Complex IV (cytochrome c oxidase; EC 1.9.3.1) is the terminal enzyme of the respiratory chain and consists of 13 polypeptide subunits, 3 of which are encoded by mitochondrial DNA. The 3 mitochondrially encoded proteins in the cytochrome oxidase ... Complex IV (cytochrome c oxidase; EC 1.9.3.1) is the terminal enzyme of the respiratory chain and consists of 13 polypeptide subunits, 3 of which are encoded by mitochondrial DNA. The 3 mitochondrially encoded proteins in the cytochrome oxidase complex are the actual catalytic subunits that carry out the electron transport function (Saraste, 1983). See 123995 for discussion of some of the nuclear-encoded subunits. Shoubridge (2001) provided a comprehensive review of cytochrome c oxidase deficiency and noted that most isolated COX deficiencies are inherited as autosomal recessive disorders caused by mutations in nuclear-encoded genes; mutations in the mtDNA-encoded COX subunit genes are relatively rare.
Cytochrome c oxidase deficiency is clinically heterogeneous, ranging from isolated myopathy to severe multisystem disease, with onset from infancy to adulthood (Shoubridge, 2001).
Van Biervliet et al. (1977) described a Dutch family in which 3 sibs, ... Cytochrome c oxidase deficiency is clinically heterogeneous, ranging from isolated myopathy to severe multisystem disease, with onset from infancy to adulthood (Shoubridge, 2001). Van Biervliet et al. (1977) described a Dutch family in which 3 sibs, including twin sisters, died of infantile mitochondrial myopathy, lactic acidosis, and de Toni-Fanconi-Debre renal syndrome due to cytochrome c oxidase deficiency. Lipid droplets and focal glycogen accumulation could be attributed to blockage of terminal oxidative metabolism. A similar defect in the renal tubule was presumably responsible for proteinuria, glycosuria, hyperphosphaturia, hypercalciuria, and generalized amino aciduria. Heart, liver, and brain were spared. Willems et al. (1977) reported an association between cytochrome c oxidase deficiency and Leigh encephalomyelopathy in a child who died at age 6 years. See 256000 for a full discussion of COX deficiency associated with Leigh syndrome. DiMauro et al. (1980) reported an infant with hypotonia, ptosis, diminished reflexes, poor suck, lactic acidosis, proteinuria, glucosuria, and amino aciduria who died at age 3.5 months. Muscle biopsy showed increased lipid droplets and abnormal mitochondria. Cytochrome c oxidase was decreased in skeletal muscle and kidney. Muller-Hocker et al. (1983) studied 2 Turkish sisters who developed apathy, failure of suckling, and generalized progressive muscular hypotonia in the newborn period and died at age 7 weeks. Both children had generalized hyperaminoaciduria. Hepatic encephalopathy was absent. Autopsy showed fatty metamorphosis of the liver, bilateral hydroureters, renotubular calcifications, and generalized lipid storage myopathy, mainly in type I fibers. Cytochrome c oxidase activity was absent not only in the myopathic fibers but also in 'most of the morphologically unchanged muscle fibers.' Eshel et al. (1991) described an inbred Bedouin kindred with 6 affected children in 3 sibships related as double first cousins. They had a mitochondrial myopathy presenting with progressive muscular weakness, failure to thrive, proximal renal tubular acidosis, and lactic acidemia leading to death. The affected children were 3 females and 3 males. Of the children studied most extensively, 2 died at age 5 months and 1 at age 16 months. Cytochrome c oxidase was markedly reduced in skeletal muscle extracts of all 3. The findings were those described originally by Van Biervliet et al. (1977). Chabrol et al. (1994) described a 3-year-old girl who, after 3 months of treatment with valproate for myoclonic epilepsy, developed fatal hepatic failure. Deficiency of cytochrome c oxidase found in circulating lymphocytes and in postmortem liver and cultured skin fibroblasts was thought to have rendered the patient susceptible to hepatic failure. A fully functional respiratory chain was found in muscle. Valproate sensitivity has been described in association with ornithine transcarbamylase deficiency (311250), argininemia (207800), and citrullinemia (215700), all causes of hyperammonemia. Bakker et al. (1996) reported the case of a boy, a second child of nonconsanguineous parents, who was born after a term pregnancy and normal delivery. It was the third pregnancy of the mother: the first ended at 19 weeks with death in utero of twins; the second ended at term with the birth of a healthy boy. The patient was admitted to hospital at the age of 1 day for evaluation of feeding difficulties and tachypnea. Laboratory investigations revealed severe metabolic acidosis with elevated lactate and pyruvate levels. In fibroblasts, lymphoblasts, and liver, complex IV showed about a 2-fold reduction in enzymatic activity; in muscle the reduction was more severe. Structural and functional abnormalities of the brain became evident after the initial lactic acidosis had been corrected by treatment. Periventricular leukomalacia was absent, whereas myelination had progressed around the lateral ventricles, the anterior and posterior capsular limbs, and the thalamus. A remarkable subcortical atrophy of the cerebellar hemispheres was present, and the cerebellum was affected by severe atrophy of both