Combined oxidative phosphorylation deficiency is an autosomal recessive multisystem disorder with variable manifestations resulting from a defect in the mitochondrial oxidative phosphorylation (OXPHOS) system. Onset occurs at or soon after birth, and features can include growth retardation, microcephaly, hypertonicity, axial hypotonia, encephalopathy, cardiomyopathy, and liver dysfunction. Death usually occurs in the first weeks or years of life (summary by Smits et al., 2011). Genetic Heterogeneity of Combined Oxidative Phosphorylation Deficiency See also COXPD2 (610498), caused by mutation in the MRPS16 gene (609204) on 10q22; COXPD3 (610505), caused by mutation in the TSFM gene (604723) on 12q14; COXPD4 (610678), caused by mutation in the TUFM gene (602389) on 16p11; COXPD5 (611719), caused by mutation in the MRPS22 gene (605810) on 3q23; COXPD6 (300816), caused by mutation in the AIFM1 gene (300169) on Xq26; COXPD7 (613559), caused by mutation in the MTRFR gene (613541) on 12q24; COXPD8 (614096), caused by mutation in the AARS2 gene (612035) on 6p21; COXPD9 (614582), caused by mutation in the MRPL3 gene (607118) on 3q22; COXPD10 (614702), caused by mutation in the MTO1 gene (614667) on 6q13; COXPD11 (614922), caused by mutation in the RMND1 gene (614917) on 6q25; COXPD12 (614924), caused by mutation in the EARS2 gene (612799) on 16p13; COXPD13 (614932), caused by mutation in the PNPT1 gene (610316) on 2p16; COXPD14 (614946), caused by mutation in the FARS2 gene (611592) on 6p25; COXPD15 (614947), caused by mutation in the MTFMT gene (611766) on 15q; COXPD16 (615395), caused by mutation in the MRPL44 gene (611849) on 2q36; COXPD17 (615440), caused by mutation in the ELAC2 gene (605367) on 17p11; COXPD18 (615578), caused by mutation in the SFXN4 gene (615564) on 10q26; COXPD19 (615595), caused by mutation in the LYRM4 gene (613311) on 6p25; COXPD20 (615917), caused by mutation in the VARS2 gene (612802) on 6p21; COXPD21 (615918), caused by mutation in the TARS2 gene (612805) on 1q21; COXPD22 (616045), caused by mutation in the ATP5A1 gene (164360) on 18q12; COXPD23 (616198), caused by mutation in the GTPBP3 (608536) gene on 19p13; COXPD24 (616239), caused by mutation in the NARS2 gene (612803) on 11q14; COXPD25 (616430), caused by mutation in the MARS2 gene (609728) on 2q33; COXPD26 (616539), caused by mutation in the TRMT5 gene (611023) on 14q23; COXPD27 (616672), caused by mutation in the CARS2 gene (612800) on 13q34; COXPD28 (616794), caused by mutation in the SLC25A26 gene (611037) on 3p14; COXPD29 (616811), caused by mutation in the TXN2 gene (609063) on 22q12; COXPD30 (616974), caused by mutation in the TRMT10C gene (615423) on 3q12; and COXPD31 (617228), caused by mutation in the MIPEP gene (602241) on 13q12; COXPD32 (617664), caused by mutation in the MRPS34 gene (611994) on 16q13; COXPD33 (617713), caused by mutation in the C1QBP gene (601269) on 17p13; and COXPD34 (617872), caused by mutation in the MRPS7 gene (611974) on 17q25; COXPD35 (617873), caused by mutation in the TRIT1 gene (617840) on 1p34; COXPD36 (617950), caused by mutation in the MRPS2 gene (611971) on 9q34; COXPD37 (618329), caused by mutation in the MICOS13 gene (616658) on 19p13; COXPD38 (618378), caused by mutation in the MRPS14 gene (611978) on 1q23; COXPD39 (618397), caused by mutation in the GFM2 gene (606544) on 5q13; COXPD40 (618835), caused by mutation in the QRSL1 gene (617209) on 6q21; COXPD41 (618838), caused by mutation in the GATB gene (603645) on 4q31; COXPD42 (618839), caused by mutation in the GATC gene (617210) on 12q24; COXPD43 (618851), caused by mutation in the TIMM22 gene (607251) on 17p13; COXPD44 (618855), caused by mutation in the FASTKD2 gene (612322) on 2q33; COXPD45 (618951), caused by mutation in the MRPL12 gene (602375) on 17q25; COXPD46 (618952), caused by mutation in the MRPS23 gene (611985) on 17q22; COXPD47 (618958), caused by mutation in the MRPS28 gene (611990) on 8q21; COXPD48 (619012), caused by mutation in the NSUN3 gene (617491) on 3q11; COXPD49 (619024), caused by mutation in the MIEF2 gene (615498) on 17p11; COXPD50 (619025), caused by mutation in the MRPS25 gene (611987) on 3p25; COXPD51 (619057), caused by mutation in the PTCD3 gene (614918) on 2p11; COXPD52 (619386), caused by mutation in the NFS1 gene (603485) on 20q11; COXPD53 (619423), caused by mutation in the C2ORF69 gene (619219) on 2q33; and COXPD54 (619737), caused by mutation in the PRORP gene (609947) on 14q13.; COXPD55 (619743), caused by mutation in the POLRMT gene (601778) on 19p13; COXPD56 (620139), caused by mutation in the TAMM41 gene (614948) on 3p25; COXPD57 (620167), caused by mutation in the CRLS1 gene (608188) on 20p12; COXPD58 (620451), caused by mutation in the TEFM gene (616422) on 17q11; and COXPD59 (620646), caused by mutation in the MRPL39 gene (611845) on 21q21.

