Molecular Advances Leading to Treatment Implications for Fragile X Premutation Carriers

Polussa, Jonathan; Schneider, Andrea; Hagerman, Randi J.

doi:10.4172/2168-975x.1000119

Cited by 39 publications

(23 citation statements)

References 219 publications

(260 reference statements)

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“…Although most of the carriers that they will see will not have overt developmental problems, there are a significant number of children who will have challenges, and there may be an increased risk of susceptibility to stressful situations for all carriers, regardless of their clinical involvement. Even among those without medical or neurocognitive concerns, it will be important to emphasize general guidance regarding staying healthy to decrease risk, 112 as well as encouraging stress reduction and positive coping mechanisms to promote resilience.…”

Section: Resultsmentioning

confidence: 99%

“…10,115, 116 Because of these problems, recommendations have been made for the use of antioxidants, healthy eating, and regular exercise to enhance mitochondrial function, increase serotonin levels, and promote neurogenesis. 112 There is limited research on treatment studies for the learning, emotional, and stress problems seen in some carriers, and the impact of multiple family members with FMR1 mutations on the family system is not clear. Studies addressing these issues could provide needed information to guide treatment of carriers with clinical problems.…”

Section: Discussionmentioning

confidence: 99%

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Implications of theFMR1Premutation for Children, Adolescents, Adults, and Their Families

Wheeler

Raspa

Hagerman³

et al. 2017

Pediatrics

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BACKGROUND AND OBJECTIVES Given the nature of FMR1 gene expansions, most biological mothers, and often multiple other family members of children with fragile X syndrome (FXS), will have a premutation, which may increase individual and family vulnerabilities. This article summarizes important gaps in knowledge and notes potential implications for pediatric providers with regard to developmental and medical risks for children and adolescents with an FMR1 premutation, including possible implications into adulthood. METHODS A structured electronic literature search was conducted on FMR1 pre- and full mutations, yielding a total of 306 articles examined. Of these, 116 focused primarily on the premutation and are included in this review. RESULTS Based on the literature review, 5 topic areas are discussed: genetics and epidemiology; phenotypic characteristics of individuals with the premutation; implications for carrier parents of children with FXS; implications for the extended family; and implications for pediatricians. CONCLUSIONS Although the premutation phenotype is typically less severe in clinical presentation than in FXS, premutation carriers are much more common and are therefore more likely to be seen in a typical pediatric practice. In addition, there is a wide range of medical, cognitive/developmental, and psychiatric associated features that individuals with a premutation are at increased risk for having, which underscores the importance of awareness on the part of pediatricians in identifying and monitoring premutation carriers and recognizing the impact this identification may have on family members.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Implications of theFMR1Premutation for Children, Adolescents, Adults, and Their Families

Wheeler

Raspa

Hagerman³

et al. 2017

Pediatrics

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“…FMR1 PM, although not responsible for FXS, predisposes ~40%–45% of the male [30,31] and ~8%–16% of the female carriers [31,32] to FXTAS, a condition that is characterized by intention tremor, cerebellar gait ataxia, peripheral neuropathy, parkinsonism, memory/cognitive function deficits and other psychological issues [33,34]. Age-dependent penetrance of FXTAS has been noted in both male and female PM carriers [31], with higher risks reported among individuals aged 70–79 years [31] and ≥80 years [30].…”

Section: Molecular Determinants Of Fxtasmentioning

confidence: 99%

“…In 2006, the ACMG did not endorse the inclusion of FXS to universal NBS panel primarily due to the lack of evidence supporting the benefits of early diagnosis and the lack of a cost-effective screening tool [133]. It is now evident that early FXS diagnosis can facilitate timely interventions that could be beneficial [72], alleviate the “diagnostic odyssey” experienced by families and inform parents of their risks of having fragile X affected children through subsequent pregnancies, and also promote cascade testing of extended family members [129,134] and identification of relatives who harbor a PM and are likely to benefit from prophylactic interventions [33] and diagnosis-based management. In addition, several pilot studies have demonstrated the cost-effectiveness and feasibility of conducting large-scale NBS for FXS [69,135,136,137,138], and surveys on attitudes toward screening also reveal the growing support for fragile X NBS [129,139,140,141,142,143,144,145,146].…”

Section: Population-based Screening For Fmr1 Expansionsmentioning

confidence: 99%

Molecular Correlates and Recent Advancements in the Diagnosis and Screening of FMR1-Related Disorders

