Molecular-Clinical Correlations in Children and Adults With Fragile X Syndrome

Staley, Louise W.; Hull, Claire; Mazzocco, Michèle M.M.; Thibodeau, Stephen N.; Snow, Karen; Wilson, Vincent L.; Taylor, Annette K.; McGavran, Loris; Weiner, Debra; Riddle, Jeannette E.; O’Connor, Rebecca; Hagerman, Randi J.

doi:10.1001/archpedi.1993.02160310025011

Cited by 20 publications

(21 citation statements)

References 18 publications

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“…We could not find cognitive differences between mosaic and full mutations, as other studies implied [Staley et al, 1993;Merenstein et al, 1996]. Still, no associations between any of the parameters analyzed and the lengths of the CGG repeat could be demonstrated.…”

Section: Discussioncontrasting

confidence: 75%

Cognitive and behavioral profile of fragile X boys: Correlations to molecular data

et al. 2000

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Fragile X syndrome (FXS) is the most common form of inherited mental retardation after Down syndrome. The expansion of a CGG repeat, located in the 5'-untranslated region (5'-UTR) of the FMR1 (fragile X mental retardation) gene, leads to the hypermethylation of the repeat and the upstream CpG island. Methylation is associated with transcriptional silencing of the FMR1 gene. The lack of FMR1 protein is believed to be responsible for the typical physical and mental characteristics of the syndrome. To analyze the specific phenotype of that syndrome as well as possible associations between the phenotype and the genotype, we examined a group of 49 fragile X boys and a control group of 16 patients with tuberous sclerosis. To determine the cognitive and behavioral phenotype, the Kaufman Assessment Battery for Children (K-ABC), the Child Behavior Checklist (4/18), and a structured psychiatric interview (Kinder DIPS) were used. The genotype was analyzed by the Southern blot method. The phenotype of boys with FXS is characterized by a specific cognitive profile with strengths in acquired knowledge and in simultaneous processing. The psychiatric comorbidity is high and ADHD (attention deficit hyperactivity disorder), oppositional defiant disorder, enuresis, and encopresis predominate. In a group of 24 fragile X boys, no significant correlations between the specific aspects of the phenotype and the genotype were found.

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Section: Discussioncontrasting

confidence: 75%

Cognitive and behavioral profile of fragile X boys: Correlations to molecular data

et al. 2000

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“…Recent analysis with cytogenetic and DNA data indicates a significant positive correlation between high fragile X chromosome expression and large DNA alterations, i.e., increased number of CGG trinucleotide repeats (de Vries et al 1992, Staley et al 1992. Therefore, our fra(X) syndrome males with high expression probably have larger DNA alterations than those patients with low expression, even though our patients have not been analyzed at a molecular level.…”

Section: Discussionmentioning

confidence: 81%

Anthropometric and craniofacial patterns in mentally retarded males with emphasis on the fragile X syndrome

et al. 1993

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Anthropometric and craniofacial profile patterns indicating the percent difference from the overall mean were developed on 34 physical parameters with 31 white, mentally retarded males (23 adults and 8 children) with the fra(X) syndrome matched for age with 31 white, mentally retarded males without a known cause of their retardation. The fra(X) syndrome males consistently showed larger dimensions for all anthropometric variables, with significant differences for height, sitting height, arm span, hand length, middle finger length, hand breadth, foot length, foot breadth, and testicular volume. A craniofacial pattern did emerge between the two groups of mentally retarded males, but with overlap of several variables. Significant differences were noted for head circumference, head breadth, lower face height, bizygomatic diameter, inner canthal distance, ear length and ear width, with the fra(X) syndrome males having larger head dimensions (head circumference, head breadth, head length, face height and lower face height), but smaller measurements for minimal frontal diameter, bizygomatic diameter, bigonial diameter, and inner canthal distance. Several significant correlations were found with the variables for both mentally retarded males with and without the fra(X) syndrome. In a combined anthropometric and craniofacial profile of 19 variables comparing 26 white fra(X) syndrome males (13 with high expression (>30%) and 13 with low expression (< 30%), but matched for age), a relatively flat profile was observed with no significant differences for any of the variables. Generally, fra(X) syndrome males with increased fragile X chromosome expression have larger amplifications of the CGG trinucleotide repeat of the FMR-1 gene. No physical differences were detectable in our study between fra(X) males with high expression and apparently larger amplifications of the CGG trinucleotide repeats compared with those patients with low expression. Our research illustrates the use of anthropometry in identifying differences between mentally retarded males with or without the fra(X) syndrome and offers a comprehensive approach for screening males for the fra(X) syndrome and selecting those individuals for cytogenetic and/or molecular genetic testing. 1983, Meaney & Farrer 1986, Meaney & Butler 1989, Butler et al. 1991a. One of these conditions is the fragile X (fra(X)) or Martin-Bell syndrome, the most common familial cause of mental retardation. This syndrome is characterized by mental retardation, macroorchidism, large or prominent ears, a long narrow face, hyperflexibility and a characteristic chromosome fragile site at Xq27.3 (Turner et al. 1986, Hagerman 1987, Butler 1988. The incidence of the fragile X syndrome is approximately one in 1000-2500 males (Herbst & Miller 1980, Turner et al. 1986, Webb et al. 1986). Unstable DNA sequence representing large increases in the number of CGG repeats have recently been located at the fragile site and characterization of the gene (FMR-1) implicated in the fra(X) syndrome is under...

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“…Mosaic males (with both a full mutation and a premutation detected by Southern blot analysis) have been shown in some studies to have higher intellectual function and adaptive-skill development than males with a full mutation [Staley et al, 1993;Cohen et al, 1996;Merenstein et al, 1996], but this was not evident in other studies [de Vries et al, 1993;Rousseau et al, 1994a]. It is possible that a high proportion of cells with the premutation could influence clinical outcome, but this has not been demonstrated.…”

Section: Introductionmentioning

confidence: 98%

FMRP expression as a potential prognostic indicator in fragile X syndrome

et al. 1999

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Absence or deficit of FMR1 protein (FMRP) resulting from methylation of full mutation genes is the fundamental defect in fragile X syndrome. We used FMRP immunocytochemistry and detailed phenotypic assessment to investigate the relationship between degree of FMRP expression and the broad clinical spectrum of impairment in 80 individuals affected with fragile X syndrome. FMRP expression correlated with IQ in mosaic males (P=0.043), males with a partially methylated full mutation (P=0.0005), and females with a full mutation (P=0.046). In the females, FMRP expression also correlated with the number of fragile X physical features (P=0.0003). Even modest deficits in FMRP result in some manifestations of fragile X syndrome. In this initial study of 53 males, FMRP expression testing had a very high positive predictive value (100%, confidence interval of 29-100%) for a nonretarded IQ among males with expression of FMRP in > or = 50% of lymphocytes (3 males), suggesting that FMRP expression may have potential as a prognostic indicator in males with fragile X syndrome.

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Molecular-Clinical Correlations in Children and Adults With Fragile X Syndrome

Cited by 20 publications

References 18 publications

Cognitive and behavioral profile of fragile X boys: Correlations to molecular data

Cognitive and behavioral profile of fragile X boys: Correlations to molecular data

Anthropometric and craniofacial patterns in mentally retarded males with emphasis on the fragile X syndrome

FMRP expression as a potential prognostic indicator in fragile X syndrome

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