Isolated complex I deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders (McFarland et al., 2004; Kirby et al., 2004). It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset ... Isolated complex I deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders (McFarland et al., 2004; Kirby et al., 2004). It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome (256000), Leber hereditary optic neuropathy (535000), and some forms of Parkinson disease (see 556500) (Loeffen et al., 2000; Pitkanen et al., 1996; Robinson, 1998). - Genetic Heterogeneity of Complex I Deficiency Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible (summary by Haack et al., 2012). However, the majority of cases are caused by mutations in nuclear-encoded genes (Loeffen et al., 2000; Triepels et al., 2001). Complex I deficiency with autosomal recessive inheritance results from mutation in nuclear-encoded subunit genes, including NDUFV1 (161015), NDUFV2 (600532), NDUFS1 (157655), NDUFS2 (602985), NDUFS3 (603846), NDUFS4 (602694), NDUFS6 (603848), NDUFS7 (601825), NDUFS8 (602141), NDUFA2 (602137), NDUFA11 (612638), NDUFAF3 (612911), NDUFA10 (603835), NDUFB3 (603839), NDUFB9 (601445), and the complex I assembly genes B17.2L (609653), HRPAP20 (611776), C20ORF7 (612360), NUBPL (613621), and NDUFAF1 (606934). The disorder can also be caused by mutation in other nuclear-encoded genes, including FOXRED1 (613622), ACAD9 (611103; see 611126), and MTFMT (611766; see 256000). X-linked inheritance is observed with mutations in the NDUFA1 gene (300078). Complex I deficiency with mitochondrial inheritance has been associated with mutation in 6 mitochondrial-encoded components of complex I: MTND1 (516000), MTND2 (516001), MTND3 (516002), MTND4 (516003), MTND5 (516005), MTND6 (516006). Most of these patients have a phenotype of Leber hereditary optic neuropathy (LHON; 535000) or Leigh syndrome (256000). Features of complex I deficiency may also be caused by mutation in other mitochondrial genes, including MTTS2 (590085).
Morgan-Hughes et al. (1979) presented the first report of isolated complex I deficiency. Two sisters had a mitochondrial myopathy characterized by weakness, marked exercise intolerance, and fluctuating lactic acidemia. Increased weakness ... - Patients with Unknown Mutations Morgan-Hughes et al. (1979) presented the first report of isolated complex I deficiency. Two sisters had a mitochondrial myopathy characterized by weakness, marked exercise intolerance, and fluctuating lactic acidemia. Increased weakness was precipitated by unaccustomed exertion, fasting, or alcohol. During exercise, blood lactate and pyruvate levels rose abruptly and markedly. Mitochondrial respiratory rates were greatly decreased with all NAD-linked substrates, but normal with succinate and with TMPD plus ascorbate. Mitochondrial cytochrome components were normal. Morgan-Hughes et al. (1979) concluded that the defect was at the level of the NADH-CoQ reductase complex. Land et al. (1981) reported a young man with weakness, exercise intolerance, muscle wasting, and exercise-induced lactic acidosis. Biochemical studies showed deficiency of NADH-cytochrome b reductase. The defect appeared to be situated between NADH dehydrogenase and the CoQ-cytochrome b complex. Land et al. (1981) postulated a derangement of a nonheme iron-sulfur center. Moreadith et al. (1984) reported a male infant with complex I deficiency who developed respiratory distress and hypoglycemia on the first day of life. At 6 weeks, he showed generalized hypotonia and concentric biventricular cardiac hypertrophy on echocardiography. Lactic acidemia was progressive, and the child died at 16 weeks of age. Skeletal muscle biopsy showed giant mitochondria in which both inner and outer membranes were arranged in whorls. Biochemical studies of mitochondria from 4 organs showed a moderate to profound decrease in the ability to oxidize pyruvate, malate plus glutamate, citrate and other NAD-linked respiratory substrates. Oxidation of succinate was normal. Further studies localized the defect to the inner membrane mitochondrial NADH-ubiquinone oxidoreductase. Electron paramagnetic resonance spectroscopy showed almost total loss of the iron-sulfur clusters of complex I. The most pronounced deficiency was in skeletal muscle, the least in kidney mitochondria. There was no record of a similar problem in the family and the parents were not related. Since the parents subsequently had a normal male child, Moreadith et al. (1984) excluded mitochondrial inheritance and suggested either autosomal recessive inheritance or a de novo dominant mutation. In a later study on tissue from the same patient, Moreadith et al. (1987) found that antisera against complex I