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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Fragile-X syndrome
From American Family Physician, 5/1/89 by Richard J. Simensen

Fragile-X Syndrome A fragile site on the X chromosome has been implicated in mental retardation and behavioral problems among both males and females. The fragile-X syndrome is second only to Down syndrome among causes of mental retardation associated with cytogenetic abnormalities. The clinical phenotype is extremely variable. During the early years, many affected children demonstrate normal or near-normal intellect and development. Folic acid may be of benefit before puberty. Because of the large number of males with mental retardation, the concept of an X-linked factor was proposed in the 1940s(1,2) and revitalized in the 1960s.(3,4) In 1969, Lubs(5) reported on a family with mental retardation and a specific "marker-X" chromosome in two brothers and their mother. This entity is now referred to as the fragile-X syndrome. It is responsible for approximately 40 percent of all X-linked mental retardation.

An evaluation of school-age children in England disclosed fragile-X-associated mental retardation in one out of 1,350 males and one out of 2,033 females, giving an overall prevalence of one per 1,634 in the children studied.(6) In Australia, the prevalence rates for intellectually handicapped persons with the fragile-X syndrome in the public school population were computed to be one in 2,610 males and one in 4,221 females.(7) The reported prevalence of this syndrome in various populations has ranged from 1.9 percent to 5.9 percent.(8,11) This makes fragile-X syndrome second only to Down syndrome among etiologies of mental retardation associated with cytogenic abnormalities.

Fragile-X syndrome primarily affects males, but unlike other X-linked diseases, it may also significantly affect females. Since this is an inherited disorder, the family physician is in a unique position to identify and counsel affected families and thus prevent recurrence of the syndrome.

Clinical Characteristics

The clinical data presented here are based on findings in members of 39 families affected with fragile-X syndrome. Within these families, there are 93 affected males and 33 affected females.

The adult male patient with this syndrome typically has a long face, large ears, prominent forehead, midfacial hypoplasia and a prominent jaw. The long face and the large ears are the two most common facial features.

Macro-orchidism is a significant diagnostic feature among the adult male population. This feature is not reported, however, in approximately half of the prepubertal males. This may represent a failure to recognize increased testicular volume in prepubertal males, either because of inadequate examination technique or because of unfamiliarity with the range of normal for this age group.

The phenotype of affected individuals is highly variable; adult males are more likely to exhibit the characteristic features than prepubertal males or females. Facial features among affected females are exceedingly variable and cannot be used to make the diagnosis. Table 1 presents the physical, findings and their frequency among males with fragile-X syndrome in our study.

Typical fragile-X syndrome pedigree. It demonstrates the pattern of X-linked inheritance. Carrier females pass the condition to their daughters (who may or may not have the fragile-X chromosome on laboratory testing), who may then pass it on to their sons. Females who have the fragile-X are frequently mentally retarded. An obligate carrier is negative for the fragile-X but, based on analysis of the family pedigree, she must carry the condition.

Within one family, 31 patients have had chromosome studies completed. There are six mentally retarded males with the fragile-X, one mentally retarded male without the fragile-X, one mentally retarded female and four nonretarded females with the fragile-X, four obligate carriers and 12 potential carriers ascertained by pedigree and laboratory analysis.


Fragile sites on chromosomes, identified as nonstaining gaps in the chromatin structure, were described in 1965.(12) It was not until 1976 and 1977 that the fragile site on the X chromosome was related to a common form of X-linked mental retardation.(13,14) The fragile site appears as a gap or break on the long arm of the X chromosome in the 27 or 28 region.

A standard chromosomal analysis will not demonstrate fragile-X. The cytogenetic expression is dependent on a culture medium deficient in folate and thymidine. The blood sample should be drawn into a sodium heparin tube, and the cell cultures can be grown from lymphocytes.

The fragile condition is not expressed in all cells. In our experience, the percentage of expression of fragile sites among males ranged from 3 to 56 percent (mean: 23 percent). Among females, the range was from 3 to 47 percent (mean: 16 percent). The percentage of cells with fragile sites (degree of expression) does not correlate with the intelligence level or the presence of characteristic craniofacial features.

