Fragile X syndrome (FXS,MIM # 309550), the most common inherited form of mental retardation, is due to a unique mutation that leads to the silencing of the FMR1gene. It has an estimated frequency of 1/4000 men and 1/8000 women. The mutation is due to an expansion of an unstable CGG repeat sequence located in the 5' untranslated region of the FMR1gene. The full mutation (FM) consists of over 200 repeats and is abnormally hypermethylated. As a consequence, no mRNA is produced and the lack of the gene product, FMRP, an RNA-binding protein, is responsible for the clinical picture of the disease (1, 2). The FMR1gene in its normal state produces a protein that is thought to play a key role in both pre- and postnatal brain development. Fragile X mental retardation protein (FMRP) is expressed in a variety of tissues, but it is most abundant in neurons. The fragile X premutation alleles (PM) are defined by a CGG expansion within the range of approximately 55-200 repeats, and generate some protein. Premutations are unstably transmitted from mother to child and associated with a significant risk of further expansion to a full mutation during oogenesis and postzygotic mitosis in succeeding generations. The prevalence of the FMR1premutation in the general population is relatively high, occurring in an estimated 1 per 813 men and 1 per 259 women (2). The clinical consequence of the expanded CGG repeat in the FMR1gene was thought to be restricted to those with full mutation. The behavioural phenotype of FXS includes hyperarousal, social anxiety and withdrawal, social deficits with peers, abnormalities in communication, unusual responses to sensory stimuli, stereotypic behaviour, gaze aversion, autism spectrum disorders, inattention, impulsivity, and hyperactivity (1, 2). The phenotype in females with fragile X is usually less distinct than in males. Cognitive defects and behavioural problems, such as shyness, attention problems, and anxiety, are less conspicuous than in affected males. There is also evidence that differences in CGG trinucleotide repeat sizes within premutation ranges may affect clinical involvement (2). However, the unmethylated long CGG tract in premutation carriers has been associated with specific phenotypes unrelated to FXS. 20-25% of carriers of PM have prominent ears, flexible finger joints, mild learning disabilities, and emotional problems such as mood lability, anxiety and social phobia. Shyness often associated with poor eye contact is a common complaint of females with the premutation and was observed in 36% of women with the premutation compared to 18% of controls (3, 4).

The aim of our study was to assess the influence of raising mentally retarded children with FXS on the mother's psychological status.

The study was conducted at the Department of General, Molecular Biology and Genetics, Medical University of Silesia in Katowice, from February to May 2008. Study participants were informed of the purpose of the study and all provided their informed consent. The procedures were conducted in accordance with Institutional Guidelines and Regulations and with the Guidelines for the Conduct of Research Involving Human Subjects approved by the appropriate institutional review board (IRB) Bioethical Committee of the Medical University of Silesia in Katowice, PL, No. L.dz. KNW-6501-185/07/08. The study included 15 mothers of children diagnosed with FXS. They were Caucasians/white. The group as a whole ranged in age from 28 to 48 years (M= 40.2, SD=5), with an average of 11.21 years of education (range 8-12, SD=1.05). The participants were asked to complete a questionnaire regarding topics such as personal and family history of mental illness, medication use, and demographic information, and were referred for psychological evaluation consisting of clinical review followed by psychological testing. The tests were administered in the following order: BDI, HAM-D and MMPI. BDI and HAM-D were used to rate the severity of a patient's depression (5, 6). MMPI is a 567-item true/false inventory used to evaluate the thoughts, emotions, attitudes, and behavioural traits that comprise personality. The results of the MMPI test reflect an adolescent's personality strengths and weaknesses, and may identify certain disturbances of personality (psychopathologies) or mental deficits caused by neurological problems. There are validity scales L, F, and K that suggest whether the patient responded to the test items in a manner that would produce valid results. The remaining scales are the clinical scales, numbered 1-9 and 0, originally labelled: Hy (hypochondria), D (depression), Hs (hysteria), Pd (psychopathic deviation), Mf (masculinity-femininity), Pa (paranoia), Pt (psychasthenia), Sc (schizophrenia), Ma (hypomania), Si (social introversion), designed to measure common types of psychopathology. There are also subscales of the clinical scales developed by Harris et al., which have come to be widely used. Statistical analyses were performed using Kruskal-Wallis test. We chose a value of p<0.0001 as the level of statistical significance. Spearman test was used to compare results obtained in BDI, HAM-D scales and clinical, Harris-Lingoes MMPI scales.

Results obtained in BDI and HAM-D were within the normal results and did not show any depressive symptoms. The results obtained in control MMPI scales showed significantly higher values of the Infrequency-Psychopathology (Fp) scale, with the mean result 76.2 T (tab. 1). The results obtained in clinical MMPI scales were within the normal range. Clinical subscales, so-called Harris-Lingoes scales, showed higher values for Hy4 (somatic complaints) subscales, with the mean score 69.27 (tab. 2). The analysis of results obtained in BDI and HAM-D scales and control, clinical and Harris-Lingoes MMPI scales showed an existing correlation. Results obtained in the BDI scale showed a statistically significant positive correlation with the results of the Pt (psychasthenia) scale and negative with the results in the Ma (hypomania) scale (tab. 3). There was a statistically significant positive correlation between BDI scale and Harris-Lingoes subscales in D1, D4, D5 and Sc3. There was also a positive correlation between HAM-D scale and Harris-Lingoes subscales in D1 and Hy3 (tab. 4). In mothers of children with FXS we could observe tension, anxiety and phobic behaviour. They may feel guilty.