immunoprecipitated NADH-ferricyanide reductase from the control but not the patient's mitochondria. Immunoprecipitation and SDS-PAGE of complex I polypeptides demonstrated that most of the 25 polypeptides comprising complex I were present in the affected mitochondria. A more detailed analysis using subunit selective antisera against the main polypeptides of the iron-protein fragments of complex I showed a selective absence of the 75- and 13-kD polypeptides, suggesting a deficiency of at least 2 polypeptides comprising the iron-protein fragment of complex I. Moreadith et al. (1987) hypothesized that the genetic defect involved transcription or translation of the polypeptides, the transport of these polypeptides into the mitochondria, or the site of assembly of complex I. Hoppel et al. (1987) investigated a mitochondrial defect in a male infant with fatal congenital lactic acidosis, high lactate-to-pyruvate ratio, hypotonia, and cardiomyopathy. His sister had died with a similar disorder. Resting oxygen consumption was 150% of controls. Pathologic findings included increased numbers of skeletal muscle mitochondria (many with proliferated, concentric cristae), cardiomegaly, fatty infiltration of the viscera, and spongy encephalopathy. Mitochondria from liver and muscle biopsies oxidized NADH-linked substrates at rates 20 to 50% of controls, whereas succinate oxidation by muscle mitochondria was increased. Mitochondrial NADH dehydrogenase activity (complex I) was 0 to 10% of controls, whereas activity of other electron transport complexes in related enzymes was normal. Hoppel et al. (1987) suggested a familial deficiency of a component of mitochondrial NADH dehydrogenase proximal to the rotenone-sensitive site. Wijburg et al. (1989) reported a sibship born to healthy first-cousin Moroccan parents with 2 well-studied children with severe congenital lactic acidosis as well as 4 others with a clinical history compatible with the same defect. Treatment initially by artificial respiration and peritoneal dialysis followed later by high doses of menadione effected a remarkable recovery. Despite the parental consanguinity, Barth et al. (1989) suggested that the defect in this family involved the mitochondrial genome: they detected a possible deletion in the mitochondrial-encoded MTND3 protein in skeletal muscle. Slipetz et al. (1991) studied 2 unrelated patients with complex I deficiency with different phenotypes. One patient had hypotonia, seizures, and hepatomegaly, and died of lactic acidosis on day 13 of life. Biochemical analysis of complex I subunits showed absence of a 20-kD protein predicted to be encoded by the nuclear genome. Complex I activity was 6% of control values. The other child had marked growth and developmental delay, and showed altered neurologic function and seizures beginning at age 8 years. Other features included ptosis, sensorineural hearing loss, hypotonia, incoordination, and hyporeflexia. Mild facial coarseness was also observed. No complex I subunit abnormalities were detected by immunoprecipitation or Western blot analysis, but complex I activity was 15% of control values. Bentlage et al. (1995) showed deficits of specific complex I protein subunits in patients with complex I deficiency. Dionisi-Vici et al. (1997) reported 2 infant sibs with fatal progressive macrocephaly and hypertrophic cardiomyopathy. Onset of symptoms was at the end of the first month of life with massive brain swelling. Light microscopy showed extensive small-vessel proliferation and gliosis. Complex I deficiency was detected in cultured fibroblasts, skeletal muscle, and heart muscle. Procaccio et al. (1999) reported 2 unrelated patients with fatal infantile lactic acidosis associated with isolated complex I deficiency. Reexpression of complex I subunits and recovery of complex I activity in patients' mitochondria after transnuclear complementation by nuclei from cells without mitochondria enabled the authors to infer the nuclear DNA origin of the defects in both patients. Patient 1 showed reduced amounts of the 24- and 51-kD subunits and normal amounts of all the other investigated subunits. Patient 2 showed severely decreased amounts of all the investigated subunits. Patient 1 developed generalized hypotonia with poor gesticulation in the first 24 hours of life. By day 2, he was very floppy with poor response to painful stimuli and required ventilatory assistance. Hepatic enlargement was noticed, and chest x-rays showed slight cardiomegaly. Cranial ultrasonography showed brain edema, and severe lactic acidosis was detected. The patient went into a deep coma and died at 11 days. Patient 2 vomited frequently in the first 2 weeks of life and at 5 weeks showed deterioration of neurologic status with hypotonia, weakness, and lethargy. In the first month, the head circumference was noted to be rapidly increasing from 33 to 40 cm. Computed tomographic scan showed a very hypodense brain with increased brain volume and extensive cerebral edema. Marked metabolic acidosis with hyperlactic acidemia was demonstrated. Despite intensive care, the neurologic state worsened rapidly and brain death occurred at 6 weeks of age. Autopsy showed acute necrotizing encephalopathy, but no hypertrophic cardiomyopathy. In a study of 157 patients with respiratory chain defects, von Kleist-Retzow et al. (1998) found complex I deficiency in 33% and combined complex I and IV deficiency in another 28%. 