Isolated complex I deficiency is a rare inborn error of metabolism due to mutations in nuclear or mitochondrial genes encoding subunits or assembly factors of the human mitochondrial complex I (NADH: ubiquinone oxidoreductase) and is characterized by a wide range of manifestations including marked and often fatal lactic acidosis, cardiomyopathy, leukoencephalopathy, pure myopathy and hepatopathy with tubulopathy. Among the numerous clinical phenotypes observed are Leigh syndrome, Leber hereditary optic neuropathy and MELAS syndrome (see these terms).

MPV17-related mitochondrial DNA (mtDNA) maintenance defect presents in the vast majority of affected individuals as an early-onset encephalohepatopathic (hepatocerebral) disease that is typically associated with mtDNA depletion, particularly in the liver. A later-onset neuromyopathic disease characterized by myopathy and neuropathy, and associated with multiple mtDNA deletions in muscle, has also rarely been described. MPV17-related mtDNA maintenance defect, encephalohepatopathic form is characterized by: Hepatic manifestations (liver dysfunction that typically progresses to liver failure, cholestasis, hepatomegaly, and steatosis); Neurologic involvement (developmental delay, hypotonia, microcephaly, and motor and sensory peripheral neuropathy); Gastrointestinal manifestations (gastrointestinal dysmotility, feeding difficulties, and failure to thrive); and Metabolic derangements (lactic acidosis and hypoglycemia). Less frequent manifestations include renal tubulopathy, nephrocalcinosis, and hypoparathyroidism. Progressive liver disease often leads to death in infancy or early childhood. Hepatocellular carcinoma has been reported.

Hereditary myopathy with lactic acidosis (HML) is an autosomal recessive muscular disorder characterized by childhood onset of exercise intolerance with muscle tenderness, cramping, dyspnea, and palpitations. Biochemical features include lactic acidosis and, rarely, rhabdomyolysis. It is a chronic disorder with remission and exacerbation of the muscle phenotype (summary by Sanaker et al., 2010).

Sengers syndrome is an autosomal recessive mitochondrial disorder characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis. Mental development is normal, but affected individuals may die early from cardiomyopathy (summary by Mayr et al., 2012). Skeletal muscle biopsies of 2 affected individuals showed severe mtDNA depletion (Calvo et al., 2012).