the vermis and the cerebellar hemispheres. Bakker et al. (1996) reported that the abnormalities found on neuroimaging reflected a progressive brain disorder rather than sequelae of perinatal injury, but noted that MRI findings typical of Leigh syndrome, another presentation of COX deficiency (DiMauro et al., 1994), were not found in this patient. The authors suggested that this case was a rare type of early-onset progressive encephalopathy associated with COX deficiency. In a study of 157 patients with respiratory chain defects, von Kleist-Retzow et al. (1998) found that the deficiency resided in complex I in 33%, in complex IV in 28%, and in complex I and IV in 28%. Deficiency of complex II and complex III accounted for 4% and 7% of cases, respectively. The main clinical features in this series were truncal hypotonia (36%), antenatal (20%) and postnatal (31%) growth retardation, cardiomyopathy (24%), encephalopathy (20%), and liver failure (20%). No correlation was found between the type of respiratory chain defect and the clinical presentation, but complex I and complex I+IV deficiencies were significantly more frequent in cases of cardiomyopathy (P less than 0.01) and hepatic failure (P less than 0.05), respectively. For the entire series the sex ratio was mostly balanced but was skewed toward males being affected with complex I deficiency. A high rate of parental consanguinity was observed in complex IV (20%) and complex I+IV (28%) deficiencies, and in North African families (76%), suggesting autosomal recessive inheritance. Rubio-Gozalbo et al. (1999) reported a boy with features of spinal muscular atrophy who presented with hypotonia, severe axial and limb weakness with frog posture, but normal bulbar musculature. The boy died at the age of 5 months from progressive respiratory failure. EMG showed a patchy distribution of positive sharp waves and fibrillation potentials, but normal motor nerve conduction velocities. Muscle biopsy showed a preponderance of type I fibers, with atrophy of both fiber types. An asymptomatic hypertrophic cardiomyopathy was present. Cytochrome c oxidase activity was absent from all but intrafusal muscle fibers and the activity was reduced in cultured skin fibroblasts. Western blot analysis demonstrated decreased levels of all COX subunits. Analysis of mitochondrial DNA and the SMN gene were unrevealing. Haller et al. (1989) found COX deficiency in a 27-year-old nurse with lifelong exercise intolerance marked by exertional dyspnea and tachycardia in association with premature fatigue of active muscles with lactic acidosis on exertion. Ghezzi et al. (2008) reported 2 children of a consanguineous Bedouin couple who had a total of 7 children. The first child was a female born at term after an uneventful pregnancy by cesarean section due to nonprogression of labor. She had bilateral congenital hip dislocation present at birth. Social and motor development were reported as normal until 7 months of age. At that time she suffered from febrile illness and developed refractory generalized tonic-clonic convulsions. Brain MRI showed generalized symmetric atrophy, and she subsequently developed psychomotor delay and left-sided hemiplegia with facial nerve involvement. CT scan at 5 years of age showed severe atrophic changes on the right hemisphere. Plasma lactate was mildly increased (2.4-3.2 mM in different samples). At 14 years of age, she was able to obey simple commands in 2 languages, could recognize colors, and had a 20-word vocabulary. She could sit herself up and move herself relatively smoothly along the floor while sitting, but was never able to stand or walk. Her hearing was intact but eyesight was impaired because of bilateral optic atrophy. She had left spastic hemiparesis; on the right side muscle tone was decreased with reduced strength. The EEG revealed bilateral epileptic activity. Biochemical assays on isolated mitochondria showed reduced activity of cytochrome C oxidase, to 21% of the control mean. All other mitochondrial respiratory chain complexes of the pyruvate dehydrogenase complex were within normal limits. The second child, male, was the sixth child of the couple, born at term with uneventful early development. After a febrile gastroenteritis at 1 year of age, the patient experienced subacute neurologic deterioration with muscle hypotonia and extrapyramidal movements, mainly in the left limbs. Brain MRI disclosed increased signal intensities on the left caudate nucleus, globus pallidus, and crus cerebri. Epilepsy, first noted at around 1 year, became refractory to treatment in the third year of life. The patient experienced prolonged episodes of status epilepticus. A brain CT scan at 30 months revealed generalized and white matter atrophy, more pronounced on the left basal ganglia, with bilateral dilatation of the ventricles and basal cysternae. At 4 years he was bedridden with neither communication nor any voluntary activity. He had bilateral optic atrophy and strabismus. Muscle tone was decreased with hyperreflexia and dystonic posturing. Cerebrospinal fluid (CSF) lactate was increased to 3.8 mM (normal less than 1.8 mM), and the activity of COX in his lymphocytes was reported as markedly decreased. Plasma lactate was normal. In both sibs echocardiography, abdominal ultrasound, blood count, and liver and renal function tests were normal.
