Ave M. Lachiewicz

Advances in the Treatment of Fragile X Syndrome

The FMR1 mutations can cause a variety of disabilities, including cognitive deficits, attention-deficit/hyperactivity disorder, autism, and other socioemotional problems, in individuals with the full mutation form (fragile X syndrome) and distinct difficulties, including primary ovarian insufficiency, neuropathy and the fragile X-associated tremor/ataxia syndrome, in some older premutation carriers. Therefore, multigenerational family involvement is commonly encountered when a proband is identified with a FMR1 mutation. Studies of metabotropic glutamate receptor 5 pathway antagonists in animal models of fragile X syndrome have demonstrated benefits in reducing seizures, improving behavior, and enhancing cognition. Trials of metabotropic glutamate receptor 5 antagonists are beginning with individuals with fragile X syndrome. Targeted treatments, medical and behavioral interventions, genetic counseling, and family supports are reviewed here.

Fragile X males with unmethylated, full mutation trinucleotide repeat expansions have elevated levels of FMR1 messenger RNA

Fragile X syndrome normally arises as a consequence of large expansions (n >200) of a (CGG)(n) trinucleotide repeat in the promoter region of the FMR1 gene. The clinical phenotype is thought to result from hypermethylation of the repeat and adjacent upstream elements, with consequent down-regulation of transcription (transcriptional silencing). However, the relationship between repeat expansion and transcription has not been defined in the full mutation range. Using the method of quantitative (fluorescence) reverse transcriptase polymerase chain reaction, we demonstrated previously that FMR1 mRNA levels are substantially elevated in premutation (55 </= n < 200) male carriers. In the current work, we report that in fragile X males with unmethylated alleles in the full mutation range (n > 200), FMR1 mRNA levels remain significantly elevated (mean 3.5-fold elevation; P = 6.7 x 10(-3)) relative to normal controls, even for alleles exceeding 300 repeats. This conclusion is independent of any assumption regarding the transcriptional activity of methylated alleles. However, if it were assumed that all methylated alleles were transcriptionally silent, the FMR1 mRNA levels for cells with unmethylated alleles would be even higher (mean 4.5-fold elevation; P = 2.1 x 10(-4)). These observations show that the full-mutation CGG expansion per se is not a strong impediment to transcription and that the apparent up-regulation of the FMR1 locus remains active in at least some cells with full-mutation alleles.

Fragile X Syndrome: A Review of Associated Medical Problems

Fragile X syndrome (FXS) is the most common known genetic cause of inherited intellectual disability and the most common known single-gene cause of autism spectrum disorder. It has been reported that a spectrum of medical problems are commonly experienced by people with FXS, such as otitis media, seizures, and gastrointestinal problems. Previous studies examining the prevalence of medical problems related to FXS have been challenging to interpret because of their marked differences in population, setting, and sampling. Through this comprehensive review, we update the literature by reviewing studies that have reported on prominent medical problems associated with FXS. We then compare prevalence results from those studies with results from a large cross-sectional database consisting of data collected by fragile X clinics that specialize in the care of children with FXS and are part of the Fragile X Clinical and Research Consortium. It is vital for pediatricians and other clinicians to be familiar with the medical problems related to FXS so that affected patients may receive proper diagnosis and treatment; improved care may lead to better quality of life for these patients and their families.

Developmental implications of changing trajectories of IQ in males with fragile X syndrome

This study examined the trajectories of cognitive development in boys under the age of 21 years with fragile X syndrome. By combining information from three centers, data from 66 boys were analyzed; only children who had been tested two or more times with the same psychometric instrument at one or more year intervals were included in this study. Results demonstrated that males with fragile X syndrome show a decline in IQ scores, with the most marked declines seen during the early pubertal period. All 22 children retested during the 11- to 15-year period showed IQ declines, suggesting a slowing of development associated with the onset of puberty. Before age 10 years, males with higher (as opposed to lower) pretest IQs were more likely to decline at subsequent testings. A single etiological factor may not be sufficient to account for the observed findings, as both changes in neurobiological- and task-related factors seem implicated in the slowing intellectual development of this population.

Psychometric Study of the Aberrant Behavior Checklist in Fragile X Syndrome and Implications for Targeted Treatment

Animal studies elucidating the neurobiology of fragile X syndrome (FXS) have led to multiple controlled trials in humans, with the Aberrant Behavior Checklist-Community (ABC-C) commonly adopted as a primary outcome measure. A multi-site collaboration examined the psychometric properties of the ABC-C in 630 individuals (ages 3–25) with FXS using exploratory and confirmatory factor analysis. Results support a six-factor structure, with one factor unchanged (Inappropriate Speech), four modified (Irritability, Hyperactivity, Lethargy/Withdrawal, and Stereotypy), and a new Social Avoidance factor. A comparison with ABC-C data from individuals with general intellectual disability and a list of commonly endorsed items are also reported. Reformulated ABC-C scores based on this FXS-specific factor structure may provide added outcome measure specificity and sensitivity in FXS clinical trials.

SNPs in dopamine D2 receptor gene (DRD2) and norepinephrine transporter gene (NET) are associated with continuous performance task (CPT) phenotypes in ADHD children and their families.

