James H. Heller

Cross-reactive immunologic material status affects treatment outcomes in Pompe disease infants

Deficiency of acid alpha glucosidase (GAA) causes Pompe disease, which is usually fatal if onset occurs in infancy. Patients synthesize a non-functional form of GAA or are unable to form native enzyme. Enzyme replacement therapy with recombinant human GAA (rhGAA) prolongs survival in infantile Pompe patients but may be less effective in cross-reactive immunologic material (CRIM)-negative patients. We retrospectively analyzed the influence of CRIM status on outcome in 21 CRIM-positive and 11 CRIM-negative infantile Pompe patients receiving rhGAA. Patients were from the clinical setting and from clinical trials of rhGAA, were 6 months of age, were not invasively ventilated, and were treated with IV rhGAA at a cumulative or total dose of 20 or 40 mg/kg/2 weeks. Outcome measures included survival, invasive ventilator-free survival, cardiac status, gross motor development, development of antibodies to rhGAA, and levels of urinary Glc(4). Following 52 weeks of treatment, 6/11 (54.5%) CRIM-negative and 1/21 (4.8%) CRIM-positive patients were deceased or invasively ventilated (p<0.0001). By age 27.1 months, all CRIM-negative patients and 4/21 (19.0%) CRIM-positive patients were deceased or invasively ventilated. Cardiac function and gross motor development improved significantly more in the CRIM-positive group. IgG antibodies to rhGAA developed earlier and serotiters were higher and more sustained in the CRIM-negative group. CRIM-negative status predicted reduced overall survival and invasive ventilator-free survival and poorer clinical outcomes in infants with Pompe disease treated with rhGAA. The effect of CRIM status on outcome appears to be mediated by antibody responses to the exogenous protein.

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.

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.

Preschool Speech and Language ScreeningA Review of Currently Available Tests

Fifty-one preschool speech-language screening tests were reviewed with regard to criteria crucial to screening test selection: professional time required, comprehensiveness, norms, and reliability/...

Clinical trials in children with Down syndrome: issues from a cognitive research perspective.

Clinical and translational research play a key role in the transition of basic research discoveries to effective therapies. In Down syndrome (DS), these research approaches are not well utilized or developed to test new therapies to improve cognitive and/or adaptive function in this population. This article reviews the history of clinical trial research in children with DS from a cognitive research perspective and discusses important issues relevant to the conduct of well designed clinical trials for this population. Specific issues addressed include: funding, study design, study medication, subject recruitment and retention, safety, and efficacy challenges. The Duke Down Syndrome Research Teams program of clinical research of cholinesterase inhibitors for individuals with DS serves as the model application for the identified research principles. It is hoped that this article will raise awareness of the unmet need for clinical research in the cognitive and adaptive function of individuals with DS, especially children with DS.

Assessment of Cognitive Scales to Examine Memory, Executive Function and Language in Individuals with Down Syndrome: Implications of a 6-month Observational Study

Down syndrome (DS) is the most commonly identifiable genetic form of intellectual disability. Individuals with DS have considerable deficits in intellectual functioning (i.e., low intellectual quotient, delayed learning and/or impaired language development) and adaptive behavior. Previous pharmacological studies in this population have been limited by a lack of appropriate endpoints that accurately measured change in cognitive and functional abilities. Therefore, the current longitudinal observational study assessed the suitability and reliability of existing cognitive scales to determine which tools would be the most effective in future interventional clinical studies. Subtests of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Cambridge Neuropsychological Test Automated Battery (CANTAB), and Clinical Evaluation of Language Fundamentals-Preschool-2 (CELF-P-2), and the Observer Memory Questionnaire-Parent Form (OMQ-PF), Behavior Rating Inventory of Executive Function®–Preschool Version (BRIEF-P) and Leiter International Performance Scale-Revised were assessed. The results reported here have contributed to the optimization of trial design and endpoint selection for the Phase 2 study of a new selective negative allosteric modulator of the GABAA receptor α5-subtype (Basmisanil), and can be applied to other studies in the DS population.

Language and speech function in children with infantile Pompe disease

Pompe disease, also known as glycogen storage disease type II and acid maltase deficiency, is a rare autosomal recessive progressive neuromuscular disorder. The natural course of the infantile form of this condition has resulted in mortality for patients prior to 1 year of age, making investigations into language and speech function in this population impossible. However, with the advent of treatment with enzyme replacement therapy (ERT) using alglucosidase alfa (Myozyme ), the lifespan of children with this condition has been extended. A retrospective study of the language and speech skills of 12 children enrolled in clinical trials for treatment with ERT at a tertiary care center was completed. Standardized language assessment instruments were administered to all participants, and six of the 12 were assessed twice. At initial assessment, overall language function was found to be age appropriate in 58% of participants, while, in those who received reassessment, overall normal language function was seen in 83%. Speech assessments were completed during all visits in which subjects were 24 months or older. Articulatory disorders and/or hypernasality were commonly encountered and were exhibited in 82% of speech assessments. Disorders in language and/or speech were found in all participants at some point in the course of the study. Overall, language delays tended to improve with time. Speech disorders were encountered more commonly, were often severe, and appeared to be motoric in nature. Children with infantile Pompe disease treated with ERT appear to be at high risk for speech disorders in particular. Further systematic investigations are needed.

Cognitive and adaptive functioning of children with infantile Pompe disease treated with enzyme replacement therapy: Long-term follow-up†‡§

This report documents the long‐term cognitive and adaptive outcome of children with infantile Pompe disease. Specifically, we describe the cognitive and adaptive functioning of seven children with classic infantile Pompe disease and two children with atypical infantile Pompe disease who have received enzyme replacement therapy (Myozyme®) for an average of 6 years, 8 months and 4 years, 1. 5 months, respectively. Multiple assessments of cognitive functioning were completed over time by means of individualized intelligence (IQ) testing. Adaptive functioning was measured by means of the Vineland Adaptive Behavior Scales‐Second Edition (VABS‐II). Consistent with our earlier findings regarding infants treated with ERT, children with classic infantile Pompe disease (ages 4 years, 11 months to 8 years, 11 months) were functioning at the lower end of the average range in comparison to their typical peers on their most recent IQ test. There was no evidence of a decline in their cognitive abilities over time. In contrast, the two children with atypical infantile Pompe disease (ages 5 years, 4 months and 5 years, 11 months) obtained above average IQ scores and demonstrated significant gains in IQ over time. For all children where adaptive functioning was assessed, their overall level of adaptive functioning on the VABS‐II was lower than their Full Scale IQ scores on cognitive testing. Motor function appears to be an important factor impacting on reduced adaptive behavior. The implication of these findings on our understanding of a possible relationship between CNS status in children with Pompe and their adaptive and cognitive function is discussed.