PLA2G6 相关神经变性的临床、放射学和遗传学谱系:一家三级医疗中心的经验

IF 2.5 Q2 CLINICAL NEUROLOGY Tremor and Other Hyperkinetic Movements Pub Date : 2024-08-21 eCollection Date: 2024-01-01 DOI:10.5334/tohm.897
Vikram V Holla, M M Samim, Riyanka Kumari, Debjyoti Dhar, Prashant Phulpagar, Neeharika Sriram, Shweta Prasad, Jitender Saini, Nitish Kamble, Ravi Yadav, Babylakshmi Muthusamy, Pramod Kumar Pal
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引用次数: 0

摘要

背景:尽管PLA2G6是第二种最常见的脑铁积聚型神经变性,但有关亚洲人,尤其是印度人的PLA2G6相关神经变性(PLAN)的文献却很有限:我们根据外显子组测序对具有致病性/可能致病性 PLA2G6 变异的患者进行了一项回顾性观察研究:结果:我们发现了 26 名经基因证实的 PLAN 患者(22 个家庭,15 名男性),中位年龄为 22.5 岁,发病年龄为 13.0 岁,包括各种亚型:婴儿神经轴性肌营养不良症(5/26;19.2%)、非典型神经轴性肌营养不良症(3/26;11.5%)、肌张力障碍-帕金森病(5/26;19.2%)、肌张力障碍-帕金森病-肌阵挛(n = 4,15.38%)、早发帕金森病(2/26;7.7%)、复杂肌张力障碍(2/26;7.7%)和复杂遗传性痉挛性截瘫(cHSP; 5/26;19.2%)。常见的初始症状包括行走困难(7/26;26.9%)、发育倒退(6/26;23.1%)和行动迟缓(4/26;15.4%)。最常见的运动症状是肌张力障碍(14/26;53.8%),其次是帕金森病(11/26;42.3%)。非运动症状包括认知能力下降(12/26;46.2%)和行为改变(6/26;23.1%)。神经影像学检查显示,23/26(88.5%)名INAD患者出现小脑萎缩,80%(4/5)名INAD患者出现锁骨肥大。14名接受左旋多巴治疗的帕金森病/肌张力障碍患者中,12人对左旋多巴有反应,10/11人出现运动障碍。基因分析显示,PLA2G6 基因共有 19 个独特变异,其中 11 个为新变异。12名患者携带c.2222G>A变体,该变体主要见于亚洲亚人群:该研究新增了 26 例 PLAN 患者和 12 例与 c.2222G>A 变异相关的患者,可能是迄今为止最广泛的单中心系列研究。该研究还扩展了 PLAN 的表型、神经影像学和基因型谱系。
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The Clinical, Radiological and Genetic Spectrum of PLA2G6-Associated Neurodegeneration: An Experience From a Tertiary Center.

Background: Despite being the second most common type of neurodegeneration with brain iron accumulation, there is limited literature on PLA2G6-associated neurodegeneration (PLAN) within the Asian ethnicity, particularly in the Indian context.

Methods: We conducted a retrospective observational study on patients with pathogenic/likely pathogenic PLA2G6 variants based on exome sequencing.

Results: We identified 26 patients (22 families, 15 males) of genetically-confirmed PLAN with a median age of 22.5 years and age at onset of 13.0 years, encompassing various subtypes: infantile neuroaxonal dystrophy (5/26;19.2%), atypical neuroaxonal dystrophy (3/26;11.5%), dystonia-parkinsonism (5/26;19.2%), dystonia-parkinsonism-myoclonus (n = 4, 15.38%), early-onset Parkinson's disease (2/26;7.7%), complex dystonia (2/26;7.7%), and complicated hereditary spastic paraparesis (cHSP; 5/26;19.2%). The common initial symptoms included walking difficulty (7/26;26.9%), developmental regression (6/26;23.1%), and slowness (4/26;15.4%). Dystonia (14/26;53.8%), followed by parkinsonism (11/26; 42.3%), was the most common motor symptom. Non-motor symptoms included cognitive decline (12/26;46.2%) and behavioral changes (6/26;23.1%). Neuroimaging revealed cerebellar atrophy in 23/26 (88.5%) patients and claval hypertrophy in 80% (4/5) of INAD patients. Levodopa responsiveness was noted in 12 of 14 patients with parkinsonism/dystonia who received levodopa, and dyskinesia was noted in 10/11 patients. Genetic analysis revealed a total of 19 unique variants in PLA2G6 gene, of which 11 were novel. Twelve patients harbored the c.2222G>A variant, which is predominantly seen in Asian subpopulations.

Conclusions: The study introduces 26 new patients of PLAN and 12 patients associated with the c.2222G>A variant, potentially forming the most extensive single center series to date. It also expands the phenotypic, neuroimaging, and genotypic spectrum of PLAN.

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4.50%
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