Developmental, Intellectual and Behavioral Characteristics

Characteristics of behavior and intellect are far more significant for lifetime functioning and are more consistent diagnostic tools than are the physical findings associated with fragile-X syndrome. Early diagnosis enables the physician to provide management, intervention and preventive services for the affected individual and the family.

Because of the lack of significant dysmorphic features, deviations from normal growth and development provide the earliest postnatal clues to the diagnosis of fragile-X syndrome. These milestones are easily and routinely monitored by family physicians and parents.

Initial reports indicated that males with fragile-X had generalized overgrowth during the prenatal period and that this extended into early childhood.(15-18) We reviewed growth data on 33 affected males and reported that "excessive prenatal growth in fragile-X males may reflect, in part, differences in commonly used newborn growth references."(19) We were able to evaluate the patient's head circumference, length and weight, retrospectively, from the time of birth.

Data on postnatal growth from the age of one month to 18 years were available for 32 males. No deviation in weight was reported, but height (length) was accelerated for the first five years of life; thereafter, stature of the males with fragile-X did not differ from that of normal children.(20)

Head circumference was measured in an institutionalized population of 34 white and 26 black postpubertal males with the syndrome, who ranged in age from 18 to 67 years. The mean head circumference was 56.96 cm. While this approximated the mean for normal adult males, it was significantly above the mean of 55.77 cm for a sample of 100 institutionalized, mentally retarded adult males without the clinical features of fragile-X. Anthropometric data probably remain too variable to be a significant aid in making the diagnosis of fragile-X syndrome.

Milestones of early development may be moderately or severely delayed.(16,21,22) Children with fragile-X syndrome may not be brought to the attention of a physician and may do quite well until difficulties with speech and language develop. Boys with the syndrome have demonstrated normal intellectual ability when assessed at an early age,(23,24) and many remain undetected until the first few years of formal education.

Mental retardation is the most significant clinical finding in the fragile-X syndrome. Table 2 presents the mean and standard deviation of intellectual abilities and percentage of expression of fragile-X sites seen on chromosomal analysis among 126 tested individuals with fragile-X syndrome. As one might expect, intellectual functioning is more severely affected in male hemizygotes than in female heterozygotes. The concept of a slowly progressive neurologic degeneration underlying the decline in IQ cannot be excluded.

One of our patients was tested with the revised Wechsler Intelligence Scale for Children when he was seven years and eight months of age. He earned a full scale IQ of 93. He was given the same test at ten years and ten months of age and earned a full scale IQ of 64. Retrospective analysis of longitudinal intellectual data among 21 males with fragile-X syndrome demonstrated a significant decrease in IQ during childhood, thereby lending support to the concept of either a progressive neurologic deterioration or an arrest in development.(24,25)

Hagerman and colleagues(23) studied four young male patients who were referred for evaluation because of mild learning disabilities and attention difficulties. These patients, ranging in age from four to seven years, had demonstrated intellectual abilities in the low-normal to mildly retarded range. It is significant that, first, these four boys had fragile-X syndrome and were not considered retarded by either their parents or their teachers and, second, that mental retardation was not the presenting complaint. The family physician should be aware that absence of frank mental retardation does not rule out fragile-X syndrome.

Autism and autistic-like behaviors have been observed in a number of males with fragile-X, especially during early childhood.(14,26-30) One investigator(31) studied 76 autistic males and found four patients (5.3 percent) who demonstrated fragile-X. Results of a study of 183 autistic males, when combined with data from 11 other investigators, showed that the fragile-X syndrome was present in 7.7 percent of autistic males, while 21.2 percent of the males with the syndrome exhibited autistic behaviors.(32)

Hyperactivity was observed in many of our patients and also has been reported by other authors.(15,23,30,33,34) Other behaviors seen among affected patients include aggressive, self-mutilating, psychotic and schizoid behaviors.(30) Retardation and behavioral difficulties are generally less severe in female patients with fragile-X. Our experience, however, has shown that some affected females fall into the severely retarded range in terms of general intellectual functioning. Other investigators have reported similar observations.(35-38)