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. The sex ratio 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. Loeffen et al. (2000) retrospectively examined clinical and biochemical characteristics of 27 patients, all of whom presented in infancy and young childhood with isolated enzymatic complex I deficiency established in cultured skin fibroblasts; common pathogenic mtDNA point mutations and major rearrangements were absent. Clinical phenotypes included Leigh syndrome in 7 patients, Leigh-like syndrome in 6, fatal infantile lactic acidosis in 3, neonatal cardiomyopathy with lactic acidosis in 3, macrocephaly with progressive leukodystrophy in 2, and a residual group of unspecified encephalomyopathy in 6, subdivided into progressive (in 4) and stable (in 2) variants. - Patients with Identified Mutations in Nuclear-Encoded Genes Schuelke et al. (1999) reported 2 brothers with complex I deficiency caused by mutations in the NDUFV1 gene (161015.0001; 161015.0002). Pregnancy, delivery, and early infancy were normal in both children. At the age of 5 months, they presented with repeated vomiting and developed strabismus, progressive muscular hypotonia, myoclonic epilepsy, and psychomotor regression. Cranial CT scans showed brain atrophy, but cranial MRIs were not available to confirm Leigh syndrome. Lactate and pyruvate concentrations in blood and cerebrospinal fluid were elevated. Isolated complex I deficiency was demonstrated in muscle and cultured fibroblasts. The boys died at 14 and 17 months from aspiration pneumonia. Schuelke et al. (1999) reported another child with complex I deficiency and mutation in the NDUFV1 gene (161015.0003). Features included infantile myoclonic epilepsy, spasticity, psychomotor regression, and macrocephaly. Serial cranial MRI scans showed brain atrophy and a progressive macrocytic leukodystrophy. At age 10 years, she had severe spasticity and blindness. Benit et al. (2001) reported an infant with complex I deficiency caused by mutations in the NDUFV1 gene (161015.0004; 161015.0005). He was first hospitalized at age 1 year for seizures and moderately elevated levels of plasma lactate. Other features included cerebellar ataxia, psychomotor regression, strabismus, and ptosis. Magnetic resonance imaging showed brain atrophy in multiple symmetric areas of hyperintensity in the brainstem. He died at age 3 years of an acute episode of metabolic acidosis. Van den Heuvel et al. (1998) reported a patient with fatal multisystemic complex I deficiency and homozygous mutation in the NDUFS4 gene (602694.0001). He had normal muscle morphology and a remarkably nonspecific fatally progressive course without increased lactate concentrations in body fluids. He presented at 8 months of age with severe vomiting, failure to thrive, and hypotonia. At the age of 13 months, he showed severe psychomotor retardation, convulsions, bradypnea, cyanosis, hypotonia, and depressed tendon reflexes. Cerebral MRI showed generalized brain atrophy and symmetric basal ganglia abnormalities. He died of cardiorespiratory failure at the age of 16 months. Loeffen et al. (2001) reported 3 unrelated families with isolated complex I deficiency caused by mutations in the nuclear-encoded NDUFS2 gene (602985.0001-602985.0003). The first family, which was consanguineous, had 2 affected children. The first affected child, a male, was normal until 6 months of age when he manifested neurologic regression, with horizontal nystagmus and bilateral muscle atrophy with decreased axial muscle tone. Brain CT showed bilateral hypodensities of the basal ganglia, and echocardiogram showed left ventricular hypertrophy. He died of apnea at 24 months of age. The third-born child, a female, had similar symptoms except that they presented earlier and her deterioration was faster. In the second family, the affected child had neonatal onset of severe lactic acidosis and hypertrophic cardiomyopathy. She died at 4 days of age. The third family, which was consanguineous, had 4 children, 3 of whom died with a