Cytochrome C Oxidase (COX) deficiency is a very rare inherited metabolic disorder characterized by a deficiency of the enzyme cytochrome C oxidase or Complex IV. Cytochrome C oxidase is an essential enzyme that is active in subcellular structures that help to regulate energy production (mitochondria). Four distinct forms of Cytochrome C Oxidase deficiency have been identified. The range and severity of symptoms varies greatly from case to case.
In the first form of this disorder, known as COX deficiency type benign infantile mitochondrial myopathy, deficiency of cytochrome C oxidase may be limited (localized) to the tissues of the skeletal muscles. Therefore, although affected infants may exhibit many of the same symptoms as those associated with the severe infantile form of the disease, the heart and kidneys are not affected. Affected infants with this form of the disorder may experience episodes characterized by the presence of abnormally high levels of lactic acid in the blood (lactic acidosis). If untreated, life-threatening complications (e.g., respiratory failure) may occur. With appropriate, intensive treatment, recovery from this form of COX deficiency may occur spontaneously within the first few years of life.
In the second form of the disorder, COX deficiency type infantile mitochondrial myopathy, deficiency of cytochrome C oxidase affects tissues of the skeletal muscles as well as several other tissues, such as the heart, kidney, liver, brain, and/or connective tissue (fibroblasts). Symptoms associated with this form of the disease typically begin within the first three to four weeks of life. Such symptoms may include generalized muscle weakness as well as heart problems (cardiomyopathy) and kidney dysfunction. Affected infants may also fail to gain weight at the expected rate (failure to thrive) and/or exhibit a weak cry; difficulties sucking, swallowing, and/or breathing; and/or “floppiness” or poor muscle tone (hypotonia). In addition, infants with COX deficiency may experience episodes of lactic acidosis, possibly leading to impairment of respiratory and kidney function. Other symptoms may result from a specific defect in the kidneys that leads to de Toni-Fanconi-Debre syndrome, a condition that causes kidney dysfunction and involves excessive urinary excretion of glucose, phosphates, amino acids, bicarbonate, calcium, and water. Symptoms due to de Toni-Fanconi-Debre syndrome may include excessive thirst (polydipsia) and excessive urination (polyuria).
Leigh’s disease, also known as subacute necrotizing encephalomyelopathy, is thought to be a generalized (systemic) form of COX deficiency. This form of the disorder is characterized by progressive degeneration of the brain and dysfunction of other organs of the body including the heart, kidneys, muscles, and/or liver. Symptoms generally begin between three months and two years of age. The most predominant symptoms of Leigh’s disease involve the brain and spinal cord (central nervous system). In most affected infants, the first noticeable signs may include loss of previously acquired motor skills or loss of head control and poor sucking ability. These symptoms may be accompanied by a profound loss of appetite, vomiting, irritability, continuous crying, and/or possible seizure activity. If the onset is later in childhood (i.e., 2 years), affected children may experience difficulty articulating words (dysarthria) and coordinating voluntary movements such as walking or running (ataxia). Previously acquired intellectual skills may diminish and mental retardation may also occur. (For more complete details on this disorder, please see NORD’s disease report on Leigh’s disease. To obtain this information, choose “Leigh” as your search term in the Rare Disease Database.)
In the fourth form of COX deficiency, known as COX deficiency French-Canadian type, deficiency of cytochrome C oxidase affects tissues of the skeletal muscles, connective tissue (fibroblasts), and, in particular, tissues of the brain (Leigh’s disease) and liver. However, tissues of the kidney and heart demonstrate near normal cytochrome C oxidase activity. Affected infants and children may demonstrate developmental delays, diminished muscle tone (hypotonia), slight facial abnormalities (mild facial dysmorphism), Leigh’s disease, crossing of the eyes (strabismus), impaired ability to control voluntary movements (ataxia), fatty accumulation within and degeneration of the liver (microvesicular steatosis), and/or episodes of lactic acidosis, which may lead to life-threatening complications such as respiratory and kidney failure.
Researchers believe that most cases of Cytochrome C Oxidase deficiency are inherited as an autosomal recessive genetic diseases. (For example, research seems to indicate that COX deficiency French-Canadian type has a recessive mode of inheritance.) Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Rarely, COX deficiency occurs as the result of a new or inherited mutation in a mitochondrial gene. Mitochondria, found by the hundreds within most cells of the body, regulate the production of cellular energy and carry the genetic blueprints for this process within their own unique DNA. The enzyme cytochrome C oxidase is comprised of 13 subunits, three of which are thought to be encoded by the mitochondrial DNA (mtDNA), while the remaining subunits are encoded by the DNA of the nucleus.
Mutations affecting the genes for mitochondria (mtDNA) are inherited from the mother. MtDNA that is found in sperm cells is typically lost during fertilization. As a result, all human mtDNA comes from the mother. An affected mother will pass on the mutation to all her children, but only her daughters will pass on the mutation to their children. Some affected individuals have a new mtDNA mutation that was not inherited.
