Autosomal-recessive cerebellar ataxia caused by a novel ADCK3 mutation that elongates the protein: clinical, genetic and biochemical characterisation

Abstract

BackgroundThe autosomal-recessive cerebellar ataxias (ARCA) are a clinically and genetically heterogeneous group of neurodegenerative disorders. The large number of ARCA genes leads to delay and difficulties obtaining an exact diagnosis in many patients and families. Ubiquinone (CoQ10) deficiency is one of the potentially treatable causes of ARCAs as some patients respond to CoQ10 supplementation. The AarF domain containing kinase 3 gene (ADCK3) is one of several genes associated with CoQ10 deficiency. ADCK3 encodes a mitochondrial protein which functions as an electron-transfer membrane protein complex in the mitochondrial respiratory chain (MRC).MethodsWe report two siblings from a consanguineous Pakistani family who presented with cerebellar ataxia and severe myoclonus from adolescence. Whole exome sequencing and biochemical assessment of fibroblasts were performed in the index patient.ResultsA novel homozygous frameshift mutation in ADCK3 (p.Ser616Leufs*114), was identified in both siblings. This frameshift mutation results in the loss of the stop codon, extending the coding protein by 81 amino acids. Significant CoQ10 deficiency and reduced MRC enzyme activities in the index patient's fibroblasts suggested that the mutant protein may reduce the efficiency of mitochondrial electron transfer. CoQ10 supplementation was initiated following these genetic and biochemical analyses. She gained substantial improvement in myoclonic movements, ataxic gait and dysarthric speech after treatment.ConclusionThis study highlights the importance of diagnosing ADCK3 mutations and the potential benefit of treatment for patients. The identification of this new mutation broadens the phenotypic spectrum associated with ADCK3 mutations and provides further understanding of their pathogenic mechanism.

Clinical Presentations of Coenzyme Q10 Deficiency Syndrome

“…The cerebellar phenotype of CoQ 10 deficiency is apparently the most common and characterized by cerebellar ataxia and atrophy variably associated with neuropathy, seizures, mental retardation, muscle weakness, hypogonadism, and low levels of CoQ 10 in fibroblasts [Musumeci et al, 2001;Lamperti et al, 2003;Gironi et al, 2004;Artuch et al, 2006;Lagier-Tourenne et al, 2008;Mollet et al, 2008;Pineda et al, 2010;Horvath et al, 2012;Liu et al, 2013;Mignot et al, 2013]. Muscle morphology did not show ragged-red fibers and lipid storage myopathy in the first reports.…”

“…Muscle morphology did not show ragged-red fibers and lipid storage myopathy in the first reports. Some patients carry mutations in APTX [Quinzii et al, 2005;Le Ber et al, 2007;D'Arrigo et al, 2008;Castelotti et al, 2011] or in ADCK3 / CABC1 [Lagier-Tourenne et al, 2008;Mollet et al, 2008;Liu et al, 2013;Mignot et al, 2013]. The condition usually begins in childhood or adolescence, except for 2 adult brothers with cerebellar ataxia and hypogonadism described by Gironi et al [2004] and 2 patients with ADCK3 mutations with adult-onset and very mild phenotype, recently reported by Horvath et al [2012].…”

“…Supplementation with CoQ 10 has been associated with increased strength and energy level and disappearance of seizures in the affected individuals with aprataxin mutations we described [Musumeci et al, 2001;Quinzii et al, 2005], and with mild clinical improvement in patients with cerebellar ataxia associated with mutations in ADCK3 / CABC1 [Lagier-Tourenne et al, 2008;Mollet et al, 2008;Liu et al, 2013;Mignot et al, 2013]. More recently, Pineda et al [2010] assessed the clinical outcome in 14 patients with cerebellar ataxia with and without documented CoQ 10 deficiency in muscle and/or fibroblasts and unknown molecular defect and observed that all patients with CoQ 10 deficiency responded to therapy.…”

“…systemic disease [Rötig et al, 2000;Rahman et al, 2001;Leshinsky-Silver et al, 2003;Salviati et al, 2005;López et al, 2006;Quinzii et al, 2006;Mollet et al, 2007;Duncan et al, 2009;Dinwiddie et al, 2013;Jakobs et al, 2013;Scalais et al, 2013], isolated nephropathy [Diomedi-Camassei et al, 2007;Ashraf et al, 2013;McCarthy et al, 2013], or associated with sensory earing loss [Heeringa et al, 2011], cerebellar ataxia [Musumeci et al, 2001;Lamperti et al, 2003;Auré et al, 2004;Gironi et al, 2004;Artuch et al, 2006;Le Ber et al, 2007;D'Arrigo et al, 2008;Lagier-Tourenne et al, 2008;Mollet et al, 2008;Pineda et al, 2010;Castellotti et al, 2011;Horvath et al, 2012;Liu et al, 2013;Mignot et al, 2013], and isolated myopathy [Lalani et al, 2005;Horvath et al, 2006;Gempel et al, 2007]. Primary CoQ 10 deficiencies are due to defects in CoQ 10 biosynthesis ( fig.…”

Molecular diagnosis of coenzyme Q10deficiency

“…Interestingly, after a WGS approach, the presence of mutations in COQ2 has been consistently associated with familial and sporadic multiple system atrophy [38]. Likewise, for the ADCK3 gene, four patients from two families have been reported as autosomal recessive cerebellar ataxias [39,40]. Strikingly, two siblings sharing the same compound heterozygosity mutations in ADCK3 display extreme phenotypic variability [40].…”