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 NDUFA13 variants and provide follow-up clinical-radiological details from the previously reported families.

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.

This study provides a cumulative phenotypic characterization of NDUFA13-related disease.