clinical phenotype including failure to thrive, horizontal nystagmus, ataxia, hypotonia, and pallor of the optic discs. CT and MRI findings revealed hypodensity of the basal ganglia and midbrain. Benit et al. (2003) reported a male infant, born of consanguineous parents of African ancestry, who had complex I deficiency caused by mutation in the NDUFV2 gene (600532.0002). He presented at 5 days of life with hypertrophic cardiomyopathy, truncal hypotonia, and encephalopathy. Persistent hyperlactatemia was observed and he died at 3 months of age. Two younger brothers subsequently died of hypertrophic cardiomyopathy in their first year of life. Benit et al. (2003) noted that the phenotype was similar to that described by Loeffen et al. (2001) in patients with mutations in the NDUFS2 gene. Benit et al. (2004) reported a boy from Reunion Island with complex I deficiency and features of Leigh syndrome caused by mutations in the NDUFS3 gene (603846.0001-603846.0002). The boy's psychomotor development was normal until 9 years of age, although a single episode of febrile convulsions occurred at 9 months of age and kyphoscoliosis had been noted. Persistent stiff neck had developed at the age of 9 years. He gradually developed severe axial dystonia with oral and pharyngeal motor dysfunction, dysphagia, and a tetraparetic syndrome. At 10 years of age, mild elevation of CFS lactate was found. Complex I deficiency was identified by skeletal muscle biopsy. Two years later, he developed acute pancreatitis and severe respiratory insufficiency. He died 1.5 years later after rapid multisystem deterioration. In 2 unrelated patients with mitochondrial complex I deficiency, Kirby et al. (2004) reported 2 unrelated patients with complex I deficiency caused by different homozygous mutations in the NDUFS6 gene (603848.0001; 603848.0002). Both patients had lethal infantile mitochondrial disease with death within the first 2 weeks of life. Spiegel et al. (2009) reported 2 unrelated infants, both of Jewish Caucasus descent, with fatal infantile lactic acidosis resulting from severe complex I deficiency due to a homozygous mutation in the NDUFS6 gene (C115Y; 603848.0003). Complex I activity was about 50% or less in muscle biopsies. The Jewish population of the Caucasus region of central Asia is believed to have originated from southern Iran and is a genetically isolated community. Martin et al. (2005) reported a Spanish child with complex I deficiency and features of Leigh syndrome caused by a homozygous mutation in the nuclear-encoded NDUFS1 gene (157655.0004). At 8.5 months of age, she was hospitalized for recurrent vomiting, hypotonia, and growth retardation. Other findings included irritability, horizontal nystagmus, hyperreflexia, and bilateral lesions in the substantia nigra and midbrain. There was increased lactic acid in serum and CSF. Her status worsened and she died at age 14 months. A younger brother with a similar clinical picture died at age 8 months. Biochemical studies showed that skeletal muscle complex I activity was reduced to 25% normal values. Ogilvie et al. (2005) reported a patient with a severe childhood-onset progressive encephalopathy caused by mutation in the gene encoding mimitin (609653.0001). The authors noted that the clinical presentation of the patient did not resemble that seen in Leigh syndrome, nor did it resemble that of most other patients with mitochondrial disease. The patient shared most of the characteristic diagnostic criteria for leukoencephalopathy with vanishing white matter (603896), which is caused by mutations in various genes encoding cytosolic translation factors. Ogilvie et al. (2005) remarked that the fact that no other patients with mutations in the mimitin gene have been found may reflect the lack of association of this clinical phenotype with mitochondrial disease. In 2 unrelated Spanish male patients with complex I deficiency, Fernandez-Moreira et al. (2007) identified hemizygous mutations in the NDUFA1 gene (300078.0001 and 300078.0002, respectively). One of the patients had a severe presentation consistent with Leigh syndrome and early death, and the other had developmental delay and myoclonic epilepsy. Berger et al. (2008) reported 3 consanguineous families of Israeli Bedouin origin in which 6 offspring had severe mitochondrial complex I deficiency associated with a homozygous mutation in the NDUFA11 gene (612638.0001). Three of the affected children presented with a fatal infantile metabolic acidosis with death between ages 6 and 40 days. Affected children in 1 family survived beyond infancy but developed severe encephalocardiomyopathy with brain atrophy, no motor development, and hypertrophic cardiomyopathy. The parents of each family did