Alta M Steward1, Edythe Wiggs1, Taylor Lindstrom1, Somto Ukwuani1, Emory Ryan1, Nahid Tayebi1, Tamanna Roshan Lal1, Grisel Lopez1, Raphael Schiffmann1, Ellen Sidransky2. 1. From the Section on Molecular Neurogenetics (A.M.S., E.W., T.L., S.U., E.R., N.T., T.R.L.G.L., E.S.), Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD; and Kimberly H. Courtwright and Joseph W. Summers Institute of Metabolic Disease (R.S.), Baylor Scott & White Research Institute, Dallas, TX. The present address for Tamanna Roshan Lal is Lysosomal Storage and Treatment Program, George Washington University School of Medicine and Children's National Rare Disease Institute, Washington DC. 2. From the Section on Molecular Neurogenetics (A.M.S., E.W., T.L., S.U., E.R., N.T., T.R.L.G.L., E.S.), Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD; and Kimberly H. Courtwright and Joseph W. Summers Institute of Metabolic Disease (R.S.), Baylor Scott & White Research Institute, Dallas, TX. The present address for Tamanna Roshan Lal is Lysosomal Storage and Treatment Program, George Washington University School of Medicine and Children's National Rare Disease Institute, Washington DC. sidranse@mail.nih.gov.
Abstract
OBJECTIVE: To identify relevant efficacy parameters essential in designing clinical trials for brain-penetrant therapies for Gaucher disease, we evaluated cognitive function longitudinally in 34 patients with Gaucher disease type 3 seen at the NIH Clinical Center. METHODS: Individuals were tested with age-appropriate Wechsler Intelligence Scales administered between 1 and 18 times over 29 years. Variation in all IQ domains was not linear with time and was best characterized with the coefficient of variation (SD/mean) for each individual. Mixed-effects regressions were used to determine whether IQ was associated with clinical features. Models were controlled for variation in test version, participant identification, and test administrator. RESULTS: Mean verbal, performance, and full-scale IQs were 81.77, 75.98, and 82.02, respectively, with a consistent discrepancy between verbal and performance IQs. Mean (SD) verbal, performance, and full-scale coefficient of variations were 0.07 (0.04), 0.09 (0.05), and 0.06 (0.02), respectively. IQ varied about a mean, with no clear trajectory, indicating no clear patterns of improvement or decline over time. EEG lateralization and behavioral issues were consistently associated with IQ. CONCLUSIONS: The observed variation in IQ in Gaucher disease type 3 across the cohort and within single individuals over time may be characteristic of other neuronopathic diseases. Therefore, to reliably use IQ as an efficacy measure in any clinical trial of neurotherapeutics, a normal variation range must be established to assess the clinical relevance of any IQ change.
OBJECTIVE: To identify relevant efficacy parameters essential in designing clinical trials for brain-penetrant therapies for Gaucher disease, we evaluated cognitive function longitudinally in 34 patients with Gaucher disease type 3 seen at the NIH Clinical Center. METHODS: Individuals were tested with age-appropriate Wechsler Intelligence Scales administered between 1 and 18 times over 29 years. Variation in all IQ domains was not linear with time and was best characterized with the coefficient of variation (SD/mean) for each individual. Mixed-effects regressions were used to determine whether IQ was associated with clinical features. Models were controlled for variation in test version, participant identification, and test administrator. RESULTS: Mean verbal, performance, and full-scale IQs were 81.77, 75.98, and 82.02, respectively, with a consistent discrepancy between verbal and performance IQs. Mean (SD) verbal, performance, and full-scale coefficient of variations were 0.07 (0.04), 0.09 (0.05), and 0.06 (0.02), respectively. IQ varied about a mean, with no clear trajectory, indicating no clear patterns of improvement or decline over time. EEG lateralization and behavioral issues were consistently associated with IQ. CONCLUSIONS: The observed variation in IQ in Gaucher disease type 3 across the cohort and within single individuals over time may be characteristic of other neuronopathic diseases. Therefore, to reliably use IQ as an efficacy measure in any clinical trial of neurotherapeutics, a normal variation range must be established to assess the clinical relevance of any IQ change.
Authors: V Koprivica; D L Stone; J K Park; M Callahan; A Frisch; I J Cohen; N Tayebi; E Sidransky Journal: Am J Hum Genet Date: 2000-05-04 Impact factor: 11.025