Shapiro E, King K, Ahmed A, Rudser K, Rumsey R, Yund B, Delaney K, Nestrasil I, Whitley C, Potegal M
University of Minnesota Department of Pediatrics.
University of Minnesota Division of Biostatistics.
Mol Genet Metab Rep. 2016 Mar 1;6:41-47. doi: 10.1016/j.ymgmr.2016.01.003.
Our goal was to describe the neurobehavioral phenotype in mucopolysaccharidosis Type IIIB (MPS IIIB). Parents report that behavioral abnormalities are a major problem in MPS III posing serious challenges to parenting and quality-of-life for both patient and parent. Our previous research on MPS IIIA identified autistic symptoms, and a Klüver-Bucy-type syndrome as indicated by reduced startle and loss of fear associated with amygdala atrophy. We hypothesized that MPS IIIB would manifest similar attributes when assessed with the same neurobehavioral protocol.
Ten patients with MPS IIIB were compared with 9 MPS IIIA patients, all older than 6. 8 younger children with Hurler syndrome (1H) were chosen as a comparison group for the Risk Room procedure; MPS IH does not directly affect social/emotional function and these younger children were closer to the developmental level of the MPS IIIB group. To examine disease severity, cognitive ability was assessed. Four evaluations were used: the Risk Room procedure (to measure social-emotional characteristics, especially fear and startle responses), the Autism Diagnostic Observation Schedule (ADOS), the Sanfilippo Behavior Rating Scale (SBRS), and amygdala brain volumes calculated from manually-traced MRI images.
The two groups are equivalent in severity and show severe cognitive impairment. On the ADOS, the MPS IIIB patients exhibited the same autistic features as IIIA. The IIIB means differed from MPS IH means on most measures. However, the IIIB group did not approach the Risk Room stranger, like the MPS IH group who kept their distance, but unlike the IIIA group who showed no fear of the stranger. On the SBRS, the MPS IIIB patients were described as more inattentive and more fearful, especially of new people than the MPS IIIA. Onsets of some disease characteristics appeared more closely spaced and slightly earlier in MPS IIIB than IIIA.
On most behavioral measures, MPS IIIB patients did not differ substantially from MPS IIIA patients over age six, demonstrating autistic features and a Klüver Bucy-like syndrome including lack of fear and poor attention. Delay in onset of behavioral symptoms was associated with later diagnosis in two patients. Lack of fear, poor attention, and autistic-like symptomatology are as characteristic of MPS IIIB as they are of MPS IIIA. A possible difference is that the some behavioral abnormalities develop more quickly in MPS IIIB, If this is so, these patients may become at risk for harm and present a challenge for parenting even earlier than do those with MPS IIIA. .In future clinical trials of new treatments, especially with respect to quality of life and patient management, improvement of these behaviors will be an essential goal. Because very young patients were not studied, prospective natural history documentation of the early development of abnormal behaviors in MPS IIIB is needed.
我们的目标是描述ⅢB型黏多糖贮积症（MPS IIIB）的神经行为表型。家长们报告称，行为异常是MPS III中的一个主要问题，给患者及其家长的养育和生活质量带来了严峻挑战。我们之前对ⅢA型MPS的研究发现了自闭症症状，以及一种类似Klüver-Bucy综合征的症状，表现为惊吓反应减弱和与杏仁核萎缩相关的恐惧缺失。我们假设，当采用相同的神经行为方案进行评估时，ⅢB型MPS会表现出类似的特征。
将10例ⅢB型MPS患者与9例ⅢA型MPS患者进行比较，所有患者年龄均超过6岁。选择8例年龄较小的Hurler综合征（1H）患儿作为“风险室”程序的对照组；1H型MPS不会直接影响社会/情感功能，且这些年龄较小的儿童更接近ⅢB型MPS组的发育水平。为了评估疾病严重程度，对认知能力进行了评估。采用了四项评估：“风险室”程序（用于测量社会情感特征，尤其是恐惧和惊吓反应）、自闭症诊断观察量表（ADOS）、Sanfilippo行为评定量表（SBRS），以及通过手动追踪MRI图像计算的杏仁核脑容量。
两组在严重程度上相当，均表现出严重的认知障碍。在ADOS上，ⅢB型MPS患者表现出与ⅢA型相同的自闭症特征。在大多数测量指标上，ⅢB型患者的均值与1H型MPS患者的均值不同。然而，ⅢB型组不像1H型MPS组那样与“风险室”中的陌生人保持距离，也不像ⅢA型组那样对陌生人毫无恐惧。在SBRS上，与ⅢA型MPS患者相比，ⅢB型MPS患者被描述为更注意力不集中、更恐惧，尤其是对陌生人。ⅢB型MPS的一些疾病特征的发病间隔似乎更短，且比ⅢA型稍早出现。
在大多数行为测量指标上，6岁以上的ⅢB型MPS患者与ⅢA型MPS患者没有显著差异，表现出自闭症特征和类似Klüver-Bucy综合征的症状，包括缺乏恐惧和注意力不集中。两名患者的行为症状出现延迟与诊断较晚有关。缺乏恐惧、注意力不集中和类似自闭症的症状是ⅢB型MPS和ⅢA型MPS的共同特征。一个可能的差异是，ⅢB型MPS的一些行为异常发展得更快。如果是这样，这些患者可能比ⅢA型MPS患者更早面临伤害风险，给养育带来挑战。在未来新治疗方法的临床试验中，尤其是在生活质量和患者管理方面，改善这些行为将是一个重要目标。由于未对非常年幼的患者进行研究，因此需要对ⅢB型MPS异常行为的早期发展进行前瞻性自然病史记录。
