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Mitochondrial Cytochrome C deficiency can show the first disease signs in the prenatal stage

European Journal of Human Genetics volume 31, pages 1344–1345 (2023)Cite this article

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Cytochrome C oxidase deficiency is a group of mitochondrial disorders characterized by defects in the COX biogenesis and/or activity. Genetically, they can be caused by maternally inherited defects in mitochondrial DNA (mtDNA) encoded core subunits proteins (MT-CO1, MT-CO2, and MT-CO3) or mendelian inherited pathogenetic variants in nuclear DNA (nDNA) encoded accessory subunits (COX4I1/I2, COX5A, COX5B, COX6A1/A2, COX6B1, COX6C, COX7A1, COX7B, COX7C, COX8A, and NDUFA4/COXFA4,) and assembly factors (COX14, COA3, TACO1, COX10, COX15, COX20, SCO1, SCO2, SURF1, COA5, COA6, COA7, COA8, PET100, PET117, FASTKD2, and LRPPRC) proteins [1]. The list is yet to be completed since an increasing number of proteins have been found to play a role in the assembly mechanism. Clinically, they are extremely variable for age at onset, signs/symptoms, affected organ/tissue (muscle, heart, brain, liver), and severity ranging from neonatal and fatal cardio-myo-encephalopathy to mild myopathy compatible with adult life. Ronchi et al. [2] reported for the first time a homozygous c.667 G > C variant (p. Asp223His) in the COX18 gene in a 19-month-old girl with cardio-myo-encephalopathy whose first sign was hypertrophic cardiomyopathy at 35th week of gestation. After birth, the disease course was characterized by failure to thrive, poor feeding, lactic acidosis, axonal polyneuropathy, psychomotor delay, and a confirmed hypertrophic ventricular cardiomyopathy together with conduction abnormalities (suggestive of Wolff-Parkinson-White syndrome) and aortic arc vascular annulus malformation.

The clinical relevance of the report is indeed in the prenatal onset of cardiac involvement, which has several important implications. Hypertrophic cardiomyopathy can be due to inborn errors of metabolism in 15–20% of cases and represents the main clinical feature in 30–40% of cases with mitochondrial disorders [3]. COX deficiency is one of the most frequent causes of neonatal onset of mitochondrial disorder and hypertrophic cardiomyopathy can be the first sign even at the prenatal gestational stage. An early detection and genetic diagnosis can prompt an appropriate surveillance and management plan at birth to prevent the rapid progression of the disease to a fatal outcome; it is fundamental for defining the natural history of the disease since the pre-symptomatic stage and identifying prognostic factors; it is important for stratifying patients based on the risk of organ failure and, consequently, guide the decision for a heart transplantation. The latter has been always a matter of debate in patients with mitochondrial disorders since they are often multiorgan and patients may develop later in life additional signs and symptoms of other affected organs. However, the heterogeneity of COX deficiency includes a subgroup of patients with tissue-specific and/or not progressive clinical syndrome that could benefit from heart transplants. Therefore, COX deficiency disease-causing genes must be included in targeted gene panels for early-onset hypertrophic cardiomyopathy, genetics testing should be considered at the earliest time point of the diagnostic workup and a knowledgeable clinical utilization and appropriate genetic counseling must be offered.

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References

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Funding

CG was supported by PNRR M4C2-Investimento 1.4 CN00000041 -mRNA National Center for Gene Therapy and Drugs based on RNA Technology - #NEXTGENERATIONEU (NGEU)—financed by European Union.

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  1. Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy

    Caterina Garone

  2. IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Neuropsichiatria dell’età pediatrica, Bologna, Italia

    Caterina Garone

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Correspondence to Caterina Garone.

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Garone, C. Mitochondrial Cytochrome C deficiency can show the first disease signs in the prenatal stage. Eur J Hum Genet 31, 1344–1345 (2023). https://doi.org/10.1038/s41431-023-01466-x

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