We did not observe any depressive symptoms in mothers of children diagnosed with fragile X syndrome. The results obtained in clinical MMPI subscales showed higher values for Hy4 (somatic complaints) subscales. In children with fragile X syndrome we could observe tension, anxiety and phobic behaviour. 20-25% of female carriers of the premutation have mild learning disabilities, and emotional problems such as mood lability, anxiety and social phobia. Shyness often associated with poor eye contact is a common complaint of females with the premutation (1, 2, 7). Premutation carriers, mothers of children with FXS examined by Franke et al. (8), had a higher frequency (three-fold) of affective disorders than mothers from the general population. Normally intelligent premutation carriers of the fragile X genetic abnormality had a similar frequency of affective disorders as mothers of autistic children. Psychiatric morbidity was not restricted to carriers of the FXS full mutation only but was also present in normal intelligent premutation carriers. The age of onset of psychiatric morbidity in both groups of mothers of FXS children as well as the group of mothers with autistic children was much earlier than the age when mental retardation was diagnosed in their children. The increased psychological burden of raising a developmentally retarded child and/or feelings of guilt of being an FXS carrier can therefore not fully explain these findings. Women carriers of the FXS upper premutation range are more susceptible to the psychological problems often associated with the premutation phenotype. Similarly to the reports of other research groups, females with a premutation have schizotypal traits, emotional difficulties, including social anxiety, and an increased prevalence of mood disorders (9). The significantly elevated rates of psychological symptoms in adults with the premutation may be due in part to environmental effects associated with family dynamics that occur by virtue of the challenge associated with caring for one or more children with FXS (7). Lewis et al. (10) compared mothers of three groups of young males according to measures of psychological well-being and stress: those with fragile X syndrome and co-morbid diagnosis of autism; those with fragile X syndrome alone; and those with Down syndrome. The results suggested that fragile X syndrome created more challenges to maternal psychological well-being than Down syndrome. Mothers of sons with fragile X syndrome, regardless of the son's autism status, reported more pessimism about the son's future and more conflict within the family than mothers of sons with Down syndrome (10). Abbeduto et al. (11) tested the psychological well-being of mothers raising a child with a developmental disability. The sample comprised mothers of a child with fragile X syndrome, Down syndrome, or autism. Mothers of individuals with fragile X syndrome displayed lower levels of well-being than those of individuals with Down syndrome, but higher levels than mothers of individuals with autism (11). FXS is not identifiable at birth. Some families learn about it through the diagnosis of a relative. Most must learn about it through a long and arduous discovery process. The FXS phenotype is not so distinct as to be immediately apparent. Variability in phenotypic expression and lack of unique physical characteristics make use of a check list problematic. Someone, usually a parent, first becomes concerned about the child's development between 9 and 13 months of age. On average the diagnosis of FXS does not occur until 30-35 months. There are consequences of delayed identification of FXS. Parents experience frustration with professionals and doubts about themselves in trying to find a professional who will acknowledge that their child's development is atypical. There are real financial costs to families, insurance companies and the health care system for the repeated visits, before a diagnosis is made (12). Children and families do not have access to early intervention. Finally, families do not have access to information about the carrier status of parents and thus many will make future reproductive decisions without knowledge of the risk that a child will have FXS. More than half of families had a second child before diagnosis of FXS in their first child. 57% of children born after the birth of their first child with FXS but before diagnosis had a full mutation. Many families had two or more children with the disorder. Early diagnosis of FXS children, together with the identification of carrier women among family members, seems to be a practical approach in preventing FXS. At present, there is no cure for the fragile X syndrome. A wide variety of therapeutic measures are used to take care of the special educational needs of individuals with FXS and to make them as independent as possible. Pharmacological agents such as antidepressants, anxiety medications and anticonvulsants can be used as per indications. The aim of management is to help children and adults with FXS learn to function in the household environment and be employed in constructive occupations in sheltered atmospheres. Speech therapy may be needed (12). The unique inheritance pattern and variable phenotype of different allelic forms lead to complicated issues related to an individual's knowledge of their own carrier status. In most cases the fragile X mutation segregating in a family is identified through a child with FXS, the full mutation, due to the child's developmental delay or mental retardation. The fragile X syndrome follows the basic rules of X-linked inheritance: 50% of offspring from carrier mothers will receive the mutation and all the daughters and none of the sons of carrier fathers receive the mutation. The risk of expansion of the CGG repeats in the premutation allele to a full mutation depends on the size of the woman's repeat (13, 14, 15). Having a child with a genetic disease has many social and psychological issues. Feelings of blame, guilt, embarrassment, and stigmatization are commonly experienced. The diagnosis of fragile X syndrome can have far-reaching genetic and emotional implications for extended family members. Newly identified mutation carriers as well as families who have been previously diagnosed usually benefit from discussion of strategies or disclosing information about fragile X syndrome to other relatives, some of whom may react with anger, guilt, blame, disbelief, or indifference. Difficult ethical situations arise when key family members refuse to relay information about fragile X syndrome to at-risk relatives. The emotional reactions of carriers with and without children with FXS to learning their carrier status were relief and guilt. Mothers of children with X-linked inherited disorders were more likely to blame themselves and feel guilty for their children's condition as compared with carrier mothers of autosomal recessive disorders. The mode of inheritance could have a psychosocial influence of families noted unique, the emotional reaction of "grandmother guilt” (16).

Mothers of children with FXS have passed the mutant gene on to their child and might blame themselves for the child's condition, thus increasing maternal feelings of guilt.

Feelings of blame, guilt, embarrassment, and stigmatization are commonly experienced.

The diagnosis of fragile X syndrome can also have far-reaching genetic and emotional implications for extended family members.

Mothers of children with FXS should be offered psychological support to relieve maternal feelings of guilt.

We thank Dr Ewa Kresimon and Dr Adam Klasik for their help in data collection and Dr Jan Szymszal for help with the statistical analysis. We also thank the mothers of children with fragile X syndrome who participated in this study.