Female relatives in families with the fragile X syndrome

Three problems--mental retardation, having retarded children, and fear of having retarded children--are described in women in families with the fragile X syndrome. The investigation of one family with a counselling dilemma is presented in detail.     

The fragile X syndrome: A study of 83 families

The present report summarizes the experience on the mar(X) syndrome in a total of 157 male patients (44 prepubertal and 113 postpubertal) ascertained through 83 index patients from 83 families under investigation.
1. In one third of the families pedigree data were consistent with X-linked recessive inheritance. In the further two thirds of the families the presenting symptom was familial mental retardation with a mentally retarded mother, or mental subnormality with hyperkinetic behaviour in the male patient.
2. No more than 60% of the adult males presented the typical clinical triad (mental retardation -long face - megalotestes). The most characteristic finding in the mar(X) boy is the psychological profile with severe hyperkinetism, hypersensitivity, handbiting and autistic features in some of them.
3. In 4 of the 27 large mar(X) pedigrees strong evidence was present of a possible transmission of the mar(X) through normal males.
4. The high incidence of mental subnormality in the female offspring of heterozygote carriers, and the relationship between mental status, phenotype, age and expression of the mar(X) in different culture conditions is discussed.     

Recurrence risks for relatives in families with an isolated case of the fragile X syndrome

The proportion of sporadic cases among affected males with fragile X-related mental impairment was reinvestigated in a new sample of family data and compared to previous studies. It was found that the estimate has increased over time from 0 in the original study to 0.24 in the present study. This difference indicated that the correction used for the ascertainment of families in the original study may not have been adequate and that the suggestion that all mothers of affected males are obligate carriers may be wrong. Based on this new information, recurrence risks for relatives in a family with an isolated case of the fragile X or Martin-Bell syndrome were calculated under different assumptions in order to investigate the effect of 1) the knowledge of the phenotype of ancestors of the proband, 2) the dependence of expression of the mutation on the sex of the carrier parent, 3) the value of the penetrance of mental impairment (MI), and 4) the equality of mutation rates in egg and sperm. The assumptions made for modelling the mutational process had the greatest effect on the recurrence risk in sibs of an isolated case, whereas small differences in penetrance parameters and assumptions based on whether the ancestors were known to be normal or of unknown phenotype made little difference. Recurrence risks for the sibs and first cousins of an isolated case calculated under different assumptions are presented.     

Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families

Within the past few years, there has been a significant change in identifying and characterizing the FMR1 premutation associated phenotypes. The premutation has been associated with elevated FMR1 mRNA levels and slight to moderate reductions in FMRP levels. Furthermore, it has been established that ∼20% of female premutation carriers present primary ovarian insufficiency (POI) and that fragile X-associated tremor/ataxia syndrome (FXTAS) occurs in one-third of all male premutation carriers older than 50 years. Besides POI and FXTAS, new disorders have recently been described among individuals (especially females) with the FMR1 premutation. Those pathologies include thyroid disease, hypertension, seizures, peripheral neuropathy, and fibromyalgia. However there are few reports related to FXTAS penetrance among female premutation carriers or regarding these disorders recently associated to the FMR1 premutation. Therefore, we have evaluated 398 fragile X syndrome (FXS) families in an attempt to provide an estimation of the premutation associated phenotypes penetrance. Our results show that signs of FXTAS are detected in 16.5% of female premutation carriers and in 45.5% of premutated males older than 50 years. Furthermore, among females with the FMR1 premutation, penetrance of POI, thyroid disease and chronic muscle pain is 18.6, 15.9 and 24.4%, respectively. The knowledge of this data might be useful for accurate genetic counselling as well as for a better characterization of the clinical phenotypes of FMR1 premutation carriers.     

Linkage analysis using multiple Xq DNA polymorphisms in normal families, families with the fragile X syndrome, and other families with X linked conditions.

