Immune mediated disorders in women with a fragile X expansion and FXTAS

Jalnapurkar, Isha; Rafika, Nuva; Tassone, Flora; Hagerman, Randi J.

doi:10.1002/ajmg.a.36748

Cited by 25 publications

(29 citation statements)

References 53 publications

(71 reference statements)

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“…A recent study looking at the frequency of gray zone alleles in a population of Spanish subjects with intellectual disability, ADHD, or autism found the frequency of these disorders to be similar to those in the general population, therefore finding no evidence between gray zone mutations and these phenotypes [55]. Anxiety, often reported in FXTAS patients, has been mentioned in two previous case reports of gray zone subjects [15,56].…”

Section: Discussionmentioning

confidence: 93%

Clinical Phenotype of Adult Fragile X Gray Zone Allele Carriers: a Case Series

et al. 2016

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Considerable research has focused on patients with trinucleotide (CGG) repeat expansions in the fragile X mental retardation 1 (FMR1) gene that fall within either the full mutation (>200 repeats) or premutation range (55-200 repeats). Recent interest in individuals with gray zone expansions (41-54 CGG repeats) has grown due to reported phenotypes that are similar to those observed in premutation carriers, including neurological, molecular, and cognitive signs. The purpose of this manuscript is to describe a series of adults with FMR1 alleles in the gray zone presenting with movement disorders or memory loss. Gray zone carriers ascertained in large FMR1 screening studies were identified and their clinical phenotypes studied. Thirty-one gray zone allele carriers were included, with mean age of symptom onset of 53 years in patients with movement disorders and 57 years in those with memory loss. Four patients were chosen for illustrative case reports and had the following diagnoses: early-onset Parkinson disease (PD), atypical parkinsonism, dementia, and atypical essential tremor. Some gray zone carriers presenting with parkinsonism had typical features, including bradykinesia, rigidity, and a positive response to dopaminergic medication. These patients had a higher prevalence of peripheral neuropathy and psychiatric complaints than would be expected. The patients seen in memory clinics had standard presentations of cognitive impairment with no apparent differences. Further studies are necessary to determine the associations between FMR1 expansions in the gray zone and various phenotypes of neurological dysfunction.

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Section: Discussionmentioning

confidence: 93%

Clinical Phenotype of Adult Fragile X Gray Zone Allele Carriers: a Case Series

et al. 2016

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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: 99%

“…The pathological mechanisms of FXTAS are under debate, but it seems to be secondary to the altered regulation of one or more proteins by excessive levels of the expanded CGG-repeat FMR1 mRNA, resulting in cell stress/toxicity. Some reports have stated that female premutation carriers with FXTAS have an increased propensity for immune-mediated disorders (IDMs) [13,14], although a pathogenic correlation remains to be established. A case of co-occurrence of MS and FXTAS was reported, suggesting that several mechanisms may contribute to the coincidence of FXTAS and MS, or alternatively, that FXTAS may stimulate the pathological process of MS [15].…”

Section: Introductionmentioning

confidence: 99%

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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“…Other case reports have indicated that environmental toxins from a chemical plant and exposure to agent orange are associated with worsening of neurological FXTAS symptoms 74 . Perhaps the most important environmental factors that have been associated with worsening of FXTAS are prolonged use of opioids and excessive alcohol intake; both have been associated with severe white matter disease and brain atrophy that suggest accelerated progression of FXTAS [75][76][77][78] . The association with opioids is particularly worrying because chronic pain -the most common reason for medical or nonmedical use of opioids in the USA 2,79,80 -is common in FXTAS.…”

Section: Key Pointsmentioning

confidence: 99%

“…FXTAS was initially thought to occur only in premutation carriers (with 55-200 CGG repeats), but FXTAS has occasionally been diagnosed in individuals with a grey-zone allele (with 45-54 CGG repeats) 78,92,93 or an unmethylated full-mutation allele, and in individuals with size mosaicism (a mixture of cells with a premutation and cells with a full mutation) and/or elevated levels of FMR1 mRNA [94][95][96] . Mild elevation of FMR1 mRNA has been observed in individuals with grey-zone alleles, so the development of FXTAS and/or Parkinson disease in some of these people is not surprising 94,97 .…”

Section: Novel Features Of Fxtasmentioning

confidence: 99%

Fragile X-associated tremor/ataxia syndrome — features, mechanisms and management

2016

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Many physicians are unaware of the many phenotypes associated with the fragile X premutation, an expansion in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene that consists of 55-200 CGG repeats. The most severe of these phenotypes is fragile X-associated tremor/ataxia syndrome (FXTAS), which occurs in the majority of ageing male premutation carriers but in fewer than 20% of ageing women with the premutation. The prevalence of the premutation is 1 in 150-300 females, and 1 in 400-850 males, so physicians are likely to see people affected by FXTAS. Fragile X DNA testing is broadly available in the Western world. The clinical phenotype of FXTAS at presentation can vary and includes intention tremor, cerebellar ataxia, neuropathic pain, memory and/or executive function deficits, parkinsonian features, and psychological disorders, such as depression, anxiety and/or apathy. FXTAS causes brain atrophy and white matter disease, usually in the middle cerebellar peduncles, the periventricular area, and the splenium and/or genu of the corpus callosum. Here, we review the complexities involved in the clinical management of FXTAS and consider how targeted treatment for these clinical features of FXTAS will result from advances in our understanding of the molecular mechanisms that underlie this neurodegenerative disorder. Such targeted approaches should also be more broadly applicable to earlier forms of clinical involvement among premutation carriers.

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Immune mediated disorders in women with a fragile X expansion and FXTAS

Cited by 25 publications

References 53 publications

Clinical Phenotype of Adult Fragile X Gray Zone Allele Carriers: a Case Series

Clinical Phenotype of Adult Fragile X Gray Zone Allele Carriers: a Case Series

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

Fragile X-associated tremor/ataxia syndrome — features, mechanisms and management

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