Evaluations of nonretarded females with the fragile-X have demonstrated unsuspected learning disabilities, with the possibility of mild, neuropsychologic dysfunction of the right cerebral hemisphere.(37,39,40) In a series of 23 females with fragile-X, 41 percent had some physical signs of the syndrome and 65 percent had one or more behavioral or emotional problems. Furthermore, five of the ten girls who were of school age had been identified by the school psychologist as "learning-disabled."(41) The data suggest that identifiable chromosomal abnormalities can be seen in patients without significant deficits or dysmorphology, and that such abnormalities should be included in the differential diagnosis among patients with learning disabilities or attention disorders.


There are reports of positive behavioral changes in males with fragile-X syndrome who were treated with folic acid.(27,42) A later study of this treatment in affected males(43) employed a double-blind crossover method of investigation. The patients were given psychologic, language and behavioral evaluations. Subjective behavioral reports from parents and caretakers were also obtained. These subjective evaluations indicated that prepubertal males showed increased attention spans and decreased levels of hyperactivity, aggressiveness, hand flapping and other abnormal movements while they were receiving folic acid. The psychologic assessment demonstrated statistically significant improvement in these patients during folic acid therapy.

We have treated a number of prepubertal males with folic acid, 10 mg daily. Parents and teachers reported improved behavior, intellectual performance and attention to tasks. Unfortunately, adult males treated with folic acid have exhibited minimal or no improvement.(43-46) Some patients demonstrated subjective behavioral improvement, while others became more hyperactive and more aggressive.(43)

Pharmacologic treatment of the attention deficit disorder in children with fragile-X syndrome has been reported to be effective. One child development unit found certain medications, including methylphenidate (Ritalin), dextroamphetamine (Dexedrine) and pemoline (Cylert), beneficial in 38 percent of the patients.(46)

As with other conditions that result in mental retardation or significant learning disabilities, the primary treatment is education. The patients should have special education and may benefit from speech and language therapy. Mildly retarded children may function effectively in resource rooms with some integration into regular educational programs. Patients with moderate to severe retardation may require placement in self-contained classes for educable or trainable mentally retarded children.

Behavioral management techniques utilizing positive reinforcement can be helpful in eliminating negative behaviors. For example, "time out" (eliminating the opportunity for positive reinforcement) is more effective than corporal punishment, which may lead to further aggression. The family physician may find school psychologic services to be both an excellent resource for materials dealing with a positive approach to changing behavior and a useful tool in appropriate class placement.

Many of the adult patients function very well in group homes and sheltered workshop situations. The goal for all handicapped patients, including those with fragile-X syndrome, is to find placement in the least restrictive environment. A valuable resource is the Fragile-X Foundation (P.O. Box 300233, Denver, CO 80203). The function of the foundation is to educate professionals, parents and the public in all aspects of fragile-X syndrome, as well as other forms of X-linked mental retardation. Information on support groups and conferences can be obtained from the foundation.

Prenatal diagnosis is available for couples at risk for fragile-X. Positive cytogenetic studies are significant, but negative results do not rule out the possibility of an affected offspring. DNA studies are more accurate but are expensive and time-consuming because samples from the extended family, including siblings, parents and grandparents, are required.

Genetic counseling is recommended for all couples seeking prenatal diagnosis. The limitations of prenatal testing must be thoroughly explained. The couple's options in the event that results are positive also must be discussed. These couples will need ongoing support from the genetic counselor and the family physician.

Final Comment

Fragile-X syndrome is an identifiable X-linked disorder that ranks second only to Down syndrome among causes of mental retardation associated with cytogenetic abnormalities. There is extreme variability in the appearance of affected males, although a characteristic phenotype has been developed. A suspected diagnosis can be confirmed with cytogenetic testing when cell cultures are grown in special media.

Folic acid may be useful in the treatment of prepubertal patients. Long-term treatment requires an appropriate educational program that may lead to a more independent lifestyle and may defer or prevent institutionalization.