not recall any relationship between the families, but haplotype analysis indicated a founder effect. RT-PCR analysis indicated that the mutation was a leaky mutation, with a 2:1 ratio of wildtype to normal transcript in patient fibroblasts. Berger et al. (2008) hypothesized a modifier gene effect or differential transcript expression in various tissues to explain the different clinical presentations observed in these families. Sugiana et al. (2008) reported a male infant, born of consanguineous Egyptian parents, with lethal neonatal complex I deficiency due to homozygous mutation in the C20ORF7 gene (612360.0001). He had intrauterine growth retardation, minor facial dysmorphism, unusual hair patterning, abnormal toes, and a small sacral pit. Cerebral ultrasound showed agenesis of the corpus callosum and ventricular septation. He also had a congenital left diaphragmatic hernia, adrenal insufficiency, and increased lactate in the blood and CSF. He died of cardiorespiratory arrest due to progressive lactic acidosis on day 7. Prenatal diagnosis identified 2 additional affected fetuses in subsequent pregnancies. Gerards et al. (2010) reported 2 adult sibs, born of consanguineous Moroccan parents, who developed symptoms of complex I deficiency with Leigh syndrome in early childhood associated with a homozygous mutation in the C20ORF7 gene (L159F; 612360.0002). The phenotype was less severe than that described by Sugiana et al. (2008). The sibs reported by Gerards et al. (2010) were aged 29 and 33 years at the time of the study, but presented with progressive spasticity at age 3, which subsequently developed into an extrapyramidal choreodystonic movement disorder. Delayed mental development also occurred, and both were moderately mentally retarded in their teens. Brain imaging of 1 patient at age 23 showed a small caudate and hyperintense lesions in the basal ganglia. Laboratory studies of 1 sib showed increased lactate in the cerebrospinal fluid, and both sibs had decreased complex I activity in skeletal muscle (36% and 48% of controls, respectively). A third affected sib died at age 36 years. Electrophoresis studies of patient leukocytes showed a decrease of mature complex I levels to 30 to 40% of normal controls. The clinically unaffected family members who were heterozygous for the mutation had mature complex I levels of 70 to 90% of normal controls. The patients studied were also homozygous for a common hypomorphic P193L variant in the CRLS1 gene (608188), which may have contributed to the phenotype. Gerards et al. (2010) noted the phenotypic overlap with infantile bilateral striatal necrosis (IBSN; 271930). Saada et al. (2009) identified mutations in the NDUFAF3 gene (612911.0001-612911.0003) in 5 patients with severe complex I deficiency. All patients died by age 6 months. Three sibs in the first family presented similarly with severe lactic acidosis. In a second family, the infant was hypoactive, sucked poorly, had macrocephaly, a weak cry, wide anterior fontanel, and axial hypotonia. He also had intermittent tonic movements and pallor of the optic discs. At 3 months of age, there was no eye contact and marked axial hypotonia with brisk tendon reflexes. In the third family, a daughter of unrelated parents of Jewish origin was affected. She developed myoclonic seizures at age 3 months, and brain MRI revealed diffuse brain leukomalacia. She died at age 6 months of respiratory failure. Complex I activity was decreased in cells derived from all patients. Dunning et al. (2007) reported a patient with mitochondrial complex I deficiency manifest as cardioencephalomyopathy who was compound heterozygous for 2 mutations in the NDUFAF1 (606934.0001 and 606934.0002). He presented at age 11 months with failure to thrive and developed severe cardiac failure due to hypertrophic cardiomyopathy in association with a viral illness at age 15 months. He had developmental delay, lactic acidosis, and hypotonia. He was diagnosed with Wolff-Parkinson-White syndrome (194200) at age 3, cortical visual dysfunction at age 7, and pigmentary retinopathy at age 11. At age 20, he had mild to moderate intellectual disability and myopathy. Fassone et al. (2011) identified compound heterozygosity for 2 mutations in the NDUFAF1 gene (606934.0003 and 606934.0004) in a French infant with fatal infantile hypertrophic cardiomyopathy and isolated complex I deficiency. The patient presented at age 6.5 months in cardiogenic shock with metabolic acidosis after a respiratory viral infection. Echocardiogram showed pericardial effusion, biventricular hypertrophy, and left ventricular dysfunction. Skeletal muscle biopsy showed increased lipid deposition and accumulation of enlarged and abnormal mitochondria and