Clinical Phenotype and Neuroimaging Findings in Siblings with <scp> <i>COX15</i> </scp> Deficiency: Case Report and Review of Previously Reported Cases

Cytochrome C oxidase assembly protein (COX15) is the terminal complex of the electron transport chain (ETC), comprises of 13 subunits, three catalytic and 10 accessory units encoded by mitochondrial and nuclear genes respectively.1, 2 A homozygous or compound heterozygous variant in COX15 gene results in mitochondrial complex IV deficiency nuclear type 6 (OMIM 615119). Fewer than 10 cases have been documented, with limited details on associated dysmorphic features and distinctive movement disorders. We present two siblings with a COX15 gene variant, highlighting their prominent coarse facial features, progressive dystonia, and MRI findings consistent with Leigh syndrome along with providing a comprehensive review of COX15. A 12-month-old girl of Iranian origin, born to third degree consanguineous parents, was evaluated for global developmental delay (GDD) and failure to thrive (FTT). Early development was normal, including independent ambulation, self-feeding, and gestural communication. No history of acute decompensations with intercurrent illness. She attended a special educational program due to learning difficulties. At 12 years of age, she developed progressive dystonia. General examination revealed weight and height less than the third centile, coarse facies, hirsutism, short and stubby fingers, and thoracic kyphosis. Neurological assessment showed dysarthria, esotropia, spasticity of lower limbs, brisk deep tendon reflexes (DTR), and generalized dystonia involving the oromandibular, cervical, and upper and lower extremities (Video 1). Her younger sibling had normal development until 12 months of age followed by regression of milestones and subsequently had GDD. She had bulbar dysfunction and FTT requiring gastrostomy tube insertion at 2 years of age. She developed progressive generalized dystonia at 14 years of age. She was non-verbal, communicated using augmentative communication devices and had no purposeful hand movements because of dystonia. Her general and neurological examination was similar to the older sister (Video 2). The brain magnetic resonance imaging (MRI) (Fig. 1) of both probands showed symmetrical hyperintensity in the bilateral cerebellar white matter, middle cerebellar peduncles, and putamen, along with volume loss and globus pallidi blooming. Magnetic resonance spectroscopy was performed on the older sibling and revealed normal results. Hand X-ray demonstrated diffuse osteopenia with broadening of the metacarpals and phalanges, whereas spinal X-ray appeared normal. Both siblings had elevated blood lactate (6.0 mmol/L in patient 1 and 4.5 mmol/L in patient 2; range, 0.6–2.1 mmol/L), liver enzymes, and triglycerides, with normal creatine kinase and carnitine levels. A homozygous likely pathogenic variant in c.T1019C (p.L340P) in the exon 8 of COX15 gene was identified. The sibling had similar MRI findings and the same genetic variant. Electrocardiogram and echocardiogram were normal in both. Muscle biopsy showed COX-negative fibers and pleomorphic mitochondria. Parental testing confirmed a heterozygous COX15 carrier. Given the clinical presentation, MRI findings, muscle biopsy results, genetic variant, and family history this provides a strong confirmation of a COX15-related mitochondrial disease. In this report, we describe two siblings with unique dysmorphic features, generalized dystonia, and MRI findings because of homozygous variants in COX15. COX15 variants were initially described in a neonate with microcephaly, dysmorphic features, seizures, hypotonia, and massive hypertrophic cardiomyopathy who succumbed at 24 days of age.3 Laboratory work revealed lactic acidosis, and autopsy results showed a significant reduction in cardiac tissue cytochrome c oxidase subunit. Subsequent studies revealed pathogenic compound heterozygous variants in the COX15 gene.3, 4 Since the initial report, only eight cases have been documented.1-8 COX15 plays a crucial role in the biosynthesis of heme A. Heme A deficiency disrupts COX1 subunit assembly, leading to impairment of the ETC and oxidative phosphorylation.1, 5, 8 As a result, high energy demand organs and tissues such as brain, heart and retina are affected explaining the phenotypic expression.1, 8 The clinical spectrum of COX15 variants is heterogeneous (Table 1). Reported neurological features include GDD, encephalopathy, seizures, dystonia, and tremor.1, 2, 4-8 The distribution and progression of dystonia has not been well documented. Both patients developed progressive generalized dystonia at ages 12 and 14, leading to wheelchair dependence in the younger sister and limited fine motor skills in the older sibling. Interestingly, despite the similar genetic variant in the siblings, the severity of their neurological manifestations varied significantly. Dysmorphic features previously reported in COX15 deficiency include midfacial hypoplasia in one case and microcephaly in five cases. In contrast, our patients exhibited distinct features, including coarse facial features and brachydactyly.1, 4 Additional features include hypertrophic cardiomyopathy, optic atrophy, hearing impairment, and FTT (File S1).1, 2, 5, 7, 8 Laboratory findings typically include lactic acidosis in blood and cerebrospinal fluid, elevated triglycerides, and liver enzymes.1, 4, 6-8 Brain MRI findings of COX15 cases were consistent with Leigh syndrome, a severe neurodegenerative mitochondrial disorder characterized by hyperintense signal abnormalities of the basal ganglia and brainstem.2, 6-8 COX15 variants are associated with high mortality, and surviving patients often experience severe neurological morbidity.1-9 The milder phenotype in our siblings may be because of residual COX activity on muscle biopsy and the missense variant. However, additional cases are needed to confirm a genotype–phenotype correlation.7 To conclude, patients with complex IV deficiency because of COX15 variants have diverse clinical phenotypes. Our patients with distinctive facies, progressive dystonia without cardiomyopathy add to the clinical phenotypes described in the literature. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. H.S.A.: 1A, 1B, 1C, 3A, 3B S.Y.: 3A, 3BB M.N.C.: 3B L.A.: 3B V.P.: 3B P.K.: 3B A.L.M.: 3B C.G.: 1A, 1B, 1C, 3B Ca.G.: 1A, 1B, 1C, 3B We thank the patients and their families for providing consent to publish the videos and images for educational purposes. Ethical Compliance Statement: The authors confirm that approval of institutional review board is not required for this work as it is a case report. We have taken the patient's informed consent for publication of this case and images. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interest: The authors declare that there are no funding sources or conflict of interest relevant to this work. Financial Disclosures for Previous 12 Months: C.G. received an honorarium and advisory board fees from Medtronic, received honorarium from Ipsen. Christos Ganos holds the Wolf Chair for Neurodevelopmental Psychiatry, a joint Hospital-University Named Chair between the University of Toronto, University Health Network and the University Health Network Foundation. The rest of the authors have no financial disclosures. The data that support the findings of this study are available from the corresponding author upon reasonable request. File S1. Summary of the phenotypical and genotypical features of patients with variants in COX15 gene. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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