Victor Kovac

A Prospective Natural History Study of Mucopolysaccharidosis Type IIIA.

OBJECTIVES To characterize the clinical course of mucopolysaccharidosis type IIIA (MPS IIIA), and identify potential endpoints for future treatment trials. STUDY DESIGN Children with a confirmed diagnosis of MPS IIIA, functioning above a developmental age of 1 year, were followed for up to 2 years. Cognitive status and brain atrophy were assessed by standardized tests and volumetric magnetic resonance imaging, respectively. Liver and spleen volumes and cerebrospinal fluid and urine biomarker levels were measured. RESULTS Twenty-five children, from 1.1 to 18.4 years old, were enrolled, and 24 followed for at least 12 months. 19 exhibited a rapidly progressing (RP) form of MPS IIIA, and 5, a more slowly progressing form. Children with RP plateaued in development by 30 months, followed by rapid regression after 40-50 months. In patients with RP, cognitive developmental quotients showed consistent steep declines associated with progressive cortical gray matter atrophy. Children with slowly progressing had a similar but more prolonged course. Liver and spleen volumes were approximately double normal size, and cerebrospinal fluid and urine heparin sulfate levels were elevated and relatively constant over time. CONCLUSION Developmental quotient and cortical gray matter volume are sensitive markers of disease progression in MPS IIIA, and may have utility as clinical endpoints in treatment trials. For optimal outcomes, treatment may need to be instituted in children before the onset of steep cognitive decline and brain atrophy. TRIAL REGISTRATION ClinicalTrials.gov: NCT01047306.

Neurocognition across the spectrum of mucopolysaccharidosis type I: Age, severity, and treatment.

OBJECTIVES Precise characterization of cognitive outcomes and factors that contribute to cognitive variability will enable better understanding of disease progression and treatment effects in mucopolysaccharidosis type I (MPS I). We examined the effects on cognition of phenotype, genotype, age at evaluation and first treatment, and somatic disease burden. METHODS Sixty patients with severe MPS IH (Hurler syndrome treated with hematopoietic cell transplant and 29 with attenuated MPS I treated with enzyme replacement therapy), were studied with IQ measures, medical history, genotypes. Sixty-seven patients had volumetric MRI. Subjects were grouped by age and phenotype and MRI and compared to 96 normal controls. RESULTS Prior to hematopoietic cell transplant, MPS IH patients were all cognitively average, but post-transplant, 59% were below average, but stable. Genotype and age at HCT were associated with cognitive ability. In attenuated MPS I, 40% were below average with genotype and somatic disease burden predicting their cognitive ability. White matter volumes were associated with IQ for controls, but not for MPS I. Gray matter volumes were positively associated with IQ in controls and attenuated MPS I patients, but negatively associated in MPS IH. CONCLUSIONS Cognitive impairment, a major difficulty for many MPS I patients, is associated with genotype, age at treatment and somatic disease burden. IQ association with white matter differed from controls. Many attenuated MPS patients have significant physical and/or cognitive problems and receive insufficient support services. Results provide direction for future clinical trials and better disease management.

OP47 – 2274: Brain MRI patterns of disease progression in Sanfilippo syndrome type A (MPS IIIA)

Objective MPS IIIA is a progressive neurological disease. Quantitative MRI and neurocognitive function testing may provide understanding of MPS IIIA disease progression. From the natural history of MPS IIIA (NCT01047306), we previously reported that baseline cognition is significantly associated with age and gray matter volumes. Here, we present longitudinal data regarding regional changes in MRI-measured brain volumes in MPS IIIA patients, and estimates of the rate of decline in both cognition and brain volumes over 24 months. Methods Longitudinal cognitive and quantitative MRI data were collected from 24 children with documented MPS IIIA. Brain volumetric analysis and developmental quotient (DQ) were obtained by automated MRI segmentation and cognitive assessment, respectively. Results For a subset of 19 patients with classic disease diagnosed prior to age six, volume decreases were noted in cortex (-7.5%/year)*, amygdalae (-15%/year)*, hippocampi (-4.9%/year)*, and very slightly in white matter (-2.2%/year). Cortical thickness narrowed with a rate of 5.9% per year*. Subcortical gray matter and cortical cerebellar volumes remained stable. Ventricular volume increased (+23.5%/year)*, presumably reflecting the brain loss. A strong correlation was found between DQ and cortical volume and similarly between DQ and cortical thickness. Other specific data will be reported (e.g., rate of decline for individual lobes of the brain). For patients diagnosed after age six, patterns were variable. *p Conclusion In this natural history study, loss of cortical and amygdalar volumes with substantial ventricular enlargement were the primary MRI patterns linked to decline in cognitive function in patients with the classical form of MPS IIIA. We have demonstrated that both DQ and Cortical Volume are markers of disease progression in MPS IIIA, and that they are closely associated. White matter, cerebellum and subcortical gray matter remained stable or declined slightly. MPS IIIA appears to be mainly a disease of cerebral cortical gray matter.