Adult Males with Fragile-X Syndrome


IQ(*) and Percentage of Expression of Fragile-X Sites

(*)-IQ = intelligence quotient. +-SD = standard deviation. REFERENCES (1)Martin JP, Bell J. A pedigree of mental defect showing sex-linkage. J Neurol Psychol 1943;6: 154-7. (2)Allan W, Herndon CN, Dudley FC. Some examples of the inheritance of mental deficiency: apparently sex-linked idiocy and microcephaly. Am J Ment Defic 1944;48:325-34. (3)Renpenning H, Gerrard JW, Zaleski WA, Tabata T. Familial sex-linked mental retardation. Can Med Assoc J 1962;87:954-6. (4)Dunn HG, Renpenning H, Gerrard JW, Mitter JR, Tabata T, Federoff S. Mental retardation as a sex-linked defect. Am J Ment Defic 1963;67:827-48. (5)Lubs HA. A marker X chromosome. Am J Hum Genet 1969;21:231-44. (6)Opitz JM. On the gates of hell and a most unusual gene [Editorial]. Am J Med Genet 1986;23(1-2): 1-10. (7)Turner G, Robinson H, Laing S, Purvis-Smith S. Preventive screening for the fragile X syndrome. N Engl J Med 1986;315:607-9. (8)Blomquist HK, Gustavson KH, Holmgren G, Nordenson I, Palsson-Strae U. Fragile X syndrome in mildly mentally retarded children in a northern Swedish county. A prevalence study. Clin Genet 1983; 24:393-8. (9)Blomquist HK, Gustavson KH, Holmgren G, Nordenson I, Sweins A. Fragile site X chromosomes and X-linked mental retardation in severely retarded boys in a northern Swedish county. A prevalence study. Clin Genet 1982;21:209-14. (10)Gustavson KH, Blomquist HK, Holmgren G. Prevalence of the fragile-X syndrome in mentally retarded boys in a Swedish county. Am J Med Genet 1986;23:581-7. (11)Jacobs PA, Mayer M, Abruzzo MA. Studies of the fragile (X) syndrome in populations of mentally retarded individuals in Hawaii. Am J Med Genet 1986;23:567-72. (12)Dekaban A. Persisting clone of cells with an abnormal chromosome in a woman previously irradiated. J Nucl Med 1965;6:740-6. (13)Giraud F, Ayme S, Mattei JF, Mattei MG. Constitutional chromosomal breakage. Hum Genet 1976;34: 125-36. (14)Harvey J, Judge C, Wiener S. Familial X-linked mental retardation with an X chromosome abnormality. J Med Genet 1977;14:46-50. (15)Turner G, Daniel A, Frost M. X-linked mental retardation, macro-orchidism, and the Xq27 fragile site. J Pediatr 1980;96:837-41. (16)Partington MW. The fragile X syndrome. II. Preliminary data on growth and development in males. Am J Med Genet 1984;17:175-94. (17)Opitz JM, Sutherland GR. Conference report: International Workshop on the fragile X and X-linked mental retardation. Am J Med Genet 1984;17:5-94. (18)Sutherland GR, Hecht F. Fragile sites on human chromosomes. New York: Oxford University Press, 1985:132-49. (19)Stevenson RE, Prouty LA, Dean JH. Fragile X syndrome. I. Prenatal growth. Proc Greenwood Genet Cent 1988;7:84-6. (20)Prouty LA, Stevenson RE, Dean JH. Fragile X syndrome. II. Postnatal growth. Proc Greenwood Genet Cent 1988;7:87-90. (21)Stevenson RE, Dean JH. Fragile X syndrome. III. Early developmental milestones. Proc Greenwood Genet Cent 1988;7:91-2. (22)Howard-Peebles PN, Stoddard GR, Mims MG. Familial X-linked mental retardation, verbal disability, and marker X chromosomes. Am J Hum Genet 1979;31:214-22. (23)Hagerman R, Kemper M, Hudson M. Learning disabilities and attentional problems in boys with the fragile X syndrome. Am J Dis Child 1985;139:674-8. (24)Lachiewicz AM, Gullion CM, Spiridigliozzi GA, Aylsworth AS. Declining