Rajan‐Babu

Chong

2016

Genes

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Fragile X syndrome (FXS) is the most common monogenic cause of intellectual disability and autism. Molecular diagnostic testing of FXS and related disorders (fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS)) relies on a combination of polymerase chain reaction (PCR) and Southern blot (SB) for the fragile X mental retardation 1 (FMR1) CGG-repeat expansion and methylation analyses. Recent advancements in PCR-based technologies have enabled the characterization of the complete spectrum of CGG-repeat mutation, with or without methylation assessment, and, as a result, have reduced our reliance on the labor- and time-intensive SB, which is the gold standard FXS diagnostic test. The newer and more robust triplet-primed PCR or TP-PCR assays allow the mapping of AGG interruptions and enable the predictive analysis of the risks of unstable CGG expansion during mother-to-child transmission. In this review, we have summarized the correlation between several molecular elements, including CGG-repeat size, methylation, mosaicism and skewed X-chromosome inactivation, and the extent of clinical involvement in patients with FMR1-related disorders, and reviewed key developments in PCR-based methodologies for the molecular diagnosis of FXS, FXTAS and FXPOI, and large-scale (CGG)n expansion screening in newborns, women of reproductive age and high-risk populations.

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“…The premutation causes premature ovarian failure (FXPOImenopause before the age of 40) in approximately 20% of female carriers [5]. Both male and female premutation carriers may develop a progressive neurodegenerative condition termed Fragile X Associated Tremor/Ataxia Syndrome (FXTAS) as they age, with a much higher rate in males (between 40-50% after the age of 55) than in females in the same age group (approximately 15%) [6][7][8][9]. Typical FXTAS neuropathological changes are of widespread intranuclear inclusions abundant in neurones and astrocytes [10], extending to autonomic nervous and neuroendocrine systems and myocardial cells [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Relationships between motor scores and cognitive functioning in FMR1 female premutation X carriers indicate early involvement of cerebello-cerebral pathways.

Storey

Bui

Stimpson

et al. 2020

Preprint

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Background Smaller expansions of CGG trinucleotide repeats in the FMR1 X-linked gene termed ‘premutation’ lead to a neurodegenerative disorder: Fragile X Associated Tremor/Ataxia Syndrome (FXTAS) in nearly half of aged carrier males, and 8-16% females. Core features include intention tremor, ataxia, and cognitive decline, and white matter lesions especially in cerebellar and periventricular locations. A ‘toxic’ role of elevated and expanded FMR1 mRNA has been linked to the pathogenesis of this disorder. The emerging issue concerns the trajectory of the neurodegenerative changes: is the pathogenetic effect confined to overt clinical manifestations? Here we explore the relationships between motor and cognitive scale scores in a sample of 57 asymptomatic adult female premutation carriers of broad age range. Methods Three motor scale scores (ICARS-for tremor/ataxia, UPDRS-for parkinsonism, and the Clinical Tremor) were related to 11 cognitive tests and two psychiatric pathology scores - DASS and SCL-90 - using Spearman’s rank correlations. Robust regression, applied in relationships between all phenotypic measures, and genetic molecular and demographic data, identified age and educational levels as common correlates of these measures, which were incorporated as confounders in correlation analysis. Results Cognitive tests demonstrating significant correlations with motor scores were those assessing psychomotor speed/visual attention (SDMT; TMT-A) and those dependent on various aspects of executive functioning for their execution: sequencing and alternation (TMTB-A); working memory (DS backwards); and non-verbal reasoning (MR). The largest number of motor x cognitive correlations involved ICARS and Tremor scales, which reflect the type of motor dysfunctions seen in FXTAS. Conclusions Subtle motor impairments correlating with cognitive deficits may occur in female premutation carriers not meeting diagnostic criteria for FXTAS. This pattern of cognitive deficits is consistent with those seen in other cerebellar disorders. Our results provide evidence that more than one category of clinical manifestation reflecting cerebellar changes – motor and cognitive - may be simultaneously affected by premutation carriage across a broad age range in asymptomatic carriers. Future longitudinal studies should determine whether cognitive dysfunction tracking motor impairments is driven by the premutation status common to all carriers, or only to a subset of carriers who will develop FXTAS in older age.

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Molecular Advances Leading to Treatment Implications for Fragile X Premutation Carriers

Cited by 39 publications

References 219 publications

Implications of theFMR1Premutation for Children, Adolescents, Adults, and Their Families

Implications of theFMR1Premutation for Children, Adolescents, Adults, and Their Families

Molecular Correlates and Recent Advancements in the Diagnosis and Screening of FMR1-Related Disorders

Relationships between motor scores and cognitive functioning in FMR1 female premutation X carriers indicate early involvement of cerebello-cerebral pathways.

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