Combined oxidative phosphorylation deficiency type 3 is an extremely rare clinically heterogenous disorder described in about 5 patients to date. Clinical signs included hypotonia, lactic acidosis, and hepatic insufficiency, with progressive encephalomyopathy or hypertrophic cardiomyopathy.

A rare mitochondrial disorder due to a defect in mitochondrial protein synthesis characterized by severe intrauterine growth retardation, neonatal limb edema and redundant skin on the neck (hydrops), developmental brain defects (corpus callosum agenesis, ventriculomegaly), brachydactyly, dysmorphic facial features with low set ears, severe intractable neonatal lactic acidosis with lethargy, hypotonia, absent spontaneous movements and fatal outcome. Markedly decreased activity of complex I, II + III and IV in muscle and liver have been determined.

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem and associated with severe developmental delay (Edvardson et al., 2007). For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).

This syndrome is characterized by severe hypotonia, lactic acidemia and congenital hyperammonemia. It has been described in three newborns born to consanguineous parents. Ultrasound examination during the 36th week of pregnancy revealed generalized edema. Hypertrophic cardiomyopathy and tubulopathy developed within the first week of life and the infants died within the first month. The activities of enzymes in the mitochondrial respiratory chain were reduced in the muscles of the patients. Mutations were identified in the MRPS22 gene on chromosome 3q23, encoding a mitochondrial ribosomal protein

TK2-related mitochondrial DNA (mtDNA) maintenance defect is a phenotypic continuum that ranges from severe to mild. To date, approximately 107 individuals with a molecularly confirmed diagnosis have been reported. Three main subtypes of presentation have been described: Infantile-onset myopathy with neurologic involvement and rapid progression to early death. Affected individuals experience progressive muscle weakness leading to respiratory failure. Some individuals develop dysarthria, dysphagia, and/or hearing loss. Cognitive function is typically spared. Juvenile/childhood onset with generalized proximal weakness and survival to at least 13 years. Late-/adult-onset myopathy with facial and limb weakness and mtDNA deletions. Some affected individuals develop respiratory insufficiency, chronic progressive external ophthalmoplegia, dysphagia, and dysarthria.

Myopathy, lactic acidosis, and sideroblastic anemia-2 (MLASA2) is an autosomal recessive disorder of the mitochondrial respiratory chain. The disorder shows marked phenotypic variability: some patients have a severe multisystem disorder from infancy, including cardiomyopathy and respiratory insufficiency resulting in early death, whereas others present in the second or third decade of life with sideroblastic anemia and mild muscle weakness (summary by Riley et al., 2013). For a discussion of genetic heterogeneity of MLASA, see MLASA1 (600462).

SUCLG1-related mitochondrial DNA (mtDNA) depletion syndrome, encephalomyopathic form with methylmalonic aciduria is characterized in the majority of affected newborns by hypotonia, muscle atrophy, feeding difficulties, and lactic acidosis. Affected infants commonly manifest developmental delay / cognitive impairment, growth retardation / failure to thrive, hepatopathy, sensorineural hearing impairment, dystonia, and hypertonia. Notable findings in some affected individuals include hypertrophic cardiomyopathy, epilepsy, myoclonus, microcephaly, sleep disturbance, rhabdomyolysis, contractures, hypothermia, and/or hypoglycemia. Life span is shortened, with median survival of 20 months.

Multiple mitochondrial dysfunctions syndrome-2 (MMDS2) with hyperglycinemia is a severe autosomal recessive disorder characterized by developmental regression in infancy. Affected children have an encephalopathic disease course with seizures, spasticity, loss of head control, and abnormal movement. Additional more variable features include optic atrophy, cardiomyopathy, and leukodystrophy. Laboratory studies show increased serum glycine and lactate. Most patients die in childhood. The disorder represents a form of 'variant' nonketotic hyperglycinemia and is distinct from classic nonketotic hyperglycinemia (NKH, or GCE; 605899), which is characterized by significantly increased CSF glycine. Several forms of 'variant' NKH, including MMDS2, appear to result from defects of mitochondrial lipoate biosynthesis (summary by Baker et al., 2014). For a general description and a discussion of genetic heterogeneity of multiple mitochondrial dysfunctions syndrome, see MMDS1 (605711).

