Combined Oxidative Phosphorylation Deficiency 10

A number sign (#) is used with this entry because combined oxidative phosphorylation deficiency-10 (COXPD10) is caused by homozygous or compound heterozygous mutation in the MTO1 gene (614667) on chromosome 6q13.

Description

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).

Clinical Features

Ghezzi et al. (2012) reported 2 Italian sibs, born of unrelated parents, with fatal infantile hypertrophic cardiomyopathy. Both patients showed reduced fetal growth. The first presented soon after birth with lactic acidosis and severe hypoglycemia. Electroencephalogram (EEG) and cerebral, hepatic, and splenic echography were normal. Interventricular septum hypertrophy of the heart was detected on the fifteenth day of life, and he died of sudden bradycardia on day 19. Skin fibroblasts showed a reduction of mitochondrial complex III (60% of control) and complex IV (56%) of control. The patient's younger sister had severe metabolic acidosis at birth with increased blood lactate. Treatment with biotin, coenzyme Q10, thiamine, and dichloroacetate (DCA) resulted in stabilization. She became tachycardic on day 7, but heart ultrasound did not show abnormalities until day 38, when hypertrophy of the septum and left ventricular wall were seen. She died of sudden bradycardia on day 40. Autopsy showed cardiomegaly, pleural effusion, and ascites. Muscle tissue showed decreased complex I and complex IV activity (both 27% of control), whereas fibroblasts showed only decreased complex I activity. An unrelated boy from northeastern Italy had a similar disorder with a better outcome. At age 1 month, he presented with poor feeding, hyperpnea, weakness, and lack of ocular fixation. Physical examination showed hepatomegaly, lactic acidosis, and hypertrophic cardiomyopathy with reduced left ventricular function. Muscle tissues showed reduced activities of complex I (12% of control) and complex IV (30%). Treatment with DCA resulted in marked improvement of both metabolic acidosis and cardiomyopathy. After 9 months of DCA therapy, a cardiac ultrasound examination showed a normal-sized heart, with normal left ventricular wall thickness and function, and low blood lactate. He showed good growth and normal neurologic development in childhood, and DCA was stopped at age 12 years. Muscle biopsy at 17 years showed severe reduction of complex I (7%) and complex IV (35%). Cardiac evaluation at age 19 years showed hypertrophic cardiomyopathy with an ejection fraction of 60% and sinus bradycardia. Neurologic examination was normal except for a small reduction of fine movements and optic atrophy.

Baruffini et al. (2013) reported 5 patients from 3 unrelated families with COXPD10 manifest as infantile cardiomyopathy and lactic acidosis. Three patients presented at birth or in the first days of life with poor feeding, hypotonia, and failure to thrive, whereas 2 sibs presented in the first months of life with cardiomyopathy. One patient had Wolff-Parkinson-White syndrome (194200). The disease course was highly variable: 2 sibs died at ages 3 and 12 months, whereas 2 other sibs and an unrelated girl were alive in their teens with stable cardiac disease. The 3 patients who survived were treated aggressively with dichloroacetate (DCA) to control severe lactic acidosis. The 3 patients who survived developed psychomotor delay and other variable neurologic features, such as poor speech, dystonia, spasticity, and seizures. Brain MRI of 2 patients showed abnormal hyperintensities in deep brain structures. Patient-derived muscle samples and fibroblasts showed variable decreases of complex I and IV as well as overall defects in mitochondrial respiration.

O'Byrne et al. (2018) identified and reviewed 35 cases of COXPD10 through international collaboration. The most common features at presentation were lactic acidosis, present in 21 (62%) of 34 cases, and hypertrophic cardiomyopathy, present in 15 (44%) of 34 cases. Eventually lactic acidosis developed in all cases, and hypertrophic cardiomyopathy was described in 27 (79%) of 34 patients with this disease. Global developmental delay and/or intellectual disability were present in 28 of 29 (97%), feeding difficulties in 17 (49%) of 35, failure to thrive in 12 (34%) of 35, seizures in 12 (34%) of 35, optic atrophy in 11 (52%) of 21 cases. Ataxia was present in 7 (21%) of 34. The average age at presentation was 10.2 months (range, day 1 to 8.0 years).

Clinical Management

O'Byrne et al. (2018) reported that among 5 patients in whom a ketogenic diet was instituted, a favorable effect on seizures was seen in 2.

Inheritance

The transmission pattern of COXPD10 in the families reported by Ghezzi et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

By whole-exome sequencing of an Italian patient with COXPD10 manifest as fatal infantile hypertrophic cardiomyopathy and lactic acidosis, Ghezzi et al. (2012) identified compound heterozygous mutations in the MTO1 gene (1858dup, 614667.0001 and A428T, 614667.0002). The patient's similarly affected sib also carried the mutations. An unrelated patient with the disorder who showed better survival was homozygous for the A428T mutation. In yeast mutants, respiration and growth defects were not corrected by the truncating mutation but were partially corrected by the missense mutation. In addition, the truncating mutation caused reduced mtDNA protein synthesis, whereas the missense mutation resulted in mtDNA protein synthesis similar to wildtype. These results reflected the more severe fatal phenotype in the sibs with the truncating mutation compared to the less severe phenotype in the patient homozygous for the missense mutation.

In 5 patients from 3 unrelated families with COXPD10 manifest as infantile cardiomyopathy and lactic acidosis, Baruffini et al. (2013) identified biallelic mutations in the MTO1 gene (614667.0002-614667.0004). Studies in yeast showed that the mutations had variable detrimental effects on oxidative growth, respiratory activity, mitochondrial protein synthesis, and complex IV activity.

O'Byrne et al. (2018) described 19 different pathogenic MTO1 variants in 35 cases: 1 splice-site, 3 frameshift, and 15 missense variants. None of the cases had biallelic variants that completely inactivated MTO1; however, patients in whom 1 variant was truncating while the second was missense appeared to have a more severe, even fatal, phenotype. O'Byrne et al. (2018) argued these data suggested that complete loss of MTO1 is not viable.