A number sign (#) is used with this entry because of evidence that coenzyme Q10 deficiency-8 (COQ10D8) is caused by homozygous or compound heterozygous mutation in the COQ7 gene (601683) on chromosome 16p12.

Primary coenzyme Q10 deficiency-8 (COQ10D8) is characterized by a clinical spectrum ranging from spasticity or mildly progressive encephaloneuronephrocardiopathy to a fatal multisystemic disorder (Kwong et al., 2019).

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

Freyer et al. (2015) reported a 9-year-old boy, born of consanguineous Syrian parents, with a complex multisystem disorder apparent since birth and mutation in the COQ7 gene. The pregnancy was complicated by oligohydramnios, fetal lung hypoplasia, and growth retardation, but the boy was born at term. At birth, he had hypotonia, contractures of the extremities, persistent pulmonary hypertension of the newborn associated with lung hypoplasia, and renal dysfunction associated with small hypoplastic kidneys. The renal dysfunction resulted in secondary systemic hypertension with left ventricular cardiac hypertrophy. However, the renal, pulmonary, and cardiac abnormalities all normalized within the first year of life. The patient also showed delayed motor development and never learned to stand or walk independently. Other features included overall growth retardation and poor feeding requiring a gastrostomy. Electrophysiologic studies showed a combined axonal and demyelinating sensorimotor polyneuropathy; brain imaging was normal. At age 9 years, he had mild learning disabilities, hearing impairment, visual dysfunction, and progressive muscle weakness resulting in an inability to sit. Laboratory studies showed mildly increased serum and cerebrospinal fluid lactate, increased urinary fumarate and malate, and combined mitochondrial respiratory complex enzyme activity deficiency in skeletal muscle and fibroblasts. CoQ10 levels were decreased in skeletal muscle and fibroblasts. CoQ10 treatment after the diagnosis of primary CoQ10 deficiency resulted in clinical improvement. Freyer et al. (2015) emphasized the prenatal onset of renal dysfunction that later normalized, suggesting that the CoQ10 is important for kidney development and function.

Kwong et al. (2019) reported a Chinese patient with COQ10D8 who had a prenatal history of intrauterine growth restriction, cardiomegaly, and tricuspid regurgitation. On day 4 of life he developed respiratory distress and heart failure. At 26 days of life he had severe hypertrophic cardiomyopathy. He required ventilation until 7 months of age, and then required noninvasive ventilation. He had hypotonia, ptosis, severe visual impairment, hearing loss, and muscle weakness, particularly in the lower extremities. He developed infantile spasms at 10 months of age. Brain MRI demonstrated cerebral atrophy and cystic changes in the bilateral corona radiata, basal ganglia, and thalami. Renal ultrasound demonstrated renal cysts. Laboratory testing showed elevated lactate and alanine. He died at 12 months of age.

Wang et al. (2022) reported a patient with COQ10D8 who had typical early developmental milestones but global developmental delay by 15 months of age. On examination at 4.5 years of age he had hypotonia, difficulty walking, speech delay, joint contractures, spasticity, easy fatigue, and ataxia. Brain MRI showed abnormal signal in the periventricular white matter.

Wongkittichote et al. (2023) reported a 19-year-old patient with COQ10D8 who had a prenatal history of oligohydramnios requiring amnioinfusion. After birth he had pulmonary hypoplasia and required mechanical ventilation. He also had poor feeding and required tube feeding. At 4 months of age he had hypotonia, opisthotonos, myotonic jerks, and failure to thrive. A brain MR spectroscopy showed lactate peaks. Laboratory testing demonstrated elevated lactate. He had global developmental delay and sensorineural hearing loss. At 8 years of age he had autistic traits and was diagnosed with impaired intellectual development. On examination at age 19 years, he had ataxia, dysarthria, and hypotonia.

