VARS2-linked mitochondrial encephalopathy: two case reports enlarging the clinical phenotype
VARS2-linked mitochondrial encephalopathy: two case reports enlarging the clinical phenotype
复制标题
DOI：
10.1186/s12881-019-0798-7
复制
发表时间：
2019-05-07
影响因子：
--
通讯作者：
Sotgiu, Stefano
中科院分区：
文献类型：
--
作者：
Begliuomini, Chiara;Magli, Giorgio;Sotgiu, Stefano
背景线粒体呼吸链由核基因组和线粒体基因组编码的五个复合体组成。线粒体氨酰-tRNA合成酶是合成这种复合物的关键酶。VARS 2（编码缬氨酰-tRNA（Val-tRNA）合成酶的核基因）的双等位基因变体与几种形式的线粒体脑病或心肌脑病相关。其中，罕见的纯合子c.1100C>T（p.Thr367Ile）突变可导致进行性发育迟缓、轴性肌张力减退、肢体痉挛、耐药性癫痫，在某些情况下可导致过早死亡。然而，只有6例，其中三个是兄弟姐妹，窝藏这种纯合子突变已被描述worldwide.Case presentationHereby，我们报告两个额外的情况下，两个非相关的年轻女孩从撒丁岛，出生的非血缘和健康的父母，携带上述纯合子VARS 2变异。发病时，两名患者均表现为精神延迟恶化、肌肉张力减退和腱反射活跃。标准的基因检测和代谢检查都是正常的。脑MRI显示非特异性进行性异常，如胼胝体发育不全（患者A）和小脑萎缩（患者A和B）。通过采用大规模并行下一代测序技术进行诊断。值得注意的是，与先前已知的病例相比，第一名患者的临床表型似乎较温和。第二名患者最终发展为难治性癫痫，目前表现为严重的全身损害。因为没有具体的治疗方法，但这两个病人的治疗与支持抗氧化剂化合物沿着与对症therapeutic.ConclusionsGiven这种非常罕见的线粒体脑病的临床数据的缺乏，我们的报告可能有助于扩大表型谱的疾病。此外，值得注意的是，三分之五的谱系迄今为止描述属于北方撒丁岛种族。
BackgroundMitochondrial respiratory chain consists of five complexes encoded by nuclear and mitochondrial genomes. Mitochondrial aminoacyl-tRNA synthetases are key enzymes in the synthesis of such complexes. Bi-allelic variants of VARS2, a nuclear gene encoding for valyl-tRNA (Val-tRNA) synthetase, are associated to several forms of mitochondrial encephalopathies or cardiomyoencephalopathies. Among these, the rare homozygous c.1100C>T (p.Thr367Ile) mutation variably presents with progressive developmental delay, axial hypotonia, limbs spasticity, drug-resistant epilepsy leading, in some cases, to premature death. Yet only six cases, of which three are siblings, harbouring this homozygous mutation have been described worldwide.Case presentationHereby, we report two additional cases of two non-related young girls from Sardinia, born from non-consanguineous and healthy parents, carrying the aforesaid homozygous VARS2 variant. At onset both the patients presented with worsening psychomotor delay, muscle hypotonia and brisk tendon reflexes. Standard genetic tests were normal, as well as metabolic investigations. Brain MRI showed unspecific progressive abnormalities, such as corpus callosum hypoplasia (patient A) and cerebellar atrophy (patient A and B). Diagnosis was reached by adopting massive parallel next generation sequencing.Notably clinical phenotype of the first patient appears to be milder compared to previous known cases. The second patient eventually developed refractory epilepsy and currently presents with severe global impairment. Because no specific treatment is available as yet, both patients are treated with supporting antioxidant compounds along with symptomatic therapies.ConclusionsGiven the paucity of clinical data about this very rare mitochondrial encephalopathy, our report might contribute to broaden the phenotypic spectrum of the disorder. Moreover, noteworthy, three out of five pedigrees so far described belong to the Northern Sardinia ethnicity.