Coenzyme Q10 Deficiency, Primary, 7

A number sign (#) is used with this entry because of evidence that primary coenzyme Q10 deficiency-7 (COQ10D7) is caused by homozygous or compound heterozygous mutation in the COQ4 gene (612898) on chromosome 9q34.

Description

Primary coenzyme Q10 deficiency-7 is an autosomal recessive disorder resulting from mitochondrial dysfunction. Most patients have onset of severe cardiac or neurologic symptoms soon after birth, usually resulting in death. Rare patients may have later onset with a more protracted course. Tissue samples from affected individuals show decreased levels of coenzyme Q10 (CoQ10) (summary by Brea-Calvo et al., 2015).

For a general phenotypic description and a discussion of genetic heterogeneity of primary coenzyme Q10 deficiency, see COQ10D1 (607426).

Clinical Features

Brea-Calvo et al. (2015) reported 6 patients from 4 unrelated families with a severe mitochondrial disorder associated with decreased CoQ10 levels. Two Italian sibs, born of unrelated parents, presented at birth with hypotonia, bradycardia, and respiratory insufficiency. One sib was confirmed to have increased serum lactate and left ventricular hypoplasia with septum hypertrophy and a patent ductus arteriosus. An unrelated patient from a second family died of hypertrophic cardiomyopathy on the first day of life, and 2 sibs from a third family had neonatal respiratory distress, cerebellar hypoplasia, and fatal epileptic encephalopathy without cardiac involvement. The last patient, an 18-year-old man with early normal development, had experienced onset of progressive motor deterioration at 10 months of age. He lost ambulation at age 6 years, developed seizures at age 12 years, and thereafter had a slowly progressive downhill course with swallowing impairment and cognitive decline. He also had a sensorimotor polyneuropathy, cerebellar atrophy, and nonspecific abnormal signal intensities on brain MRI. Skeletal muscle samples from most patients showed decreased activity of coupled complexes in the electron transport chain; however, samples from 1 patient showed increased activity of the electron transport chain. Laboratory studies showed increased serum lactate in all patients and increased urinary levels of 2-OH glutaric acid in 3 patients.

Chung et al. (2015) reported 6 girls from 4 unrelated families with severe COQ10D7 resulting in death in the first days or weeks of life or in infancy (range, 36 hours to 19 months of age). The patients presented soon after birth with hypotonia, respiratory insufficiency, feeding difficulties, and lactic acidosis. Common clinical abnormalities included encephalopathy with EEG abnormalities, neonatal seizures, cerebellar atrophy, and hypertrophic cardiomyopathy. Muscle biopsy performed on 1 patient showed decreased activity of mitochondrial respiratory complexes II and III and decreased CoQ10 levels. Neuropathologic examination of 2 patients showed neuronal loss and astrocytosis in the cerebellum, brainstem, basal ganglia, and thalamus, as well as microdysgenesis.

Inheritance

The transmission pattern of COQ10D7 in the families reported by Brea-Calvo et al. (2015) was consistent with autosomal recessive inheritance.

Cytogenetics

Salviati et al. (2012) reported a boy with a severe encephalomyopathic disorder, including poor growth, hypotonia, and delayed psychomotor development with moderate mental retardation and an inability to walk at age 3 years, associated with a de novo heterozygous 3.9-Mb deletion of chromosome 9q34; the deleted region included at least 80 genes, 1 of which was COQ4. Laboratory studies showed a reduction of mitochondrial respiratory complexes II and III in fibroblasts and a decrease of coenzyme Q content (43% of control), consistent with coenzyme Q deficiency (607426). Supplementation of coenzyme Q in patient fibroblasts resulted in correction of the complex II and III deficiencies. A 50% knockdown of COQ4 mRNA in HeLa cells resulted in an approximately 50% decrease in COQ4 protein, and haploinsufficiency of Coq4 in yeast caused a reduction in complex II and III activity. Oral supplementation with coenzyme Q using ubiquinone and subsequently ubiquinol in the patient resulted in clinical improvement. Salviati et al. (2012) maintained that haploinsufficiency for the COQ4 gene in this patient caused the CoQ deficiency, while noting that the disorder is usually inherited as an autosomal recessive trait.

Molecular Genetics

In 5 patients from 4 unrelated families with COQ10D7, Brea-Calvo et al. (2015) identified 6 different homozygous or compound heterozygous mutations in the COQ4 gene (612898.0001-612898.0006). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. In vitro functional expression studies in Coq4-null yeast showed that all the mutations resulted in a severe defect in oxidative growth, consistent with a pathogenic effect. Patient fibroblasts showed reduced COQ4, and patient skeletal muscle samples showed reduced CoQ10 content.

In 6 girls from 4 unrelated families with COQ10D7, Chung et al. (2015) identified biallelic missense mutations in the COQ4 gene (see, e.g., 612898.0003; 612898.0007-612898.0008). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. Two unrelated patients, both of Ashkenazi Jewish descent, shared the same mutation (R240C; 612898.0003), consistent with a founder effect in this population. Functional studies of the variant and studies of patient cells were not performed. The severe phenotype suggested that COQ4 is an essential component of the complex required for CoQ10 biosynthesis.