Introduction

Isolated complex I deficiency causes several clinical syndromes, including Leigh syndrome (LS), Leber hereditary optic neuropathy (LHON) and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). Here we reported two new patients carrying the rare m.3890G>A/MT-ND1 (p.Arg195Gln) mitochondrial DNA (mtDNA) pathogenic variant, revisited another two previously reported cases, and reviewed the remaining published cases, to refine the clinical and neuroimaging features. We also quantitatively assessed the mtDNA heteroplasmy in all available tissues.

Cases presentation

The first patient was a 25-year-old male presenting with axonal polyneuropathy, optic atrophy consistent with LHON, gaze palsy and parkinsonism. MRI correlates included transient centromedullary T2 hyperintensity in the conus medullaris, transient signal intensity and increased lactate in the midbrain periaqueductal gray matter, and late atrophy of the optic nerves and chiasm, dorsal midbrain and conus medullaris.

The second patient was a 65-year-old woman with a classical LHON phenotype and a normal MRI.

Discussion

Including the previously published cases, the clinical spectrum ranged from LHON to Leigh-like syndrome with peculiar CNS lesions and encephalopatic clinical symptoms. The most severe and complex cases were associated with very high heteroplasmy, or nearly homoplasmic m.3890G>A/MT-ND1 pathogenic variant in skeletal muscle, displaying neurological symptoms/signs consistent with Leigh-like lesions on brain MRI. Lower heteroplasmic mutational loads were instead associated with isolated LHON-like optic neuropathy of variable severity.

Conclusion

The m.3890G>A/MT-ND1 mtDNA pathogenic variant increasingly impairs complex I function dependent on heteroplasmic loads, leading to a spectrum of LHON and Leigh-like encephalopathy with distinguishing MRI features.

中文翻译：

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m.3890G>A/MT-ND1 mtDNA 罕见致病变异：扩大临床和 MRI 表型

介绍

孤立的复合体 I 缺乏会导致多种临床综合征，包括 Leigh 综合征 (LS)、Leber 遗传性视神经病变 (LHON) 和线粒体脑肌病、乳酸性酸中毒和中风样发作 (MELAS)。在这里，我们报告了两名携带罕见 m.3890G>A/ MT-ND1 (p.Arg195Gln) 线粒体 DNA (mtDNA) 致病性变异的新患者，重新审视了另外两个先前报道的病例，并回顾了其余已发表的病例，以完善临床和神经影像学特征。我们还定量评估了所有可用组织中的 mtDNA 异质性。

案例展示

第一名患者是一名 25 岁男性，表现为轴索性多发性神经病、符合 LHON 的视神经萎缩、凝视麻痹和帕金森症。MRI相关性包括脊髓圆锥中短暂的中心髓质T2高信号、中脑导水管周围灰质中短暂的信号强度和乳酸增加，以及视神经和视交叉、中脑背侧和髓质圆锥的晚期萎缩。

第二名患者是一名 65 岁的女性，具有典型的 LHON 表型和正常的 MRI。

讨论

包括以前发表的病例，临床范围从 LHON 到具有特殊 CNS 病变和脑病临床症状的 Leigh 样综合征。最严重和最复杂的病例与骨骼肌中非常高的异质性或接近同质性的 m.3890G>A/ MT-ND1致病性变异相关，在脑 MRI 上显示出与 Leigh 样病变一致的神经症状/体征。相反，较低的异质突变负荷与不同严重程度的孤立的 LHON 样视神经病变相关。

结论

m.3890G>A/ MT-ND1 mtDNA 致病性变异越来越多地损害依赖于异质负荷的复杂 I 功能，导致一系列具有明显 MRI 特征的 LHON 和 Leigh 样脑病。