The nuclear genes COX10, SURF1, and SCO2, all linked to isolated COX deficiency, are involved in the maturation and assembly of COX, emphasizing the major role of such genes in COX pathology. Valnot et al. (2000) noted the ... The nuclear genes COX10, SURF1, and SCO2, all linked to isolated COX deficiency, are involved in the maturation and assembly of COX, emphasizing the major role of such genes in COX pathology. Valnot et al. (2000) noted the difference in clinical phenotype caused by mutations in these 3 genes. SURF1 mutations are associated with subacute necrotizing encephalomyopathy, known as Leigh syndrome. Patients with SCO2 mutations present with encephalocardiomyopathy. Patients with the COX10 mutation present with tubulopathy and leukodystrophy. Bohm et al. (2006) published a retrospective, multicenter study of 180 children with COX deficiency in the Slavonic population, including 101 patients with isolated complex IV deficiency and 79 with combined respiratory chain complex deficiency. Pathogenic mutations were identified in 75 patients. Mutations in the SURF1 gene were found in 47 children from 35 families, with a specific 2-bp deletion (845delCT; 185620.0014) present in 89% of independent alleles. All children with SURF1 mutations had Leigh syndrome. Nine children with encephalomyopathy and/or cardiomyopathy had mutations in the SCO2 gene, all of whom carried the 1541G-A allele (604272.0002). Nine children with combined deficiency had different mitochondrial DNA deletions or depletions, including 6 with a common MTTL1 mutation (3243A-G; 590050.0001). Clinically, patients presented in infancy or early childhood with encephalopathy and nervous system impairment combined with failure to thrive. Blood and CSF lactate were increased in 85% and 81% of examined cases, respectively. Children with earlier disease onset, especially those with mutations in the SURF1 and SCO2 genes, had more severe disease. Sixty-six percent of the patients died in childhood, nearly half of them within the first 18 months of life.
In a 15-year-old girl with COX deficiency manifesting as exercise-induced muscle cramps and myoglobinuria, Keightley et al. (1996) identified a 15-bp deletion in the MTCO3 gene (516050.0003). In a 36-year-old woman ... - Mutations in Mitochondrial-encoded Genes In a 15-year-old girl with COX deficiency manifesting as exercise-induced muscle cramps and myoglobinuria, Keightley et al. (1996) identified a 15-bp deletion in the MTCO3 gene (516050.0003). In a 36-year-old woman with COX deficiency, exercise intolerance, proximal myopathy, and episodes of encephalopathy accompanied by lactic acidemia, Hanna et al. (1998) identified a nonsense mutation in the MTCO3 gene (516050.0004). Tiranti et al. (2000) identified a frameshift mutation in the MTCO3 gene (516050.0005) in a COX-deficient girl with spastic paraparesis, ophthalmoplegia, moderate mental retardation, lactic acidosis, and 'Leigh-like lesions' in the basal ganglia. Jaksch et al. (1998) studied 21 unrelated individuals with mitochondrial disorders and predominant (7 individuals) or isolated (14 individuals) COX deficiency. Twenty-five mitochondrial genes (3 COX subunit genes and 22 tRNA genes) and 10 nuclear COX subunit genes were examined for disease-associated mutations. Two distinct tRNA mutations (590080.0001 and 590080.0003) were found in each of 4 patients in a subgroup with sensorineural hearing loss, ataxia, myoclonic epilepsy, and mental retardation. One of these patients, as well as her mother and sister, also had a mutation (516030.0004) in the mitochondrial encoded COX subunit I gene (MTCO1). Bruno et al. (1999) reported a 21-year-old Italian woman who at the age of 3 years had been found to have bilateral cataracts, which required surgical treatment. At age 7 years, she developed progressive sensorineural hearing loss. During the following years, she developed myoclonic epilepsy with electroencephalographic (EEG) evidence of slow waves and isolated spikes, cerebellar ataxia, mild muscle weakness, and progressive visual loss. At 12 years, she showed hyperlactic acidemia and elevated serum creatine kinase. Clinical examination at age 21 years showed diffuse muscle atrophy, severe generalized muscle weakness, limb ataxia, severe visual defect with optic atrophy, and complete deafness. Brain MRI showed diffuse cerebellar atrophy and bilateral symmetric hyperintensities in the basal ganglia. Mitochondrial DNA analysis revealed a mutation in the COX subunit I gene (516030.0006). In a family with COX deficiency, Clark et