As cells divide, the number of normal mtDNA and mutated mtDNA are distributed in an unpredictable fashion among different tissues. Consequently, mutated mtDNA accumulates at different rates among different tissues in the same individual. Thus, family members who have the identical mutation in mtDNA may exhibit a variety of different symptoms and signs at different times and to varying degrees of severity.
Cytochrome C Oxidase (COX) Deficiency is a very rare metabolic disorder that appears to affect males and females in equal numbers. The overall incidence rates of various forms of the disorder (i.e., infantile mitochondrial myopathic forms and Leigh’s disease) are unclear. However, COX deficiency French-Canadian type has been reported in the French-Canadian population of the Saguenay-Lac-Saint-Jean region of northeastern Quebec with an estimated incidence of 1 in 2,473 births.
In most cases of the infantile mitochondrial myopathic forms of this disorder, onset occurs within the first month of life. Leigh’s disease usually becomes apparent between three months and two years of age. COX deficiency French-Canadian type also tends to become apparent during infancy or childhood. However, in some rare cases, symptoms of COX deficiency may not develop until adolescence or adulthood.
Cytochrome C Oxidase (COX) deficiency may be diagnosed after birth (postnatally) based upon a thorough clinical evaluation, characteristic findings, a detailed patient history, and a variety of specialized tests. According to the medical literature, a diagnosis of COX deficiency should be considered in infants or children who exhibit episodes of lactic acidosis.
Specialized laboratory studies may be performed to help confirm such a diagnosis including enzyme tests (assays) of connective tissue cells (fibroblasts) that may reveal reduced activity of the cytochrome C oxidase enzyme. In addition, muscle biopsy studies may reveal “ragged-red fibers” (a striking, unique abnormality of muscle tissue that is apparent when viewed under a microscope) that demonstrate markedly reduced levels of COX activity as well as alterations or abnormalities of the mitochondrial structure. Other laboratory tests may include specialized staining techniques that reveal which subunits of the COX enzyme are affected.
In infants with COX deficiency type infantile mitochondrial myopathy who also exhibit de Toni-Fanconi-Debre syndrome, laboratory studies may reveal signs of kidney dysfunction including abnormally high levels of glucose, phosphates, amino acids, bicarbonate, calcium, and water in the blood.
The diagnosis of the Leigh’s disease form of COX deficiency may be aided by advanced imaging techniques. Computerized tomography (CT) scanning or magnetic resonance imaging (MRI) of the brain may reveal abnormalities of certain areas of the brain (e.g., the brain stem, cerebellum, basal ganglia). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of the brain’s tissue structure. During MRI, a magnetic field and radio waves are used to create cross-sectional images of the brain. In addition, laboratory studies may reveal a generalized reduction of cytochrome C oxidase enzyme activity within tissues cells of the brain, skeletal muscle, connective tissue (fibroblasts), heart, liver, and kidneys. Laboratory tests may also demonstrate high levels of acidic waste products in the blood (lactic acidosis).
In individuals with COX deficiency French-Canadian type, laboratory studies and advanced imaging tests may reveal findings characteristic of the Leigh’s disease form of COX deficiency. In addition, enzyme assays may demonstrate that the severity of reduced cytochrome C oxidase enzyme activity varies greatly in various tissue cells. For example, whereas assays may reveal almost normal levels of COX activity in the heart and kidneys, COX enzyme activity may be approximately 50 percent of normal within skeletal muscle and connective tissue cells (fibroblasts) and severely reduced in brain and liver tissue cells. In addition, imaging studies or other tests may reveal abnormal fatty accumulation within and degeneration of the liver (microvesicular steatosis).
Molecular genetic testing is available to identify some of the nuclear and mitochondrial gene mutations associated with COX deficiency.
Treatment of all forms of COX deficiency is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists who may need to systematically and comprehensively plan an affected child’s treatments. Such specialists may include pediatricians; physicians who diagnose and treat abnormalities of the kidneys (nephrologists), musculoskeletal system (orthopedists), heart (cardiologists), lungs (pulmonologists), nervous system (neurologists), and/or liver (hepatologists); and/or other health care professionals. In the case of benign infantile mitochondrial myopathy, it is important that early diagnosis and intensive treatment be pursued until spontaneous recovery is realized.
Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Bennett JC, Plum F, eds. Cecil Textbook of Medicine, 20th ed. W.B. Saunders Co.;1996:2167.
Behrman RE, ed.; Nelson Textbook of Pediatrics, 15th Ed. W.B. Saunders Company;1996:1754.
Lyon G, et al., eds. Neurology of Hereditary Metabolic Diseases in Childhood, 2nd Ed. McGraw-Hill;1996:27.
Scriver CR, et al., eds. The Metabolic and Molecular Bases of Inherited Disease, 7th Ed. McGraw-Hill, Inc.;1995:1537-38,1615-16.
