A Randomized Double-Blind, Placebo-Controlled Trial of Minocycline in Children and Adolescents with Fragile X Syndrome

Leigh, Mary Jacena; Nguyen, Danh V.; Mu, Yi; Winarni, Tri Indah; Schneider, Andrea; Chechi, Tasleem; Polussa, Jonathan; Doucet, Paul; Tassone, Flora; Rivera, Susan M.; Hessl, David; Hagerman, Randi J

doi:10.1097/dbp.0b013e318287cd17

Cited by 217 publications

(156 citation statements)

References 33 publications

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“…Second, numerous targeted therapeutics for FXS are being developed, 45,46 and some FXS patients are already benefiting from some of these treatments. 47,48 …”

Section: Discussionmentioning

confidence: 99%

Intragenic FMR1 disease-causing variants: a significant mutational mechanism leading to Fragile-X syndrome

Quartier¹,

Poquet²,

Gilbert‐Dussardier³

et al. 2017

Eur J Hum Genet

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Fragile-X syndrome (FXS) is a frequent genetic form of intellectual disability (ID). The main recurrent mutagenic mechanism causing FXS is the expansion of a CGG repeat sequence in the 5′-UTR of the FMR1 gene, therefore, routinely tested in ID patients. We report here three FMR1 intragenic pathogenic variants not affecting this sequence, identified using high-throughput sequencing (HTS): a previously reported hemizygous deletion encompassing the last exon of FMR1, too small to be detected by array-CGH and inducing decreased expression of a truncated form of FMRP protein, in three brothers with ID (family 1) and two splice variants in boys with sporadic ID: a de novo variant c.990+1G4A (family 2) and a maternally inherited c.420-8A4G variant (family 3). After clinical reevaluation, the five patients presented features consistent with FXS (mean Hagerman's scores = 15). We conducted a systematic review of all rare non-synonymous variants previously reported in FMR1 in ID patients and showed that six of them are convincing pathogenic variants. This study suggests that intragenic FMR1 variants, although much less frequent than CGG expansions, are a significant mutational mechanism leading to FXS and demonstrates the interest of HTS approaches to detect them in ID patients with a negative standard work-up.

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“…Second, numerous targeted therapeutics for FXS are being developed, 45,46 and some FXS patients are already benefiting from some of these treatments. 47,48 …”

Section: Discussionmentioning

confidence: 99%

Intragenic FMR1 disease-causing variants: a significant mutational mechanism leading to Fragile-X syndrome

Quartier¹,

Poquet²,

Gilbert‐Dussardier³

et al. 2017

Eur J Hum Genet

View full text Add to dashboard Cite

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“…Lithium, thought to reduce excess mGluRdependent activation of translation by attenuating GSK3β activity and possibly phosphatidyl-inositol turnover, resulted in significant improvement in behavioral scales, verbal memory, and abnormal ERK phosphorylation rates in lymphocytes in a 2-month pilot open-label proof-of-concept trial in children and young adults with FXS [200]. A pilot placebo-controlled crossover trial of minocycline, an antibiotic that inhibits overexpressed synaptic MMP-9 in FXS models, conducted in children with FXS demonstrated mild global clinical improvement and reduction of MMP-9 levels in the blood of responders [205].…”

Section: Translation Of Targeted Treatments To Humans With Fxsmentioning

confidence: 99%

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

et al. 2015

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Fragile X syndrome (FXS), an inherited intellectual disability often associated with autism, is caused by the loss of expression of the fragile X mental retardation protein. Tremendous progress in basic, preclinical, and translational clinical research has elucidated a variety of molecular-, cellular-, and system-level defects in FXS. This has led to the development of several promising therapeutic strategies, some of which have been tested in larger-scale controlled clinical trials. Here, we will summarize recent advances in understanding molecular functions of fragile X mental retardation protein beyond the well-known role as an mRNAbinding protein, and will describe current developments and emerging limitations in the use of the FXS mouse model as a preclinical tool to identify therapeutic targets. We will review the results of recent clinical trials conducted in FXS that were based on some of the preclinical findings, and discuss how the observed outcomes and obstacles will inform future therapy development in FXS and other autism spectrum disorders.Key Words Fragile X syndrome . FMRP . mRNA translation . clinical trials . biomarkers . language development Fragile X syndrome (FXS) is one of the first single gene disorders manifesting features of autism spectrum disorder (ASD) in which extensive study of the neurobiology and synaptic mechanisms of disease in cellular and animal models has been possible. The enormous progress in basic and preclinical and clinical translational work in FXS in the last several decades has allowed FXS to emerge as an important model to illustrate successes and hurdles in the development of future targeted treatments for autism and related developmental disorders. FXS is the most common known genetic cause of intellectual disability and ASD, with an estimated frequency of about 1 in 4000-5000 [1]. The disorder affects all ethnic groups worldwide. Genetics and Phenotype of FXSFXS is one of the fragile X-associated disorders (FXDs), all of which arise from a trinucleotide repeat (CGG) expansion mutation in the promoter region of FMR1. The CGG sequence is transcribed into the 5' untranslated region of FMR1 mRNA and thus length of the repeat sequence does not affect the sequence of the protein product of FMR1 [fragile X mental retardation protein (FMRP)] [2]. Small expansions in the gene (55-200 CGG repeats), termed the Bpremutation^, occur in about 1 in 430-468 males and 1 in 151-209 females in the USA [3,4], and is associated with risk for fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency. Although the premutation is transcribed and translated to give FMRP, toxicity in fragile X-associated tremor/ataxia

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“…The mGluR5 antagonists developed by Roche and Novartis have not demonstrated efficacy in adult and childhood studies, but further studies are planned for an mGluR5 antagonist. Minocycline has been studied in children with FXS and has demonstrated some efficacy so it is often utilized clinically (35,36). Other trials included at multiple centers included metadoxine for improving attention and focus and the IGF-1 analogue developed by Neuren for the treatment of behavioral problems.…”

Section: Clinicaltrialsgov [Nct]: Id Number Nct01725152)mentioning

confidence: 99%