al. (1999) identified a mutation in the initiation codon of the MTCO2 gene (516040.0001). The index case was the mother, a 57-year-old woman of normal intellect with a 5- to-10-year history of fatigue and unsteadiness of gait. There was no clinical evidence of retinal disease, deafness, muscle weakness, or cardiac disease. Her 34-year-old son was severely affected. Although normal at birth and in early childhood, at age 5 years he developed progressive gait ataxia, becoming wheelchair-bound by age 25 years. He was severely cognitively impaired. Clinical examination demonstrated bilateral optic atrophy, pigmentary retinopathy, a marked decrease in color vision, and mild distal muscle wasting. The mutation load was present at 67% in muscle from the index case and at 91% in muscle from the clinically affected son. Muscle biopsy samples revealed isolated COX deficiency and mitochondrial proliferation. Sacconi et al. (2003) performed a broad search for mutations using 25 mitochondrial genes (3 COX subunit genes and 22 tRNA genes) and 7 nuclear COX subunit genes in 30 patients with known cytochrome C deficiency and varying clinical phenotypes. Only 3 mutations were found, all in nuclear genes. The authors suggested that mtDNA COX mutations are rare. Meulemans et al. (2006) reported a 13-year-old boy with combined deficiency of mitochondrial complex I (252010) and IV associated with a mutation in the MTTN gene (590010.0003). He had a complex phenotype involving multiple organ systems. As a young child, he had failure to thrive, renal failure, and mental retardation. He later developed progressive ataxia, muscle weakness, seizures, and increased serum and CSF lactate. Brain CT scan showed basal ganglia calcifications. Mitochondrial mutation load in the patient's skeletal muscle and fibroblasts was 97% and 50%, respectively. - Mutations in Nuclear-encoded Genes In a series of 18 patients with isolated COX deficiency, Parfait et al. (1997) failed to detect mutations in the 3 mitochondrially encoded COX subunits of complex IV (MTCO1, MTCO2, and MTCO3). The authors concluded that disease-causing mutations may lie in nuclear genes encoding COX subunits or proteins involved in assembly of the complex. Zhu et al. (1998) and Tiranti et al. (1998) identified mutations in the SURF1 gene (see, e.g., 185620.0001) in patients with Leigh syndrome due to cytochrome c oxidase deficiency. Papadopoulou et al. (1999) identified mutations in the SCO2 gene (see, e.g., 604272.0001) in 3 unrelated infants COX deficiency associated with fatal infantile cardioencephalomyopathy (604377). Immunohistochemical studies implied that the enzymatic deficiency, which was most severe in cardiac and skeletal muscle, was due to the loss of mitochondrial DNA-encoded COX subunits. Valnot et al. (2000) performed a genetic linkage study of a consanguineous family with an isolated cytochrome c oxidase defect and mapped the disease gene to chromosome 17p13.1-q11.1, near COX10, a gene that encodes a complex IV assembly protein. A homozygous missense mutation in the COX10 gene (602125.0001) was identified. Western blot analysis of patient fibroblasts revealed almost undetectable levels of COX subunit II. Furthermore, the mutant allele failed to correct a yeast cox10 mutant strain, thus confirming the biochemical effects of the mutation. Valnot et al. (2000) described COX deficiency caused by mutation in the SCO1 gene (603644.0001-603644.0002). Patients presented with hepatic failure and neurologic disturbance. In 21 of 22 patients with the French-Canadian type of Leigh syndrome associated with COX deficiency, Mootha et al. (2003) identified a homozygous mutation in the LRPPRC gene (607544.0001). The remaining patient was a compound heterozygote for 607544.0001 and 607544.0002. Sacconi et al. (2003) performed a broad search for mutations using 25 mitochondrial genes and 7 nuclear COX subunit genes in 30 patients with known cytochrome C deficiency and varying clinical phenotypes. Only 3 mutations were found; a novel SURF1 mutation in a Leigh syndrome patient and 1 novel and 1 known SCO2 mutation in a patient with hypertrophic cardiomyopathy. In a patient with Leigh syndrome due cytochrome c oxidase deficiency, Oquendo et al. (2004) identified homozygosity for a mutation in the COX15 gene (603646.0001). Antonicka et al. (2003) reported 2 unrelated patients with COX deficiency caused by mutations in the COX10 gene (602125.0002-602125.0005). One of the patients had sensorineural hearing loss, anemia, and hypertrophic cardiomyopathy, whereas the other patient had