Primary CoQ10 deficiency is a rare, clinically heterogeneous autosomal recessive disorder caused by mutation in any of the genes encoding proteins directly involved in the synthesis of coenzyme Q (review by Quinzii and Hirano, 2011). Coenzyme Q10 (CoQ10), ... Primary CoQ10 deficiency is a rare, clinically heterogeneous autosomal recessive disorder caused by mutation in any of the genes encoding proteins directly involved in the synthesis of coenzyme Q (review by Quinzii and Hirano, 2011). Coenzyme Q10 (CoQ10), or ubiquinone, is a mobile lipophilic electron carrier critical for electron transfer by the mitochondrial inner membrane respiratory chain (Duncan et al., 2009). The disorder has been associated with 5 major phenotypes, but the molecular basis has not been determined in most patients with the disorder and there are no clear genotype/phenotype correlations. The phenotypes include an encephalomyopathic form with seizures and ataxia (Ogasahara et al., 1989); a multisystem infantile form with encephalopathy, cardiomyopathy and renal failure (Rotig et al., 2000); a predominantly cerebellar form with ataxia and cerebellar atrophy (Lamperti et al., 2003); Leigh syndrome with growth retardation (van Maldergem et al., 2002); and an isolated myopathic form (Lalani et al., 2005). The correct diagnosis is important because some patients may show a favorable response to CoQ10 treatment. - Genetic Heterogeneity of Primary Coenzyme Q10 Deficiency See also COQ10D2 (614651), caused by mutation in the PDSS1 gene (607429) on chromosome 10p12; COQ10D3 (614652), caused by mutation in the PDSS2 gene (610564) on chromosome 6q21; COQ10D4 (612016), caused by mutation in the COQ8 gene (ADCK3; 606980) on chromosome 1q42; COQ10D5 (614654), caused by mutation in the COQ9 gene (612837) on chromosome 16q21; and COQ10D6 (614650), caused by mutation in the COQ6 gene (614647) on chromosome 14q24. A single patient with primary CoQ10 deficiency associated with a de novo heterozygous 3.9-Mb deletion on chromosome 9q34 has been reported; the deleted region included at least 80 genes, 1 of which was COQ4 (612898) (Salviati et al., 2012). Secondary CoQ10 deficiency has been reported in association with glutaric aciduria type IIC (MADD; 231680), caused by mutation in the ETFDH gene (231675) on chromosome 4q, and with ataxia-oculomotor apraxia syndrome-1 (AOA1; 208920), caused by mutation in the APTX gene (606350) on chromosome 9p13.
Ogasahara et al. (1989) reported 2 sisters with progressive muscle weakness, abnormal fatigability, and central nervous system dysfunction since early childhood. Both sisters developed a learning disability and showed epileptiform abnormalities on EEG, although only the younger sister ... Ogasahara et al. (1989) reported 2 sisters with progressive muscle weakness, abnormal fatigability, and central nervous system dysfunction since early childhood. Both sisters developed a learning disability and showed epileptiform abnormalities on EEG, although only the younger sister developed a seizure disorder. The older sister developed progressive cerebellar symptoms at the age of 12 years. Both sisters had lactic acidemia at rest and episodic myoglobinuria. Measurement of skeletal muscle mitochondria coenzyme Q10 (CoQ10) in both girls was severely reduced (3.7% and 5.4% of normal), although levels in serum and fibroblasts were normal. The authors postulated a tissue-specific deficiency of CoQ10 in skeletal muscle and brain. Muscle mitochondrial complexes I, II, III, and IV were normal, but activities of complex I-III and complex II-III, both of which require CoQ10 as an electron carrier, were reduced. Although liquid chromatographic analysis did not show accumulation of intermediates of CoQ10 biosynthesis, Ogasahara et al. (1989) suggested that a block in CoQ10 biosynthesis was likely. Sobreira et al. (1997) reported a patient with delayed motor development, proximal weakness, exertional fatigue, episodic exercise-induced myoglobinuria, and seizures. Serum creatine kinase and lactate were elevated. Skeletal muscle biopsy showed ragged-red fibers, cytochrome c oxidase-deficient fibers, and excess lipid; mitochondrial CoQ10 concentration was less than 25% of normal. Boitier et al. (1998) reported a boy with delayed motor development, proximal weakness, elevated creatine kinase, cerebellar