Cardiac dysfunction is a common phenotypic manifestation of primary mitochondrial disease with multiple nuclear and mitochondrial DNA pathogenic variants as a cause, including disorders of mitochondrial translation. To date, five patients have been described with pathogenic variants in MRPL44, encoding the ml44 protein which is part of the large subunit of the mitochondrial ribosome (mitoribosome). Three presented as infants with hypertrophic cardiomyopathy, mild lactic acidosis, and easy fatigue and muscle weakness, whereas two presented in adolescence with myopathy and neurological symptoms.

We describe two infants who presented with cardiomyopathy from the neonatal period, failure to thrive, hypoglycemia and in one infant lactic acidosis. A decompensation of the cardiac function in the first year resulted in demise. Exome sequencing identified compound heterozygous variants in the MRPL44 gene including the known pathogenic variant c.467 T > G and two novel pathogenic variants. We document a combined respiratory chain enzyme deficiency with emphasis on complex I and IV, affecting heart muscle tissue more than skeletal muscle or fibroblasts. We show this to be caused by reduced mitochondrial DNA encoded protein synthesis affecting all subunits, and resulting in dysfunction of complex I and IV assembly. The degree of oxidative phosphorylation dysfunction correlated with the impairment of mitochondrial protein synthesis due to different pathogenic variants. These functional studies allow for improved understanding of the pathogenesis of MRPL44-associated mitochondrial disorder.

心脏功能障碍是原发性线粒体疾病的常见表型表现，其原因包括多种核和线粒体 DNA 致病变异，包括线粒体翻译障碍。迄今为止，已有 5 名患者被描述为 MRPL44 的致病性变异，编码 ml44 蛋白，该蛋白是线粒体核糖体（线粒体核糖体）大亚基的一部分。三人在婴儿期出现肥厚型心肌病、轻度乳酸性酸中毒、易疲劳和肌肉无力，而两名在青春期出现肌病和神经系统症状。

我们描述了两名婴儿在新生儿期出现心肌病、发育迟缓、低血糖和一名婴儿乳酸酸中毒。第一年心脏功能失代偿导致死亡。外显子组测序鉴定了MRPL44中的复合杂合变体基因包括已知的致病变异 c.467 T > G 和两个新的致病变异。我们记录了复合呼吸链酶缺乏症，重点是复合物 I 和 IV，对心肌组织的影响比骨骼肌或成纤维细胞更多。我们表明这是由影响所有亚基的线粒体 DNA 编码蛋白质合成减少引起的，并导致复合物 I 和 IV 组装功能障碍。氧化磷酸化功能障碍的程度与不同致病变异导致的线粒体蛋白质合成受损相关。这些功能研究有助于更好地理解 MRPL44 相关线粒体疾病的发病机制。