features consistent with Leigh syndrome. The authors emphasized the different phenotypic characteristics. Massa et al. (2008) identified a homozygous mutation in the COX6B1 gene (124089.0001) in 2 sibs with COX deficiency. After a normal development, the boys had onset of muscle weakness and pain or unsteady gait and visual disturbances at ages 8 and 6, respectively. The older boy had rapidly progressive neurologic deterioration with leukodystrophic brain changes and seizures and died at age 10 years. The younger boy had ataxia, muscle weakness, cognitive decline, decreased visual acuity, and leukodystrophic changes in the brain. Both had increased serum and CSF lactate and decreased COX activity (20% of normal) in muscle biopsy. In 2 children with COX deficiency born of first-cousin Bedouin parents, Ghezzi et al. (2008) identified homozygosity for a nonsense mutation in the FASTKD2 gene (612322.0001). Both patients had normal early development, with development of neurologic deterioration, including hemiplegia and epilepsy, after a febrile illness. In affected members of a family with childhood-onset and slowly progressive Leigh syndrome due to mitochondrial complex IV deficiency, Weraarpachai et al. (2009) identified a homozygous 1-bp insertion (472insC; 612958.0001) in the TACO1 gene. Synthesis of the MTCO1 subunit was decreased by approximately 65%, and there was a greatly reduced steady-state level of fully assembled complex IV. Expression of wildtype TACO1 rescued the MTCO1 assembly defect and complex IV activity. In 2 Turkish sibs, born of consanguineous Turkish parents, with cytochrome c oxidase deficiency manifest as lethal neonatal hypertrophic cardiomyopathy, Huigsloot et al. (2011) identified a homozygous mutation in the C2ORF64 gene (A53P; 613920.0001). The patients died at ages 8 and 10 days of life, respectively. Postmortem examination showed accumulation of lipid droplets in cardiomyocytes and mitochondrial proliferation; however, neither patient had documented functional impairment of brain or skeletal muscle. The activity and amount of complex IV was severely reduced in patient fibroblasts and heart muscle, In 3 sibs, born of consanguineous Portuguese parents, with COX deficiency, Weraarpachai et al. (2012) identified a homozygous mutation in the C12ORF62 gene (M19I; 614478.0001). The proband presented with neurologic and respiratory distress immediately after birth. She was dysmorphic with hypotelorism, microphthalmia, an ogival palate, and a single unilateral palmar crease. She developed severe metabolic lactic acidosis and ketonuria, and died 24 hours after birth. Postmortem examination showed brain hypertrophy, altered myelination, numerous cavities throughout the brain, hepatomegaly, hypertrophic cardiomyopathy, renal hypoplasia, and adrenal hyperplasia. Her sibs had a similar disease course. Biochemical analysis of patient fibroblasts showed reduced COX activity at 30 to 40% of controls, which was associated with a specific reduction in the amount of fully assembled COX. The mutation was found using a combination of microcell-mediated chromosome transfer, homozygosity mapping, and transcript profiling. In a boy, born of consanguineous Turkish parents, with complex IV deficiency, Szklarczyk et al. (2013) identified a homozygous mutation in the COX20 gene (T52P; 614698.0001). The boy was born at term with low birth weight and length and decreased head circumference. He showed muscular hypotonia and delayed walking with unsteady gait that developed into cerebellar ataxia with intention tremor and pyramidal signs. Speech was delayed. Laboratory studies showed increased serum and CSF lactate suggestive of a mitochondrial disorder. Respiratory chain complex studies showed reduced activity of mitochondrial complex IV. Brain MRI, echocardiography, and hearing and vision tests were all normal. At age 10 years, he had short stature and low weight with a normal head circumference. The mutation was found by analyzing candidate genes. No mutation in the COX20 gene was found in 39 additional patients with COX deficiency.
In the French Canadian population of the Saguenay-Lac-Saint-Jean region of Quebec Province, De Braekeleer (1991) estimated the prevalence at birth of cytochrome c oxidase deficiency to be 1 in 2,473, giving a carrier frequency of 1 in 28. ... In the French Canadian population of the Saguenay-Lac-Saint-Jean region of Quebec Province, De Braekeleer (1991) estimated the prevalence at birth of cytochrome c oxidase deficiency to be 1 in 2,473, giving a carrier frequency of 1 in 28.