Open-Label Treatment Trial of Lithium to Target the Underlying Defect in Fragile X Syndrome

Berry‐Kravis, Elizabeth; Sumis, Allison; Hervey, Crystal; Nelson, Michael N.; Porges, Stephen W.; Weng, Ning; Weiler, Ivan Jeanne; Greenough, William T.

doi:10.1097/dbp.0b013e31817dc447

Cited by 208 publications

(185 citation statements)

References 35 publications

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“…Significant improvement in behavior was seen with lithium on the total ABC-C score and three of the ABC-C subscales, the Maladaptive Behavior subscore from the Vineland Adaptive Behavior Scale, a parent visual analog scale for target behaviors, the CGI, and in verbal memory on the RBANS List Learning task. In addition, ERK1/2 phosphorylation rates, shown to be reduced in lymphocytes from humans with FXS (Weng et al, 2008), were normalized during lithium treatment (Berry-Kravis et al, 2008a), suggesting that ERK1/2 activation rates could be a biomarker for measuring changes in signaling during treatment with agents targeted to receptor-activated translational regulatory pathways. The side effects were generally mild to moderate and included polydipsia, polyuria, and abnormal thyroid measurements in a few subjects.…”

Section: Agents Reducing Overactive Signaling Between Receptors and Tmentioning

confidence: 98%

“…Thus, MMP-9 antagonists might improve dysregulated signaling through several pathways. Both lithium and minocycline have already been tested in clinical studies in patients with FXS (Berry- Kravis et al, 2008a;Paribello et al, 2010, see below).…”

Section: Targeting Downstream Signaling Molecules In Fxsmentioning

confidence: 99%

“…One exception is lithium, for which the preclinical findings in the dfmr mutant fly and Fmr1 KO mouse suggested promise of therapeutic benefit. The effects of short-term (2 months) treatment with lithium were systematically explored for a broad range of phenotypes including behavior, cognition, and biophysical measures in a pilot open-label trial in 15 subjects with FXS (Berry-Kravis et al, 2008a) in order to test the concept of inhibition of mGlu 1/5 -activated translational signaling pathways as a treatment strategy for FXS. Significant improvement in behavior was seen with lithium on the total ABC-C score and three of the ABC-C subscales, the Maladaptive Behavior subscore from the Vineland Adaptive Behavior Scale, a parent visual analog scale for target behaviors, the CGI, and in verbal memory on the RBANS List Learning task.…”

Section: Agents Reducing Overactive Signaling Between Receptors and Tmentioning

confidence: 99%

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Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Groß

Berry‐Kravis

Bassell

2011

Neuropsychopharmacol

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Fragile X syndrome (FXS) is an inherited neurodevelopmental disease caused by loss of function of the fragile X mental retardation protein (FMRP). In the absence of FMRP, signaling through group 1 metabotropic glutamate receptors is elevated and insensitive to stimulation, which may underlie many of the neurological and neuropsychiatric features of FXS. Treatment of FXS animal models with negative allosteric modulators of these receptors and preliminary clinical trials in human patients support the hypothesis that metabotropic glutamate receptor signaling is a valuable therapeutic target in FXS. However, recent research has also shown that FMRP may regulate diverse aspects of neuronal signaling downstream of several cell surface receptors, suggesting a possible new route to more direct disease-targeted therapies. Here, we summarize promising recent advances in basic research identifying and testing novel therapeutic strategies in FXS models, and evaluate their potential therapeutic benefits. We provide an overview of recent and ongoing clinical trials motivated by some of these findings, and discuss the challenges for both basic science and clinical applications in the continued development of effective disease mechanism-targeted therapies for FXS.

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Section: Agents Reducing Overactive Signaling Between Receptors and Tmentioning

confidence: 98%

Section: Targeting Downstream Signaling Molecules In Fxsmentioning

confidence: 99%

Section: Agents Reducing Overactive Signaling Between Receptors and Tmentioning

confidence: 99%

See 1 more Smart Citation

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Groß

Berry‐Kravis

Bassell

2011

Neuropsychopharmacol

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“…In addition, drug screens in easily obtainable peripheral patient cells measuring FXS-specific biomarkers would accelerate the identification of even more efficient therapies, which might differ for individual patients (13). An assay quantifying ERK1/2 activation kinetics has been suggested and used as a biomarker in FXS clinical trials, however, the underlying mechanisms of the detected ERK1/2 dysfunctions are not fully understood (14)(15)(16). Studies in Fmr1 knockout (KO) mice suggest that the ERK1/2 pathway is hypersensitive to receptor activation, but the precise mechanisms remain obscure (1).…”

