Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
Neuromuscular Diseases Unit, Department of Neurology, Hospital Universitari i Politècnic La Fe, Valencia, Spain.
Neuropathol Appl Neurobiol. 2022 Aug;48(5):e12817. doi: 10.1111/nan.12817. Epub 2022 Apr 10.
We aim to present data obtained from three patients belonging to three unrelated families with an infantile onset demyelinating neuropathy associated to somatic and neurodevelopmental delay and to describe the underlying genetic changes.
We performed whole-exome sequencing on genomic DNA from the patients and their parents and reviewed the clinical, muscle and nerve data, the serial neurophysiological studies, brain and muscle MRIs, as well as the respiratory chain complex activity in the muscle of the three index patients. Computer modelling was used to characterise the new missense variant detected.
All three patients had a short stature, delayed motor milestone acquisition, intellectual disability and cerebellar abnormalities associated with a severe demyelinating neuropathy, with distinct morphological features. Despite the proliferation of giant mitochondria, the mitochondrial respiratory chain complex activity in skeletal muscle was normal, except in one patient in whom there was a mild decrease in complex I enzyme activity. All three patients carried the same two compound heterozygous variants of the TRMT5 (tRNA Methyltransferase 5) gene, one known pathogenic frameshift mutation [c.312_315del (p.Ile105Serfs*4)] and a second rare missense change [c.665 T > C (p.Ile222Thr)]. TRMT5 is a nuclear-encoded protein involved in the post-transcriptional maturation of mitochondrial tRNA. Computer modelling of the human TRMT5 protein structure suggests that the rare p.Ile222Thr mutation could affect the stability of tRNA binding.
Our study expands the phenotype of mitochondrial disorders caused by TRTM5 mutations and defines a new form of recessive demyelinating peripheral neuropathy.
我们旨在呈现三例起病于婴儿期的脱髓鞘神经病患者的资料，这些患者伴有躯体和神经发育迟缓，我们还将描述其潜在的遗传改变。
我们对这 3 名患者及其父母的基因组 DNA 进行了全外显子组测序，并对这 3 名指数患者的临床、肌肉和神经数据、连续的神经生理学研究、脑和肌肉磁共振成像以及肌肉中的呼吸链复合物活性进行了回顾。使用计算机建模来对新发现的错义变异进行特征描述。
所有 3 名患者均身材矮小，运动发育里程碑延迟，智力残疾和小脑异常，伴有严重的脱髓鞘神经病，具有明显的形态特征。尽管巨线粒体大量增殖，但骨骼肌中的线粒体呼吸链复合物活性正常，只有 1 名患者的复合物 I 酶活性轻度降低。这 3 名患者均携带 TRMT5（tRNA 甲基转移酶 5）基因的两种复合杂合变异，一种是已知的致病性移码突变[c.312_315del(p.Ile105Serfs*4)]，另一种是罕见的错义改变[c.665T>C(p.Ile222Thr)]。TRMT5 是一种核编码蛋白，参与线粒体 tRNA 的转录后成熟。对人类 TRMT5 蛋白质结构的计算机建模表明，罕见的 p.Ile222Thr 突变可能影响 tRNA 结合的稳定性。
我们的研究扩展了由 TRTM5 突变引起的线粒体疾病表型，并定义了一种新的隐性脱髓鞘周围神经病形式。
