Sibling phenotype concordance in classical infantile Pompe disease.

Pompe disease (acid-alpha-glucosidase deficiency) encompasses a clinical spectrum, ranging from severe infantile-onset disease with clinical symptoms appearing before 1 year of age with rapid progression to an early death, to late-onset disease with a much more variable age at onset and disease course. Sibling phenotype discordance has been reported for late-onset Pompe disease, but has not been studied in classical infantile disease. We reviewed the medical literature for affected sibships in which at least one sibling had clinical and pathology or biochemical findings consistent with infantile Pompe disease including symptoms beginning in infancy, early hypotonia, cardiomegaly documented by 6 months of age, and early death. The age at symptom onset, age at death, and clinical course were compared between probands and affected siblings. Our results showed that since 1931, publications document 13 families with 31 affected infants (11 probands; 20 affected siblings). The median age at symptom onset for all affected infants was 3 months (range 0-6 months) with significant correlation (R = 0.60, P = 0.04) between probands and affected siblings. The median age at death for all affected infants was 6 months (range 1.5-13 months); probands were slightly older at death than their siblings. The median length of disease course for all affected infants was 3 months (0-10 months) and was slightly longer for probands. Unlike late-onset Pompe disease, there appears to be minimal phenotypic and lifespan variation among siblings with infantile Pompe disease. This prognostic information is vital for families with affected infants and allows for appropriate genetic counseling.

Preliminary study of the safety and efficacy of donepezil hydrochloride in children with Down syndrome: a clinical report series.

There is growing evidence to support the use of early central cholinergic enhancement to improve cognitive functioning in individuals with Down syndrome (DS). This report summarizes preliminary safety and cognitive efficacy data for seven children (8-13 years) with DS who participated in a 22-week, open-label trial of donepezil hydrochloride. Donepezil was dosed once daily at 2.5 mg and, based on tolerability, increased to 5 mg/day. Safety assessments were conducted at Week 1 (baseline), Week 8 (2.5 mg donepezil), Week 16 (5 mg) and Week 22 (after the donepezil had been discontinued). Measures of cognitive function were administered at each visit, encompassing the following domains: memory; attention; mood; and adaptive functioning. Donepezil was well tolerated at the 2.5 and 5 mg doses. The side effects were mild, transient, and consistent with the adverse events noted with cholinesterase inhibitors. Some children showed improvement on measures of memory (NEPSY Memory for Names and Narrative Memory) and sustained attention to tasks (Conners' Parent Rating Scales), although increased irritability and/or assertiveness were noted in some patients. Overall, this clinical report series adds to our initial findings of language gains in children with DS treated with donepezil. It also supports the need for larger, double-blind studies of the safety and efficacy of donepezil and other cholinesterase inhibitors for children with DS.

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 Team's 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.