X-linked recessive inheritance
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Fragile X syndrome

Fragile X Syndrome is the most common inherited cause of mental retardation, and is associated with autism. more...

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The fragile X syndrome is a genetic disorder caused by mutation of the FMR1 gene on the X chromosome. Mutation at that site is found in 1 out of about every 2000 males and 1 out of about every 4000 females.

Normally, the FMR1 gene contains between 6 and 53 repeats of the CGG codon (trinucleotide repeats). In people with the fragile X syndrome, the FMR1 allele has over 230 repeats of this codon.

Expansion of the CGG repeating codon to such a degree results in a methylation of that portion of the DNA, effectively silencing the expression of the FMR1 protein.

This methylation of the FMR1 locus in chromosome band Xq27.3 is believed to result in constriction and fragility of the X chromosome at that point, a phenomenon that gave the syndrome its name.

The mutation and methylation of the FMR1 gene lead to the transcriptional silencing of the fragile X-mental retardation protein, FMRP. In normal individuals, FMRP binds and facilitates the translation of a number of essential neuronal RNAs. In fragile X patients, however, these RNAs are not translated into proteins. The various sequelae of fragile X syndrome result.

Transmission of the Fragile X

The diagram (above) of X-linked recessive inheritance is not entirely inappropriate but it markedly oversimplifies the situation and does not provide a sufficient foundation for genetic counseling with the fragile X syndrome.

Because males normally have only one copy of the X chromosome, those males with significant trinucleotide expansion at the FMR1 locus are symptomatic. They are mentally retarded and may show various physical features of the fragile X syndrome.

Females have two X chromosomes and thus have double the chance of having a working FMR1 allele. Females carrying one X chromosome with an expanded FMR1 gene can have some signs and symptoms of the disorder or be normal.

Males with the fragile X cannot transmit it to any of their sons (since males contribute a Y chromosome, not an X, to their male offspring.)

Females carrying one copy of the fragile X can transmit it to their sons or daughters. Sons who receive the fragile X are at high risk for mental retardation. Daughters who receive the fragile X may appear normal or they may be mentally retarded, usually to a lesser degree than boys with the syndrome.


Aside from mental retardation, prominent characteristics of the syndrome include an elongated face, large or protruding ears, large testicles (macroorchidism), and low muscle tone. Behavioral characteristics may include stereotypic movements (e.g., hand-flapping) and atypical social development, particularly shyness and limited eye contact. Some individuals with the fragile X syndrome also meet the diagnostic criteria for autism.

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Delayed diagnosis of Fragile X syndrome - inherited mental retardation - Statistical Data Included
From Morbidity and Mortality Weekly Report, 8/23/02

Delayed Diagnosis of Fragile X Syndrome -- United States, 1990-1999.

Fragile X syndrome (FXS) is the leading cause of inherited mental retardation, affecting approximately 50,000 persons in the United States (1). FXS occurs when a mutation on the X chromosome is passed from mother to child. Preliminary data suggest that children affected by FXS experience a delay in diagnosis, a pattern common to other single-gene disorders (2). The molecular test used to definitively diagnose FXS became available in 1991. The first indication of FXS within a family is usually the diagnosis of FXS in a child. Although no proven treatments exist for FXS, prompt diagnosis enables children to receive early intervention services and families to receive genetic counseling (3,4). To assess the timing of a diagnosis of FXS in an affected child and genetic counseling for the family, the Frank Porter Graham Child Development Institute (University of North Carolina at Chapel Hill) conducted a survey during August-October 2001 of 140 parents whose first child affected by FXS was born and had the conditi on diagnosed during 1990-1999. This report summarizes the results of that survey, which indicate that approximately half of the families did not learn the diagnosis for more than a year after first concerns about their child's development or behavior, and half reported having subsequent pregnancies before FXS was diagnosed in their first child. These findings emphasize the importance of increased opportunities for early diagnosis so children and families can receive all possible benefits, including genetic counseling and intervention services.

No population-based registries for FXS exist in the United States, and few children are identified by routine surveillance systems for birth defects and developmental disabilities. To gather an adequate number of families in a short time frame, investigators used a convenience sample from mailing lists of research institutions and parent-based groups. The families surveyed were identified through two sources: the Carolina Fragile X Project, comprising families in the southeastern United States ascertained for a longitudinal cohort study of FXS (2), and the FRAXA Research Foundation, a parent-based group focused on FXS education and research. The questionnaire asked about the process of finding out about the FXS diagnosis and the impact of the diagnosis on the family. Each parent of a child with FXS was asked to complete the questionnaire, with the assurance that answers were confidential and could not be linked to names. Approximately 535 questionnaires were mailed, and 460 questionnaires representing 299 di stinct families were completed. If both parents from the same family responded, the mother's questionnaire was chosen for analysis. Nonbiologic parents (n=nine), parents who knew their FXS carrier status before the index pregnancy (n=16), and parents whose children were born before 1990 (n=134) were excluded; 140 families (126 boys) were included in the survey.

At the time the questionnaire was completed, the mean age of the 140 respondents was 37.6 years (standard deviation: 5.8 years); 93% of the respondents were white, 61% had completed at least an undergraduate degree, and 37% had an annual household income >$100,000. Before becoming pregnant with the first child affected by FXS, 40 (29%) of 139 respondents knew that they had a family history of mental retardation, learning problems, or behavioral problems.

