A number sign (#) is used with this entry because primary coenzyme Q10 deficiency-4 (COQ10D4), also known as autosomal recessive spinocerebellar ataxia-9 (SCAR9), is caused by homozygous or compound heterozygous mutation in the ADCK3 gene (COQ8A; 606980) on chromosome 1q42.

Primary coenzyme Q10 deficiency-4 (COQ10D4) is an autosomal recessive disorder characterized by childhood-onset of cerebellar ataxia and exercise intolerance. Some affected individuals develop seizures and have mild mental impairment, indicating variable severity. Oral coenzyme Q10 supplementation does not result in significant improvement of neurologic symptoms (summary by Mollet et al., 2008 and Lagier-Tourenne et al., 2008).

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

Mollet et al. (2008) reported 4 patients, including 2 sisters, with coenzyme Q10 deficiency manifest as childhood-onset cerebellar ataxia. One patient was able to walk unaided at 1 year of age but fell frequently. He developed cerebellar ataxia and strabismus at 2 years of age. At age 2.5 years, he presented generalized tonic seizures with high lactate levels in cerebrospinal fluid (CSF). He also had truncal hypotonia and slight intellectual regression. He received oral CoQ10 for several years with no clinical benefit. His neurologic condition worsened at age 12; he became unable to walk or speak, and seizures increased in frequency, becoming consistent with epilepsia partialis continua. Brain MRI showed severe cerebellar atrophy and stroke-like anomalies. Two French sisters had childhood-onset progressive cerebellar atrophy with cerebellar ataxia, seizures, and developmental delay. Oral CoQ10 therapy yielded no clinical benefit. The fourth patient had previously been reported by Aure et al. (2004) as having early childhood-onset exercise intolerance that later progressed to cerebellar ataxia with tremor and myoclonic jerks. Laboratory studies showed decreased coenzyme Q10 and increased serum lactate and creatine kinase. Skeletal muscle biopsy showed abnormal mitochondrial aggregates and lipid accumulation. Treatment with oral coenzyme Q10 improved the exercise intolerance, but did not have much of an effect on the neurologic impairment.

Lagier-Tourenne et al. (2008) identified 7 patients with a form of autosomal recessive cerebellar ataxia, 4 from a consanguineous Algerian family. All of the patients had childhood-onset gait ataxia and cerebellar atrophy with slow progression and few associated features. Some patients had brisk tendon reflexes and Hoffmann sign. Three patients had mild psychomotor retardation, and 1 patient had mild axonal degeneration of the sural nerve. None had renal dysfunction or seizures. Exercise intolerance and elevated serum lactate were present in 3 patients. Laboratory studies showed variable coenzyme Q10 deficiency and impaired activities of respiratory complexes II+III and I+III.

Traschutz et al. (2020) reported the clinical features in 59 patients with COQ10D4. Disease onset occurred before 6 years of age in half of the patients and in all patients before 45 years of age. Cerebellar ataxia was present in all patients and was the initial presenting feature of disease in 68%. Movement abnormalities, including myoclonus, dystonia, head tremor, and postural/action tremor, were seen in 41% of patients. Cognitive impairment was reported in 49% of patients, of whom about 50% had impaired intellectual development, 33% had epilepsy, 25% had myopathic features, and 25% had neuropsychiatric symptoms. Hearing loss, stroke-like episodes, cataracts, diabetes, or optic atrophy occurred in a minority of patients. Ataxia progression over time in the patient cohort was estimated by plotting the cross-sectional ratio of ataxia severity, as quantitated by the Scale for Assessment and Rating Ataxia (SARA) score, in 34 patients. The median ataxia progression rate was estimated to be 0.47 SARA points per year, indicating a mild to moderate ataxia progression, although there was notable variability. MRIs were reported in 54 of the patients and showed cerebellar atrophy in 94%, cerebral atrophy in 8%, stroke-like abnormalities in 8%, infratentorial signal abnormalities in 4%, and brainstem atrophy in 2%. A few patients had a comparatively severe disease trajectory, including one patient (P31) who never learned to walk due to severe motor and cognitive impairment and eventually developed drug-resistant epilepsy and tetraparesis, and another patient (P24) who had intractable seizures and died at age 17 years of dilated cardiomyopathy.