Haplotype‐tagging SNP analyses were conducted to identify molecular genetic substrates of quantitative phenotypes derived from performance on a Continuous Performance Task (CPT). Three hundred sixty‐four individuals were sampled from 152 families ascertained on the basis of at least one child having ADHD. Probands, their affected and unaffected siblings, and parents were administered a CPT. Four different components of performance were analyzed and tested for association with SNPs from 10 candidate genes involved in monoaminergic function. After correcting for multiple comparisons and controlling for multiple individuals from the same family, significant associations were identified between commission errors and SNPs in the DRD2 gene (rs2075654, rs1079596), and between reaction time variability and a SNP in the NET gene (rs3785155). These findings suggest that commission errors and reaction time variability are excellent candidates as ADHD endophenotypes based on previously published criteria. Results also shed light on the molecular genetic basis of specific processes that may underlie the disorder.

Physical Characteristics of Young Boys With Fragile X Syndrome: Reasons for Difficulties in Making a Diagnosis in Young Males

Fragile X syndrome is the leading form of hereditary mental retardation, but the condition is still underdiagnosed in young children. Because of concern that the fragile X phenotype is subtle in young boys and therefore contributes to underdiagnosis of the disorder, we evaluated 73 boys (36 with fragile X and 37 same-age boys who were fragile X negative) using a checklist that we devised to learn which characteristics might be the most useful for alerting professionals to this diagnosis. After a multiple comparisons adjustment, only 4 of 42 characteristics differed significantly in their distributions between the two groups of boys (P < 0.0012), but 10 other items may also have predictive value for fragile X syndrome (P < 0.01). Four additional items occurred in at least 80% of boys with fragile X and may also be helpful for the clinician. Professionals who work with developmentally delayed children should be aware of these 18 clinical characteristics and some of the behavior characteristics commonly seen in boys with fragile X so that they can readily diagnose patients.

Carrier testing in the fragile X syndrome: Attitudes and opinions of obligate carriers

This study surveyed obligate carriers of the fragile X syndrome fra(X) to ascertain opinions and attitudes regarding carrier testing. Female carriers of fra(X) syndrome were recruited during their visits to the Fragile X Clinic at Duke University Medical Center. Twenty-eight obligate carriers completed a 48 question structured interview and a visual analog scale (VAS). Strong trends in the responses were identified. Fra(X) syndrome was viewed as a very serious problem and the risk to offspring high. Subjects reported that prior knowledge of carrier status would have changed their reproductive plans. All felt that relatives should be informed about the inheritance of fra(X) syndrome; the mean age given for preferred age to inform their children of the inheritance of fra(X) syndrome was 12 years, and mean age given for optimal timing of carrier testing was 10 years. The women interviewed indicated that growing up with knowledge of their carrier status would have been preferable to learning this information as adults and they endorsed an aggressive approach to informing and testing their children. Further investigation is warranted to determine the psychological consequences of carrier testing for fra(X) syndrome in order to develop appropriate guidelines for testing and informing individuals at risk for fra(X) syndrome.

Parental attitudes regarding carrier testing in children at risk for fragile X syndrome

Sixty-five parents of individuals affected by fragile X syndrome who attended the National Fragile X Conference in Portland, Oregon (1996), were asked to complete a survey assessing parental level of concern about carrier testing in children at risk for fragile X syndrome. All subjects completed a 15-item paper and pencil Likert response scale measure that was developed specifically for this study. The items included parental rights and duties, psychological adjustment, adaptation, discrimination, harm, childbearing, and interpersonal relationships. The major concern of the parents was that their children have knowledge of their carrier status prior to becoming sexually active and that their children be able to marry informed of their genetic risk. Mothers were significantly more concerned than fathers about raising their children with the knowledge of their carrier status. A sense of parental right to make the decision regarding carrier testing for children was associated with concerns about (1) behavioral or educational problems, (2) knowledge of carrier status prior to sexual activity or marriage, and (3) adjustment of the children to knowledge of their carrier status. As the sample was drawn from a unique population of parents, the results of this survey should be interpreted with caution. The findings of this study suggest a model of parents providing anticipatory guidance for their children to help them adjust to carrier information and for their children to have this knowledge prior to the possibility of reproduction.

Trajectories and profiles of adaptive behavior in males with fragile X syndrome : Multicenter studies

We conducted two multicenter studies on adaptive trajectories and profiles in males with fragile X syndrome. Study 1 longitudinally assessed 29 males ages 1–20 years using ageequivalent scores from the Vineland Adaptive Behavior Scales. Fragile X boys ages 1–10 years showed significant gains in adaptive skills from first to second testing; males ages 11–20 years were stable in their adaptive development. Study 2 cross-sectionally examined 132 males ages 1–20 years. Significant age-related gains were found in boys ages 1–10, particularly in preschool children. Subjects ages 11–20 showed increased variability and nonsignificant relations between age and adaptive skills. Preliminary findings from 26 young adults with fragile X syndrome ages 21–40 years showed stable age-equivalent adaptive scores during these years. Relative strengths in daily living skills and weaknesses in communication were only evident among older subjects. Significant relations were found between adaptive behavior standard scores and IQ; these two scores also showed age-related declines that likely parallel one another. Findings are related to adaptive features in other genetic syndromes, and to directions for future adaptive behavior research.