In this sample, all children had FXS diagnosed after birth when symptoms began to develop. After the first contact with a health-care provider, 34 (24%) of 140 respondents reported visiting a health-care provider about the child's development >10 times before the genetic rest for FXS was ordered (Figure). Because girls with FXS might have less distinct physical features, historical endpoints were calculated only for boys. A substantial gap existed between the child's age at the time someone became concerned about the child's development or behavior (median age: 12 months; range: 0-50 months) and the child's age at diagnosis of FXS (median age: 26 months; range: 6-101 months).

For many parents, the delay between the birth of the child and FXS diagnosis precluded informed reproductive decisions. Of the 140 parents, 70 (50%) reported having another child before their first child had FXS diagnosed; of these 70 parents, 30 (43%) had another child affected by FXS before the first child had FXS diagnosed. Overall, 124 (89%) of 139 parents reported receiving genetic counseling, and 99 (73%) of 136 reported that the diagnosis affected their decision to have another child. When parents were asked to choose the best time to offer voluntary generic testing for FXS, 103 (75%) of 138 indicated that the best time would be before a woman becomes pregnant.

Reported by: DB Bailey, PhD, D Skinner, PhD, K Sparkman, Frank Porter Graham Child Development Institute, Univ of North Carolina at Chapel Hill. CA Moore, MD, RS Olney, MD, National Center on Birth Defects and Developmental Disabilities; DC Crawford, PhD, EIS Officer, CDC.

Editorial Note: This report documents both the occurrence of a delayed diagnosis for a child with FXS and the impact this delay has on family planning. Early identification provides benefits for both the family and the affected child. First, early identification provides parents with a diagnosis, potentially reducing the psychosocial impact they face in searching for the cause of their child's disorder and providing more impetus for participation in early intervention programs. Second, early identification could provide parents an opportunity to receive genetic counseling for family planning. Third, early identification would allow the child to receive available intervention services. Infants who have FXS diagnosed are immediately eligible for publicly funded developmental services (e.g., early intervention programs) in all 50 states under Part C of the Individuals with Disabilities Education Act (5). Finally, early identification allows researchers to better understand the natural history of the disorder and provides an opportunity for testing the effectiveness of new interventions (5).

Despite the potential benefits of early identification, strategies for obtaining an early diagnosis in a child are limited. Two such strategies are newborn screening (3,6,7) and early clinical recognition (8,9). Adding disorders such as FXS to newborn screening programs would guarantee a timely diagnosis. However, FXS does not have a proven treatment that must be administered shortly after birth, which is the fundamental criterion used to justify rapid, universal identification of a disorder in a newborn (3,6). Similarly, the clinical screening strategy might not be optimal for early identification of disorders such as FXS. The signs for FXS clinical recognition often are subtle, and no single factor (e.g., severity of mental retardation or behavior) is associated with the variability in the length of time from a child's birth to diagnosis of FXS (5). Strategies to enhance early clinical identification of FXS could include education programs for health-care providers that emphasize the importance of developme ntal screening and ascertaining family history as part of routine well-child health care, and focusing on improved recognition of the signs and symptoms of FXS and other developmental disorders in young children.

The findings in this report are subject to at least two limitations. First, the convenience sample used for this survey probably does not represent all families affected by FXS in the United States. Respondents were parents who have elected to participate in research in the past or have an active interest in research and policy concerning FXS. Second, because the analyses were limited to a specific time frame, the sample size was relatively small.

Despite these limitations, this survey documents the consequences of a delayed diagnosis of FXS for both the child and the family. Although the strategies to obtain an early diagnosis for disorders such as FXS are limited, new approaches are needed to optimize access to services and information for personal health decisions and family planning.



(1.) Crawford DC, Acuna JM, Sherman SL. FMR1 and the fragile X syndrome: human genome epidemiology review. Genet Med 2001;3:359-71.

(2.) Bailey DB, Skinner DA, Hattan D, Roberts J. Family experiences and factors associated with the diagnosis of fragile X syndrome. J Dev Behav Pediatr 2000;21:315-21.

(3.) Levy HL, Albers S. Genetic screening of newborns. Annu Rev Genomics Hum Genet 2000;1:139-77.

(4.) Barnicoat A. Screening for fragile X syndrome: a model for genetic disorders? BMJ 1997;315:1174-5.

(5.) Bailey DB, Roberts JE, Mirrett P, Hatton DD. Identifying infants and toddlers with fragile X syndrome: issue and recommendations. Infants and Young Children 2001;14:24-33.

(6.) Andrews LB, Fullarton JE, Holtzman NA, Motulsky AG, eds. Assessing genetic risks: implications for health and social policy. Washington, DC: National Academy Press, 1994.

(7.) Clayton EW. What should be the role of public health in newborn screening and prenatal diagnosis? Am J Prev Med 1999;16:111-5.

(8.) American College of Medical Genetics. Fragile X syndrome: diagnostic and carrier testing. Am J Med Genet 1994;53:380-1.

(9.) American Academy of Pediatrics, Committee on Children with Disabilities. Developmental surveillance and screening of infants and young children. Pediatrics 2001;108:192-6.

COPYRIGHT 2002 U.S. Government Printing Office
COPYRIGHT 2004 Gale Group

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