Benussi Alberto, Cotelli Maria S, Cantoni Valentina, Bertasi Valeria, Turla Marinella, Dardis Andrea, Biasizzo Jessica, Manenti Rosa, Cotelli Maria, Padovani Alessandro, Borroni Barbara
Neurology Unit, Department of Clinical and Experimental Sciences University of Brescia Brescia Italy.
Neurology Unit Valle Camonica Hospital Brescia Italy.
JIMD Rep. 2019 Jun 28;49(1):80-88. doi: 10.1002/jmd2.12059. eCollection 2019 Sep.
Niemann-Pick disease type C (NPC) is an uncommon lysosomal storage disorder, which is characterized neuropathologically by cholinergic dysfunction and presents clinically with a broad series of neurological signs and symptoms. NPC is inherited as an autosomal recessive trait, caused by mutations in the or genes. However, recent reports have raised concerns on heterozygous gene mutation carriers, which historically have been considered as clinically unaffected, occasionally presenting with clinical parkinsonian syndromes or dementia. In the present study, we aimed at comprehensively assessing clinical, biochemical, and neurophysiological features in heterozygous gene mutation carriers. We assessed cholinergic intracortical circuits with transcranial magnetic stimulation, executive functions and plasma oxysterol levels in two families comprising two monozygotic twins with a homozygous mutation, four patients with a compound heterozygous and mutation, 10 heterozygous carriers, 1 heterozygous carrier, and 11 noncarrier family members. We observed a significant impairment in cholinergic circuits, evaluated with short-latency afferent inhibition (SAI), and executive abilities in homozygous/compound heterozygous patients and heterozygous asymptomatic carriers, compared to noncarriers. Moreover, we reported a significant correlation between executive functions performances and both plasma oxysterol levels and neurophysiological parameters. These data suggest that heterozygous carriers show subclinical deficits in cognition, possibly mediated by an impairment of cholinergic circuits, which in turn may mediate the onset of neurological disorders in a subset of patients.
尼曼-皮克病C型（NPC）是一种罕见的溶酶体贮积症，其神经病理学特征为胆碱能功能障碍，临床上表现为一系列广泛的神经体征和症状。NPC以常染色体隐性性状遗传，由 或 基因的突变引起。然而，最近的报告引发了对杂合 基因突变携带者的关注，这些携带者在历史上被认为临床上未受影响，但偶尔会出现临床帕金森综合征或痴呆。在本研究中，我们旨在全面评估杂合 基因突变携带者的临床、生化和神经生理特征。我们在两个家族中评估了胆碱能皮质内回路（采用经颅磁刺激）、执行功能和血浆氧化甾醇水平，这两个家族包括两对具有纯合 突变的同卵双胞胎、四名具有复合杂合 和 突变的患者、十名杂合 携带者、一名杂合 携带者以及十一名非携带者家庭成员。与非携带者相比，我们观察到在纯合/复合杂合患者以及杂合无症状 携带者中，用短潜伏期传入抑制（SAI）评估的胆碱能回路和执行能力存在显著损害。此外，我们报告了执行功能表现与血浆氧化甾醇水平和神经生理参数之间存在显著相关性。这些数据表明，杂合 携带者在认知方面存在亚临床缺陷，可能由胆碱能回路受损介导，而这反过来可能在一部分患者中介导神经疾病的发作。
