The neurobiology of the Prader-Willi phenotype of fragile X syndrome

Muzar, Zukhrofi; Lozano, Reymundo; Kolevzon, Alexander; Hagerman, Randi J

doi:10.5582/irdr.2016.01082

Cited by 18 publications

(24 citation statements)

References 70 publications

(66 reference statements)

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“…FMRP is important for neurologic function and cognitive development; hence, its absence results in varying levels of ID. 1,2 Comorbid conditions common in FXS include behavioral problems such as ADHD, anxiety, ASD, self-injurious behaviors and aggression. 3,4 Medical comorbidities include recurrent otitis media, gastrointestinal reflux, seizures, strabismus, sleep problems, obesity and growth disorders.…”

Section: Introductionmentioning

confidence: 99%

“…Unlike Prader-Willi syndrome (PWS), this phenotype does not have a deletion of 15q11-q13 or maternal uniparental disomy. 2,6 Studies have shown that FMRP binds to cytoplasmic interacting FMR1 protein (CYFIP1), a protein that affects synaptic remodeling. CYFIP1 is localized to 15q11-13, a critical region in PWS.…”

Section: Introductionmentioning

confidence: 99%

“…Use of metformin in this study had been able to rescue and restore memory deficits. 2,19 Further studies performed in the Sonenberg lab 21 showed that adult treatment in FXS Knock out (KO) mouse rescued multiple phenotypes, including social novelty, grooming, and dendritic spine morphology in the hippocampus. 21 The mechanism for this effect is by normalizing ERK signaling, EIF4E phosphorylation and lowering expression of MMP9 to normal.…”

Section: Introductionmentioning

confidence: 99%

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Metformin as targeted treatment in fragile X syndrome

Tassone

Eldeeb

et al. 2017

Clinical Genetics

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Metformin as targeted treatment in fragile X syndrome

Tassone

Eldeeb

et al. 2017

Clinical Genetics

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“…Pathogenically overactive signaling pathways in FXS in the central nervous system, mTOR and PI3K, could be normalized by metformin (Gantois et al, ). This medication inhibits MMP9 production which is elevated in FXS (Dziembowska et al, ; Hoeffer et al, ; Muzar, Lozano, Kolevzon, & Hagerman, ).…”

Section: Discussionmentioning

confidence: 99%

“…Pathogenically overactive signaling pathways in FXS in the central nervous system, mTOR and PI3K, could be normalized by metformin (Gantois et al, 2017). This medication inhibits MMP9 production which is elevated in FXS (Dziembowska et al, 2013;Hoeffer et al, 2012;Muzar, Lozano, Kolevzon, & Hagerman, 2016). Baseline 50 61 53 65 72 53 59 51 Follow-up 52 66 57 65 66 56 71 60 Case 2 Baseline 47 58 50 68 66 50 48 57 Follow-up 51 68 58 68 72 61 56 63 Note: Baseline-IQ testing before introduction of metformin; Follow-up-IQ testing after one-year usage of metformin.…”

Section: Discussionmentioning

confidence: 99%

Cognitive and behavioral improvement in adults with fragile X syndrome treated with metformin‐two cases

Protić

Aydin

Tassone

et al. 2019

Molec Gen & Gen Med

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Background The majority of individuals with fragile X syndrome (FXS) have intellectual disability, behavioral problems, autism, and language deficits. IQ typically declines with age in boys with the full mutation. The results of preclinical studies demonstrated that metformin, a biguanide used to treat type 2 diabetes, rescues multiple phenotypes of FXS in both Drosophila and mouse models. Preliminary studies of patients with FXS demonstrated improvements in behavior. Methods Here, we present two cases of individuals who have been treated with metformin clinically for one year. Results Both patients demonstrated significant cognitive and behavioral improvements. They also improved eating habits and normalization of their weight percentiles. Conclusion Metformin may be a candidate drug for treatment of several types of symptoms in individuals with FXS.

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Metformin treatment in young children with fragile X syndrome

Biag

Potter

Wilkins

et al. 2019

Molec Gen & Gen Med

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BackgroundMetformin is a drug commonly used in individuals with type 2 diabetes, obesity, and impaired glucose tolerance. It has a strong safety profile in both children and adults. Studies utilizing the Drosophila model and knock out mouse model of fragile X syndrome (FXS) have found metformin to rescue memory, social novelty deficits, and neuroanatomical abnormalities. These studies provided preliminary evidence that metformin could be used as a targeted treatment for the cognitive and behavioral problems associated with FXS. Previously, a case series of children and adults with FXS treated with metformin demonstrated improvements in irritability, social responsiveness, language, and hyperactivity.MethodsHere, we present nine children with FXS between 2 and 7 years of age who were treated clinically with metformin and monitored for behavioral and metabolic changes.ResultsParent reports and developmental testing before and after metformin are presented. There were improvements in language development and behavior (such as lethargy and stereotypy) in most of the patients.ConclusionThese results support the need for a controlled trial of metformin in children with FXS under 7 years old whose brains are in a critical developmental window and thus may experience a greater degree of clinical benefit from metformin.

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The neurobiology of the Prader-Willi phenotype of fragile X syndrome

Cited by 18 publications

References 70 publications

Metformin as targeted treatment in fragile X syndrome

Metformin as targeted treatment in fragile X syndrome

Cognitive and behavioral improvement in adults with fragile X syndrome treated with metformin‐two cases

Metformin treatment in young children with fragile X syndrome

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