an isolated severe deficiency of complex I activity (25% of controls). She died soon after, despite aggressive treatment. Postmortem examination showed an enlarged globular heart and myocardial hypertrophy with foci of myofiber loss and replacement fibrosis. Liver histology showed macrovesicular steatosis, but respiratory chain enzymes in the liver were normal. NDUFAF1 protein levels were severely reduced in patient mitoplasts, and there was a severe reduction in the complex I holoenzyme compared to controls. In addition, patient fibroblasts showed an accumulation of abnormal complex I assembly intermediates, suggesting a defect in the assembly process. Ferreira et al. (2011) reported 2 sibs, born of consanguineous parents, with complex I deficiency due to a homozygous mutation in the NDUFS1 gene (T595A; 157655.0005). The patients had a neurodegenerative disorder of the white matter beginning around the first year of life. One showed loss of early developmental milestones and the other showed early delayed psychomotor development and irritability. Both had dystonic posturing, difficulty swallowing, and increased lactate in bodily fluids. Although there were episodes of deterioration, there was also some improvement in symptoms with age. Brain MRI showed progressive cavitating leukoencephalopathy with multiple cystic lesions in the white matter. Muscle biopsy of 1 sib showed significantly decreased complex I activity (45% of controls) and a decreased amount of complex I subunits. Reduced fully assembled complex I was seen in mitochondria isolated from fibroblasts from the other sib, but only under stress conditions. Modeling of the mutation in yeast showed that reduced complex I activity was due mainly to decreased accumulation of fully assembled active complex I in the membrane and not to diminished activity of the mutant enzyme. In a patient with severe complex I deficiency resulting in early death at age 4 months (patient 2 in Lamont et al., 2004), Calvo et al. (2012) identified a homozygous mutation in the NDUFB3 gene (W22R; 603839.0001). The pregnancy was complicated by intrauterine growth retardation and premature birth at 31 weeks' gestation; respiratory insufficiency required extensive artificial ventilation in the neonatal period. After discharge home, she showed hypotonia with poor feeding and significant lactic acidosis and died unexpectedly at age 4 months. Skeletal muscle biopsy showed variation in the shape and size of muscle fibers, and atrophic fibers containing nemaline rods. Biochemical analysis showed complex I deficiency with borderline low complex III deficiency, the latter of which may have been an artifact. Fibroblasts from the patient showed 2 to 15% residual complex I protein levels and activity, depending on the method used, and expression of wildtype NDUFB3 rescued the defect. In 2 brothers with mitochondrial complex I deficiency, Haack et al. (2012) identified a homozygous mutation in the NDUFB9 gene, (L64P; 601445.0001). The mutation, which was found by sequencing of 75 candidate genes in 152 patients with complex I deficiency, segregated with the disorder in the family and was not found in the dbSNP or 1000 Genomes databases or in 200 control chromosomes. Patient fibroblasts showed 39% residual complex I activity, which was restored upon transfection with wildtype NDUFB9. Western blot analysis showed decreased levels of NDUFB9 and complex I subunits, consistent with reduced assembly of the overall complex. The proband had onset in infancy of progressive hypotonia associated with increased serum lactate. Kevelam et al. (2013) reported 6 patients, including 2 sibs, with complex I deficiency due to biallelic mutations in the NUBPL gene (613621.0001; 613621.0003-613621.0006). The first mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. All patients had a characteristic leukoencephalopathic pattern on brain MRI. Initial studies showed confluent or multifocal cerebral white matter lesions, predominantly affecting the deep white matter while sparing the U-fibers and internal and external capsules. There were also signal abnormalities and swelling of the corpus callosum. Signal abnormalities were present in the cerebellar cortex, but not in the deep white matter. Later imaging of most patients showed improvement of the cerebral white matter and corpus callosum abnormalities, but worsening of the cerebellar abnormalities and additional brainstem abnormalities. One patient had severe atrophy of the corpus callosum. All patients developed motor problems due to ataxia in the first years of life, but other features were somewhat variable: some patients showed continuous regression and others showed episodic regression. Five patients had spasticity