Traschutz et al. (2020) reported outcomes of coenzyme Q10 supplementation in 30 patients with COQ10D4 who were treated with an average daily dose of 11 mg/kg/day. Based on clinical reports, 13 of the patients had a positive clinical response, and 15 were considered to be nonresponders; 2 had side-effects (anorexia or diarrhea). Qualitative descriptions of treatment effects included improvement of ataxia, tremor, dystonia, epilepsy, and/or muscle weakness. No associations were observed between treatment response and age of disease onset, age and disease duration at treatment initiation, ataxia severity, cumulative daily dose, or COQ8A mutation type. Longitudinal treatment assessment of ataxia using the SARA score was available for 11 of the 30 patients. Annual change in SARA score across the 11 patients showed an average improvement of -0.88 points per year with CoQ10 treatment.

The transmission pattern of CoQ10 deficiency in the families reported by Mollet et al. (2008) and Lagier-Tourenne et al. (2008) was consistent with autosomal recessive inheritance.

By a single-nucleotide polymorphism (SNP)-based genomewide scan in a large consanguineous Algerian family, Lagier-Tourenne et al. (2008) mapped a locus for autosomal recessive ataxia on chromosome 1q41.

In 4 patients from 3 families with primary coenzyme Q deficiency-4 manifest as autosomal recessive childhood-onset cerebellar ataxia, Mollet et al. (2008) found homozygosity or compound heterozygosity for mutations in the ADCK3 gene (606980.0001-606980.0005). Mollet et al. (2008) introduced the missense mutations into the yeast Coq8 gene and expressed them in a Saccharomyces cerevisiae strain in which Coq8 was deleted. All the missense mutations resulted in a respiratory phenotype with no or decreased growth on glycerol medium and a severe reduction in ubiquinone synthesis, demonstrating that these mutations alter the protein function.

In affected members of a consanguineous Algerian family with childhood-onset cerebellar ataxia, Lagier-Tourenne et al. (2008) identified a homozygous splice site mutation in the ADCK3 gene (606980.0006). Five additional mutations in ADCK3 were found in 3 patients with sporadic ataxia, including 1 known to have coenzyme Q10 deficiency in muscle (Lamperti et al., 2003).

Traschutz et al. (2020) studied 64 patients from 51 families with biallelic variants in the COQ8A gene from 15 different ataxia centers in Europe and North America. Twenty-six patients were from families with 2 affected sibs, and 21 patients from 14 families were born to consanguineous parents. Fifty-nine patients, 39 of whom were not previously reported, had 2 likely pathogenic mutations, whereas 5 patients had variants of unknown significance on one or both copies of the COQ8A gene. In the 64 patients, Traschutz et al. (2020) identified 44 different likely pathogenic mutations, 18 of which were novel, including 26 missense mutations and 18 presumed loss-of-function (LOF) mutations (10 frameshift, 4 stop, 3 splice site, and 1 in-frame deletion). The mutations were spread across the COQ8A gene, with many missense mutations clustered near or within functional motifs.

Traschutz et al. (2020) studied genotype/phenotype correlations in 17 patients with biallelic presumed loss-of-function mutations in the COQ8A gene and 28 patients with biallelic missense mutations in COQ8A gene. They found that patients with an 'ataxia-simplex phenotype,' i.e., cerebellar ataxia without cognitive impairment, epilepsy, myoclonus/dystonia or exercise intolerance, was more frequent in patients with biallelic LOF variants than in patients with missense variants, and conversely, missense variants were more often associated with multisystemic involvement beyond ataxia. Among the patients with biallelic missense variants, the 'ataxia simplex phenotype' and absence of epilepsy was found only for missense variants within the AAAS motif, suggesting that these mutations may be functionally equivalent to LOF mutations. Compared to other missense variants, variants affecting helix GQ-alpha-1 in the KxGQ domain were more frequently associated with developmental delay, epilepsy, and pyramidal signs. Collectively, these data indicated that multisystemic phenotypes, including epilepsy and myoclonus, may be more frequently associated with missense variants than LOF variants, suggesting that missense variants may have a possible gain-of-function or dominant-negative mechanism of pathogenicity.

Because cerebellar ataxia dominated the clinical presentation, Lagier-Tourenne et al. (2008) proposed to name this entity ARCA2 for 'autosomal recessive cerebellar ataxia-2,' following the identification of ARCA1 (610743).