Gail A. Spiridigliozzi

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.

Donepezil for treatment of cognitive dysfunction in children with Down syndrome aged 10–17

The objective of this 10‐week, randomized, double‐blind, placebo‐controlled multicenter study was to assess the efficacy and safety of donepezil for the treatment of cognitive dysfunction exhibited by children with Down syndrome (DS). Intervention comprised donepezil (2.5–10 mg/day) in children (aged 10–17 years) with DS of mild‐to‐moderate severity. The primary measures were the Vineland‐II Adaptive Behavior Scales (VABS‐II) Parent/Caregiver Rating Form (PCRF) the sum of nine subdomain standardized scores and standard safety measures. Secondary measures included the VABS‐II/PCRF scores on the following domains and their respective individual subdomains: Communication (receptive, expressive, and written); Daily Living Skills (personal, domestic, and community); Socialization (interpersonal relationships, play and leisure time, and coping skills), and scores on the Test of Verbal Expression and Reasoning, a subject‐performance‐based measure of expressive language. At baseline, 129 participants were assigned treatment with donepezil or placebo. During the double‐blind phase, VABS II/PCRF sum of the nine subdomain standardized scores, called v‐scores, improved significantly from baseline in both groups (P < 0.0001), with no significant between‐group differences. This trial failed to demonstrate any benefit for donepezil versus placebo in children and adolescents with DS, although donepezil appeared to be well tolerated.

Donepezil for the treatment of language deficits in adults with Down syndrome: a preliminary 24-week open trial.

At present, there is no proven pharmacologic treatment for cognitive or language impairments in Down syndrome (DS). Cholinergic deficits have been documented in DS and linked to cognitive deficits. This study is a 24‐week open‐label clinical trial of donepezil hydrochloride for the treatment of language deficits in adults with DS. To our knowledge, this is the first prospective study to evaluate systematically the effects of donepezil, a cholinesterase inhibitor, on specific language domains in DS. The main finding that emerged was an improvement in expressive language performance following donepezil therapy. Despite the multiple methodological limitations, the results raise important questions regarding the role of the cholinergic system in language function and the specific effect of cholinergic therapy in the treatment of language impairment in DS. The results support the need for large‐scale controlled studies of the effects of donepezil treatment on language and on other cognitive domains in DS.

Donepezil effects on language in children with Down syndrome: Results of the first 22-week pilot clinical trial

To the Editor: In earlier pilot studies, we reported improvements in global function [Kishnani et al., 1999] and expressive language function [Heller et al., 2003] in adults with Down syndrome (DS) following cholinergic therapy (donepezil hydrochloride). In this study, we report results of a small open-label clinical trial of donepezil in children with DS. To our knowledge, this is the first study evaluating the effects of donepezil on language in children with DS. After obtaining IRB approval and written informed consent, we enrolled seven children (2M:5F) between the ages of 8 and 13 years (mean age = 10.5 years) with DS (trisomy 21 by blood chromosome analysis) and their primary caregivers in a prospective open trial of donepezil. All subjects were verbal, able to hear speech at a conversational level, and able to ingest oral medication. None of the subjects had active thyroid disease, vitamin B12 deficiency, clinically-confirmed pregnancy, or clinically-significant systemic disorders, (e.g., bradycardia (HR < 50), insulin-dependent diabetes mellitus, active peptic ulcer, celiac disease, significant reactive airways, or seizure disorder) at the time of entry into the trial. They had not previously ingested cholinesterase inhibitors or any other investigational or alternative therapies used to treat the symptoms of DS in the 30 days prior to or during the trial. IQs of six subjects (obtained from school reports) ranged from 46 to 66 (mean IQ = 50). The IQ of one subject could not be determined from records. This 22-week trial (16 week open treatment study followed by a 6-week washout) was completed at the General Clinical Outpatient Research Unit at Duke University Medical Center. Subjects attended four sessions, week 0 (baseline), week 8 (low dose), week 16 (high dose), and week 22 (washout). At the completion of the baseline visit, donepezil was dosed orally at 2.5 mg once daily for 8 weeks. Based on tolerability, the dose was increased to 5 mg daily for the remaining 8 weeks. Subjects were monitored closely for safety by regular phone calls in between scheduled visits. Two language measures were used, the Test of Problem Solving [TOPS, Zachman et al., 1984] and the Clinical Evaluation of Language Fundamentals-3 [CELF-3, Semel et al., 1995]. The CELF-3 was administered at baseline, week 16, and week 22. The TOPS was completed at all four visits. Because the CELF-3 and TOPS have not been standardized for individuals with DS and the subjects’ language performance was significantly below standard age norms, performance-based comparisons were made with raw scores and age equivalencies. The effect of the medication on language performance was measured by change from baseline performance at the week 8 and week 16 assessments. One subject was excluded from all analyses because of a protocol deviation in administered dosage. No patient experienced serious adverse effects or withdrew from the study. Performance comparisons (completed by repeated measure t-tests) were based on a total n of 6 (five subjects for the baseline vs. week 8 TOPS comparison). Due to the preliminary and exploratory nature of the study, we did not correct for multiple comparisons. P values at or below 0.05 (two-tailed) were viewed as significant. Overall, language performance levels were low. The average TOPS age score was below the 3 years 5 months test basal for all sessions, and the average CELF-3 age score was 4 years 3 months at baseline, and 4 years 7 months at week 16. Essentially no change in language performance with treatment was noted on the TOPS at week 8 (the difference between mean baseline and week 8 scores was <1) and at week 16 (Table I). However, a significant improvement (t = 3.11; P = 0.0265) in overall CELF-3 performance from baseline to week 16 was found (Table I). TABLE I Changes in Raw Score Language Performance From Baseline to 16 Weeks as Measured by the Test of Problem Solving (TOPS) and the Clinical Evaluation of Language Fundamentals (CELF)-3 Additional analyses of the expressive and receptive components of the CELF-3 Total Language Score showed a statistically significant gain of 5 points in expressive language performance (t = 3.14; P = 0.0256) and a similar gain of 4.5 points (approaching statistical significance) in receptive language performance (t = 2.55; P = 0.0513). A review of subject performance on individual expressive and receptive language subtests of the CELF-3 revealed that the largest improvements were made on the word structure and sentence structure subtests. As we noted in our adult study [Heller et al., 2003], these findings should be viewed as preliminary and interpreted with caution because of methodological limitations such as an extremely small sample size, lack of power for formal statistical control, repeated comparisons across a relatively short time span (16 weeks), and the lack of an untreated control group. Our primary finding, which is consistent with the results of our two adult studies, was an improvement in selective aspects of language performance (particularly aspects of expressive language) in children with DS following donepezil therapy. This result is noteworthy in the context of similar findings of language improvement in autistic children treated with two different cholinesterase inhibitors, donepezil hydrochloride [Chez et al., 2000, 2001] and rivastigmine [Chez et al., 2004]. Taken together the results of our work with individuals with DS and Chez’s studies of individuals with autism suggest a relationship between language performance and the cholinergic system that extends across syndromes and that cholinergic therapy is a potential treatment for language impairment in children and adults with significant developmental delays.

