Screen for Excess FMR1 Premutation Alleles Among Males With Parkinsonism

Kraff, Jeremy; Tang, Han; Cilia, Roberto; Canesi, Margherita; Pezzoli, Gianni; Goldwurm, Stefano; Hagerman, Paul J.; Tassone, Flora

doi:10.1001/archneur.64.7.1002

Cited by 39 publications

(33 citation statements)

References 29 publications

(17 reference statements)

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“…34 A similar study of ϳ600 adult females, using the CGG targeting method, has also been conducted (K. Amiri, J. Kraff, H.-T. Tang, R. Pan, S. Goldworm, J.P. Hagerman, F. Tassone, unpublished results), with no false-positive or negative genotypes to date. Furthermore, in the validation study performed in conjunction with Kimball Genetics, Inc., we were able to correctly identify all fifty females with full-mutation alleles (apparent homozygosity by standard PCR); this number corresponds to the expected number of full mutations in a general population of ϳ150,000 females.…”

Section: Discussionmentioning

confidence: 93%

A Rapid Polymerase Chain Reaction-Based Screening Method for Identification of All Expanded Alleles of the Fragile X (FMR1) Gene in Newborn and High-Risk Populations

Tassone

Pan

Amiri

et al. 2008

The Journal of Molecular Diagnostics

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Fragile X syndrome , the most common inherited cause of intellectual impairment and the most common single gene associated with autism , generally occurs for fragile X mental retardation 1 (FMR1) alleles that exceed 200 CGG repeats (full-mutation range). Currently, there are no unbiased estimates of the number of full-mutation FMR1 alleles in the general population; a major obstacle is the lack of an effective screening tool for expanded FMR1 alleles in large populations. We have developed a rapid polymerase chain reaction (PCR)-based screening tool for expanded FMR1 alleles. The method utilizes a chimeric PCR primer that targets randomly within the expanded CGG region , such that the presence of a broad distribution of PCR products represents a positive result for an expanded allele. The method is applicable for screening both males and females and for allele sizes throughout the premutation (55 to 200 CGG repeats) and full-mutation ranges. Furthermore , the method is capable of rapid detection of expanded alleles using as little as 1% of the DNA from a single dried blood spot. The methodology presented in this work is suitable for screening large populations of newborn or those at high risk (eg , autism , premature ovarian failure , ataxia , dementia) for expanded FMR1 alleles. The test described herein costs less than $5 per sample for materials; with suitable scale-up and automation , the cost should approach $1 per sample. (J Mol

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Section: Discussionmentioning

confidence: 93%

A Rapid Polymerase Chain Reaction-Based Screening Method for Identification of All Expanded Alleles of the Fragile X (FMR1) Gene in Newborn and High-Risk Populations

Tassone

Pan

Amiri

et al. 2008

The Journal of Molecular Diagnostics

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“…A previous study done in Indonesia reported a frequency of 8.7% for alleles with 36 CGG repeats, whereas higher frequencies were reported for alleles with 34, 35, and 36 CGG repeats in an Asian population (Zhong et al, 1994;Chiang et al, 1999;Faradz et al, 2001). A recent report showed evidence of broad clinical involvement in FMR1 gene mutations reported among premutation and gray zone alleles (Hall et al, 2006;Loesch et al, 2009) including Idiopathic Parkinson's diseases, ASD and ADHD, FXPOI, and FXTAS (Tassone et al, 2000;Jacquemont et al, 2003;Goodlin-Jones et al, 2004;Jacquemont et al, 2004;Sullivan et al, 2005;Toft et al, 2005;Kraff et al, 2007;Cilia et al, 2009). Thus, a robust screening method is needed to accommodate future directions of early intervention and anticipation.…”

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Identification of Expanded Alleles of theFMR1Gene Among High-Risk Population in Indonesia by Using Blood Spot Screening

