Alternative titles; symbols
ORPHA: 1561; DO: 0080357;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 22q13.33 | Mitochondrial complex IV deficiency, nuclear type 2 | 604377 | Autosomal recessive | 3 | SCO2 | 604272 |
A number sign (#) is used with this entry because of evidence that mitochondrial complex IV deficiency nuclear type 2 (MC4DN2) is caused by homozygous or compound heterozygous mutation in the SCO2 gene (604272), a COX assembly gene, on chromosome 22q13.
Mitochondrial complex IV deficiency nuclear type 2 (MC4DN2) is an autosomal recessive multisystem metabolic disorder characterized by the onset of symptoms at birth or in the first weeks or months of life. Affected individuals have severe hypotonia, often associated with feeding difficulties and respiratory insufficiency necessitating tube feeding and mechanical ventilation. The vast majority of patients develop hypertrophic cardiomyopathy in the first days or weeks of life, which usually leads to death in infancy or early childhood. Patients also show neurologic abnormalities, including developmental delay, nystagmus, fasciculations, dystonia, EEG changes, and brain imaging abnormalities compatible with a diagnosis of Leigh syndrome (see 256000). There may also be evidence of systemic involvement with hepatomegaly and myopathy, although neurogenic muscle atrophy is more common and may resemble spinal muscular atrophy type I (SMA1; 253300). Serum lactate is increased, and laboratory studies show decreased mitochondrial complex IV protein and activity levels in various tissues, including heart and skeletal muscle. Most patients die in infancy of cardiorespiratory failure (summary by Papadopoulou et al., 1999).
For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Papadopoulou et al. (1999) reported 3 unrelated infants with cytochrome c oxidase (COX) deficiency caused by mutation in the SCO2 gene who presented with a fatal infantile cardioencephalomyopathy. The infants presented in the first weeks or months of life with hypotonia and respiratory failure due to hypertrophic cardiomyopathy. Serum lactate was increased. Variable signs of neurologic dysfunction were also present, including limb dystonia, axonal and demyelinating sensorimotor neuropathy, and EEG abnormalities. One patient had dysmorphic features and distal anomalies of hands and feet. All died of cardiorespiratory failure in the first months of life. Neuropathologic examination showed neuronal loss, gliosis, and spongiform necrosis in several brain regions, including the basal ganglia, olives, cerebellum, and spinal cord; some features were compatible with a diagnosis of Leigh syndrome. One patient had abnormal gyral patterns. There was also hepatomegaly and evidence of a myopathy, suggesting systemic involvement. Heart and skeletal muscle showed reductions in COX activity, whereas liver and fibroblasts had mild COX deficiencies. Histochemistry of muscle from 2 of the patients showed reductions in COX enzyme activity in all fibers, but succinate dehydrogenase (see 600857) activity appeared normal; there were no ragged-red fibers. Immunohistochemistry showed a severe reduction of the mitochondrially encoded COX I (516030) and II (516040) subunits, whereas the nuclear-encoded COX subunits IV (123864) and Va (603773) were present but reduced in intensity.
Jaksch et al. (2000) reported 3 patients from 2 unrelated families who presented at birth or in the first months of life with hypotonia, respiratory difficulties, increased blood and CSF lactate, hypertrophic cardiomyopathy, seizures, and severely reduced COX activity in muscle tissue. All 3 patients died in infancy.
Salviati et al. (2002) reported an infant girl who presented at birth with severe hypotonia, minimal spontaneous movements, weak cry, absent reflexes, stridor, high-arched palate, and tongue fasciculations. Serum lactate was increased, and EMG showed spontaneous activity. She developed hypertrophic cardiomyopathy and died at 7 weeks of age. Analysis of patient muscle showed severe isolated COX deficiency and neurogenic abnormalities. Brain imaging and neuropathologic examination of the brain was unremarkable, but there was moderate to severe loss of motor neurons and gliosis in the ventral horns of the spinal cord, resembling SMA type I.
Tay et al. (2004) reported a woman whose first pregnancy resulted in spontaneous abortion at 11 weeks' gestation and whose second child died at age 53 days from fatal infantile cardioencephalomyopathy with compound heterozygosity for 2 mutations in the SCO2 gene (604272.0001; 604272.0002; Papadopoulou et al., 1999). Her third pregnancy also resulted in spontaneous abortion at 10 weeks' gestation, and genetic analysis showed that the aborted fetus had the same SCO2 mutations as the second affected child. Tay et al. (2004) noted that SCO2 mutations may be associated with early spontaneous abortions.
