LARS2 variants are associated with Perrault syndrome, characterized by premature ovarian failure and hearing loss, and with an infantile lethal multisystem disorder: Hydrops, lactic acidosis, sideroblastic anemia (HLASA) in one individual. Recently we reported LARS2 deafness with (ovario) leukodystrophy. Here we describe five patients with a range of phenotypes, in whom we identified biallelic LARS2 variants: three patients with a HLASA‐like phenotype, an individual with Perrault syndrome whose affected siblings also had leukodystrophy, and an individual with a reversible mitochondrial myopathy, lactic acidosis, and developmental delay. Three HLASA cases from two unrelated families were identified. All were males with genital anomalies. Two survived multisystem disease in the neonatal period; both have developmental delay and hearing loss. A 55‐year old male with deafness has not displayed neurological symptoms while his female siblings with Perrault syndrome developed leukodystrophy and died in their 30s. Analysis of muscle from a child with a reversible myopathy showed reduced LARS2 and mitochondrial complex I levels, and an unusual form of degeneration. Analysis of recombinant LARS2 variant proteins showed they had reduced aminoacylation efficiency, with HLASA‐associated variants having the most severe effect. A broad phenotypic spectrum should be considered in association with LARS2 variants.

中文翻译：

---

不断扩大的 LARS2 表型谱：HLASA、伴有脑白质营养不良的 Perrault 综合征和线粒体肌病。

LARS2变体与 Perrault 综合征有关，其特征是卵巢早衰和听力损失，以及婴儿致命的多系统疾病：一个人的水肿、乳酸性酸中毒、铁粒幼细胞性贫血 (HLASA)。最近我们报道了LARS2耳聋伴（卵巢）脑白质营养不良。在这里，我们描述了具有一系列表型的五名患者，我们在他们身上发现了双等位基因LARS2变异：三名具有 HLASA 样表型的患者，一名患有 Perrault 综合征的个体，其受影响的兄弟姐妹也患有脑白质营养不良，以及一名患有可逆性线粒体肌病、乳酸性酸中毒和发育迟缓的个体。确定了来自两个无关家庭的三个 HLASA 病例。都是有生殖器异常的男性。2例新生儿期多系统疾病存活；两者都有发育迟缓和听力损失。一名 55 岁耳聋男性没有出现神经系统症状，而他患有 Perrault 综合征的女性兄弟姐妹患上脑白质营养不良并在 30 多岁时死亡。对患有可逆性肌病的儿童肌肉的分析显示 LARS2 和线粒体复合体 I 水平降低，以及一种不寻常的退化形式。对重组 LARS2 变异蛋白的分析表明，它们的氨酰化效率降低，其中与 HLASA 相关的变异具有最严重的影响。应考虑广泛的表型谱LARS2变体。