Phenotypic variability in ARCA2 and identification of a core ataxic phenotype with slow progression
Year: 2013
Type: article
Study design: Observational Study
Abstract: Autosomal recessive cerebellar ataxia 2 (ARCA2) is a recently identified recessive ataxia due to ubiquinone deficiency and biallelic mutations in the ADCK3 gene. The phenotype of the twenty-one patients reported worldwide varies greatly. Thus, it is difficult to decide which ataxic patients are good candidates for ADCK3 screening without evidence of ubiquinone deficiency. We report here the clinical and molecular data of 10 newly diagnosed patients from seven families and update the disease history of four additional patients reported in previous articles to delineate the clinical spectrum of ARCA2 phenotype and to provide a guide to the molecular diagnosis. First signs occurred before adulthood in all 14 patients. Cerebellar atrophy appeared in all instances. The progressivity and severity of ataxia varied greatly, but no patients had the typical inexorable ataxic course that characterizes other childhood-onset recessive ataxias. The ataxia was frequently associated with other neurological signs. Importantly, stroke-like episodes contributed to significant deterioration of the neurological status in two patients. Ubidecarenone therapy markedly improved the movement disorders, including ataxia, in two other patients. The 7 novel ADCK3 mutations found in the 10 new patients were two missense and five truncating mutations. There was no apparent correlation between the genotype and the phenotype. Our series reveals that the clinical spectrum of ARCA2 encompasses a range of ataxic phenotypes. On one end, it may manifest as a pure ataxia with very slow progressivity and, on the other end, as a severe infantile encephalopathy with cerebellar atrophy. The phenotype of most patients, however, lies in between. It is characterized by a very slowly progressive or apparently stable ataxia associated with other signs of central nervous system involvement. We suggest undergoing the molecular analysis of ADCK3 in patients with this phenotype and in those with cerebellar atrophy and a stroke-like episode. The diagnosis of patients with a severe ARCA2 phenotype may also be performed on the basis of biological data, i.e. low ubiquinone level or functional evidence of ubiquinone deficiency. This diagnosis is crucial since the neurological status of some patients may be improved by ubiquinone therapy.
Authors: Cyril Mignot, Emmanuelle Apartis, Alexandra Durr, Charles Marques Lourenço, Perrine Charles, David Devos, Caroline Moreau, Pascale de Lonlay, Nathalie Drouot, Lydie Burglen, Nadine Kempf, Elsa Nourisson, Sandra Chantot-Bastaraud, Anne-Sophie Lebre, Marlène Rio, Yves Chaix, Eric Bieth, Emmanuel Roze, Isabelle Bonnet, Sandrine Canaple, Coralie Rastel, Alexis Brice, Agnès Rötig, Isabelle Desguerre, Christine Tranchant, Michel Koenig, Mathieu Anheim
Institutions: Hôpital Armand-Trousseau, Assistance Publique – Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Université Pierre-et-Marie-Curie, Inserm, Hôpital Saint-Antoine, Centre National de la Recherche Scientifique, Institut du Cerveau, Centre Hospitalier Universitaire de Lille, Université Lille Nord de France, Institut des Maladies Génétiques Imagine, Université Paris Descartes, Institut de génétique et de biologie moléculaire et cellulaire, Université de Strasbourg, Hôpitaux Universitaires de Strasbourg, Hôpital Civil, Strasbourg, Hôpital Necker-Enfants Malades, Hôpital Purpan, Hôpital des Enfants, Centre Hospitalier Universitaire Amiens-Picardie, Laboratoire de neurosciences fonctionnelles et pathologies, Sorbonne Paris Cité, Hôpital d'Hautepierre
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,990
OpenAlex ID: W2169075874