Coenzyme Q10 Deficiency, Primary, 4

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.

Description

Primary coenzyme Q10 deficiency-4 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).

Clinical Features

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.

Inheritance

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.

Mapping

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.

Molecular Genetics

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).

Nomenclature

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).