Leigh Syndrome Caused by Compound Heterozygous Variants c.1162A_C and c.1138G_C in the NDUFV1 Gene: A Case Report.

Early-onset Leigh syndrome is usually a genetically and phenotypically heterogeneous, severe, rapidly progressive mitochondrial disorder with a fatal outcome. Leigh syndrome is genetically heterogeneous as it is based on mutations in mtDNA or nDNA genes, which mostly encode subunits of respiratory chain complexes or assembly factors. It is phenotypically heterogeneous because it is genetically heterogeneous and due to the peculiarities of mitochondrial genetics. One of the more than 100 mutated genes responsible for Leigh syndrome is NDUFV1. Here we present the case of an infant with Leigh syndrome who suffered from a novel heterozygous variant of the NDUFV1 gene, which is phenotypically characterized by a number of previously unknown features. The patient was a four-month-old girl with Leigh syndrome due to the compound heterozygous variants c.1162+4A>C (previously described, inherited from the mother) and c.1138G>C (novel, inherited from the father) in NDUFV1. The mutation c.1162+4A>C is a non-canonical splice site variant that has been demonstrated to result in loss of function. The bioinformatic analysis supports that the missense variant c. 1138G>C has a deleterious effect on protein structure or function. The mutations manifested phenotypically with typical cerebral lesions on imaging, developmental delay, cognitive decline, epileptiform discharges in the electroencephalography without seizures, atrioventricular (AV) block II, agenesis of a subclavian vein, right heart failure, patent foramen ovale, pulmonary hypertension, hypoaldosteronism, and abdominal hernias. Within five weeks of hospitalization, the disease took a progressive course, and the patient died of infectious complications despite maximum treatment. This case shows that the described new heterozygous variant in NDUFV1 can occur with previously undescribed phenotypic features. It is important to diagnose mitochondrial disorders due to NDUFV1 mutations early in order not to miss the time for appropriate symptomatic treatment.