title: A prospective one-year natural history study of mucopolysaccharidosis types IIIA and IIIB: Implications for clinical trial design.
abstract: 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.
authors: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States; Division of Molecular and Human Genetics, Nationwide Children's Hospital, Columbus, OH, United States; Department of Pediatrics, The Ohio State University, Columbus, OH, United States.
authors: K V
authors: KV
authors: Truxal
authors: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States; Department of Pediatrics, The Ohio State University, Columbus, OH, United States.
authors: H
authors: H
authors: Fu
authors: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States; Department of Pediatrics, The Ohio State University, Columbus, OH, United States.
authors: D M
authors: DM
authors: McCarty
authors: Center for Biobehavioral Outcomes Core, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States; Division of Neuropsychology, Nationwide Children's Hospital, Columbus, OH, United States; Department of Pediatrics, The Ohio State University, Columbus, OH, United States.
authors: K A
authors: KA
authors: McNally
authors: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.
authors: K L
authors: KL
authors: Kunkler
authors: Division of Radiology, Nationwide Children's Hospital, Columbus, OH, United States; Department of Radiology, The Ohio State University, Columbus, OH, United States.
authors: N A
authors: NA
authors: Zumberge
authors: Division of Radiology, Nationwide Children's Hospital, Columbus, OH, United States; Department of Radiology, The Ohio State University, Columbus, OH, United States.
authors: L
authors: L
authors: Martin
authors: Division of Neurology, Nationwide Children's Hospital, Columbus, OH, United States; Department of Neurology, The Ohio State University, Columbus, OH, United States.
authors: S C
authors: SC
authors: Aylward
authors: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.
authors: L N
authors: LN
authors: Alfano
authors: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.
authors: K M
authors: KM
authors: Berry
authors: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.
authors: L P
authors: LP
authors: Lowes
authors: Division of Anesthesiology, Nationwide Children's Hospital, Columbus, OH, United States; Department ofAnesthesiology, The Ohio State University, Columbus, OH, United States.
authors: M
authors: M
authors: Corridore
authors: Division of Anesthesiology, Nationwide Children's Hospital, Columbus, OH, United States.
authors: C
authors: C
authors: McKee
authors: Center for Cardiovascular and Pulmonary Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States; Division of Molecular and Human Genetics, Nationwide Children's Hospital, Columbus, OH, United States; Department of Pediatrics, The Ohio State University, Columbus, OH, United States.
authors: K L
authors: KL
authors: McBride
authors: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States; Division of Neurology, Nationwide Children's Hospital, Columbus, OH, United States; Department of Pediatrics, The Ohio State University, Columbus, OH, United States; Department of Neurology, The Ohio State University, Columbus, OH, United States. Electronic address: kevin.flanigan@nationwidechildrens.org.
authors: K M
authors: KM
authors: Flanigan
mesh_terms: D000118:Acetylglucosaminidase / Q000134:cerebrospinal fluid / Q000235:genetics*; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D018450:Disease Progression; D005260:Female; D006025:Glycosaminoglycans / Q000378:metabolism; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D006867:Hydrolases / Q000134:cerebrospinal fluid / Q000235:genetics*; D007223:Infant; D008099:Liver / Q000000981:diagnostic imaging / Q000378:metabolism; D008297:Male; D009084:Mucopolysaccharidosis III / Q000134:cerebrospinal fluid / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D013154:Spleen / Q000000981:diagnostic imaging / Q000473:pathology
chemical_list: D000118:Acetylglucosaminidase; D006025:Glycosaminoglycans; D006497:Heparan Sulfate; D006867:Hydrolases; C022708:N-sulfoglucosamine sulfohydrolase; C033079:alpha-N-acetyl-D-glucosaminidase
keywords: Mucopolysaccharidosis; NAGLU; Natural history; SGSH; Sanfilippo syndrome