1. Dr. David Hessl of the UC Davis MIND Institute

Dr. David Hessl of the UC Davis MIND Institute will be undertaking a project to extend autism behavioral intervention to young children with Fragile X syndrome. Identifying the pros and cons and the particulars of behavioral interventions will be crucial to improving the lives of children with FXS, regardless of new medications. (One year, $50,000)

Specific Aims: Current treatment regimens for patients with Fragile X syndrome (FXS) rely heavily on medications to manage behavior and psychiatric symptoms, and the animal models of the disorder have given rise to multiple additional pharmacological targets now under intense study in various clinical trials. In contrast, although early intervention for this disorder is heavily emphasized, currently there is no comprehensive and developmentally appropriate behavioral treatment that has been empirically validated for young children with FXS. As such, the evaluation of the best available behavioral interventions is a critical unmet need in the field. Furthermore, when targeted pharmacological agents demonstrate efficacy, it will be essential to provide these treatments in the context of the most optimal behavioral therapeutic milieu so that learning, socialization, and communication can be maximized.

The proposed pilot project will evaluate, in a single subject multiple baseline design, the efficacy of the Early Start Denver Model (ESDM; [1-4]), a parent training curriculum originally developed for autism, for families of young children with FXS. The first two cohorts of families will receive direct, or “inperson”, training at our center. In anticipation of the need to disseminate effective therapy to geographically isolated families affected by FXS, the third cohort will be treated using telehealth or communication technology systems. The results of the study will provide critical pilot data in support of a future application for funding for a larger controlled trial.

2. Dr. Stephanie Sherman at Emory University

Dr. Stephanie Sherman at Emory University is attempting to better understand the health consequences of the FMR1 premutation in women. This topic is at the cutting edge of research on the premutation. It is very timely in light of recent papers by other premutation researchers strongly suggesting that other, yet to be confirmed, health issues resulting from the premutation are more common than previously believed. (One year, $50,000)

Specific Aims: Fragile X-associated primary ovarian insufficiency (FXPOI) is among a family of disorders caused by the expansion of a CGG repeat sequence located in the 5′ untranslated region of the X-linked gene FMR1. Twenty percent of women who carry an allele with 55-200 unmethylated CGG repeats, called the premutation (PM) allele, develop hypergonadotropic hypogonadism and cease menstruation prior to the age of 40. This is generally referred to as premature ovarian failure (POF) or primary ovarian insufficiency (POI), a term that may also include the period of diminished ovarian reserve that precedes POF. Premutation carriers (PMC) who continue to menstruate have elevated levels of follicle stimulating hormone (FSH) and low levels of anti-Müllerian hormone (AMH), both established markers of low ovarian reserve. FXPOI is just one of the 3 clinically significant Fragile X-associated disorders (FXD) that occur in families with the FMR1 mutation.

The PM also causes Fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder that occurs in women, but is more common among men with the PM. The PM can expand to the full mutation during transmission from mother to her offspring. The full mutation (>200 methylated repeats) causes Fragile X syndrome (FXS), the most common genetic form of inherited intellectual and developmental disorders and autism. Importantly, the effect of the PM may be multifaceted. Some women with the PM suffer from neuropsychological disorders such as depression, attention and memory deficits, impulsivity, and emotional lability. Some studies suggest a higher risk for medical conditions, such as thyroid disease and fibromyalgia among PMC. Whether these presentations are secondary to the hypogonadal effects of FXPOI, are due to the stress of caring for children with FXS or a parent with FXTAS, or are variable manifestations of FXTAS is unknown. To begin to answer these questions, we will develop and administer a questionnaire to PMC and noncarrier (NC) control women to assess medical and reproductive history, to obtain an accurate hormone treatment history in order to identify the number of years with hypoestrogenism, and to assess perceived stress due to caring for relatives with FXD.