ORPHA: 254905; DO: 0070495;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q23.3 | Mitochondrial complex IV deficiency, nuclear type 8 | 619052 | Autosomal recessive | 3 | TACO1 | 612958 |
A number sign (#) is used with this entry because of evidence that mitochondrial complex IV deficiency nuclear type 8 (MC4DN8) is caused by homozygous mutation in the TACO1 gene (612958) on chromosome 17q23.
Mitochondrial complex IV deficiency nuclear type 8 (MC4DN8) is an autosomal recessive metabolic disorder characterized by the onset of neuromuscular symptoms in the first decade of life after normal early development. Affected individuals develop a slowly progressive decline in neurologic function with gait difficulties, spasticity, dysarthria, hypotonia, and variable intellectual disability. Other features may include facial hypotonia, optic atrophy with visual impairment, nystagmus, muscle rigidity, and loss of ambulation. Rare patients may have renal tubulopathy. Brain imaging shows T2-weighted hyperintensities in the basal ganglia, consistent with a clinical diagnosis of Leigh syndrome (see 256000). Serum lactate is often increased, and patient tissues show decreased levels and activity of mitochondrial respiratory complex IV (summary by Seeger et al., 2010).
For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Seeger et al. (2010) reported the clinical and neuropathologic findings of members of a consanguineous Kurdish family previously found by Weraarpachai et al. (2009) to have cytochrome c oxidase deficiency with late-onset Leigh syndrome (see 256000) and a homozygous mutation in the TACO1 gene. The 5 reported patients ranged in age from 12.5 to 26 years. All had normal early development with onset of the disorder between 4 and 13 years of age. The clinical course, features, and severity were highly variable. Two male patients presented with gait abnormalities, and later had spastic gait, spastic tetraparesis, dystonia, and dysarthria. These patients also had mild to moderate mental retardation. One was more severely affected, with optic atrophy, hypotonia, pyramidal signs, and renal tubulopathy. Three female patients had a slightly milder phenotype, but also had mild to moderate motor symptoms and mild cognitive impairment; 1 had optic atrophy. Other features included poor overall growth and hypotonia with facial weakness. Brain MRI of all patients showed T2-weighted hyperintense lesions in the basal ganglia and cortical regions. The degree of motor impairment seemed to correlate with putaminal lesions. Muscle biopsy of 1 patient showed severe COX deficiency (15% residual activity). Seeger et al. (2010) noted the relatively late onset of neurologic dysfunction and slow progression in these patients.
Makrythanasis et al. (2014) reported 2 sibs (family 37), born of consanguineous Egyptian parents, with delayed development, impaired intellectual development, extrapyramidal signs, rigidity, hyperreflexia, nystagmus, regression in walking, dystonia, and muscle wasting. Brain imaging showed white matter abnormalities in the basal ganglia.
The transmission pattern of MC4DN8 in the family reported by Weraarpachai et al. (2009) was consistent with autosomal recessive inheritance.
In affected members of a family with childhood-onset and slowly progressive mitochondrial complex IV deficiency manifest as Leigh syndrome, Weraarpachai et al. (2009) identified a homozygous frameshift mutation (612958.0001) in the TACO1 gene. Synthesis of the MTCO1 subunit was decreased by approximately 65%, and there was a greatly reduced steady-state level of fully assembled complex IV. Expression of wildtype TACO1 rescued the MTCO1 assembly defect and complex IV activity.
In 2 sibs, born of consanguineous Egyptian parents, mitochondrial complex IV deficiency manifest as Leigh syndrome, Makrythanasis et al. (2014) identified a homozygous truncating mutation in the TACO1 gene (R141X; 612958.0002). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies were not performed.
Makrythanasis, P., Nelis, M., Santoni, F. A., Guipponi, M., Vannier, A., Bena, F., Gimelli, S., Stathaki, E., Temtamy, S., Megarbane, A., Masri, A., Aglan, M. S., and 23 others. Diagnostic exome sequencing to elucidate the genetic basis of likely recessive disorders in consanguineous families. Hum. Mutat. 35: 1203-1210, 2014. [PubMed: 25044680] [Full Text: https://doi.org/10.1002/humu.22617]
Seeger, J., Schrank, B., Pyle, A., Stucka, R., Lorcher, U., Muller-Ziermann, S., Abicht, A., Czermin, B., Holinski-Feder, E., Lochmuller, H., Horvath, R. Clinical and neuropathological findings in patients with TACO1 mutations. Neuromusc. Disord. 20: 720-724, 2010. [PubMed: 20727754] [Full Text: https://doi.org/10.1016/j.nmd.2010.06.017]
Weraarpachai, W., Antonicka, H., Sasarman, F., Seeger, J., Schrank, B., Kolesar, J. E., Lochmuller, H., Chevrette, M., Kaufman, B. A., Horvath, R., Shoubridge, E. A. Mutation in TACO1, encoding a translational inactivator of COX I, results in cytochrome c oxidase deficiency and late-onset Leigh syndrome. Nature Genet. 41: 833-837, 2009. [PubMed: 19503089] [Full Text: https://doi.org/10.1038/ng.390]