Screening for intermediate CGG alleles of FMR1 gene in male Iranian patients with Parkinsonism

Entezari, Atefeh; Khaniani, Mahmoud Shekari; Bahrami, Tayyeb; Derakhshan, Sima Mansoori; Darvish, Hossein

doi:10.1007/s10072-016-2723-6

Cited by 4 publications

(4 citation statements)

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“…This study highlights intermediate alleles as an opportunity for future research. Prior investigations of intermediate alleles have focused primarily on movement disorders and reproductive function (e.g., Bodega et al, 2005; Debrey et al, 2016; Entezari et al, 2017; Wang et al, 2017) and findings are controversial, as not all reports indicate increased risk in these areas (Toft et al, 2005; Bennett et al, 2010; Kline et al, 2014). To our knowledge, no prior studies have investigated cognitive or linguistic phenotypes relative to intermediate alleles, which is a fruitful avenue of future investigation as intermediate alleles affect a significant proportion of the population (about 1:57 individuals; Cronister et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Curvilinear Association Between Language Disfluency and FMR1 CGG Repeat Size Across the Normal, Intermediate, and Premutation Range

et al. 2018

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Historically, investigations of FMR1 have focused almost exclusively on the clinical effects of CGG expansion within the categories of the premutation (55–200 CGG repeats) and fragile X syndrome (>200 CGG repeats). However, emerging evidence suggests that CGG-dependent phenotypes may occur across allele sizes traditionally considered within the “normal” range. This study adopted an individual-differences approach to determine the association between language production ability and CGG repeat length across the full range of normal, intermediate, and premutation alleles. Participants included 61 adult women with CGG repeats within the premutation (n = 37), intermediate (i.e., 41–54 repeats; n = 2), or normal (i.e., 6–40 repeats; n = 22) ranges. All participants were the biological mothers of a child with a developmental disorder, to control for the potential effects of parenting stress. Language samples were collected and the frequency of language disfluencies (i.e., interruptions in the flow of speech) served as an index of language production skills. Verbal inhibition skills, measured with the Hayling Sentence Completion Test, were also measured and examined as a correlate of language disfluency, consistent with theoretical work linking language disfluency with inhibitory deficits (i.e., the Inhibition Deficit Hypothesis). Blood samples were collected to determine FMR1 CGG repeat size. A general linear model tested CGG repeat size of the larger allele (allele-2) as the primary predictor of language disfluency, covarying for education level, IQ, age, and CGG repeats on the other allele. A robust curvilinear association between CGG length and language disfluency was detected, where low-normal (∼ <25 repeats) and mid-premutation alleles (∼90–110 repeats) were linked with higher rates of disfluency. Disfluency was not associated with inhibition deficits, which challenges prior theoretical work and suggests that a primary language deficit could account for elevated language disfluency in FMR1-associated conditions. Findings suggest CGG-dependent variation in language production ability, which was evident across individuals with and without CGG expansions on FMR1.

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Section: Discussionmentioning

confidence: 99%

Curvilinear Association Between Language Disfluency and FMR1 CGG Repeat Size Across the Normal, Intermediate, and Premutation Range

et al. 2018

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“…Another study included 2,362 participants with a prevalence of 5.2% for carriers of the FMR1 gene GZ allele, and GZ alleles were associated with signs of Parkinsonism in men ( Hall et al, 2020 ). These studies suggested that the FMR1 GZ allele might contribute to the etiology of disorders associated with male Parkinsonism ( Entezari et al, 2017 ). A similar study in China, including 360 Chinese patients with Parkinsonism (6.8%) and 295 controls, also supported this result ( Zhang et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the role of FMR1 CGG repeat allele in Parkinson’s disease from the Chinese population

Chen

Zhao

Zhou

et al. 2023

Front. Aging Neurosci.