ataxia, seizures, mild pigmentary degeneration of the retina, and elevated serum and CSF lactate. Muscle biopsy showed ragged-red fibers, abnormal mitochondria, and lipid droplets. The patient had markedly decreased skeletal muscle mitochondria CoQ10 content (6% of normal). Di Giovanni et al. (2001) reported 2 brothers with myopathic 'partial' CoQ10 deficiency (39% and 35% of normal). Rotig et al. (2000) reported a family in which 3 affected sibs had CoQ10 deficiency in multiple tissues, affecting multiple organ systems in addition to skeletal muscle and CNS. A boy developed nephrotic syndrome resulting in renal failure and necessitating kidney transplant, progressive ataxia, generalized amyotrophy, retinitis pigmentosa, bilateral sensorineural deafness, and hypertrophic cardiomyopathy. He was wheelchair-bound by age 12 years. An older sister had a severe form of the disorder, with symptoms similar to her brother, and died at age 8 years after rapid neurologic deterioration. Another sister had sensorineural deafness, nystagmus, ataxia, mild mental retardation, and nephrotic syndrome with glomerular sclerosis. Biochemical activity analysis indicated CoQ10 deficiency in lymphocytes and fibroblasts, and direct measurement detected no CoQ10 in fibroblasts. Further analysis showed a specific defect in the ability to synthesize CoQ10, which prompted Rotig et al. (2000) to examine trans-prenyltransferase (PDSS1; 607429), the enzyme that elongates the prenyl side-chain of the quinone. However, sequence analysis of PDSS1 failed to detect a disease-causing mutation. Musumeci et al. (2001) reported 6 patients, 3 of whom were sibs, with similar clinical features including cerebellar ataxia, cerebellar atrophy, and muscle CoQ10 deficiency that was responsive to CoQ10 supplementation. Variable findings included seizures, cognitive impairment, myoclonus, weakness, and scoliosis. CoQ10 concentration in muscle ranged from 26 to 35% and in fibroblasts from 54 to 71%, both of which were significantly decreased from controls. In the 3 sibs with cerebellar ataxia, cerebellar atrophy, and muscle CoQ10 deficiency that was responsive to CoQ10 supplementation reported by Musumeci et al. (2001), Quinzii et al. (2005) identified a mutation in the aprataxin gene (APTX; 606350.0006), consistent with ataxia-oculomotor-apraxia syndrome (AOA; 208920). The CoQ10 deficiency was believed to be secondary in these patients. Quinzii et al. (2005) found that 2 other patients reported by Musumeci et al. (2001) and 11 additional patients with CoQ10 deficiency did not have mutations in the APTX gene, suggesting that it is not a common cause of CoQ10 deficiency. Van Maldergem et al. (2002) reported 2 sisters with facial dysmorphism who had axial hypotonia and failure to thrive in infancy. Other phenotypic characteristics included mental retardation, abnormal gait, spasticity, hyperreflexia, muscle atrophy, elevated lactic acid, and hypersignals in the caudate and putamen in 1 patient. They were both given a diagnosis of Leigh syndrome (256000). Supplementation with CoQ10 resulted in marked clinical improvement. Investigation revealed markedly decreased muscle CoQ10 levels: 5% in 1 sister before treatment and 60% in the other during treatment. Lymphoblasts from both sisters showed 50% reduction of CoQ10. Van Maldergem et al. (2002) suggested that CoQ10 deficiency can present as Leigh syndrome. Lamperti et al. (2003) detected marked CoQ10 deficiency in 18 of 135 muscle biopsies from patients with genetically undefined cerebellar ataxia. Thirteen of the patients developed ataxia affecting the trunk, limbs, and speech by age 10 years; some had onset in infancy. Variable associated features included seizures, developmental delay, mental retardation, pyramidal signs, myoclonus, and ophthalmoparesis. The disease course was progressive. All patients showed cerebellar atrophy on MRI, and most had normal muscle biopsies. Gironi et al. (2004) reported 2 brothers with late-onset CoQ10 deficiency at ages 39 and 30, respectively, characterized by cerebellar ataxia, muscle cramps, exercise intolerance, and memory impairment. Brain imaging showed cerebellar atrophy. In addition, both patients had hypergonadotropic hypogonadism with decreased serum testosterone, decreased luteinizing hormone, and increased follicle-stimulating hormone. Treatment