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COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 45; COXPD45

COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 45; COXPD45

Combined oxidative phosphorylation deficiency-45 (COXPD45) is an autosomal recessive multisystem disorder characterized by poor overall growth apparent from infa...

Combined oxidative phosphorylation deficiency-45 (COXPD45) is an autosomal recessive multisystem disorder characterized by poor overall growth apparent from infancy, global developmental delay, seizures, and acute progressive neurologic deterioration with loss of skills. Other features may include dysmorphic facies and lesions on brain imaging. Laboratory studies show increased serum lactate and COXPD in patient tissues, consistent with a mitochondrial defect (summary by Serre et al., 2013).

For discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

▼ Clinical Features

Serre et al. (2013) reported a boy, born of consanguineous Roma Gypsy parents, with COXPD45. He presented at birth with severe hypotrophy and later showed failure to thrive with poor overall growth. He had mild muscle weakness, but started walking with aid at 12 months. Increased plasma lactate prompted analysis of mitochondrial respiratory chain enzyme activity, which demonstrated a combined OXPHOS deficiency in muscle, liver, and skin fibroblasts. Complexes I and IV were particularly affected. At age 2, he developed seizures and had rapid neurologic deterioration associated with an acute infection and fever. He then showed psychomotor retardation, severe trunk hypotonia, inability to sit or stand unaided, no speech, intermittent horizontal nystagmus, cerebellar ataxia, and tremor. Brain imaging showed white matter abnormalities and lesions in the basal ganglia. His condition continued to deteriorate and he died after cardiac arrest. Mild facial dysmorphisms were noted, including round face, epicanthic folds, arched palate, short neck, low-set ears, and median palmar crease. During the next pregnancy, the mother expected dizygotic twins, but prenatal diagnosis based on assessment of respiratory chain enzyme activities showed a severe complex IV deficiency in fetal cells, leading to termination of the pregnancy.

▼ Inheritance

The transmission pattern of COXPD45 in the family reported by Serre et al. (2013) was consistent with autosomal recessive inheritance.

▼ Molecular Genetics

In a boy, born of consanguineous Roma Gypsy parents, with COXPD45, Serre et al. (2013) identified a homozygous missense mutation in the MRPL12 gene (A181V; 602375.0001). The mutation, which was found by a combination of homozygosity mapping and candidate gene sequencing, segregated with the disorder in the family. The mutation was not found in the dbSNP database or in 100 ethnically matched controls. In a subsequent pregnancy, affected dizygotic twin fetuses were also found to carry this homozygous mutation; the pregnancy was terminated. The steady-state level of MRPL12 in patient fibroblasts was reduced to 30% of control values, and there was altered integration into the large ribosomal subunit. In vitro translation studies showed a reduction in the synthesis of subunits in mitochondrial complexes I, II, and III, but no aberrant translation products were identified.

Tags: 17q25.3