Mitochondrial Complex I Deficiency Associated with Biallelic NDUFA13 Variants Lead to Leigh Syndrome (P11-9.008)

Abstract

<h3>Objective:</h3> To report on further 8 affected individuals from 7 independent families with one missense and three ultra-rare or novel predicted loss-of-function (LOF) biallelic <i>NDUFA13</i> variants and provide follow-up clinical-radiological details from the previously reported families. <h3>Background:</h3> Biallelic variants in NADH-ubiquinone oxidoreductase 1 alpha subcomplex 13 (<i>NDUFA13</i>) have been associated with mitochondrial Complex I (CI) deficiency, nuclear type 28 in three affected individuals from two families. Currently, with only two families reported, the clinical and molecular spectrum of <i>NDUFA13</i>-related CI deficiency remains poorly characterized. <h3>Design/Methods:</h3> Using the Gene Matcher platform and extensive international data sharing, 7 families reported here were identified. Proband only or trio exome sequencing (ES), variant filtering, and Sanger segregation analysis in 7 families were carried out in 4 different centers following the protocols described previously. Skin biopsies were obtained and cultured fibroblasts were prepared for whole-cell lysates and subsequent SDS-PAGE/western blot analysis was performed. <h3>Results:</h3> There were 6 females and 5 males, 10 of whom are currently alive with a mean age of 8.9 ±5.4 years. The disease was mostly of infantile onset and progressed slowly in 64%. Moderate-to-severe developmental delay/intellectual disability (64%), microcephaly (27%), encephalopathy (54%), epileptic seizures (54%), optic atrophy (54%), oculomotor abnormalities (91%), and neuromuscular phenotype including dysarthria (54%), hypotonia (73%), and spasticity (70%) were among the frequent features. Choreoathetoid movements (60%), dyskinesia (70%), bradykinesia (55%), and truncal ataxia (60%) were frequently displayed movement abnormalities. Bilateral symmetric T2 hyperintense lesions in the substantia nigra (72.7%), basal ganglia lesions (27.2%), periaqueductal gray matter and/or dentate nuclei signal alterations (54.5%), mild cerebellar atrophy (45.4%), and supratentorial white matter volume loss (27.2%) were frequent neuroimaging features. Complex I activity was decreased and complex IV activity was increased in the patient-derived skin fibroblasts, whereas NDUFA13 protein levels were undetectable. <h3>Conclusions:</h3> This study provides a cumulative phenotypic characterization of <i>NDUFA13-</i>related disease. <b>Disclosure:</b> Dr. Kaiyrzhanov has nothing to disclose. Dr. Kaiyrzhanov has nothing to disclose.