Autosomal recessive mitochondrial complex III deficiency is a severe multisystem disorder with onset at birth of lactic acidosis, hypotonia, hypoglycemia, failure to thrive, encephalopathy, and delayed psychomotor development. Visceral involvement, including hepatopathy and renal tubulopathy, may also occur. Many patients die in early childhood, but some may show longer survival (de Lonlay et al., 2001; De Meirleir et al., 2003). Genetic Heterogeneity of Mitochondrial Complex III Deficiency Mitochondrial complex III deficiency can be caused by mutation in several different nuclear-encoded genes. See MC3DN2 (615157), caused by mutation in the TTC19 gene (613814) on chromosome 17p12; MC3DN3 (615158), caused by mutation in the UQCRB gene (191330) on chromosome 8q; MC3DN4 (615159), caused by mutation in the UQCRQ gene (612080) on chromosome 5q31; MC3DN5 (615160), caused by mutation in the UQCRC2 gene (191329) on chromosome 16p12; MC3DN6 (615453), caused by mutation in the CYC1 gene (123980) on chromosome 8q24; MC3DN7 (615824), caused by mutation in the UQCC2 gene (614461) on chromosome 6p21; MC3DN8 (615838), caused by mutation in the LYRM7 gene (615831) on chromosome 5q23; MC3DN9 (616111), caused by mutation in the UQCC3 gene (616097) on chromosome 11q12; and MC3DN10 (618775), caused by mutation in the UQCRFS1 gene (191327) on chromosome 19q12. See also MTYCB (516020) for a discussion of a milder phenotype associated with isolated mitochondrial complex III deficiency and mutations in a mitochondrial-encoded gene.

Mitochondrial complex III deficiency nuclear type 2 is an autosomal recessive severe neurodegenerative disorder that usually presents in childhood, but may show later onset, even in adulthood. Affected individuals have motor disability, with ataxia, apraxia, dystonia, and dysarthria, associated with necrotic lesions throughout the brain. Most patients also have cognitive impairment and axonal neuropathy and become severely disabled later in life (summary by Ghezzi et al., 2011). The disorder may present clinically as spinocerebellar ataxia or Leigh syndrome, or with psychiatric disturbances (Morino et al., 2014; Atwal, 2014; Nogueira et al., 2013). For a discussion of genetic heterogeneity of mitochondrial complex III deficiency, see MC3DN1 (124000).

Mitochondrial complex III deficiency is a genetic condition that can affect several parts of the body, including the brain, kidneys, liver, heart, and the muscles used for movement (skeletal muscles). Signs and symptoms of mitochondrial complex III deficiency usually begin in infancy but can appear later.\n\nThe severity of mitochondrial complex III deficiency varies widely among affected individuals. People who are mildly affected tend to have muscle weakness (myopathy) and extreme tiredness (fatigue), particularly during exercise (exercise intolerance). More severely affected individuals have problems with multiple body systems, such as liver disease that can lead to liver failure, kidney abnormalities (tubulopathy), and brain dysfunction (encephalopathy). Encephalopathy can cause delayed development of mental and motor skills (psychomotor delay), movement problems, weak muscle tone (hypotonia), and difficulty with communication. Some affected individuals have a form of heart disease called cardiomyopathy, which can lead to heart failure. \n\nMost people with mitochondrial complex III deficiency have a buildup of a chemical called lactic acid in the body (lactic acidosis). Some affected individuals also have buildup of molecules called ketones (ketoacidosis) or high blood glucose levels (hyperglycemia). Abnormally high levels of these chemicals in the body can be life-threatening.\n\nMitochondrial complex III deficiency can be fatal in childhood, although individuals with mild signs and symptoms can survive into adolescence or adulthood.

