Ghezzi Daniele, Canavese Carlotta, Kovacevic Gordana, Zamurovic Dragan, Barzaghi Chiara, Giorgi Carlotta, Zorzi Giovanna, Zeviani Massimo, Pinton Paolo, Garavaglia Barbara, Nardocci Nardo
Molecular Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy.
Neuropediatrics Unit, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy.
Eur J Paediatr Neurol. 2015 Jan;19(1):64-8. doi: 10.1016/j.ejpn.2014.10.003. Epub 2014 Oct 18.
Paroxysmal nonkinesigenic dyskinesia (PNKD) is a rare movement disorder characterized by sudden attacks of involuntary movements. Familial PNKD is an autosomal dominant trait, caused by mutations in the myofibrillogenesis regulator 1 (MR-1) gene on chromosome 2q35. Three different mutations have been described; all of them reside in the N-terminal region common to isoforms L and S, that has been suggested to code for a mitochondrial targeting sequence, necessary for the correct sub-cellular localization of the protein into mitochondria.
We report on four patients of the same family, affected by PNKD. Skin fibroblasts were used to analysed oxygen consumption and to measure mitochondrial matrix calcium response after agonist stimulation. Mitotracker-based visualization was also used to assess fragmentation of the mitochondrial network.
the paroxysmal movements were dystonic in two patients and dystonic/choreiform in the other ones; in three cases the symptoms started in one limb and then generalized, while in one case remained focal. Three had a very early onset, within the first two years of life. The frequency of episodes showed a great variability, ranging from 2 times a day to 3 times a year, while the duration of the attacks ranged from 2 min to 1,5 h, always with sudden onset and end and complete recover in between. All affected subjects harbored a heterozygous C to T substitution in MR-1, causing an Ala9Val amino acid change in the N-terminal region. A significant reduction of oxygen consumption and altered calcium homeostasis were found in mutant fibroblasts compared to controls, while no difference was detected in mitochondrial network.
The data on reduced oxygen consumption and altered calcium homeostasis obtained on mutant fibroblasts are the first evidences, in physiological conditions, of a mitochondrial dysfunction in PNKD.
阵发性非运动诱发性运动障碍（PNKD）是一种罕见的运动障碍，其特征为突发的不自主运动。家族性PNKD是一种常染色体显性性状，由位于2q35染色体上的肌纤蛋白生成调节因子1（MR-1）基因突变引起。已描述了三种不同的突变；所有这些突变都位于异构体L和S共有的N端区域，该区域被认为编码线粒体靶向序列，这是蛋白质正确亚细胞定位到线粒体中所必需的。
我们报告了同一家庭中4名受PNKD影响的患者。使用皮肤成纤维细胞分析氧气消耗，并在激动剂刺激后测量线粒体基质钙反应。基于线粒体示踪剂的可视化也用于评估线粒体网络的碎片化。
两名患者的阵发性运动为张力障碍性，另外两名患者为张力障碍性/舞蹈样运动；3例症状始于一个肢体，然后扩散，而1例症状仍局限于局部。3例在生命的头两年内发病非常早。发作频率差异很大范围从每天2次到每年3次，而发作持续时间从2分钟到1.5小时不等，总是突然发作和结束，其间完全恢复。所有受影响的受试者在MR-1基因中均存在杂合的C到T替换，导致N端区域的Ala9Val氨基酸变化。与对照组相比，突变成纤维细胞中的氧气消耗显著降低，钙稳态改变，而线粒体网络未检测到差异。
在突变成纤维细胞上获得的关于氧气消耗减少和钙稳态改变的数据是在生理条件下PNKD中线粒体功能障碍的首个证据。
