Combined Oxidative Phosphorylation Deficiency 12

A number sign (#) is used with this entry because combined oxidative phosphorylation deficiency-12 (COXPD12) is caused by homozygous or compound heterozygous mutation in the EARS2 gene (612799) on chromosome 16p.

Description

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).

Clinical Features

Steenweg et al. (2012) reported a 6-year-old Italian boy with a leukoencephalopathy apparent since early infancy. Hypotonia was noted at 1 month of age, and he did not have head control at 3 months. The patient developed seizures at age 6 months, which later remitted. At age 6 years, he had spastic tetraparesis, dystonia, bradykinesia, ptosis, ophthalmoplegia, visual deficits, and absence of speech. He never achieved postural or head control and could not chew. Laboratory studies showed intermittent increases of serum transaminases, increased alpha-fetoprotein (AFP; 104150), and increased serum lactate. Muscle biopsy showed cytochrome c oxidase (COX)-negative fibers and reduced complex I, III, and IV, indicating a mitochondrial defect. Steenweg et al. (2012) identified 11 additional patients with a similar brain magnetic resonance imaging (MRI) pattern from a database of patients with leukoencephalopathies of unknown origin. Three of the patients had a more severe phenotype similar to that of the Italian boy. The severe phenotype was characterized by onset soon after birth of hypotonia and lack of psychomotor development followed by spastic tetraparesis, dystonia, visual impairment, and seizures. These patients later stabilized, but failed to improve and remained severely disabled and eventually were tube-fed. Eight of the additional patients had a milder form of the disorder. They had normal or mildly delayed early development with onset of regression later in the first year of life. Regression included spasticity, loss of milestones, and sometimes seizures and extreme irritability. However, from the second year on, these patients showed clinical and biochemical improvement. They regained milestones, including walking, and seizures and spasticity improved. Lactate levels decreased and normalized, and brain MRI abnormalities improved. Of note, there were 2 affected brothers: 1 had the milder phenotype and the other had the more severe phenotype. Steenweg et al. (2012) interpreted the data as pointing to a biphasic clinical course. The severity of an initial hit early in life predicts whether or not a patient shows neurologic recovery and progress or has severe and permanent handicap.

Talim et al. (2013) reported a male infant, born of consanguineous parents, with multiple congenital anomalies and multisystem dysfunction resulting in death at age 3 months from bronchopneumonia. Hypospadias and incomplete cleft palate were noted at birth, and he presented with hypotonia, failure to thrive, and lactic acidosis in the neonatal period. Brain MRI at age 1 month showed dysgenesis in the posterior part of corpus callosum; white matter abnormalities were not noted. He did not have seizures, but did not achieve any motor milestones. Other features included hepatomegaly, elevated liver enzymes, and mild hypertrophy of the cardiac interventricular septum. Skeletal muscle biopsy showed ragged-red and ragged-blue fibers, COX deficiency, and severe combined deficiency of respiratory chain complexes I and IV. Postmortem examination of the liver showed macrovesicular steatosis with mild fibrosis and cholestasis.

Neuroradiologic Findings

Brain MRI of the Italian boy reported by Steenweg et al. (2012) showed T2-weighted hyperintensities of the deep cerebral white matter, including the thalami and hypothalami, as well as in the brainstem and cerebellum, with sparing of the periventricular region. The posterior part of the corpus callosum was abnormally thin. Proton magnetic resonance spectroscopy (MRS) showed increased lactate in the cerebral white matter. Eleven additional patients with a similar brain MRI pattern were identified from a large database. They had signal abnormalities and swelling of the deep cerebral white matter with sparing of the periventricular rim. The corpus callosum, thalamus, basal ganglia, midbrain, pons, medulla, and cerebellar white matter were consistently affected. In 5 patients, the posterior part of the corpus callosum was abnormally thin. Three patients with a more severe clinical phenotype had a dysplastic corpus callosum with agenesis of the posterior part and abnormal positioning of the lateral ventricles.

Inheritance

The transmission pattern of COXPD12 in the families reported by Steenweg et al. (2012) and Talim et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In an Italian boy with COXPD12 manifest as leukoencephalopathy with thalamus and brainstem involvement and high lactate, Steenweg et al. (2012) identified compound heterozygosity for 2 mutations in the EARS2 gene (612799.0001 and 612799.0002). The mutations were found by exome sequencing in the patient. Subsequent analysis of the EARS2 gene in additional patients with a similar phenotype identified compound heterozygous mutations in 11 patients (see, e.g., 612799.0001; 612799.0003-612799.0006).

Talim et al. (2013) identified a homozygous mutation in the EARS2 gene (612799.0007) in a Turkish patient with COXPD12. The mutation was identified by exome sequencing.