Mitochondrial complex III deficiency can be fatal in childhood, although individuals with mild signs and symptoms can survive into adolescence or adulthood.\n\nMost people with mitochondrial complex III deficiency have a buildup of a chemical called lactic acid in the body (lactic acidosis). Some affected individuals also have buildup of molecules called ketones (ketoacidosis) or high blood glucose levels (hyperglycemia). Abnormally high levels of these chemicals in the body can be life-threatening.\n\nThe severity of mitochondrial complex III deficiency varies widely among affected individuals. People who are mildly affected tend to have muscle weakness (myopathy) and extreme tiredness (fatigue), particularly during exercise (exercise intolerance). More severely affected individuals have problems with multiple body systems, such as liver disease that can lead to liver failure, kidney abnormalities (tubulopathy), and brain dysfunction (encephalopathy). Encephalopathy can cause delayed development of mental and motor skills (psychomotor delay), movement problems, weak muscle tone (hypotonia), and difficulty with communication. Some affected individuals have a form of heart disease called cardiomyopathy, which can lead to heart failure. \n\nMitochondrial complex III deficiency is a genetic condition that can affect several parts of the body, including the brain, kidneys, liver, heart, and the muscles used for movement (skeletal muscles). Signs and symptoms of mitochondrial complex III deficiency usually begin in infancy but can appear later.

Mitochondrial complex III deficiency nuclear type 6 (MC3DN6) is an autosomal recessive disorder caused by mitochondrial dysfunction. It is characterized by onset in early childhood of episodic acute lactic acidosis, ketoacidosis, and insulin-responsive hyperglycemia, usually associated with infection. Laboratory studies show decreased activity of mitochondrial complex III. Psychomotor development is normal (summary by Gaignard et al., 2013). For a discussion of genetic heterogeneity of mitochondrial complex III deficiency, see MC3DN1 (124000).

FBXL4-related encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome is a multi-system disorder characterized primarily by congenital or early-onset lactic acidosis and growth failure, feeding difficulty, hypotonia, and developmental delay. Other neurologic manifestations can include seizures, movement disorders, ataxia, autonomic dysfunction, and stroke-like episodes. All affected individuals alive at the time they were reported (median age: 3.5 years) demonstrated significant developmental delay. Other findings can involve the heart (hypertrophic cardiomyopathy, congenital heart malformations, arrhythmias), liver (mildly elevated transaminases), eyes (cataract, strabismus, nystagmus, optic atrophy), hearing (sensorineural hearing loss), and bone marrow (neutropenia, lymphopenia). Survival varies; the median age of reported deaths was two years (range 2 days – 75 months), although surviving individuals as old as 36 years have been reported. To date FBXL4-related mtDNA depletion syndrome has been reported in 50 individuals.

Any mitochondrial complex III deficiency in which the cause of the disease is a mutation in the UQCC2 gene.

Mitochondrial complex III deficiency, nuclear type 8, is an autosomal recessive disorder characterized by progressive neurodegeneration with onset in childhood. Affected individuals may have normal or delayed early development, and often have episodic acute neurologic decompensation and regression associated with febrile illnesses. The developmental regression results in variable intellectual disability and motor deficits, such as hypotonia, axial hypertonia, and spasticity; some patients may lose the ability to walk independently. Laboratory studies show increased serum lactate and isolated deficiency of mitochondrial complex III in skeletal muscle and fibroblasts. Brain imaging shows a characteristic pattern of multifocal small cystic lesions in the periventricular and deep cerebral white matter (summary by Dallabona et al., 2016). For a discussion of genetic heterogeneity of mitochondrial complex III deficiency, see MC3DN1 (124000).

Any mitochondrial complex III deficiency in which the cause of the disease is a mutation in the UQCC3 gene.

