A prospective one-year natural history study of mucopolysaccharidosis types IIIA and IIIB: Implications for clinical trial design.

Mucopolysaccharidosis type III is a group of four autosomal recessive enzyme deficiencies leading to tissue accumulation of heparan sulfate. Central nervous system disease is prominent, with initial normal development followed by neurocognitive decline leading to death. In order to define outcome measures suitable for gene transfer trials, we prospectively assessed disease progression in MPS IIIA and IIIB subjects >2years old at three time points over one year (baseline, 6 and 12months). Fifteen IIIA (9 male, 6 female; age 5.0±1.9years) and ten IIIB subjects (8 male, 2 female; age 8.6±3years) were enrolled, and twenty subjects completed assessments at all time points. Cognitive function as assessed by Mullen Scales maximized at the 2.5 to 3year old developmental level, and showed a significant age-related decline over a 6month interval in three of five subdomains. Leiter nonverbal IQ (NVIQ) standard scores declined toward the test floor in the cohort by 6 to 8years of age, but showed significant mean declines over a 6month interval in those <7years old (p=0.0029) and in those with NVIQ score≥45 (p=0.0313). Parental report of adaptive behavior as assessed by the Vineland-II composite score inversely correlated with age and showed a significant mean decline over 6month intervals (p=0.0004). Abdominal MRI demonstrated increased volumes in liver (mean 2.2 times normal) and spleen (mean 1.9 times normal) without significant change over one year; brain MRI showed ventriculomegaly and loss of cortical volume in all subjects. Biochemical measures included urine glycosaminoglycan (GAG) levels, which although elevated showed a decline correlating with age (p<0.0001) and approached normal values in older subjects. CSF protein levels were elevated in 32% at enrollment, and elevations of AST and ALT were frequent. CSF enzyme activity levels for either SGSH (in MPS IIIA subjects) or NAGLU (in MPS IIIB) significantly differed from normal controls. Several other behavioral or functional measures were found to be uninformative in this population, including timed functional motor tests. Our results suggest that cognitive development as assessed by the Mullen and Leiter-R and adaptive behavior assessment by the Vineland parent interview are suitable functional outcomes for interventional trials in MPS IIIA or IIIB, and that CSF enzyme assay may be a useful biomarker to assess central nervous system transgene expression in gene transfer trials.

The 2-min walk test is sufficient for evaluating walking abilities in sporadic inclusion body myositis.

Sporadic inclusion body myositis causes progressive functional loss due to declining muscle strength. Although the underlying cause is unknown, clinical trials are underway to improve strength and function. Selection of appropriate outcome measures is critical for the success of these trials. The 6-min walk test has been the de facto standard for assessing function in neuromuscular disease; however, the optimal walking test has not been determined in this disease. In this study, 67 individuals with sporadic inclusion body myositis completed a battery of quantitative strength and functional tests including timed walking tests, patient-reported outcomes, and other tasks. The 2-min and 6-min walk tests are highly correlated to each other (r=0.97, p<0.001) and to all lower extremity strength, patient-reported, and functional measures in this population. All subjects completed the 2-min walk test, but 7% of subjects were unable to walk the full 6-min of the 6-min walk test due to fatigue. The 2-min walk test demonstrates similar correlation to all outcomes compared to the 6-min walk test, is less fatiguing and better tolerated. Results suggest that the 2-min walk test is a better alternative to tests of longer duration. Further research is needed to determine longitudinal changes on this outcome.

Evaluation of postural stability in children: current theories and assessment tools.

Children with many types of motor dysfunction have problems maintaining postural stability. Because maintenance of postural stability is an integral part of all movements, therapists evaluate and treat to improve postural stability in these children. This article reviews current pediatric assessment tools for postural stability and issues affecting testing this construct in children. The tests and measurements are classified according to their testing purpose and the National Center for Medical Rehabilitation Research disablement framework, focusing on the impairment and functional limitation dimensions. Postural stability is defined from a systems perspective with tests related to the sensory, motor, and biomechanical systems described. Reliability and validity information on the measurements is discussed. Relatively few measurements of postural stability in children are available that have acceptable reliability and validity documentation. Suggestions for research on test development in this area are discussed.

Validity of the Peabody Developmental Gross Motor Scale as an evaluative measure of infants receiving physical therapy.

BACKGROUND AND PURPOSE: The purpose of this study was to examine the validity of the Peabody Developmental Gross Motor Scale (PDMS-GM) as an evaluative measure of infants receiving physical therapy. SUBJECTS AND METHODS: Infants who attended an early intervention program (N = 124) were grouped by diagnosis: cerebral palsy, Down syndrome, hydrocephalus, preterm with developmental delay, full term with developmental delay, and other. The PDMS-GM was administered to each infant three times over a 6-month period by a therapist who did not provide treatment. RESULTS: Mean scaled scores and age-equivalent scores increased for each group. Individual change was examined using the reliable change index. The results indicated that the change in total raw score for 62% of the infants was greater than what could be attributed to measurement error. When minimal clinically important change was defined as 10 scaled score points, the index of responsiveness was equal to 0.5. This finding indicates that a sample size of 68 subjects per group would be needed when the PDMS-GM is used as an outcome measure in research. CONCLUSION AND DISCUSSION: The mean change scores for each group support the use of the PDMS-GM as an evaluative measure. For many infants, particularly infants with cerebral palsy, the PDMS-GM was not responsive to change over a 6-month period. The index of responsiveness suggests that the PDMS-GM should be used only as an outcome measure in large clinical trials. The PDMS-GM is not recommended for evaluating the direct effects of physical therapy but is recommended for providing a global measure of change in motor development as part of a multidimensional assessment.