The m.3890G>A/MT-ND1 mtDNA rare pathogenic variant: Expanding clinical and MRI phenotypes
The m.3890G>A/MT-ND1 mtDNA rare pathogenic variant: Expanding clinical and MRI phenotypes
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DOI：
10.1016/j.mito.2021.08.007
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发表时间：
2021-08-19
期刊：
影响因子：
4.4
通讯作者：
Carelli, Valerio
中科院分区：
文献类型：
--
作者：
Vacchiano, Veria;Caporali, Leonardo;Carelli, Valerio
简介：孤立的复合物I缺乏引起几种临床综合征，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，我们报告了两个新的患者携带罕见的m.3890G>A/MT-ND 1（p.Arg195Gln）线粒体DNA（mtDNA）致病性变异，重新访问了另外两个先前报道的病例，并审查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tissues.Cases介绍：第一个病人是一个25岁的男性轴突性多发性神经病，视神经萎缩符合LHON，凝视麻痹和帕金森综合征的mtDNA异质性。MRI相关性包括脊髓圆锥的短暂中央髓T2高信号，中脑导水管周围灰质的短暂信号强度和乳酸盐增加，以及视神经和视交叉、背侧中脑和脊髓圆锥的晚期萎缩。第二个病人是一个65岁的妇女与经典的LHON表型和正常的MRI。讨论：包括以前发表的病例，临床光谱范围从LHON到利样综合征特有的中枢神经系统病变和脑病的临床症状。最严重和复杂的病例与骨骼肌中非常高的异质性或几乎同质的m.3890G>A/MT-ND 1致病变体相关，显示出与脑MRI上的Leigh样病变一致的神经症状/体征。较低的异质性突变负荷，而不是与孤立的LHON样视神经病变的变量severity.Conclusion：m.3890G>A/MT-ND 1 mtDNA致病变异越来越损害复杂的I功能依赖于异质性负荷，导致光谱LHON和Leigh样脑病与区分MRI功能。
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.