Endocrinological features and epileptic encephalopathy in COX deficiency due to SCO1 mutations: case series and review of literature

Abstract

Context: Cytochrome C oxidase (COX) is the fourth component of the respiratory chain and is located within the internal membrane of mitochondria. COX deficiency causes an inherited mitochondrial disease with significant genetic and phenotypic heterogeneity. Four clinical subtypes have been identified, each with distinct phenotypes and genetic variants. Mitochondrial complex IV deficiency nuclear type 4 (MC4DN4) is a form of COX deficiency associated with pathogenic variants in the SCO1 gene.

Case description: We describe three patients with MC4DN4 with developmental and epileptic encephalopathy (DEE), hypopituitarism, and SCO1 pathogenic variants. These patients' phenotypes considerably differ from previously reported MC4DN4 phenotypes as they associate DEE with progressive hypopituitarism and survival beyond the first months after birth. Pituitary deficiency in these patients progressively worsened and mainly involved growth hormone secretion and thyroid function.

Conclusions: Our findings expand knowledge of phenotypic variability in MC4DN4 and suggest that SCO1 is a candidate gene for genetic hypopituitarism and DEE.

Significance statement: Our paper describes three patients affected by MC4DN4 with hypopituitarism and developmental and epileptic encephalopathy (DEE), two features that have never been associated with this condition. In addition, we reviewed the clinical features of all previous cases of MC4DN4 to give the other clinicians a wide picture of the clinical phenotype of this genetic disease. We hope that the publication of our data may help others to identify this disease and consider the chance to analyze the SCO1 gene in cases of DEE associated with pituitary dysfunction. Our article contributes to expanding the spectrum of genetic hypopituitarism and proposes a model to explain an association between this condition, mitochondrial anomalies, and neurodevelopmental defects.

Keywords: COX deficiency; SCO1 gene; developmental epileptic encephalopathy phenotypes; epilepsy; growth; hypopituitarism; pathogenic variant; short stature.

Figure 1

Brain MRI images: A, B, C patient n1, D, E, F patient n2. (A, D) sagittal T1-weighted image; (B, E) coronal T2-weighted image; (C, F) axial FLAIR T2-weighted image. The study shows cerebellar atrophy (white arrow), cerebral atrophy with widening of the Sylvian fissures, bilateral superior olivary nuclei increased signal on FLAIR and T2-weighted images (arrowhead), and posterior parietal and cerebellar white matter hyperintensity on FLAIR and T2-weighted images (empty arrow).

Figure 2

(A) Location on SCO1 gene of the two identified mutations modified from Valnot et al.; (B) 3D model of SCO1 protein with mutation site c.685 G>A (p.Gly229Ser); (C) 3D model of SCO1 protein with mutation site c.424C>G (p.Leu142Val). 3D models were realized with AlphaFold on www.uniprot.org.