CHCHD10-related disorders are characterized by a spectrum of adult-onset neurologic phenotypes that can include: Mitochondrial myopathy (may also be early onset): weakness, amyotrophy, exercise intolerance. Amyotrophic lateral sclerosis (ALS): progressive degeneration of upper motor neurons and lower motor neurons. Frontotemporal dementia (FTD): slowly progressive behavioral changes, language disturbances, cognitive decline, extrapyramidal signs. Late-onset spinal motor neuronopathy (SMA, Jokela type): weakness, cramps, and/or fasciculations; areflexia. Axonal Charcot-Marie-Tooth neuropathy: slowly progressive lower-leg muscle weakness and atrophy, small hand muscle weakness, loss of tendon reflexes, sensory abnormalities. Cerebellar ataxia: gait ataxia, kinetic ataxia (progressive loss of coordination of lower- and upper-limb movements), dysarthria/dysphagia, nystagmus, cerebellar oculomotor disorder. Because of the recent discovery of CHCHD10-related disorders and the limited number of affected individuals reported to date, the natural history of these disorders (except for SMAJ caused by the p.Gly66Val pathogenic variant) is largely unknown.

MTDPS12A is characterized by severe hypotonia due to mitochondrial dysfunction apparent at birth. Affected infants have respiratory insufficiency requiring mechanical ventilation and have poor or no motor development. Many die in infancy, and those that survive have profound hypotonia with significant muscle weakness and inability to walk independently. Some patients develop hypertrophic cardiomyopathy. Muscle samples show mtDNA depletion and severe combined mitochondrial respiratory chain deficiencies (summary by Thompson et al., 2016). For a discussion of genetic heterogeneity of mtDNA depletion syndromes, see MTDPS1 (603041).

COXPD33 is an autosomal recessive multisystem disorder resulting from a defect in mitochondrial energy metabolism. The phenotype is highly variable, ranging from death in infancy to adult-onset progressive external ophthalmoplegia (PEO) and myopathy. A common finding is cardiomyopathy and increased serum lactate (summary by Feichtinger et al., 2017). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Combined oxidative phosphorylation deficiency-12 (COXPD12) is an autosomal recessive mitochondrial neurologic disorder characterized by onset in infancy of hypotonia and delayed psychomotor development, or early developmental regression, associated with T2-weighted hyperintensities in the deep cerebral white matter, brainstem, and cerebellar white matter. Serum lactate is increased due to a defect in mitochondrial respiration. There are 2 main phenotypic groups: those with a milder disease course and some recovery of skills after age 2 years, and those with a severe disease course resulting in marked disability (summary by Steenweg et al., 2012). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Combined oxidative phosphorylation deficiency-10 (COXPD10) is an autosomal recessive disorder resulting in variable defects of mitochondrial oxidative respiration. Affected individuals present in infancy with hypertrophic cardiomyopathy and lactic acidosis. The severity is variable, but can be fatal in the most severe cases (summary by Ghezzi et al., 2012). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

The two forms of deoxyguanosine kinase (DGUOK) deficiency are a neonatal multisystem disorder and an isolated hepatic disorder that presents later in infancy or childhood. The majority of affected individuals have the multisystem illness with hepatic disease (jaundice, cholestasis, hepatomegaly, and elevated transaminases) and neurologic manifestations (hypotonia, nystagmus, and psychomotor retardation) evident within weeks of birth. Those with isolated liver disease may also have renal involvement and some later develop mild hypotonia. Progressive hepatic disease is the most common cause of death in both forms.