Clinical Variability

Wang et al. (2017) reported a patient with COQ10D8 who presented with developmental delay that became noticeable after a urinary tract infection at 14 months of age. At 2 years of age, she was still not walking and was found to have increased tone in the lower extremities. At 5 years of age she was diagnosed with sensorineural hearing loss. Laboratory testing demonstrated elevated lactate in the cerebrospinal fluid.

Hashemi et al. (2021) reported a patient with COQ10D8 who developed muscle weakness and stiffness in her lower extremities at 14 months of age. At 8 years of age she was diagnosed with mild hearing impairment and had decreased concentration and learning abilities. On examination, she had increased tone in the lower extremities and a scissoring gait. EMG/NCV and brain MRI were normal.

The transmission pattern of COQ10D8 in the family reported by Freyer et al. (2015) was consistent with autosomal recessive inheritance.

In a patient with COQ10D8, Freyer et al. (2015) identified a homozygous missense mutation in the COQ7 gene (V141E; 601683.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Treatment of patient cells with the CoQ10 analog 2,4-dihydroxybensoic acid (2,4DHB) was able to specifically bypass the COQ7 deficiency, increase cellular coenzyme Q10 levels, and rescue the mitochondrial biochemical defect in patient fibroblasts. Transfection of patient cells with wildtype CoQ7 also resulted in improved mitochondrial respiration.

In a patient, born of consanguineous parents, with COQ10D8, Wang et al. (2017) identified a homozygous missense mutation in the COQ7 gene (L111P; 601683.0002). The L111P mutation was present in the ExAC database at an allele frequency of 0.00001726. COQ7 with the L111P mutation was expressed in Mclk1 (the ortholog of COQ7) knockout MEF cells, and mutant COQ7 protein expression was almost undetectable and ubiquinone production was reduced compared to wildtype. The L111P mutation on both alleles was in cis with a T103M substitution, which was considered likely to be a benign polymorphism due to the allele frequency of 0.627 and 24,314 homozygotes reported in the ExAC database. Interestingly, when COQ7 with both the L111P and T103M mutations was expressed in Mclk1 knockout MEF cells, a greater decrease in ubiquinone was seen compared to the L111P mutant alone.

In an Iranian patient, born of consanguineous parents, with COQ10D8, Hashemi et al. (2021) identified homozygosity for both the L111P mutation and the T103M polymorphism in the COQ7 gene. The variants were identified by whole-exome sequencing.

In a Chinese patient, born of nonconsanguineous parents, with COQ10D8, Kwong et al. (2019) identified compound heterozygous mutations in the COQ7 gene (c.599_600delinsTAATGCATC, 601683.0003 and R107W, 601683.0004). The mutations were identified by whole-exome sequencing. Studies in patient fibroblasts demonstrated reduced COQ10 content and a reduction in complex II+III of the mitochondrial respiratory chain.

In a Turkish patient, born to consanguineous parents, with COQ10D8, Wang et al. (2022) identified a homozygous missense mutation in the COQ7 gene (R54Q; 601683.0005). The mutation, which was identified by whole-exome sequencing, was present in heterozygous state in the parents and an unaffected sib. Analysis of patient fibroblasts showed decreased COQ7 protein expression, an increase in the coenzyme Q10 biosynthetic intermediate DMQ10, and a decrease in coenzyme Q10.

In a patient (patient 1) with COQ10D8, Wongkittichote et al. (2023) identified compound heterozygous mutations in the COQ7 gene (R54Q, 601683.0005 and Y149C, 601683.0012). Mutations corresponding to the R54Q and Y149C mutations in COQ7 were generated in the yeast ortholog, cat5 (R54Q and Y154C, respectively), and expressed in yeast that were cat5 knockouts. The resultant yeast had reduced expression of cat5 protein and demonstrated reduction in respiration rate. The R54Q mutation resulted in reduced ability of the yeast to grow on acetate, and the Y154C mutation resulted in complete inability of the yeast to grow on acetate. COQ8 overexpression in the presence of 2,4-dihydroxybenzoic acid partially rescued oxidative growth in the yeast expressing the R54Q mutant, but not the yeast expressing the Y154C mutant.