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

A. Barbato; G. Gori; M. Sacchini; F. Pochiero; S. Bargiacchi; G. Traficante; V. Palazzo; L. Tiberi; C. Bianchini; D. Mei; E. Parrini; T. Pisano; E. Procopio; R. Guerrini; A. Peron; S. Stagi

doi:10.1530/ey.22.1.7

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 1.7 | DOI: 10.1530/ey.22.1.7

ESPEYB25 1. Pituitary and Neuroendocrinology Novel Genes (4 abstracts)

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

A. Barbato , G. Gori , M. Sacchini , F. Pochiero , S. Bargiacchi , G. Traficante , V. Palazzo , L. Tiberi , C. Bianchini , D. Mei , E. Parrini , T. Pisano , E. Procopio , R. Guerrini , A. Peron & S. Stagi

Endocr Connect 13(10) (2024).PMID: 39214134

Brief Summary: The retrospective case series describes 3 children with pathogenic SCO1 mutations leading to early-onset encephalopathy and progressive panhypopituitarism.

SCO1 is a nuclear gene that is essential for the proper assembly of mitochondrial complex IV (cytochrome c oxidase, COX), which plays a critical role in oxidative phosphorylation. Biallelic SCO1 mutations have been associated with fatal mitochondrial encephalopathy, often with metabolic acidosis and liver failure. To date, only 6 patients with SCO1 mutations have been reported, 5 of whom died at an early age [1-5].

Here, growth hormone deficiency and central hypothyroidism was observed in all 3 patients. In addition, 2 showed adrenal insufficiency and hypogonadotropic hypogonadism. Notably, hepatic dysfunction was absent, and cardiac involvement was mild or not observed. The authors hypothesise that this relatively milder phenotype and extended survival may be due to the presence of missense variants in SCO1, as opposed to previously reported truncating variants. Therefore, the development of hypopituitarism may have been only observable due to the longer survival afforded by their milder mitochondrial phenotype.

In summary, this article describes the first reported association between panhypopituitarism and SCO1-related COX deficiency, thereby expanding the phenotypic spectrum of SCO1-associated mitochondrial disease. Furthermore, the study highlights the necessity for regular endocrine surveillance in individuals with SCO1 variants in order to monitor the progression of pituitary dysfunction.

References: 1. Brix, N., et al., Mitochondrial disease caused by a novel homozygous mutation (Gly106del) in the SCO1 gene. Neonatology, 2019. 116(3): p. 290–294.2. Stiburek, L., et al., Loss of function of Sco1 and its interaction with cytochrome c oxidase. American Journal of Physiology-Cell Physiology, 2009. 296(5): p. C1218–C1226.3. Valnot, I., et al., Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy. The American Journal of Human Genetics, 2000. 67(5): p. 1104–1109.4. Leary, S.C., et al., Novel mutations in SCO 1 as a cause of fatal infantile encephalopathy and lactic acidosis. Human mutation, 2013. 34(10): p. 1366–1370.5. Kose, M., et al., The utility of next-generation sequencing technologies in diagnosis of Mendelian mitochondrial diseases and reflections on clinical spectrum. Journal of Pediatric Endocrinology and Metabolism, 2021. 34(4): p. 417–430.