Multipoint linkage analysis was undertaken with eight Xq cloned DNA sequences which identify one or more restriction fragment length polymorphisms in 26 families. These families comprise seven phase known normal families with three or more males in the third generation, seven families segregating for haemophilia B, one large family with dyskeratosis congenita, and 11 families with the fragile X syndrome. Phase known meioses informative for three or more loci supported the order centromere--DXYS1--DXS107--DXS102, DXS51--F9--FRAXA--DXS15, DXS52, F8--Xqter in each group of families studied. One of the normal families was segregating for protan colour blindness and showed a phase known recombination which would support the order centromere--F9--DXS52--CBP--Xqter. With the exception of DXYS1, all of these sequences have been localised to Xq27----qter by in situ hybridisation or hybridisation to Xq fragment panels, and on this basis should lie within 20 cM of one another. No recombination was observed between the sequences localised to Xq28, namely DXS52, F8, and DXS15 (between DXS15 and DXS52 Z = 12.25 at theta = 0 with confidence limits of 0 to 5 cM). However, an excess of recombination was apparent in the region of FRAXA with maximal lod scores as follows: F9 versus FRAXA (Z = 2.05, theta = 0.19), DXS52 versus FRAXA (Z = 1.85, theta = 0.26), and DXS15 versus FRAXA (Z = 1.33, theta = 0.27). No consistent differences were observed in the frequency of recombination when families with the fragile X syndrome were compared with normal families or families segregating for other X linked conditions. These results are compared with other published work and support the conclusion that although measurable linkage exists between these flanking markers and FRAXA, the intervals as measured by the frequency of meiotic recombination will seriously limit their clinical usefulness.     

Heritable unstable DNA sequences and hypermethylation associated with fragile X syndrome in Japanese families

Fragile X syndrome, associated with the fragile site at Xq27.3 (FRAXA), is the most common form of familial mental retardation. The fragile X mutation has recently been characterized as a heritable unstable DNA sequence, p(CCG)n/p(CGG)n, in the FRAXA locus. In the present study, a correlation between fragile X-genotypes in the FRAXA locus and hypermethylation of an adjacent CpG island was examined in four Japanese families with fragile X syndrome. We show here that the heritable unstable DNA sequences in the fragile X chromosome usually increase in size when transmitted by female carriers, and that the degree of methylation in the CpG island correlated with the increased sizes of the unstable DNA sequences. When a hypermethylated full mutation was transmitted by a male to his daughters, both the size of the unstable DNA sequence and the degree of the methylation reduced to the premutation range. Our observations suggest that female meiosis has a greater potential for amplifying unstable DNA sequences and that amplified DNA sequences can be transmitted through germ cells, while male germ cells seem not to be able to tolerate highly amplified unstable DNA sequences.     

Twelve families with fragile X(q27).

Through a community study of boys requiring special education for the severely mentally retarded, 12 families were ascertained in which the fragile X was found to be segregating. By assiduous follow up of these families, it was found that in only four of them could male transmission be ruled out from the grandparents' or great grandparents' generation and that the segregation ratios are disturbed.     

Dilemmas in counselling females with the fragile X syndrome

The dilemmas in counselling a mildly retarded female with the fragile X syndrome and her retarded partner are presented. The fragile X syndrome is an X linked mental retardation disorder that affects males and, often less severely, females. Affected females have an increased risk of having affected offspring. The counselling of this couple was complicated by their impaired comprehension which subsequently impaired their thinking on the different options. The woman became pregnant and underwent CVS, which showed an affected male fetus. The pregnancy was terminated. Whether nondirective counselling for this couple was the appropriate method is discussed and the importance of a system oriented approach, through involving relatives, is stressed.     

Survey of the fragile X syndrome and the fragile X E syndrome in a special education needs population

To begin to understand the population dynamics of the fragile X (FRAXA) mutation and to learn more about the fragile X E (FRAXE) syndrome, we have initiated a survey of children in special needs education programs in the public school system. With respect to the FRAXA syndrome, we found approximately 1/1,000 full mutations among males. No large alleles at the FRAXE locus were observed among 462 individuals. The allele distributions at the two loci among Caucasians and among African Americans were examined as well as the level of heterozygosity. We found a significant difference in the FRAXA allele distribution among the two ethnic groups; the major difference was due to the lack of smaller alleles among the African Americans. No difference was found for the FRAXE allele distribution among the two groups. The level of heterozygosity was less than predicted by the allele distribution at both loci. This is probably due to unidentified large alleles among females with a test result of a single band. Alternatively, this excess may indicate that the population is not at equilibrium. © 1996 Wiley-Liss, Inc.     