Tarnopolsky et al. (2004) reported a male neonate with MC4DN2 who presented at birth with severe hypotonia with absent reflexes, inspiratory stridor, and respiratory insufficiency requiring mechanical ventilation. Plasma lactate was increased and EMG showed fibrillations. He developed progressive hypertrophic cardiomyopathy resulting in death at 4 weeks of age. The phenotype strongly resembled spinal muscular atrophy type I.
Verdijk et al. (2008) reported 2 sibs with fatal infantile cardioencephalomyopathy. The proband presented at birth with hypotonia and respiratory insufficiency. He later developed seizures and inspiratory stridor thought to be partly due to brainstem abnormalities. Laboratory studies revealed increased lactate and pyruvate. He died at age 25 days from hypertrophic cardiomyopathy. Chest studies showed progressive hypertrophic cardiomyopathy, and postmortem examination showed cardiomyocyte cytoplasmic vacuolization. Brain imaging showed changes in the periventricular white matter, corticospinal tract, and corpus callosum compatible with mitochondrial disease. COX IV activity was decreased in heart (1% of normal control values), muscle (19%), and cultured fibroblasts (16%). Genetic analysis identified compound heterozygosity for 2 mutations in the SCO2 gene (E140K; 604272.0002 and W36X; 604272.0008). Amniocentesis performed in the second trimester of the second pregnancy identified the same mutations, and the pregnancy was terminated at 23 weeks' gestation. Autopsy showed a female fetus with a grossly enlarged heart and decreased complexity in cerebral gyral pattern indicating antenatal onset of cardiac and brain anomalies.
The transmission pattern of MC4DN2 in the families reported by Papadopoulou et al. (1999) was consistent with autosomal recessive inheritance.
In 3 unrelated infants with MC4DN2 with fatal infantile cardioencephalomyopathy, Papadopoulou et al. (1999) identified compound heterozygous mutations in the SCO2 gene (Q53X, 604272.0001; E140K, 604272.0002; S225F, 604272.0003).
In 3 affected patients from 2 families with MC4DN2 with infantile cardioencephalomyopathy, Jaksch et al. (2000) identified compound heterozygosity for mutations in the SCO2 gene (E140K; R171W, 604272.0004; 604272.0005).
In a male neonate with MC4DN2, Tarnopolsky et al. (2004) identified compound heterozygous missense mutations in the SCO2 gene (E140K; C133Y, 604272.0007). Each unaffected parent was heterozygous for one of the mutations.
Jaksch et al. (2001) reported 3 infants with MC4DN2 and slightly delayed onset of hypertrophic cardiomyopathy associated with a homozygous E140K mutation in the SCO2 gene. The infants presented between 3 and 6 months of age with poor feeding, severe hypotonia, and delayed development. All had various neurologic abnormalities, including limited extraocular movements, tongue fasciculations, abnormal respiratory pattern, limb spasticity, and EEG changes. Electrophysiologic studies showed a neurogenic myopathy and peripheral neuropathy. Serum lactate was increased. Brain imaging in 2 patients showed T2-weighted hyperintense lesions in the subcortical white matter, consistent with Leigh syndrome, and increased lactate peaks. Two patients (patients A and B) developed hypertrophic cardiomyopathy at 11 and 18 months of age, whereas the third (patient C) developed cardiomyopathy at 8 months of age. Patient C died at 8 months and patient A at 13 months; patient B was alive at 25 months. The authors noted that the phenotype in these infants was somewhat protracted compared to that of other infants with the disorder, and suggested that the genotype was associated with the variable manifestations.
Freisinger et al. (2004) reported follow-up of a patient (patient A), who was previously reported by Jaksch et al. (2001) as patient B. Freisinger et al. (2004) found that treatment of their patient A with subcutaneous and oral copper resulted in clinical improvement of the cardiomyopathy, but no improvement of the myopathic or neurologic abnormalities. This patient had severe hypotonia, including tube feeding and permanent ventilatory support, reminiscent of spinal muscular atrophy. The patient died from pneumonia at age 42 months.
Yang et al. (2010) generated mice harboring a Sco2 knockout allele and a Sco2 knockin allele expressing a E129K mutation, corresponding to the E140K (604272.0002) mutation found in almost all human SCO2-mutated patients. Whereas homozygous knockout mice were embryonic lethal, homozygous knockin and compound heterozygous knockin/knockout mice were viable, but had muscle weakness. Biochemical assay of viable mice showed respiratory chain deficiencies as well as complex IV assembly defects in multiple tissues. There was a concomitant reduction in mitochondrial copper content, but the total amount of copper in examined tissues was not reduced.