IQs of young males with the fragile X syndrome. Am J Ment Retard 1987;92:272-8. (25)Rogers RC, Simensen RJ. Fragile X syndrome: a common etiology of mental retardation. Am J Ment Defic 1987;91:445-9. (26)Proops R, Webb T. The "fragile" X chromosome in the Martin-Bell-Renpenning syndrome in males with other forms of familial mental retardation. J Med Genet 1981;18:366-73. (27)Lejeune J. Is the fragile X syndrome amenable to treatment? [Letter] Lancet 1982;1(8266):273-4. (28)Brown WT, Friedman E, Jenkins EC, et al. Association of fragile X syndrome with autism [Letter]. Lancet 1982;1(8263):100. (29)Gillberg C. Identical triplets with infantile autism and the fragile-X syndrome. Br J Psychiatry 1983;143:256-60. (30)Nielsen KB. Diagnosis of the fragile X syndrome (Martin-Bell syndrome). Clinical findings in 27 males with the fragile site at Xq28. J Ment Defic Res 1983;27(Pt 3):211-26. (31)Watson MS, Leckman JF, Annex B, et al. Fragile X in a survey of 75 autistic males [Letter]. N Engl J Med 1984;310:1462. (32)Brown WT, Jenkins EC, Cohen IL, et al. Fragile X and autism: a multicenter survey. Am J Med Genet 1986;23:341-52. (33)Bowen P, Biederman B, Swallow KA. The X-linked syndrome of macroorchidism and mental retardation: further observations. Am J Med Genet 1978;2:409-14. (34)Chudley AE, Hagerman RJ. Fragile X syndrome. J Pediatr 1987;110:821-31. (35)Webb GC, Halliday JL, Pitt DB, Judge CG, Leversha M. Fragile (X) (q27) sites in a pedigree with female carriers showing mild to severe mental retardation. J Med Genet 1982;19:44-8. (36)Brondum-Nielsen K, Tommerup N, Poulsen H, Mikkelsen M. X-linked mental retardation with fragile (X). A pedigree showing transmission by apparently unaffected males and partil expression in female carriers. Hum Genet 1981;59:23-5. (37)Hagerman RJ, Smith AC. The heterozygous female. In: Hagerman RJ, McBogg PM, eds. The fragile X syndrome: diagnosis, biochemistry, and intervention. Dillon, Colo.: Spectra, 1983. (38)Hagerman RJ, Chudley AE, Knoll JH, Jackson AW 3d, Kemper M, Ahmad R. Autism in fragile X females. Am J Med Genet 1986;23:375-80. (39)Miezejeski CM, Jenkins EC, Hill AL, Wisniewski K, Brown WT. Verbal vs. nonverbal ability, fragile X syndrome, and heterozygous carriers [Letter]. Am J Hum Genet 1984;36:227-9. (40)Miezejeski CM, Jenkins EC, Hill AL, Wisniewski K, French JH, Brown WT. A profile of cognitive deficit in females from fragile X families. Neuropsychologia 1986;24:405-9. (41)Kemper MB, Hagerman RJ, Ahmad RS, Mariner R. Cognitive profiles and the spectrum of clinical manifestations in heterozygous fra (X) females. Am J Med Genet 1986;23:139-56. (42)Harpey JP. Treatment of fragile X [Letter]. Pediatrics 1982;69:670. (43)Hagerman RJ, Jackson AW, Levitas A, et al. Oral folic acid versus placebo in the treatment of males with the fragile X syndrome. Am J Med Genet 1986;23:241-62. (44)Froster-Iskenius U, Bodeker K, Oepen T, Mathes R, Piper U, Schwinger E. Folic acid treatment in males and females with fragile-(X)-syndrome. Am J Med Genet 1986;23:272-89. (45)Rosenblatt DS, Duschenes EA, Hellstrom FV, et al. Folic acid blinded trial in identical twins with fragile X syndrome. Am J Hum Genet 1985;37:543-52. (46)Wells TE, Madison LS. Assessment of behavior change in a fragile-X syndrome male treated with folic acid. Am J Med Genet 1986;23:291-6.

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