The neurobehavioral phenotype in mucopolysaccharidosis Type IIIB: An exploratory study

Abstract

ObjectivesOur 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.MethodsTen 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.ResultsThe 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.ConclusionsOn 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.

Klüver–Bucy syndrome associated with a recessive variant in HGSNAT in two siblings with Mucopolysaccharidosis type IIIC (Sanfilippo C)

“…As pointed out by Potegal et al 4 and Shapiro et al, 5 MPSIII is the first inherited pediatric disease presenting systematically with clinical features of KBS.…”

“…In adults KBS may result from amyotrophic lateral sclerosis, 11 bilateral temporal lobectomy, 2 adrenoleukodystrophy, 12 Alzheimer`s disease, 13 herpes encephalitis, 14 and rapid correction of hyponatremia. 2 In children KBS has been observed after herpes encephalitis, 15 hypoxic insult, 16 in neuronal ceroid-lipofuscinosis, 17 MPSIIIA, 4 MPSIIIB, 5 and as a result of congenital bilateral anterior temporal malformation of the amygdalar-hippocampal complex. 18 We report two siblings with MPSIIIC and severely altered emotional behavior who meet the diagnostic criteria for KBS with onset at MPSIII stage 2.…”

“…6 This finding is in line with a two prospective studies on children with MPSIIIA and MPSIIB that were the first to describe an association between MPSIII and KBS. 4,5 A subset of the study group showed a decline of brain volume affecting more the amygdala than the hippocampus. 4 This finding supports former observations on amygdalectomized versus hippocampectomized monkeys, suggesting that dysfunction of the amygdala is associated with many characteristic symptoms of KBS.…”

“…These patients may exhibit symptoms resembling KBS including a volume loss of the amygdala. 4,5 Progression of MPSIII (including all subtypes A-D) is characterized by delay of language development (stage 1), behavioral disturbances and mental deterioration (stage 2), and finally a neurologic disorder with seizures and spasticity (stage 3). 6 We applied autozygosity mapping and whole-exome sequencing (WES) to identify the genetic defect in two siblings with KBS from a consanguineous marriage.…”

Behavioral deficits and cholinergic pathway abnormalities in male Sanfilippo B mice

“…Affected children experience progressive neurological deterioration and early death. Work by others showed that behavioral abnormalities in Sanfilippo children with the phenotypically-similar type A include a Klüver-Bucy like syndrome with reduced fearfulness [4,5]. This reduced fear response was found to correlate with volume loss in the amygdala [4].…”