Freisinger, P., Horvath, R., Macmillan, C., Peters, J., Jaksch, M. Reversion of hypertrophic cardiomyopathy in a patient with deficiency of the mitochondrial copper binding protein Sco2: is there a potential effect of copper? J. Inherit. Metab. Dis. 27: 67-79, 2004. [PubMed: 14970747] [Full Text: https://doi.org/10.1023/B:BOLI.0000016614.47380.2f]
Jaksch, M., Horvath, R., Horn, N., Auer, D. P., Macmillan, C., Peters, J., Gerbitz, K.-D., Kraegeloh-Mann, I., Muntau, A., Karcagi, V., Kalmanchey, R., Lochmuller, H., Shoubridge, E. A., Freisinger, P. Homozygosity (E140K) in SCO2 causes delayed infantile onset of cardiomyopathy and neuropathy. Neurology 57: 1440-1446, 2001. [PubMed: 11673586] [Full Text: https://doi.org/10.1212/wnl.57.8.1440]
Jaksch, M., Ogilvie, I., Yao, J., Kortenhaus, G., Bresser, H.-G., Gerbitz, K.-D., Shoubridge, E. A. Mutations in SCO2 are associated with a distinct form of hypertrophic cardiomyopathy and cytochrome c oxidase deficiency. Hum. Molec. Genet. 9: 795-801, 2000. [PubMed: 10749987] [Full Text: https://doi.org/10.1093/hmg/9.5.795]
Papadopoulou, L. C., Sue, C. M., Davidson, M. M., Tanji, K., Nishino, I., Sadlock, J. E., Krishna, S., Walker, W., Selby, J., Glerum, D. M., Van Coster, R., Lyon, G., and 9 others. Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene. Nature Genet. 23: 333-337, 1999. [PubMed: 10545952] [Full Text: https://doi.org/10.1038/15513]
Salviati, L., Sacconi, S., Rasalan, M. M., Kronn, D. F., Braun, A., Canoll, P., Davidson, M., Shanske, S., Bonilla, E., Hays, A. P., Schon, E. A., DiMauro, S. Cytochrome c oxidase deficiency due to a novel SCO2 mutation mimics Werdnig-Hoffmann disease. Arch. Neurol. 59: 862-865, 2002. Note: Erratum: Arch. Neurol. 60: 749 only, 2003. [PubMed: 12020273] [Full Text: https://doi.org/10.1001/archneur.59.5.862]
Tarnopolsky, M. A., Bourgeois, J. M., Fu, M.-H., Kataeva, G., Shah, J., Simon, D. K., Mahoney, D., Johns, D., MacKay, N., Robinson, B. H. Novel SCO2 mutation (G1521A) presenting as a spinal muscular atrophy type I phenotype. Am. J. Med. Genet. 125A: 310-314, 2004. Note: Erratum: Am. J. Med. Genet. 130A: 218 only, 2004. [PubMed: 14994243] [Full Text: https://doi.org/10.1002/ajmg.a.20466]
Tay, S. K. H., Shanske, S., Kaplan, P., DiMauro, S. Association of mutations in SCO2, a cytochrome c oxidase assembly gene, with early fetal lethality. Arch. Neurol. 61: 950-952, 2004. [PubMed: 15210538] [Full Text: https://doi.org/10.1001/archneur.61.6.950]
Verdijk, R. M., de Krijger, R., Schoonderwoerd, K., Tiranti, V., Smeets, H., Govaerts, L. C. P., de Coo, R. Phenotypic consequences of a novel SCO2 gene mutation. Am. J. Med. Genet. 146A: 2822-2827, 2008. [PubMed: 18924171] [Full Text: https://doi.org/10.1002/ajmg.a.32523]
Yang, H., Brosel, S., Acin-Perez, R., Slavkovich, V., Nishino, I., Khan, R., Goldberg, I. J., Graziano, J., Manfredi, G., Schon, E. A. Analysis of mouse models of cytochrome c oxidase deficiency owing to mutations in Sco2. Hum. Molec. Genet. 19: 170-180, 2010. [PubMed: 19837698] [Full Text: https://doi.org/10.1093/hmg/ddp477]