Brianna Yund

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.

Methods of Neurodevelopmental Assessment in Children with Neurodegenerative Disease: Sanfilippo Syndrome

OBJECTIVES (1) Develop a methodology for obtaining reliable cognitive and developmental data in children with neurodegenerative disease and cognitive impairment and in turn monitor disease state and treatment outcomes. (2) Demonstrate validity of age-equivalent scores. METHODS We present guidelines for obtaining accurate test scores in low-functioning and behaviorally disruptive pediatric patients, followed by a method validation study: (1) using disease-specific protocols to assess salient aspects of the known phenotype, (2) selecting appropriate tests, (3) managing behavior, and (4) using age-equivalent scores on standardized tools. We used the Bayley Scales of Infant Development-III or Kaufman Assessment Battery for Children-II with a group of 25 children with mucopolysaccharidosis type IIIA (MPS IIIA or Sanfilippo syndrome type A) with dementia. To demonstrate concurrent validity, we used the Vineland Adaptive Behavior Scales-II, comparing parent-reported age-equivalent scores (AEs) with those of the cognitive measures. RESULTS We were successful in obtaining cognitive age-equivalents for 25 patients with MPS IIIA including those with severe behavioral disruption and a correlation of 0.95 was obtained comparing scores on the parent measure with cognitive age-equivalents validating the age-equivalent approach. CONCLUSION An approach to the assessment of severely impaired children including those with behavioral disruption was implemented and is applicable to children with other severe neurological diseases. This approach will enhance the assessment of disease progression and monitoring of treatment outcome in clinical trials.

Mucopolysaccharidosis Type IIIA presents as a variant of Klüver-Bucy syndrome

Mucopolysaccharidosis Type IIIA (MPS IIIA) is a neurodegenerative disease with behavioral symptoms unique among the mucopolysaccharidoses. Children with MPS IIIA reportedly mouth things, explore novel environments almost continuously, disregard danger, and empathize/socialize and comply less with parents. These characteristics resemble Klüver–Bucy syndrome (K-Bs). To test the K-Bs hypothesis, 30 children with MPS IIIA were compared to 8 “posttransplant” mucopolysaccharidosis Type IH patients in an experimental “risk room.” The room contained attractive and mildly frightening objects, exposure to a 92-dB startle noise triggered by contact with an attractive toy, mothers return after a brief absence, and compliance with her cleanup directive. Children with MPS IIIA: (a) left mother sooner, (b) wandered more, (c) were more likely to approach frightening objects, (d) were less likely to respond to loud noise with whole body startle, (e) were less likely to avoid the toy associated with the startle noise, (f) interacted less with mother upon her return, and (g) complied less with her cleanup command. K-Bs is associated with loss of amygdala function. Brain magnetic resonance imaging (MRI) of a subset of the children with MPS IIIA showed volume loss that was greater in the amygdala than in the hippocampus; only amygdala loss correlated with reduced fearfulness. MPS IIIA may be the first identified pediatric disease presenting systematically as a K-Bs variant. If validated by further studies, the K-Bs hypothesis of MPS IIIA would provide important clinical and theoretical information for the guidance of families as well as markers for natural disease progression and treatment effects.

Neurocognitive and neuropsychiatric phenotypes associated with the mutation L238Q of the α-L-iduronidase gene in Hurler–Scheie syndrome

UNLABELLED The lysosomal enzyme α-L-iduronidase hydrolyzes terminal iduronic acid from heparan sulfate and dermatan sulfate, and is an essential step in GAG degradation. Mutations of its gene, IDUA, yield a spectrum of mucopolysaccharidosis (MPS) type I clinical disorders. The IDUA mutation, c.712T>A (p.L238Q) was previously noted as a mild mutation. In a longitudinal study of MPS brain structure and function (Lysosomal Disease Network), we found this mutation in 6 of 14 Hurler-Scheie syndrome patients in the age range of 15 to 25 years. We hypothesized that L238Q, when paired with a nonsense mutation, is significantly more severe than other missense-nonsense combinations. METHODS Of 6 patients with a L238Q mutation, the L238Q allele was paired with a nonsense mutation in 4 patients, paired with a deletion in 1, and with a splice site mutation in another. This group was compared to 6 Hurler-Scheie patients closely matched in age and mutation type. IQ and other neuropsychological tests were administered as part of the protocol. Medical history was compiled into a Physical Symptom Score (PSS). Assessment of IQ, attention, memory, spatial ability, adaptive function and psychological status were measured. RESULTS No group differences were found in mean age at evaluation (17.8 and 19.0 years), duration of ERT, or PSS. By history, all were reported to be average in IQ (4/6 with documentation) in early childhood. All (100%) of the L238Q group had a psychiatric history and sleep problems compared to none (0%) of the comparison group. Significant differences were found in depression and withdrawal on parent report measures. IQ was lower in the L238Q group (mean IQ 74) than the comparison group (mean IQ 95; p<0.016). Attention, memory, and visual-spatial ability scores were also significantly lower. Three occurrences of shunted hydrocephalus, and 4 of cervical cord compression were found in the L238Q group; the comparison group had one occurrence of unshunted hydrocephalus and two of cord compression. DISCUSSION The missense mutation L238Q, when paired with a nonsense mutation, is associated with significant, late-onset brain disease: psychiatric disorder, cognitive deficit, and general decline starting at a later age than in Hurler syndrome with a mutation-related rate of GAG accumulation and its pathologic sequelae. This particular genotype-phenotype may provide insight into the genesis of psychiatric illnesses more broadly. Consideration of methods for early, brain-targeted treatment in these patients might be considered.

A longitudinal study of emotional adjustment, quality of life and adaptive function in attenuated MPS II

Objectives The behavioral, adaptive and quality of life characteristics of attenuated mucopolysaccharidosis type II (MPS II) have not been well studied. Understanding changes over time in the attenuated phenotype may assist in helping achieve better outcomes in long-term function. This longitudinal study investigates these outcomes in relation to age, somatic disease burden, and IQ. Specifically, somatic disease burden is a major challenge for these patients, even with treatment with enzyme replacement therapy. Methods 15 patients, 10 between ages 6 and < 12 and 5 between ages ≥ 12 and 18, were selected who had at least 2 yearly visits. The occurrence of physical signs, the Physical Symptom Score, and IQ in these two groups was studied as well as the longitudinal association of age with standardized measures of quality of life, adaptive function, and behavioral symptoms as rated by parents and the childs self-report. Slopes by age across and within patients were calculated for these measures. Results All but one child had hearing loss, most had joint contractures and short stature. Somatic disease burden increased with age. IQ, although normal for most, also improved with age in those under 12 years of age. Physical quality of life decreased while psychosocial quality of life increased with age. Although other adaptive skills were in the broad average range, daily living skills were low at baseline relative to normative data and decreased over time. Behavior ratings indicated improvement in attention and hyperactivity over time. No patient had severe psychopathology, but older children reported an increasing sense of inadequacy and low self-esteem on self-report, presumably due to increasing awareness of differences from peers over time. Conclusions Attenuated MPS II patients have increasing somatic disease burden and poor physical quality of life as they develop as well as decreasing self-esteem and sense of adequacy. Psychosocial quality of life, adaptive skills, and attention improve. Recognition of and intervention around these issues will be beneficial to MPS II attenuated patients who have the resources to use such assistance to improve their long-term outcomes.

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.