Fragile X syndrome is caused by an expansion of a CGG repeat in the FMR1 gene. The CGG repeat number of the FMR1 mutation and the percentage of cells with methylation of the gene were studied in 218 male patients. Physical and cognitive measurements were also performed. Patients were divided into three groups; those with full mutation and complete methylation (n = 160), those with full mutation and partial methylation (n = 12), and those with a mosaic pattern (n = 46). Statistical comparisons were made between males with the fully methylated full mutation and those with a mosaic pattern. Males having full mutation with complete methylation had the lowest IQ scores and greatest physical involvement. These significant differences were seen only in ages after puberty. CGG repeat length did not correlate with IQ or the physical index score in any group. These findings suggest that a partial production of FMR1 protein may predict milder clinical involvement in some males with fragile X syndrome. © 1996 Wiley‐Liss, Inc.
Females who are affected by fragile X syndrome (FXS) can have significant physical, neuropsychological and emotional involvement. This study was designed to explore the relationships between these three domains and to learn how the degree of involvement in each of these phenotypic areas relates to molecular parameters including CGG repeat length and activation ratio (the proportion of normal FMR1 alleles on the active X chromosome). Three groups of females were studied: 35 women who grew up in a fragile X family but do not carry an FMR1 mutation, 92 women with a premutation, and 29 women with a full mutation. Correlations between neurocognitive, physical and emotional traits were calculated for each of the three groups. Within the full mutation group significant correlations were seen between schizotypal traits and full scale IQ. The Lie scale was significantly correlated with the physical findings index. The activation ratio correlated significantly with the measure of executive function (r = .50, P = .01). There was a trend toward correlations of activation ratio with the physical index score, outer ear prominence and IQ. CGG repeat number significantly correlated only with the physical index (r = .44, P = .01). Thus, activation ratio may be the more pertinent molecular parameter in full mutation women in determining the degree of cognitive and physical phenotypic involvement.
The aim is this study is to compare the longitudinal changes in IQ scores of females and males with fragile X syndrome and controls and to assess the impact on IQ of molecular variations of the FMR‐1 gene in males. Medical records from the child development unit at a university‐affiliated children's hospital were retrospectively reviewed. Chart review yielded 35 males with fragile X (19 with a fully methylated full mutation, 9 with a mosaic pattern, and 7 with a partially unmethylated full mutation) 16 females with fragile X and a full mutation, 9 female controls, and 9 male controls who had repeated standardized IQ testing separated by 7 months to 13 years. The differences between the first and last IQ scores from the same IQ test were compared by t tests and subsequently by analysis of variance. Overall, a significant IQ decline was seen in 10/35 (28%) of fragile X males, 0/9 (0%) of control males, 6/16 (36%) of fragile X females, and 1/9 (11%) of control females. The initial t tests and analysis of variance showed a significant difference in IQ (p = 0.02) between fragile X males and control males but did not show a significant difference between males and females with fragile X syndrome or between fragile X and control females. When an analysis of covariance was carried out with the initial IQ as a covariable, a significant difference persisted between fragile X and control males, with a greater IQ decline in fragile X males. There were limitations in using the same IQ test. A comparison among the molecular subgroups of males yielded a significant IQ decline in 3/9 (33%) of mosaic males, 6/19 (32%) of fully methylated full mutation males, and 1/7 (14%) of partially methylated full mutation males. An analysis of covariance using the initial IQ and the intertest interval as covariables demonstrated significant differences between the fragile X molecular subgroups and the controls. Our findings show that a substantial percentage of both male and female fragile X patients and female control patients demonstrated significant IQ decline. There was a significant differences in the IQ change between fragile X and control males. There were no significant differences between fragile X and female controls. There were also significant differences in IQ decline among males with different molecular patterns compared with controls. Males with a mosaic pattern versus control males had the most significant decline of the molecular subtypes. Although the numbers were limited, there was no significant IQ decline in males with less than 50% methylation of the full mutation. This suggests that a small amount of FMR‐1 protein production, which is often seen in males with less than 50% methylation, protects against significant IQ decline. © 1996 Wiley‐Liss, Inc.
Fragile X syndrome is caused by an expansion of a CGG repeat in the FMR1 gene. The CGG repeat number of the FMR1 mutation and the percentage of cells with methylation of the gene were studied in 218 male patients. Physical and cognitive measurements were also performed. Patients were divided into three groups; those with full mutation and complete methylation (n = 160), those with full mutation and partial methylation (n = 12), and those with a mosaic pattern (n = 46). Statistical comparisons were made between males with the fully methylated full mutation and those with a mosaic pattern. Males having full mutation with complete methylation had the lowest IQ scores and greatest physical involvement. These significant differences were seen only in ages after puberty. CGG repeat length did not correlate with IQ or the physical index score in any group. These findings suggest that a partial production of FMR1 protein may predict milder clinical involvement in some males with fragile X syndrome.
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