and only 2 achieved unsupported walking. Cognitive capabilities varied between normal and significantly deficient. Complex I deficiency ranged between 27% and 83% of normal, and there was no correlation between residual complex I activity and clinical severity. - Patients with Identified Mutations in Mitochondrial-Encoded Genes Taylor et al. (2001) reported a 42-year-old man who had onset of migraine symptoms associated with flashing lights in his vision and right arm weakness at age 24 years. He subsequently developed myoclonus, seizures, cognitive decline, ataxia, peripheral neuropathy, eye movement abnormalities, and optic atrophy. Muscle biopsy showed a deficit (40% of controls) in complex I activity, but no ragged-red fibers. A heteroplasmic 10191T-C transition in the mitochondrial-encoded MTND3 gene (516002.0001) was identified in his skeletal muscle (77%) and blood (14%), as well as in his mother (3% in blood) and 2 unaffected sibs (barely detectable in blood). McFarland et al. (2004) identified a mutation in the MTND3 gene (516002.0001) in a patient with infantile encephalopathy and complex I deficiency. From birth, he was lethargic with hypotonia, areflexia, and muscle atrophy. Micrognathia and talipes equinovarus were noted. Meulemans et al. (2006) reported a 13-year-old boy with combined deficiency of mitochondrial complex I and IV (220110) 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. Musumeci et al. (2000) studied a 43-year-old man, originally reported by Bet et al. (1990), who had complained of severe exercise intolerance and myalgia since childhood. A heteroplasmic 7-bp inversion was found in the MTND1 gene (516000.0009) Morphologic and biochemical studies of muscles showed 40% ragged-red fibers and an approximately 40% reduction of complex I activity consistent with complex I deficiency. At age 43 years, he still complained of exercise intolerance; neurologic examination showed mild proximal limb weakness but was otherwise normal. His family history was noncontributory. The mother was alive and had always been a very active person. Blakely et al. (2006) reported a female infant with the same 7-bp inversion in the MTND1 gene described by Musumeci et al. (2000). However, the infant had a much more severe phenotype and died at age 1 month with marked biventricular hypertrophy, aortic coarctation, and severe lactic acidosis. The mutation was present at high levels in several tissues including the heart (85%), muscle (84%), liver (87%), and cultured skin fibroblasts (70%). Complex I activity was estimated to be 24% of control values. There was no evidence of the mutation or respiratory complex I defect in a muscle biopsy from the patient's mother. Blakely et al. (2006) noted that their findings illustrated the enormous phenotypic diversity that exists among pathogenic mtDNA mutations and reemphasized the need for appropriate genetic counseling for families affected by mtDNA disease. - Neuroradiologic Features Lebre et al. (2011) performed a retrospective review of the neuroradiologic features of 30 patients with complex I deficiency due to either nuclear (10 patients) or mitochondrial (20 patients) mutations. All patients had MRI abnormalities in the brainstem that were hyperintense on T2-weighted images and hypointense on T1-weighted images. Brainstem lesions were associated with at least 1 striatal anomaly (putamen or caudate) in 27 of 30 patients. Ten patients had thalamic anomalies, all of whom also had striatal lesions. Caudate lesions were more common in patients with mtDNA (50%) compared to those with nuclear (10%) mutations. Stroke-like lesions predominantly affecting the gray matter were observed in 40% of patients with mtDNA mutations, but in none of patients with nuclear mutations. A diffuse supratentorial leukoencephalopathy involving the deep lobar white matter was observed in over 50% of patients with nuclear mutations, but in none of patients with mtDNA mutations. Cerebellar hyperintensities were found in 45% of patients, regardless of the mutated genome, but cerebellar atrophy was found only in those with mtDNA mutations. All 10 patients studied had increased lactate on magnetic resonance spectroscopy.
