An Investigation of FRAXA Intermediate Allele Phenotype in A Longitudinal Sample

Ennis, Sarah; Murray, Anna; Youings, Sheila; Brightwell, Gale; Herrick, David; Ring, Susan M.; Pembrey, Marcus; Morton, N. E.; Jacobs, Patricia A.

doi:10.1111/j.1529-8817.2005.00220.x

Cited by 16 publications

(10 citation statements)

References 25 publications

(25 reference statements)

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“…A population screening of 1013 boys with learning disabilities and their mothers (n = 760) showed a significant excess of gray zone alleles (41–60 CGG) in the affected boys 7. However, a follow‐up study in boys with special education needs (n = 5084) did not confirm this result 9. Primary ovarian insufficiency has been shown to be increased in women with 41–58 CGG repeats 6, 10.…”

Section: Discussionmentioning

confidence: 99%

Fragile X–associated tremor ataxia syndrome in FMR1 gray zone allele carriers

et al. 2011

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Purpose Carriers of fragile X mental retardation 1 (FMR1) repeat expansions in the premutation range (55–200 CGG repeats) often develop a syndrome of kinetic tremor, cerebellar ataxia, and parkinsonism; designated the fragile X-associated tremor ataxia syndrome (FXTAS). Neurological signs have not been reported in carriers of gray zone (45–54 CGG repeats) expansions. Methods/Results We describe three patients with FMR1 gray zone alleles who meet diagnostic criteria for FXTAS. Conclusions Our cases suggest that the definition of the FXTAS may need to be broadened to include individuals with FMR1 repeat expansions in the gray zone. These neurological signs may be due to elevated levels of expanded CGG repeat FMR1 mRNA in the gray zone carriers, similar to the changes seen in premutation carriers with FXTAS.

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Section: Discussionmentioning

confidence: 99%

Fragile X–associated tremor ataxia syndrome in FMR1 gray zone allele carriers

et al. 2011

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“…[35][36][37][38] Nevertheless, a definitive association between the presence of IAs and clinical manifestations remains unclear. [39][40][41] The clinical phenotypes associated with premutation alleles and severity of neurological problems associated with the FMR1 premutation allele. Finally, the progression of FXTAS has been shown to be more rapid in patients that have been exposed to environmental toxins such as chronic use of addictive substances (opiates, alcohol, and cocaine) or chemotherapy.…”

Section: Clinical Involvement In Fmr1 Premutation Carriersmentioning

confidence: 99%

Fragile X syndrome: An overview and update of the FMR1 gene

et al. 2017

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Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and the leading form of the monogenic cause of autism. Fragile X mental retardation type 1 (FMR1) gene premutation is the first single-gene cause of primary ovarian failure (Fragile X-associated primary ovarian insufficiency [FXPOI]) and one of the most common causes of ataxia (fragile X-associated tremor/ataxia syndrome [FXTAS]), multiple additional phenotypes such as fibromyalgia, hypothyroidism, migraine headaches, sleep disturbances, sleep apnea, restless legs syndrome, central pain syndrome, neuropathy and neuropsychiatric alterations has been described. Clinical involvement in men and women carrying the FMR1 premutation currently constitutes a real health problem in the society that should be taken into account. It is important to highlight that while in FXS there is a loss-of-function of the FMR1 gene, in premutation associated disorders there is a gain of FMR1 mRNA function. To date, the tremendous progress achieved in the understanding of the pathophysiology of FXS, has led to the development of several targeted therapies aimed at preventing or improving the neurological manifestations of the disease. This review is an update of the diseases associated with the FMR1 gene. tions. In 1999, the study of fragile X pedigrees revealed a higher incidence of primary ovarian insufficiency related to the FMR1 gene, and this condition was named premature ovarian failure (POF) and then later fragile X premature ovarian insufficiency (FXPOI). 6 This term encompasses a continuum of severity in ovarian dysfunction ranging from normal menses and normal hormonal levels, although reduced fertility, to the most severe form of this condition in which folliclestimulating hormone is elevated, menses are abnormal or absent, and fertility is drastically reduced. 7 After further studies, Hagerman et al described a neurological disease related to the FMR1 premutation that was named fragile X-associated tremor/ataxia syndrome (FXTAS). 8 Finally, since 2007 the spectrum of the clinical phenotype associated with the FMR1 premutation has continuously widened. This review is an update of the diseases associated with the FMR1 gene.2 | FRAGILE X SYNDROME FXS (#MIM300624; ORPHA 908) is the most common cause of inherited ID (1%-2% of all ID) and the leading form of the monogenic cause of autism and autism spectrum disorders (ASD) (Figure 1). The

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“…Hessl et al (2005) reported elevated levels of mRNA in individuals with premutations who had psychiatric symptoms; and MRI changes were found to correlate with anxiety in women with FMR1 premutations, even in those without a clinical diagnosis of FXTAS (Adams et al, 2010 (Loesch et al, 2009b), primary ovarian insufficiency (Bodega et al, 2006), and autism and cognitive disabilities (Aziz et al, 2003;Loesch et al, 2009a). However, these findings have not consistently been supported by other studies (Ennis et al 2006;Bennett et al, 2010) and can be difficult to interpret due to inconsistencies in the way researchers have defined the intermediate range. Additional research is needed to clarify the clinical relevance of intermediate alleles.…”

Section: Other Premutation-associated Issuesmentioning

confidence: 97%

Genetic Counseling and Testing for FMR1 Gene Mutations: Practice Guidelines of the National Society of Genetic Counselors

Finucane

Abrams

Cronister

et al. 2012

Journal of Genetic Counseling

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PURPOSE Fragile X syndrome (FXS) is one of several clinical disorders associated with mutations in the Xlinked Fragile X Mental Retardation-1 (FMR1) gene. With evolving knowledge about the phenotypic consequences of FMR1 transcription and translation, sharp clinical distinctions between pre-and full mutations have become more fluid. The complexity of the issues surrounding genetic testing and management of FMR1-associated disorders has increased; and several aspects of genetic counseling for FMR1 mutations remain challenging, including risk assessment for intermediate alleles and the widely variable clinical prognosis for females with full mutations. FMR1 mutation testing is increasingly being offered to women without known risk factors, and newborn screening for FXS is underway in researchbased pilot studies. Each diagnosis of an FMR1 mutation has far-reaching clinical and reproductive implications for the extended family. The interest in large-scale population screening is likely to increase due to patient demand and awareness, and as targeted pharmaceutical treatments for FXS become available over the next decade. Given these developments and the likelihood of more widespread screening, genetic counselors across a variety of healthcare settings will increasingly be called upon to address complex diagnostic, psychosocial, and management issues related to FMR1 gene mutations. The following guidelines are intended to assist genetic counselors in providing accurate risk assessment and appropriate educational and supportive counseling for individuals with positive test results and families affected by FMR1-associated disorders.

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An Investigation of FRAXA Intermediate Allele Phenotype in A Longitudinal Sample

Cited by 16 publications

References 25 publications

Fragile X–associated tremor ataxia syndrome in FMR1 gray zone allele carriers

Fragile X–associated tremor ataxia syndrome in FMR1 gray zone allele carriers

Fragile X syndrome: An overview and update of the FMR1 gene

Genetic Counseling and Testing for FMR1 Gene Mutations: Practice Guidelines of the National Society of Genetic Counselors

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