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

Alessandro Barbato; Giulia Gori; Michele Sacchini; Francesca Pochiero; Sara Bargiacchi; Giovanna Traficante; Viviana Palazzo; Lucia Tiberi; Claudia Bianchini; Davide Mei; Elena Parrini; Tiziana Pisano; Elena Procopio; Renzo Guerrini; Angela Peron; Stefano Stagi

doi:10.1530/EC-24-0221

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

Endocr Connect. 2024 Sep 28;13(10):e240221. doi: 10.1530/EC-24-0221. Print 2024 Oct 1.

Authors

Alessandro Barbato^{1

2}, Giulia Gori³, Michele Sacchini⁴, Francesca Pochiero⁴, Sara Bargiacchi³, Giovanna Traficante³, Viviana Palazzo³, Lucia Tiberi³, Claudia Bianchini⁵, Davide Mei⁵, Elena Parrini⁵, Tiziana Pisano⁵, Elena Procopio⁴, Renzo Guerrini^{5

6}, Angela Peron^{3

7}, Stefano Stagi^{1

2}

Affiliations

¹ Auxo-endocrinology Unit, Meyer Children's Hospital IRCCS, Florence, Italy.
² Department of Health Sciences, University of Florence, Florence, Italy.
³ Medical Genetics Unit, Meyer Children's Hospital IRCCS, Florence, Italy.
⁴ Metabolic and Muscular Unit, Meyer Children's Hospital IRCCS, Florence, Italy.
⁵ Pediatric Neurology and Neurogenetics Unit and Laboratories, Meyer Children's Hospital IRCCS, Florence, Italy.
⁶ NEUROFARBA Department, University of Florence, Florence, Italy.
⁷ Department of Clinical and Experimental Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.

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.