Hypertension in <i>FMR1</i> premutation males with and without fragile X‐associated tremor/ataxia syndrome (FXTAS)

Hamlin, Alyssa; Sukharev, Dina; Campos, Luis; Mu, Yi; Tassone, Flora; Hessl, David; Nguyen, Danh V.; Loesch, Danuta Z.; Hagerman, Randi J.

doi:10.1002/ajmg.a.35323

Cited by 48 publications

(50 citation statements)

References 37 publications

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“…These are usually healthy individuals who are at risk of developing fragile X-associated tremor/ataxia syndrome, a neurodegenerative disorder seen in aging carriers 3. They are also at an increased risk for anxiety and mood disorders,4 immune-mediated disorders,5 migraine headaches,6 hypertension,7 and primary ovarian insufficiency,8 all of which range in severity and prevalence. Adult female carriers have evidence of gamma-aminobutyric acid (GABA) dysfunction 9…”

Section: Introductionmentioning

confidence: 99%

Modulation of the GABAergic pathway for the treatment of fragile X syndrome

Lozano¹,

Hare²,

Hagerman³

2014

NDT

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Fragile X syndrome (FXS) is the most common genetic cause of intellectual disability and the most common single-gene cause of autism. It is caused by mutations on the fragile X mental retardation gene (FMR1) and lack of fragile X mental retardation protein, which in turn, leads to decreased inhibition of translation of many synaptic proteins. The metabotropic glutamate receptor (mGluR) hypothesis states that the neurological deficits in individuals with FXS are due mainly to downstream consequences of overstimulation of the mGluR pathway. The main efforts have focused on mGluR5 targeted treatments; however, investigation on the gamma-aminobutyric acid (GABA) system and its potential as a targeted treatment is less emphasized. The fragile X mouse models (Fmr1-knock out) show decreased GABA subunit receptors, decreased synthesis of GABA, increased catabolism of GABA, and overall decreased GABAergic input in many regions of the brain. Consequences of the reduced GABAergic input in FXS include oversensitivity to sensory stimuli, seizures, and anxiety. Deficits in the GABA receptors in different regions of the brain are associated with behavioral and attentional processing deficits linked to anxiety and autistic behaviors. The understanding of the neurobiology of FXS has led to the development of targeted treatments for the core behavioral features of FXS, which include social deficits, inattention, and anxiety. These symptoms are also observed in individuals with autism and other neurodevelopmental disorders, therefore the targeted treatments for FXS are leading the way in the treatment of other neurodevelopmental syndromes and autism. The GABAergic system in FXS represents a target for new treatments. Herein, we discuss the animal and human trials of GABAergic treatment in FXS. Arbaclofen and ganaxolone have been used in individuals with FXS. Other potential GABAergic treatments, such as riluzole, gaboxadol, tiagabine, and vigabatrin, will be also discussed. Further studies are needed to determine the safety and efficacy of GABAergic treatments for FXS.

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Section: Introductionmentioning

confidence: 99%

Modulation of the GABAergic pathway for the treatment of fragile X syndrome

Lozano¹,

Hare²,

Hagerman³

2014

NDT

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“…According to these criteria, a categorization of definite, probable, and possible FXTAS may be established. However, several neurological and psychiatric problems related to the premutation have been described, both with and without FXTAS, including psychiatric dysfunction [28], hypertension [29], chronic pain, IDMs [13,14], and neuropathy [30,31]. A relationship between the clinical phenotypes and the size of CGG expansion was also reported [32].…”

Section: Discussionmentioning

confidence: 90%

A genetic study of the FMR1 gene in a Sardinian multiple sclerosis population

et al. 2015

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Multiple sclerosis (MS) is a complex autoimmune disease originated from the interplay between genetic and environmental factors. An overlap of clinical and neuroradiological parameters has been described between MS and an adult-onset neurodegenerative disorder, the fragile-X-associated tremor/ataxia syndrome (FXTAS). This syndrome is caused by a trinucleotide premutation expansion of a CGG sequence in the 55-200 repeat range, which is located in the fragile-X mental retardation 1 (FMR1) gene. Female premutation carriers have an increased propensity for immune-mediated disorders. Recently, a case of co-occurrence of MS and FXTAS was reported. Assuming that the premutation expansion may play a role in the MS susceptibility, we evaluated its frequency in a cohort of MS patients from Sardinia, an island characterized by a very high frequency of MS. Nuclear DNA was extracted by standard methods, purified with bisulfite treatment and then amplified twice by PCR with specific primers. Microsatellite analysis was performed and emizogotic subjects were sequenced. Clinical data of patients were also collected. Only 1/755 MS patients exhibited the premutation expansion with a heterozygosis pattern (30/58). No pathogenic repeat expansions (>200 repeats) were found in the entire cohort. Repeats labeled as the gray zone (45-60 repeats) were observed in 15/755 patients. No specific clinical features concerning disease course, disease activity, and disability were reported for these patients. Our results do not support a possible role for premutation or gray zone alleles in MS Sardinian patients. Further studies are needed to better understand the relationship between FXTAS and MS.

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“…Falls occur later in the course of the disease, leading to dependence on walking aids and wheelchairs. Men with FXTAS often have diabetes, hypertension, and hyperlipidemia, placing them at risk of heart disease and cerebrovascular accidents [48,49]. Women develop FXTAS less often and may have less severe symptoms when they do, likely due to the protective effects of the second X chromosome [50].…”

Section: Caring For Patients With Fxtasmentioning

confidence: 99%

Caregiver Burden in Fragile X Families

Iosif¹,

Sciolla²,

Brahmbhatt³

et al. 2013

CPSR

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Complex caregiving issues occur in multigenerational families carrying the fragile X mutation and premutation. The same family members may care for children or siblings with fragile X syndrome (FXS) and for elderly parents with fragile X-associated tremor/ataxia syndrome (FXTAS). Family caregivers experience anxiety, depression, neglect of personal health care needs, employment difficulties, and loss of social support, leading to isolation and further psychiatric consequences. There is growing awareness of caregiver burden with regard to parents of children with FXS, but much less is known about the needs of informal caregivers of patients with FXTAS. In this paper, we review the available literature to date and provide suggestions for further exploration of caregivers' needs. Evidence-based strategies to address these needs are included. Many more research studies exploring caregiver burden in multigenerational fragile X families are needed, as well as studies aimed at investigating interventions and their impact on reduction.

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Hypertension in FMR1 premutation males with and without fragile X‐associated tremor/ataxia syndrome (FXTAS)

Cited by 48 publications

References 37 publications

Modulation of the GABAergic pathway for the treatment of fragile X syndrome

Modulation of the GABAergic pathway for the treatment of fragile X syndrome

A genetic study of the FMR1 gene in a Sardinian multiple sclerosis population

Caregiver Burden in Fragile X Families

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