Coenzyme Q10 Deficiency, Primary, 5

A number sign (#) is used with this entry because of evidence that primary coenzyme Q10 deficiency-5 (COQ10D5) is caused by homozygous mutation in the COQ9 gene (612837) on chromosome 16q13.

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

Clinical Features

Rahman et al. (2001) reported a boy, the seventh child of healthy unrelated Pakistani parents, who presented in the first day of life with poor feeding, hypothermia, and seizures. There was a possible history of reduced fetal movements in the last trimester. Physical examination showed a passive neonate, unresponsive to his immediate environment, with a weak cry. He had generalized increased peripheral tone with decreased truncal tone. He also had lactic acidosis, renal tubulopathy, and mild left ventricular hypertrophy with global hypokinesia. MRI of the brain showed generalized cerebral and cerebellar atrophy and abnormal parenchyma. Muscle biopsy at 10 months of age showed CoQ10 deficiency. Family history revealed that 5 older sibs were healthy, but another sib had died on day 1 of life with seizures, aminoaciduria, and acidosis. The mother had previously had 5 first-trimester miscarriages.

Danhauser et al. (2016) reported a male infant, born of consanguineous Turkish parents, with COQ10D5. He was born at 36 weeks' gestation due to anhydramnion. He was small for gestational age and showed poor respiratory effort, hypotonia, bradycardia, and severe lactic acidosis. Cranial ultrasound showed multiple choroid plexus cysts and abnormal signals in the basal ganglia, suggesting a neonatal Leigh-like syndrome. He had reduced spontaneous movements with intermittent opisthotonus, seizures, and recurrent episodes of apnea, and died at 18 days of age. Patient fibroblasts showed reduced activity of mitochondrial respiratory chain complex II/III and decreased CoQ10; histologic analysis of muscle and liver biopsy were unremarkable.

Inheritance

The transmission pattern of CoQ10 deficiency in the family reported by Rahman et al. (2001) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a patient originally reported by Rahman et al. (2001), Duncan et al. (2009) demonstrated a homozygous mutation in the COQ9 gene (R244X; 612837.0001).

In a male infant, born of consanguineous Turkish parents, with COQ10D5, Danhauser et al. (2016) identified a homozygous splice site mutation in the COQ9 gene (612837.0002), resulting in a loss of function. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. COQ9 was undetectable in patient cells by immunostaining; COQ7 (601683) and CoQ10 levels were also decreased in patient cells. Expression of wildtype COQ9 in patient cells rescued the reduced activity of mitochondrial complex II/III and restored CoQ10 and COQ7 levels. In addition, treatment of patient cells with CoQ10 rescued complex II/III activity, suggesting a possible treatment strategy.

Animal Model

Garcia-Corzo et al. (2013) found that transgenic mice with a homozygous truncating R239X mutation in the Coq9 gene, which is homologous to the human R244X mutation, developed a severe encephalomyopathy with poor overall growth, impaired motor function, and progressive paralysis resulting in early death between 3 and 6 months of age. Neuropathologic examination showed neuronal death, demyelination, vacuolization, spongiform degeneration, and astrogliosis. The heart showed signs of fibrosis. The brain showed the largest impairment of mitochondrial respiratory function, with loss of ATP and respiratory complex I activity resulting in energy depletion and caspase-independent apoptosis. Mutant mice had a severe reduction of CoQ10, Coq7, and accumulation of demethoxyubiquinone-9, which is the substrate of Coq7.