ESPE Abstracts

Background: Cytochrome C oxidase (COX) is the fourth component of the respiratory chain. This protein is located within the internal membrane of mitochondria. COX deficiency is an inherited mitochondrial disease associated with considerable genetic and clinical variability(1). In fact, four clinical subtypes of this condition have been identified, each one with several phenotypic and genetic variants. Mitochondrial complex IV deficiency nuclear type 4 is a rare genetic disease caused by compound heterozygous/homozygous mutations of SCO1 gene. This condition is characterized by hypotonia, psychomotor regression, hepatic steatosis, lactate acidosis cardiomyopathy with early onset and poor prognosis(2–5).

Methods: A retrospective review of all cases of MC4DN4 identified at Meyer Children’s Hospital was performed. Three cases with two different SCO1 missense mutations and previously undescribed endocrinologic features were identified. Two patients (aged 10 and 13) were siblings, while the third patient was 34 and unrelated to the former family. All of them were affected by hypopituitarism. Pituitary dysfunction in these patients shows a progressive worsening and an unexpected hyper responsiveness to substitution therapy over time. A thorough genetic and metabolic characterization of each case was performed to exclude other possible mutations and metabolic disorders associated with panhypopituitarism.

Results: Our case series shows peculiar clinical features which consistently differ from previously described phenotype of MC4DN4: patients developed panhypopituitarism, were not affected by cardiomyopathy and had long term survival.

Conclusions: We propose panhypopituitarism as a new part of phenotypic spectrum of MC4DN4, moreover we propose a model to explain these findings and the other alterations in central nervous system found in these patients

1. Brischigliaro M et al. Cytochrome c oxidase deficiency. Biochimica et Biophysica Acta (BBA) - Bioenergetics. 2021;1862(1):148335. 2. Valnot I et al. Mutations of the SCO1 Gene in Mitochondrial Cytochrome c Oxidase Deficiency with Neonatal-Onset Hepatic Failure and Encephalopathy. Vol. 67, Am. J. Hum. Genet. 2000. 3. Stiburek L et al. Loss of function of Sco1 and its interaction with cytochrome c oxidase. American Journal of Physiology-Cell Physiology. 2009 May 1;296(5):C1218–26. 4. Leary SC, et al. Novel Mutations in SCO1 as a Cause of Fatal Infantile Encephalopathy and Lactic Acidosis. Hum Mutat. 2013 Oct 1;34(10):1366–70. 5. Brix N, et al. Mitochondrial Disease Caused by a Novel Homozygous Mutation (Gly106del) in the SCO1 Gene. Neonatology. 2019 Oct 1;116(3):290–4.