restriction for phenylketonuria and miglustat for Niemann–Pick disease type C105.”

    From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [105]

  • A 2015 review identified 169 trials assessing dietary interventions and drug treatments for cognitive function in patients with 32 genetic disorders.

    “A review carried out in 2015 identified 169 trials assessing dietary interventions and drug treatments to address cognitive function in patients with 32 genetic disorders.”

    From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [105]

  • The median sample size for randomized controlled trials in that review was 25 patients, with a range of 2 to 537, and less than one third had an acceptable Jadad score above 3.

    “The median sample size for RCTs was 25 patients (range: 2–537), and less than a third of RCTs had an acceptable Jadad score exceeding 3.”

    From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [105]

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Authors
van der Vaart, T., Overwater, I. E., Oostenbrink, R., Moll, H. A., & Elgersma, Y.
Affiliations
  • Department of Neuroscience, Erasmus MC, University Medical Center, Rotterdam, the Netherlands2Department of Pediatrics, Erasmus MC, University Medical Center, Rotterdam, the Netherlands3ENCORE–Expertise Center for Neurodevelopmental Disorders, Erasmus MC,
  • Erasmus MC (NL)
ORCID
Venue
JAMA Neurology
Publisher
American Medical Association (AMA)
Published
2015-09-01
Volume
72
Issue
9
Pages
1052
ISSN
2168-6149 (ISSN-L)
DOI
10.1001/jamaneurol.2015.0443
OpenAlex
W1480207804
Cited by
17
References
34
Citations by year
2025: 3 · 2023: 1 · 2022: 3 · 2021: 2 · 2019: 2 · 2018: 2 · 2017: 2 · 2016: 1 · 2015: 1
FWCI
1.37
Type
journal article
Language
en
Open access
closed
Locations
  • JAMA Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords
intellectual disability, genetic disorders, cognitive impairment, clinical trial quality, clinical trial registries, outcome reporting, phenylketonuria, dietary restriction, miglustat, Niemann-Pick disease type C, drug efficacy
MeSH terms
Clinical Trials as Topic, Cognition Disorders, Humans, Genetic Diseases, Inborn

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