Section: Introductionmentioning

confidence: 99%

Excess Protein Synthesis in FXS Patient Lymphoblastoid Cells Can Be Rescued with a p110β-Selective Inhibitor

Groß

Bassell

2011

Mol Med

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“…A recently completed open-label, singledose pilot trial (n = 12) of the mGluR5 agonist, fenobam, demonstrated no significant adverse effects and a trend toward improvement, as measured by improved prepulse inhibition (at least a 20% improvement over baseline in 6 of 12 individuals) (45). A second open-label treatment trial (n = 15) tested the effects of lithium, which reduces mGluR5 activation of downstream processes (46). There was significant improvement in several behavioral and learning measures, along with enhanced ERK activation, indicating the need for larger clinical trials.…”

Section: Clinical Correlations and Prospects For Therapeutic Intervenmentioning

confidence: 99%

Origins of Epilepsy in Fragile X Syndrome

Hagerman

Stafstrom

2009

Epilepsy Curr

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Fragile X syndrome is the leading heritable form of cognitive impairment and the leading known monogenic disorder associated with autism. Roughly one-quarter of children with this disorder have seizures, most of which are relatively benign and are resolved beyond childhood. Because of the prevalence of fragile X syndrome, numerous animal models have been developed and electrophysiological studies have taken place to investigate its pathogenesis. The investigations have yielded a wealth of information regarding the synaptic dysfunction that underlies the hyperexcitability and epileptiform features associated with this disorder.Fragile X syndrome is the most common heritable form of cognitive impairment and the principal single-gene disorder associated with autism currently known (1,2). The disorder arises when a CGG-repeat tract in the 5 noncoding region of the fragile X mental retardation 1 (FMR1) gene exceeds approximately 200 repeats (i.e., the full mutation range), at which point the gene becomes hypermethylated and transcriptionally silent (3). The absence of the FMR1 protein, FMRP, is responsible for the syndrome's clinical phenotype (4-7). The frequency of full mutation alleles in the general population is approximately 1 in 2,500 (8,9). Physical features of fragile X syndrome typically include prominent ears, long face, higharched palate, macroorchidism, and hyperextensibility of finger joints. Approximately 85% of males and 25% of females experience cognitive impairment (IQ < 70); however, nearly all patients present with behavioral dysregulation, with males tending to present with attention deficit hyperactivity disorder and FMRP is an RNA-binding protein that is believed to have multiple functions, including involvement in the dendritic transport of various mRNA species (11) and the translational regulation of mRNAs whose protein products are involved in synaptic development, function, and plasticity (12). Among known targets of FMRP-coupled translational downregulation are: 1) the microtubule-associated protein 1B (MAP1B), which is important for modulating microtubule-coupled growth of dendritic spines and for dendritic arborization (13,14), and 2) Arc, which plays a role in the internalization of subunits of AMPA (15,16) and GABA A (17) receptors.One important characteristic of fragile X syndrome is the cooccurrence of seizures in 10 to 20 percent of individuals with full mutations (18,19). Seizure patterns on EEG typically reflect features of benign focal epilepsy of childhood (especially benign childhood epilepsy with centrotemporal spikes, also known as benign Rolandic epilepsy). In the study by Berry-Kravis involving 16 children with fragile X syndrome and epilepsy, 12 children exhibited partial seizures, with 10 of the 12 having an EEG with centrotemporal spikes (19). In addition, 23% of the children who did not have seizures displayed abnormal patterns on EEG, typically centrotemporal spikes. For most individuals, seizures are readily controlled and tend to disappear in adolescence. Therefore, ...

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Open-Label Treatment Trial of Lithium to Target the Underlying Defect in Fragile X Syndrome

Abstract: Results from this study are consistent with results in mouse and fly models of FXS, and suggest that lithium is well-tolerated and provides functional benefits in FXS, possibly by modifying the underlying neural defect. A placebo-controlled trial of lithium in FXS is warranted.

Cited by 208 publications

References 35 publications

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Excess Protein Synthesis in FXS Patient Lymphoblastoid Cells Can Be Rescued with a p110β-Selective Inhibitor

Origins of Epilepsy in Fragile X Syndrome

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