Problem behavior in boys with fragile X syndrome

This study examines problem behavior over time in 59 boys with fragile X syndrome (FXS), aged 4-12 years, using the Child Behavior Checklist (CBCL). Approximately 49% of the boys scored within the borderline or clinical range on total problem behavior, while 56-57% scored in the borderline or clinical range on the attention and thought problems subscales, and 26% scored in this range on the social problems subscale. With a mean of 2.5 assessments per child, behavior problems were stable during the 3-year period of study. Total problem behavior was higher for children who displayed autistic behavior, were rated as low in adaptability, had mothers with higher maternal education levels, and were on medication. Mothers with more education also rated their children as having more attention, thought, and total problems. Children taking medication differed from boys who were not taking medication on social problems, but not on attention and thought problems. Low adaptability and more autistic characteristics predicted thought problems.     

Prevalence of fragile X syndrome

The much-quoted prevalence figure of 1:1,000 males for fragile X syndrome is an overestimate in a mixed ethnic population. A reexamination of the individuals from whom those data were derived using molecular diagnostic techniques demonstrates a more realistic figure of 1:4,000 males. © 1996 Wiley-Liss, Inc.     

Reverse mutations in the fragile X syndrome

Three females were identified who have apparent reversal of fragile X premutations. Based on haplotype analysis of nearby markers, they were found to have inherited a fragile X chromosome from their premutation carrier mothers, and yet had normal size FMR1 repeat alleles. The changes in repeat sizes from mother to daughter was 95 to 35 in the first, 145 to 43 in the second, and 82 to 33 in the third. In the first family, mutations of the nearby microsatellites FRAXAC2 and DXS548 were also observed. In the other two, only mutations involving the FMR1 repeats were found. We suggest differing mutational mechanisms such as gene conversion versus DNA replication slippage may underlie such reversions. We estimate that such revertants may occur among 1% or less of premutation carrier offspring. Our results indicate that women identified to be carriers by linkage should be retested by direct DNA analysis. © 1996 Wiley-Liss, Inc.     

Cognitive profiles of boys with the fragile X syndrome

Testing 20 boys with the fragile X (or Martin-Bell) syndrome with the Kaufman Assessment Battery for Children (K-ABC) showed a consistent pattern of strengths and weaknesses that may be useful in predicting a fragile X positive result from cytogenetic testing. This K-ABC pattern included 1) Sequential Scale score less than the Simultaneous Scale score; 2) Mental Processing Composite less than the Achievement Scale score; 3) Spatial Memory subtest score less than the Matrix Analogies subtest score; and 4) Arithmetic subtest score less than the mean of the Achievement subtest scores. A comparison group of 20 boys did not demonstrate such a pattern. Testing with the K-ABC should be considered for boys who present as learning disabled, hyperactive with attentional problems, or mildly retarded. Boys with three or four of the four features of the K-ABC fragile X pattern should be considered for medical evaluation and cytogenetic testing.     

Prader-Willi-like phenotype in fragile X syndrome

Henk Meyer¹
A 3-year-old boy was referred to the pediatric department because of unexplained extreme obesity. Height and occipitofrontal circumference were just above the 90th centile. Endocrine studies failed to show any significant abnormality. Motor and speech development were generally delayed. On clinical-cytogenetic-molecular grounds, Prader-Willi syndrome was excluded. Fragile X syndrome was diagnosed by the presence of the classical FMR-1 mutation and confirmed by cytogenetic studies, revealing 20% fragile X positive cells. We compare the clinical features in the present patient with the nine reported patients with fra(X) syndrome and extreme obesity. In pathogenesis, hypothalamic dysregulation is hypothesized. In differential diagnosis of Prader-Willi syndrome, fragile X has to be considered, especially when laboratory workup for Prader-Willi syndrome is negative. Clinical behavior can be of help.