Smith Laura A, Olkhova Elizaveta A, Lax Nichola Z, Ng Yi Shiau, Taylor Robert W, Gorman Grainne S, Erskine Daniel, McFarland Robert
Mitochondrial Research Group, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK.
Translational Biosciences, Applied Sciences, Ellison Building, Northumbria University, Newcastle Upon Tyne, NE1 8ST, UK.
Acta Neuropathol. 2025 May 30;149(1):53. doi: 10.1007/s00401-025-02891-6.
Cerebellar ataxia is a frequent, debilitating neurological manifestation of primary mitochondrial disease and is associated with extensive neurodegeneration of the cerebellar cortical circuitry. However, the precise neuropathological mechanisms resulting in cerebellar degeneration in paediatric and adult forms of mitochondrial disease remain unclear. We therefore sought to perform a comparative neuropathological study using post-mortem cerebellar tissues from 28 paediatric and adult patients with pathogenic bi-allelic POLG variants and pathogenic mitochondrial DNA variants (m.3243A > G, m.8344A > G, m.13094T > C, and m.14709T > C), in addition to 18 neurologically normal control cases. We also sought to assess the prevalence and progression of cerebellar ataxia in an adult mitochondrial disease patient clinical cohort (n = 310) harbouring the same pathogenic variants as the post-mortem cases. Analysis of the clinical patient cohort revealed that at least 23.5-39.7% of adult patients with primary mitochondrial disease had predominantly cerebellar ataxia, with disease progression evident in 38.8% of patients. In the mitochondrial disease post-mortem tissue cohort, there was clear evidence of selective loss of inhibitory Purkinje cells, with corresponding oxidative phosphorylation protein deficiencies, which were more severe in comparison to mainly excitatory neuronal populations of the granule cell layer and dentate nucleus. Remaining Purkinje cells also demonstrated an increased expression of mitophagy-related proteins, including LC3B and BNIP3. Focal necrotic cerebellar cortical lesions, identified in eight patients, were characterised by decreased parvalbumin immunoreactivity, and sporadic c-Fos immunoreactivity was observed throughout the cerebellar cortices of 14 patients, suggestive of cerebellar cortical hyperactivity. Overall, these neuropathological features were more severe in the early onset POLG-related disease group and patients who had epilepsy. Our findings provide an important insight to the pathological mechanisms contributing to the degeneration of the cerebellar cortex in paediatric and adult forms of primary mitochondrial disease, highlighting an increased burden of pathology in early onset POLG-related disease which may have important prognostic and therapeutic implications.
小脑共济失调是原发性线粒体疾病常见的、使人衰弱的神经学表现，与小脑皮质神经回路的广泛神经变性有关。然而，导致儿童和成人形式线粒体疾病小脑变性的确切神经病理学机制仍不清楚。因此，我们试图使用28例患有致病性双等位基因POLG变异和致病性线粒体DNA变异（m.3243A > G、m.8344A > G、m.13094T > C和m.14709T > C）的儿童和成人患者的死后小脑组织进行比较神经病理学研究，另外还有18例神经学正常的对照病例。我们还试图评估一个成年线粒体疾病患者临床队列（n = 310）中小脑共济失调的患病率和进展情况，该队列患者携带与死后病例相同的致病性变异。对临床患者队列的分析显示，至少23.5%-39.7%的成年原发性线粒体疾病患者主要表现为小脑共济失调，38.8%的患者有疾病进展。在线粒体疾病死后组织队列中，有明确证据表明抑制性浦肯野细胞选择性丢失，伴有相应的氧化磷酸化蛋白缺乏，与颗粒细胞层和齿状核主要为兴奋性神经元群体相比，这种缺乏更为严重。剩余的浦肯野细胞还表现出与线粒体自噬相关蛋白（包括LC3B和BNIP3）的表达增加。在8例患者中发现的局灶性坏死性小脑皮质病变的特征是小白蛋白免疫反应性降低，在14例患者的整个小脑皮质中观察到散在的c-Fos免疫反应性，提示小脑皮质活动亢进。总体而言，这些神经病理学特征在早发性POLG相关疾病组和患有癫痫的患者中更为严重。我们的研究结果为导致儿童和成人形式原发性线粒体疾病小脑皮质变性的病理机制提供了重要见解，突出了早发性POLG相关疾病中病理负担的增加，这可能具有重要的预后和治疗意义。