with oral CoQ10 supplementation resulted in improvement of symptoms. Lalani et al. (2005) reported a boy with exercise intolerance, ragged-red fibers, and muscle CoQ10 deficiency (46% of normal), but without myoglobinuria or central nervous system involvement. Treatment with CoQ10 supplementation resulted in significant clinical improvement. The case expanded the clinical spectrum of the disorder. - Patients with Demonstrated Mutations in the COQ2 Gene Salviati et al. (2005) reported a 33-month-old boy with infantile encephalomyopathy, nephropathy, and deficiency of coenzyme Q10. The disease appeared to be an autosomal recessive trait because the patient's parents were first cousins and his 9-month-old sister with nephropathy also had coenzyme Q10 deficiency in fibroblasts. The proband presented with proteinuria at age 12 months; a renal biopsy revealed focal and segmental glomerulosclerosis. Neurologic evaluation showed hypotonia, mild psychomotor delay, and optic atrophy. After the demonstration of coenzyme Q10 deficiency and initiation of CoQ10 supplementation, the neurologic manifestations improved dramatically. Diomedi-Camassei et al. (2007) reported 2 unrelated children with CoQ10 deficiency who manifested with severe early-onset nephrotic syndrome. The first patient was a 22-month-old boy of Eastern European origin who developed rapidly progressive steroid-resistant nephrotic syndrome at age 18 months and began peritoneal dialysis. Renal biopsy showed podocyte hypertrophy and collapsing glomerulopathy. The tubulointerstitial compartment showed extensive microcyst formation, focal tubular atrophy, and interstitial fibrosis. Ultrastructural examination showed podocytes that had extensive foot process effacement and contained abnormal mitochondria. He had no sign of neuromuscular involvement. The second patient was a 6-month-old Italian boy who presented in the neonatal period with nephrotic syndrome. Renal biopsy showed crescentic glomerulonephritis. At age 3 months, he developed drug-resistant seizures, status epilepticus, and encephalopathy, leading to an unresponsive state, respiratory failure, and death at age 6 months. Brain MRI showed stroke-like lesions and cerebral atrophy. He also had increased CSF lactate. An older sister had died at age 18 hours of metabolic acidosis and respiratory distress. Both patients had decreased CoQ10 and decreased activity of mitochondrial complex II+III in renal cortex and skeletal muscle. Mollet et al. (2007) reported a French family with CoQ10 deficiency due to mutation in COQ2 that manifested in 2 sibs as fatal infantile multiorgan disease including anemia, pancytopenia, liver failure, and renal insufficiency. Enzymologic analysis showed low quinone-dependent oxidative phosphorylation activity in affected members, and CoQ10 deficiency was confirmed by restoration of oxidative phosphorylation activity after quinone addition.
In 2 sibs with consanguineous parents and the infantile form of coenzyme Q10 deficiency, described clinically by Salviati et al. (2005), Quinzii et al. (2006) identified a homozygous missense mutation in the COQ2 gene (Y297C; 609825.0001). The mutation ... In 2 sibs with consanguineous parents and the infantile form of coenzyme Q10 deficiency, described clinically by Salviati et al. (2005), Quinzii et al. (2006) identified a homozygous missense mutation in the COQ2 gene (Y297C; 609825.0001). The mutation occurred at a highly conserved residue within a predicted transmembrane domain. Radioisotope assays confirmed the severe defect of coenzyme Q10 biosynthesis in the fibroblasts of 1 of the sibs. This mutation in COQ2 was the first molecular cause of primary coenzyme Q10 deficiency to be identified. Mollet et al. (2007) reported a French family with coenzyme Q10 deficiency in which a son and daughter died shortly after birth due to anemia, liver failure, and renal insufficiency. In the affected son, they identified a homozygous 1-bp deletion in exon 7 of the COQ2 gene (609825.0002), resulting in a premature stop codon. The parents were heterozygous for the mutation, which was absent in controls. In 2 unrelated patients with infantile-onset rapidly progressive nephrotic syndrome, Diomedi-Camassei et al. (2007) identified homozygous or compound heterozygous mutations in the COQ2 gene (609825.0003-609825.0005).