Combined oxidative phosphorylation deficiency-39 (COXPD39) is an autosomal recessive multisystem disorder resulting from a defect in mitochondrial energy metabolism. Affected individuals show global developmental delay, sometimes with regression after normal early development, axial hypotonia with limb spasticity or abnormal involuntary movements, and impaired intellectual development with poor speech. More variable features may include hypotonia, seizures, and features of Leigh syndrome (256000) on brain imaging. There are variable deficiencies of the mitochondrial respiratory chain enzyme complexes in patient tissues (summary by Glasgow et al., 2017). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Combined oxidative phosphorylation deficiency-40 (COXPD40) is an autosomal recessive mitochondrial disorder with onset in utero or soon after birth. Affected individuals have severe hypertrophic cardiomyopathy, poor growth, and sensorineural hearing loss. Laboratory studies show evidence of mitochondrial dysfunction, such as lactic acidosis. Patient-derived tissues and cells show variably decreased activities of mitochondrial respiratory complexes I, III, IV, and V. The disorder is lethal, with no reported patients surviving past infancy (summary by Friederich et al., 2018). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Combined oxidative phosphorylation deficiency-42 (COXPD42) is an autosomal recessive metabolic disorder characterized by onset of cardiomyopathy, respiratory insufficiency, lactic metabolic acidosis, and anemia in the first months of life. Patient tissue shows variable impairment of mitochondrial oxidative phosphorylation affecting mtDNA-encoded subunits I, III, and IV. All reported affected infants have died in the first year of life (summary by Friederich et al., 2018). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Mitochondrial form of axonal Charcot-Marie-Tooth disease-1 (CMTMA1) is inherited only through the maternal line. The disorder is characterized by onset of distal muscle weakness and atrophy mainly affecting the lower limbs and resulting in difficulty walking in the second decade of life, although both earlier and later onset can occur. Upper limb involvement often develops with time, and affected individuals have weakness and atrophy of the intrinsic hand muscles. Other features may include distal sensory impairment, foot deformities, scoliosis, hypo- or hyperreflexia, spastic paraparesis, and neurogenic bladder. Electrophysiologic studies are compatible with an axonal sensorimotor peripheral neuropathy, and muscle and nerve biopsy show evidence of mitochondrial dysfunction with decreased activities of respiratory complexes, mtDNA deletions, and mitochondrial hyperplasia (summary by Fay et al., 2020).

Combined oxidative phosphorylation deficiency-52 (COXPD52) is an autosomal recessive infantile mitochondrial complex II/III deficiency characterized by lactic acidemia, multiorgan system failure, and abnormal mitochondria. Intrafamilial variability has been reported (Farhan et al., 2014; Hershkovitz et al., 2021). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

A rare mitochondrial oxidative phosphorylation disorder with characteristics of microcephaly, global developmental delay, spastic-dystonic movement disorder, intractable seizures, optic atrophy, autonomic dysfunction and peripheral neuropathy. Serum lactate is increased, and muscle biopsy shows decreased activity of mitochondrial respiratory complexes I and III. Brain imaging reveals progressive cerebellar atrophy and delayed myelination.

Combined oxidative phosphorylation deficiency-27 (COXPD27) is an autosomal recessive multisystem disorder characterized mainly by neurologic features, including delayed development, seizures, abnormal movements, and neurologic regression. Age at onset, ranging from infancy to late childhood, and severity are variable. Other features include hypotonia, myoclonus, brain imaging abnormalities, and evidence of mitochondrial dysfunction in skeletal muscle. Liver dysfunction has also been reported (summary by Samanta et al., 2018). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Peripheral neuropathy with variable spasticity, exercise intolerance, and developmental delay (PNSED) is an autosomal recessive multisystemic disorder with highly variable manifestations, even within the same family. Some patients present in infancy with hypotonia and global developmental delay with poor or absent motor skill acquisition and poor growth, whereas others present as young adults with exercise intolerance and muscle weakness. All patients have signs of a peripheral neuropathy, usually demyelinating, with distal muscle weakness and atrophy and distal sensory impairment; many become wheelchair-bound. Additional features include spasticity, extensor plantar responses, contractures, cerebellar signs, seizures, short stature, and rare involvement of other organ systems, including the heart, pancreas, and kidney. Biochemical analysis may show deficiencies in mitochondrial respiratory complex enzyme activities in patient tissue, although this is not always apparent. Lactate is frequently increased, suggesting mitochondrial dysfunction (Powell et al., 2015; Argente-Escrig et al., 2022). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Mitochondrial complex III deficiency nuclear type 11 (MC3DN11) is an autosomal recessive disorder characterized by recurrent episodes of severe lactic acidosis, hyperammonemia, hypoglycemia, and encephalopathy (Vidali et al., 2021) For a discussion of genetic heterogeneity of mitochondrial complex III deficiency, see MC3DN1 (124000).

Combined oxidative phosphorylation deficiency-57 (COXPD57) is an autosomal recessive multisystem mitochondrial disease with varying degrees of severity from premature death in infancy to permanent disability in young adulthood (Lee et al., 2022). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).