Mutations in the nuclear-encoded genes NDUFS1, NDUFS4, NDUFS7, NDUFS8, and NDUFV1 result in neurologic diseases, mostly Leigh syndrome or Leigh-like syndrome. Mutations in NDUFS2 and NDUFV2 have been associated with hypertrophic cardiomyopathy and encephalomyopathy. Mutations in the mitochondrial-encoded ... Mutations in the nuclear-encoded genes NDUFS1, NDUFS4, NDUFS7, NDUFS8, and NDUFV1 result in neurologic diseases, mostly Leigh syndrome or Leigh-like syndrome. Mutations in NDUFS2 and NDUFV2 have been associated with hypertrophic cardiomyopathy and encephalomyopathy. Mutations in the mitochondrial-encoded genes are associated with a wide variety of clinical symptoms, ranging from organ-specific to multisystem diseases (Benit et al., 2004). Swalwell et al. (2011) reviewed the clinical and genetic findings in a large cohort of 109 pediatric patients with isolated complex I deficiency from 101 families. Pathogenic mtDNA mutations were found in 29% of probands: 21 in MTND subunit genes and 8 in mtDNA tRNA genes. Nuclear gene defects were inferred in 38% of probands based on cell hybrid studies, mtDNA sequencing, or mutation analysis. The most common clinical presentation was Leigh or Leigh-like disease in patients with either mtDNA or nuclear genetic defects. The median age at onset was later in mtDNA patients (12 months) compared to patients with a nuclear gene defect (3 months), although there was considerable overlap. The report confirmed that pathogenic mtDNA mutations are a significant cause of complex I deficiency in children.
Smeitink and van den Heuvel (1999) reviewed the nuclear gene mutations that had been identified in patients with isolated complex I deficiency. These included a 5-bp duplication in the NDUFS4 gene (602694.0001), a double mutation in the NDUFS8 ... Smeitink and van den Heuvel (1999) reviewed the nuclear gene mutations that had been identified in patients with isolated complex I deficiency. These included a 5-bp duplication in the NDUFS4 gene (602694.0001), a double mutation in the NDUFS8 gene (P79L, R102H; see 602141.0001), a mutation in the NDUFS7 gene (V122M; 601825.0001), and 2 mutations in the NDUFV1 gene: a double mutation (R59X, T423M; see 161015.0001) and a single-amino acid substitution (A341V; 161015.0003). In a patient with a severe progressive form of encephalopathy, Ogilvie et al. (2005) identified a homozygous mutation in the B17.2L gene (609653.0001). Calvo et al. (2010) used high-throughput, pooled sequencing of candidate genes to analyze 60 patients with complex I deficiency. Using this method, a molecular basis for the disorder was found in 13 of 60 previously unsolved cases. Mutations in known disease-associated genes were found in 11 patients, and 2 unrelated patients had mutations in 2 novel disease-associated genes: NUBPL (613621) and FOXRED1 (613622). Fassone et al. (2010) described an Iranian-Jewish child with complex I deficiency caused by homozygosity for an arg354-to-trp mutation in FOXRED1 (613622.0003). Silencing of FOXRED1 in human fibroblasts resulted in reduced complex I steady-state levels and activity, while lentiviral-mediated FOXRED1 transgene expression rescued complex I deficiency in the patient fibroblasts. The authors concluded that this FAD-dependent oxidoreductase is a complex I-specific molecular chaperone. In 4 patients from 3 families with severe mitochondrial complex I deficiency and very low complex I activity (less than 30% of normal), Hoefs et al. (2010) identified 5 different biallelic mutations in the NDUFS1 gene (see, e.g., 157655.0006-157655.0008). Patient cells also showed decreased amounts of fully assembled complex I and accumulation of subcomplexes, indicating disturbance in the assembly or stability of complex I. All patients had a severe, progressive disease course resulting in death in childhood due to neurologic disability. Brain MRI performed in 2 patients showed severe and progressive white matter abnormalities. Hoefs et al. (2010) suggested that patients with very low complex I deficiency should be specifically screened for NDUFS1 mutations. Using exome sequencing, Haack et al. (2012) identified biallelic mutations in nuclear-encoded genes in 7 (70%) of 10 unrelated index patients with isolated complex I deficiency. The genes mutated included NDUFB3 (603839.0001 and 603839.0002), NDUFS3 (603846.0002), NDUFS8 (602141.0005-602141.0007), ACAD9 (611103.0006; see 611126), and MTFMT (611766.0001 and 611766.0004; see 256000). Swalwell et al. (2011) reviewed the clinical and genetic findings in a large cohort of 109 pediatric patients with isolated complex I deficiency from 101 families. Pathogenic mtDNA mutations were found in 29% of probands: 21 in MTND subunit genes and 8 in mtDNA tRNA genes. Nuclear gene defects were inferred in 38% of probands based on cell hybrid studies, mtDNA sequencing, or mutation analysis. The most common clinical presentation was Leigh or Leigh-like disease in patients with either mtDNA or nuclear genetic defects. The median age at onset was later in mtDNA patients (12 months) compared to patients with a nuclear gene defect (3 months), although there was considerable overlap. The report confirmed that pathogenic mtDNA mutations are a significant cause of complex I deficiency in children.