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.

The efficacy, safety, and tolerability of donepezil for the treatment of young adults with Down syndrome

The objective of our study was to assess the efficacy and safety of donepezil in young adults with Down syndrome (DS) but no evidence of Alzheimer disease (AD). A 12‐week, randomized, double‐blind, placebo‐controlled study with a 12‐week, open‐label extension was conducted. The intervention consisted of donepezil (5–10 mg/day) in young adults (aged 18–35 years) with DS, but no AD. The primary measure was the Severe Impairment Battery (SIB) test and secondary measures were the Vineland Adaptive Behavior Scales (VABS), the Rivermead Behavioral Memory Test for Children, and the Clinical Evaluation of Language Fundamentals, Third Edition. At baseline, 123 subjects were randomly assigned treatment with donepezil or placebo. During the double‐blind phase, SIB scores improved significantly from baseline in both groups, with no significant between‐group differences. During the open‐label phase, SIB scores in the original donepezil group remained stable; the original placebo group showed an improvement similar to that seen in the double‐blind phase. VABS scores improved for donepezil, but not placebo, during the double‐blind phase (observed cases, P = 0.03; last observation carried forward, P = 0.07). Post hoc responder analyses were significant for donepezil using three of five response definitions (P ≤ 0.045). Adverse event rates were comparable to AD studies. In this first large‐scale, multicenter trial of a pharmacological agent for DS, donepezil appears safe. Efficacy interpretation was limited for the primary measure due to apparent learning/practice and ceiling effects. Outcomes in post hoc analyses suggested efficacy in some, but not all subjects, consistent with phenotypic variability of DS. Additional studies are required to confirm potential benefits of donepezil in this population.

Arithmetic difficulties in females with the fragile X premutation

Females with the fragile X full mutation have been reported to have difficulty learning mathematics. Women with the fragile X premutation often give a history of mathematics difficulties in themselves especially with higher level math. In order to evaluate whether women with the premutation have difficulty with math, we asked women with both the fragile X premutation and full mutation to complete the Wide Range Achievement Test‐3. For the group of 39 women with the fragile X premutation, the median standard score on the Arithmetic portion was 93, which was significantly lower (P = 0.001) than the median of the standardized norm of 100. Only nine of the women had Arithmetic scores at or above the 50th centile, while over half of the women had standard scores at or above the 50th centile in Reading and Spelling. The eight women with the full mutation also had lower Arithmetic scores than Reading and Spelling scores. These data suggest that mathematics may be an area of relative weakness for the women with the premutation as well as the full mutation. This possibility should be evaluated further by using other measures. This information is important both for counseling purposes and to understand whether a mathematics deficit is evidence of low expression of the FMR1 gene in the premutation state.

Carrier testing in fragile X syndrome: Effect on self‐concept

The purpose of the study was to explore self-concept in women at risk for inheriting the fragile X mutation. Time 1 measures were obtained prior to carrier testing and Time 2 measures were collected approximately 5 months after learning carrier status. The sample consisted of 42 women from 17 families. Measures included the Tennessee Self-Concept Scale (TSCS), the fragile X Visual Analog Scale (VAS), and a structured interview. The TSCS provided a global measure of self-concept and the fragile X VAS and structured interview provided a contextual measure of self related to carrier status. Results indicated that there were no differences initially between carriers and noncarriers and no change from Time 1 to Time 2 on the TSCS. Analysis of the Time 1 fragile X VAS means for the total sample found a reduction in positive feelings about self. Analysis of the Time 2 fragile X VAS found that noncarriers reported improvement in feelings about self, with no change in feelings about self found in the carriers. Responses from the structured interview indicated that the feelings regarding self in the context of genetic testing are not related to global self-concept, but result from concerns regarding the implications of a positive carrier test for themselves and their families. This information highlights areas related to carrier testing that warrant further investigation and may ultimately result in modifications to the genetic counseling.