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

Abstract

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 ‘post-transplant’ 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, mother’s return after a brief absence, and compliance with her clean-up directive. Children with MPS IIIA: 1) left mother sooner, 2) wandered more, 3) were more likely to approach frightening objects, 4) were less likely to respond to loud noise with whole body startle, 5) were less likely to avoid the toy associated with the startle noise, 6) interacted less with mother upon her return, and 7) complied less with her clean-up command. K-Bs is associated with loss of amygdala function. Brain MRIs of a subset of the children with MPS IIIA showed volume loss that was greater in the amygdala than 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.

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.…”

“…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. 19 However, as shown in further studies, KBS cannot solely be explained by dysfunction of the amygdala.…”

“…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.…”