| #300816 | ||||||||||
| COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 6; COXPD6 | ||||||||||
| Alternative titles; symbols | ||||||||||
| ENCEPHALOMYOPATHY, MITOCHONDRIAL, X-LINKED | ||||||||||
| Phenotype Gene Relationships | ||||||||||
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| Phenotypic Series | ||||||||||
| Clinical Synopsis | ||||||||||
| TEXT | ||||||||||
| A number sign (#) is used with this entry because combined oxidative phosphorylation deficiency-6 (COXPD6) is caused by mutation in the AIFM1 gene (300169). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060). | ||||||||||
| Clinical Features | ||||||||||
| Ghezzi et al. (2010) reported 2 Italian male infants, born of monozygotic twin sisters and unrelated fathers, who had an early-onset neurodegenerative disorder associated with dysfunction of the mitochondrial respiratory chain. Both boys had normal development in the first months of life, until psychomotor delay was noted at 5 and 11 months of age, respectively. The first child had decreased spontaneous movement of the lower right limb and continuous involuntary movements of the hands and feet. Brain MRI at age 1 year showed abnormal signals in the basal ganglia. By age 15 months, he could not stand alone, had delayed development, and showed fasciculations of the tongue, hypotonia, and areflexia. EMG and nerve conduction studies showed an axonal sensory and motor neuropathy, and lactate and pyruvate were moderately increased in plasma and cerebrospinal fluid. Muscle biopsy showed decreased mtDNA copy number (20% of control), and cultured fibroblasts showed reduced mitochondrial complexes I, II, III, and IV, ranging from 51 to 73% of normal values. He had continuing psychomotor regression, with seizures and loss of environmental contact. Supplementation with riboflavin offered some improvement, but at age 5 years, he was tetraplegic, wheelchair-bound, unable to communicate, and required permanent artificial ventilation. The other child showed a similar course, with psychomotor regression, abnormal signals in the basal ganglia, hypotonia, areflexia, and muscle weakness and wasting. Skeletal muscle biopsy showed ragged-red fibers, mtDNA depletion (35% of controls), and decreased activities of mitochondrial complexes I, II, III, IV, and V, ranging from 11 to 63% of normal values. Cultured fibroblasts showed complex III and IV activity that was below the normal range. He died suddenly in his sleep at age 16 months. | ||||||||||
| Molecular Genetics | ||||||||||
| In 2 Italian first-cousin male patients with an X-linked encephalomyopathy due to combined oxidative phosphorylation deficiency, Ghezzi et al. (2010) identified a hemizygous deletion in the AIFM1 gene (300169.0001). In vitro studies showed that the AIFM1 mutation resulted in destabilization of the inner mitochondrial membrane with subsequent damage to respiratory chain structure and activities. In addition, the mutation resulted in impaired control of mitochondrion-derived programmed cell death. | ||||||||||
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