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ObjectiveThere is controversial evidence that FMR1 premutation or “gray zone” (GZ) allele (small CGG expansion, 45–54 repeats) was associated with Parkinson’s disease (PD). We aimed to explore further the association between FMR1 CGG repeat expansions and PD in a large sample of Chinese origin.MethodsWe included a cohort of 2,362 PD patients and 1,072 controls from the Parkinson’s Disease and Movement Disorders Multicenter Database and Collaborative Network in China (PD-MDCNC) in this study and conducted repeat-primed polymerase chain reaction (RP-PCR) for the size of FMR1 CGG repeat expansions.ResultsTwo PD patients were detected with FMR1 premutation (61 and 56 repeats), and the other eleven PD patients were detected with the GZ allele of FMR1 CGG repeat expansions. Those thirteen PD patients responded well to levodopa and were diagnosed with clinically established PD. Specifically, one female PD patient with GZ allele was also found with premature ovarian failure. However, compared to healthy controls, we found no significant enrichment of GZ allele carriers in PD patients or other subgroups of PD cases, including the subgroups of female, male, early-onset, and late-onset PD patients. Furthermore, we did not find any correlation between the FMR1 gene CGG repeat sizes and age at onset of PD.ConclusionIt suggested that FMR1 premutation was related to PD, but the GZ allele of FMR1 CGG repeat expansions was not significantly enriched in PD cases of Chinese origin. Further larger multiple ethnic studies are needed to determine further the role of the FMR1 GZ allele in PD.

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“…23 In fact, the association has been more often found between FMR1 gray zone alleles (40-54 CGG repeats) and clinical PD in both males and females. [24][25][26][27] In premutation carriers, De Pablo-Fernandez and colleagues 28 reported 2 cases of concomitant FXTAS and PD, both also carrying a lower end CGG repeat number. Our findings expand on the concept that the parkinsonism found in patients with FXTAS is sometimes indistinguishable from the parkinsonism described in the diagnostic criteria of idiopathic PD, 29 and many premutation carriers with FXTAS are still erroneously diagnosed with PD alone.…”

Section: Discussionmentioning

confidence: 99%

“…and a very low prevalence of FMR1 premutation in patients with clinical PD (0%–1%) . In fact, the association has been more often found between FMR1 gray zone alleles (40–54 CGG repeats) and clinical PD in both males and females . In premutation carriers, De Pablo‐Fernandez and colleagues reported 2 cases of concomitant FXTAS and PD, both also carrying a lower end CGG repeat number.…”

Section: Discussionmentioning

confidence: 99%

Parkinsonism Versus Concomitant Parkinson's Disease in Fragile X–Associated Tremor/Ataxia Syndrome

Salcedo-Arellano

Wolf‐Ochoa

Hong

et al. 2020

Movement Disord Clin Pract

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Background Fragile X–associated tremor/ataxia syndrome (FXTAS) is a late‐onset neurodegenerative disorder associated with premutation alleles (55–200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. FXTAS is characterized by the presence of ubiquitin‐positive inclusions in neurons and astrocytes and by cerebellar tremor and ataxia. Parkinsonism has been reported in FXTAS, but most patients lack the characteristic rest tremor and severe rigidity seen in idiopathic Parkinson's disease (PD). Objective To describe the frequency of concomitant PD in FXTAS. Methods We reviewed the medical record of 40 deceased patients diagnosed with FXTAS and performed a pathology analysis to confirm both FXTAS and PD. Results Clinical histories indicated that 5 FXTAS patients were diagnosed with idiopathic PD and 2 with atypical parkinsonian syndrome. After pathological examination, we found that 7 patients in the PD clinical diagnosis group had dopaminergic neuronal loss; however, only 2 of 7 presented Lewy bodies (LBs) in the substantia nigra. Therefore, a total of 5% of the 40 cohort patients met the pathologic criteria for the concomitant diagnosis of FXTAS and PD. In addition, 2 patients not clinically diagnosed with PD also had nigral neuronal loss with LBs in substantia nigra. In total 10% of these 40 patients had LBs. Conclusion This report expands our understanding of clinical symptoms and unusual presentations in patients with FXTAS and the concept that the parkinsonism found in FXTAS is sometimes indistinguishable from PD. We propose that FMR1 should be recognized as one of the exceptional genetic causes of parkinsonism with presynaptic dopaminergic loss and LBs.

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Screening for intermediate CGG alleles of FMR1 gene in male Iranian patients with Parkinsonism

Cited by 4 publications

References 50 publications

Curvilinear Association Between Language Disfluency and FMR1 CGG Repeat Size Across the Normal, Intermediate, and Premutation Range

Curvilinear Association Between Language Disfluency and FMR1 CGG Repeat Size Across the Normal, Intermediate, and Premutation Range

Evaluation of the role of FMR1 CGG repeat allele in Parkinson’s disease from the Chinese population

Parkinsonism Versus Concomitant Parkinson's Disease in Fragile X–Associated Tremor/Ataxia Syndrome

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