Winarni

Utari

Mundhofir

et al. 2012

Genetic Testing and Molecular Biomarkers

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The prevalence of Fragile X Syndrome (FXS) is 1 in 4000 in males and 1 in 2500 in males and females, respectively, in the general population. Several screening studies aimed at determining the prevalence of FXS have been conducted in individuals with intellectual disabilities (IDs) with a prevalence varying from 1.15% to 6.3% across different ethnic groups. A previous study in Indonesia showed an FXS prevalence of 1.9% among the ID population. A rapid, effective, and inexpensive method for FMR1 screening, using dried blood spots capable of detecting an expanded FMR1 allele in both males and females, was recently reported. We used this approach to screen 176 blood spots, collected from Central Java, Indonesia, for the presence of expanded FMR1 gene alleles. Samples were collected from high-risk populations: 112 individuals with ID, 32 obtained from individuals with diagnosis of autism spectrum disorders, and 32 individuals with a known family history of FXS. Fourteen subjects carrying an FMR1 expanded allele were identified including 7 premutations (55-200 CGG repeats) and 7 full mutations ( > 200 repeats). Of the seven subjects identified with a full mutation, one subject was from a nonfragile X family, and six from were families with a history of FXS.Introduction F ragile X syndrome (FXS), with a prevalence of 1:2500 to 1:4000 in the general population (Turner et al., 1996;Crawford et al., 2002;Hagerman, 2008), is the most common genetic cause of intellectual disability (ID) and the leading genetic cause of autism. Although prevalence estimates vary across studies, there is agreement that the risk of autism spectrum disorders (ASD) is higher in FXS than in many other neuro-developmental disorders. From recent studies, *2% to 6% of children with ASD have FXS (Li et al., 1993;Wassink et al., 2001;Estecio et al., 2002;Hagerman, 2002;Reddy, 2005), and *30% of children with FXS have ASD (see Appendix in Rogers et al., 2001;Kaufmann et al., 2004); Pervasive Developmental Disorder-Not Otherwise Specified is seen in an additional 30% (Harris et al., 2008). In fact, FXS is characterized by a broad spectrum of behavioral and emotional impairment, psychological problems, and learning disabilities in those without mental retardation or ID. In addition, specific physical features such as long face, macrognathia, prominent ears, hyperextensible joints, flat feet, and macroorchidism in puberty are observed (Hagerman et al., 1991;Lachiewicz and Dawson, 1994;Giangreco et al., 1996). The milder phenotypes are not accounted for in the current prevalence figures (Tassone et al., 1999;Hagerman, 2006). In addition, significant phenotypic involvement has emerged in some individuals with the premutation (55-200 CGG repeats), including fragile X-associated premature ovarian insufficiency (FXPOI) in females, and fragile X-associated tremor/ataxia syndrome (FXTAS) in both male and female aging carriers Sullivan et al., 2005). Prevalence for premutation alleles was *1 in 110-250 for females and 1 in 250-800 for males (Rousseau et al., 199...

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“…Although a higher prevalence of these alleles was found among males over 50 with cerebellar ataxia, OMIM# 164400 or multiple system atrophy-cerebellar type, OMIM# 146500, it was not significantly increased in small samples of males with idiopathic Parkinson disease (iPD) or parkinsonism. 10–13 In a larger study of 776 patients with iPD, three carriers of the PM allele were identified, 14 which is approximately 3-fold higher than the normal population prevalence.…”

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confidence: 99%

Evidence for the toxicity of bidirectional transcripts and mitochondrial dysfunction in blood associated with small CGG expansions in the FMR1 gene in patients with parkinsonism

Loesch

Godler

Evans

et al. 2011

Genetics in Medicine

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Purpose Our previous results showed that both gray zone and lower end premutation range (40–85 repeats) fragile X mental retardation 1 (FMR1) alleles were more common among males with parkinsonism than in the general population. This study aimed to determine whether these alleles have a significant role in the manifestations and pathogenesis of parkinsonian disorders. Methods Detailed clinical assessment and genetic testing were performed in 14 male carriers of premutation and gray zone FMR1 alleles and in 24 noncarriers identified in a sample of males with parkinsonism. Results The premutation + gray zone carriers presented with more severe symptoms than disease controls matched for age, diagnosis, disease duration, and treatment. The Parkinson disease (Unified Parkinson’s Disease Rating Scale) motor score and the measures of cognitive decline (Mini-Mental State Examination and/or Addenbrooke’s Cognitive Examination Final Revised Version A scores) were significantly correlated with the size of the CGG repeat and the (elevated) levels of antisense FMR1 and Cytochrome C1 mRNAs in blood leukocytes. In addition, the carriers showed a significant depletion of the nicotinamide adenine dinucleotide, reduced dehydrogenase subunit 1 mitochondrial gene in whole blood. Conclusion Small CGG expansion FMR1 alleles (gray zone and lower end premutation) play a significant role in the development of the parkinsonian phenotype, possibly through the cytotoxic effect of elevated sense and/or antisense FMR1 transcripts involving mitochondrial dysfunction and leading to progressive neurodegeneration.

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Screen for Excess FMR1 Premutation Alleles Among Males With Parkinsonism

Cited by 39 publications

References 29 publications

A Rapid Polymerase Chain Reaction-Based Screening Method for Identification of All Expanded Alleles of the Fragile X (FMR1) Gene in Newborn and High-Risk Populations

A Rapid Polymerase Chain Reaction-Based Screening Method for Identification of All Expanded Alleles of the Fragile X (FMR1) Gene in Newborn and High-Risk Populations

Identification of Expanded Alleles of theFMR1Gene Among High-Risk Population in Indonesia by Using Blood Spot Screening

Evidence for the toxicity of bidirectional transcripts and mitochondrial dysfunction in blood associated with small CGG expansions in the FMR1 gene in patients with parkinsonism

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