Buyse ML, editor-in-chief. Birth Defects Encyclopedia. Blackwell Scientific Publications;1990:1202-03.
Vogt, Sebastian, Volker Ruppert, Sabine Pankuweit, JÃžrgen pj Paletta, and Petra Weber. Reduced Cytochrome C Oxidase Subunit Iv in Patients with Dilated Cardiomyopathy. Exp Clin Card 2014;20: 1009-1028.
Hüttemann M, Klewer S, Lee I, Pecinova A, Pecina P, Liu J, Lee M, Doan JW, Larson D, Slack E, Maghsoodi B, Erickson RP, Grossman LI, Mice deleted for heart-type cytochrome c oxidase subunit 7a1 develop dilated cardiomyopathy. Mitochondrion 2012;12:294-304.
Huigsloot M, Nijtmans LG, Szklarczyk R, Baars MJ, van den Brand MA, Hendriksfranssen MG, van den Heuvel LP, Smeitink JA, Huynen MA, Rodenburg RJ, A mutation in C2orf64 causes impaired cytochrome c oxidase assembly and mitochondrial cardiomyopathy. Am J Hum Genet. 2011;88:488-9.
Vogt S, Portig I, Irqsusi M, Ruppert V, Weber P, Ramzan R, Heat shock protein expression and change of cytochrome c oxidase activity: presence of two phylogenic old systems to protect tissues in ischemia and reperfusion. J Bioenerg Biomembr 2011;43:425-35.
Arbustini E, Diegoli M, Fasani R, et al.. Mitochondrial DNA mutations and mitochondrial abnormalities in dilated cardiomyopathy. Am J Pathol 1998;153:1501-1510.
DiMauro S, et al. Cytochrome C oxidase deficiency. Pediatr Res. 1990;28(5):536-41.
Von Kleist-Retzow JC, et al. A high rate (20% – 30%) of parental consanguinity in cytochrome-oxidase deficiency. Am J Hum Genet. 1998;63(2):428-35.
Isobe K, et al. Nuclear-recessive mutations of factors involved in mitochondrial translation are responsible for age-related respiration deficiency of human skin fibroblasts. J Biol Chem. 1998;273(8):4601-06.
Possekel S, et al. Immunohistochemical analysis of muscle cytochrome C oxidase deficiency in children. Histochem Cell Biol. 1995;103(1):59-68.
Tiranti V, et al. Nuclear DNA origin of cytochrome C oxidase deficiency in Leigh’s syndrome: genetic evidence based on patient’s-derived RHO degrees transformants. Hum Mol Genet. 1995;4(11):2017-23.
Saunier P, et al. Cytochrome C oxidase deficiency presenting as recurrent neonatal myoglobinuria. Neuromuscul Disord. 1995;5(4):285-89.
Morin C, et al. Clinical, metabolic, and genetic aspects of cytochrome C oxidase deficiency in Saguenay-Lac-Saint-Jean. Am J Hum Genet. 1993;53(2):488-96.
Merante F, et al. A biochemically distinct form of cytochrome oxidase (COX) deficiency in the Saguenay-Lac-Saint-Jean region of Quebec. Am J Hum Genet. 1993;53(2):481-87.
DiMauro S, et al. Mitochondrial encephalomyopathies. Arch Neurol.1993;50(11):1197-208.
Salo MK, et al. Reversible mitochondrial myopathy with cytochrome C oxidase deficiency. Arch Dis Child. 1992;67(8):1033-35.
Keppler K, et al. Variable presentation of cytochrome C oxidase deficiency. Am J Dis Child. 1992;146(11):1349-52.
Eshel G, et al. Autosomal recessive lethal infantile cytochrome C deficiency. Am J Dis Child. 1991;145(6):661-64.
Lutz R et al.An atypical case of cytochrome C oxidase deficiency with biochemical heterogeneity in fibroblasts. Neurology. 1991;41(12):1957-60.
Lombes A, et al. Biochemical and molecular analysis of cytochrome C oxidase deficiency in Leigh’s syndrome. Neurology. 1991;41(4):491-98.
Tritschler HJ, et al. Differential diagnosis of fatal and benign cytochrome C oxidase-deficient myopathies of infancy: an immunohistochemical approach. Neurology. 1991;41(2 Pt 1):300-05.
Adamovich K, et al. Cytochrome C oxidase deficiency. Orv Hetil. 1990;131(32):1761-63.
Buchwald A, Till H, Unterberg C, Oberschmidt R, et al. Alterations of the mitochondrial respiratory chain in human dilated cardiomyopathy. Eur Heart J 1990; 11:509- 516.
Nozaki H, et al. Cytochrome C oxidase deficiency with acute onset and rapid recovery. Pediatr Neurol. 1990;6(5):330-32.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Entry Number: 220110 http://omim.org/entry/220110 ; Last Update: 10/07/2014 and Entry Number: 220111 http://omim.org/entry/220111; Last Edit Date: 12/05/2011. Accessed March 12, 2015.