Phenotypic variability in ARCA2 and identification of a core ataxic phenotype with slow progression

Orphanet Journal of Rare Diseases

Mathieu Anheim⁷  Michel Koenig^1,12  Christine Tranchant⁷  Isabelle Desguerre^1,14  Agnès Rötig¹  Alexis Brice^1,10  Coralie Rastel²  Sandrine Canaple^2,21  Isabelle Bonnet^1,15  Emmanuel Roze^1,11  Eric Bieth^1,16  Yves Chaix⁶  Marlène Rio³  Anne-Sophie Lebre^1,19  Sandra Chantot-Bastaraud^1,18  Elsa Nourisson^1,12  Nadine Kempf^1,12  Lydie Burglen⁸  Nathalie Drouot^2,22  Pascale de Lonlay⁵  Caroline Moreau^1,17  David Devos⁴  Perrine Charles⁹  Charles Marques Lourenço^1,13  Alexandra Durr^1,10  Emmanuelle Apartis^2,20  Cyril Mignot⁹ 

[1] Institut Imagine and INSERM U781, Université Paris Descartes-Sorbonne Paris Cité, Paris, France;Centre de Référence des Déficiences Intellectuelles de Causes Rares, Paris, France;Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France;Department of Medical Pharmacology & Department of Movement Disorders and Neurology, EA 4559/1046, Lille Nord de France University, CHU Lille, Lille, France;Inserm U781, Imagine Institut des Maladies Génétiques, Université Paris Descartes et Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Necker, AP-HP, Paris, France;Unité de Neurologie Pédiatrique, Hôpital des Enfants, Toulouse, France; INSERM U825, Hôpital de Purpan Toulouse, Toulouse, France;Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UdS), Strasbourg, France;Centre de Référence des malformations et maladies congénitales du cervelet, Paris, France;Groupe de Recherche Clinique (GRC) 'déficience intellectuelle et autisme’, UPMC Univ Paris 06, Paris, France;CNRS UMR 7225, Paris, F-75013, France;Physiopathology and Treatment of Neurodegenerative Disorders, Inserm, UMR_S975, CRICM, Team Molecular Bases, Paris, F-75013, France;Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg - Nouvel Hôpital Civil, Strasbourg, France;Department of Neuroscience and Behaviour Sciences, School of Medicine of Ribeirão Preto, University of Sao Polo, Sao Polo, Brazil;Service de Neurologie Pédiatrique, APHP, Hôpital Necker-Enfants Malades, Paris, France;Cabinet de Neurologie, Amiens, France;Service de Génétique, Hôpital Purpan, Toulouse, France;Department of Movement Disorders and Neurology, EA 4559/1046, Lille Nord de France University, CHU Lille, Lille, France;Service de Génétique et d’Embryologie Médicale, AP-HP, Hôpital Armand Trousseau, Paris, France;Université Paris Descartes; INSERM U781, Assistance Publique-Hôpitaux de Paris - Hôpital Necker-Enfants Malades, Paris, 75015, France;UPMC Univ Paris 06, UMR_S975, Paris, F-75013, France;Laboratoire de Neurosciences Fonctionnelles et Pathologies, Service de Neurologie, CHU Amiens, 80054 Amiens Cedex, Amiens, EA4559, France;Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Illkirch, 67404, France

关键词: Mitochondrial disorders;    Seizure disorder;    Movement disorder;    Recessive;    Genes;    Cerebellar ataxia;   

Others  :  863433
DOI  :  10.1186/1750-1172-8-173

 received in 2013-09-06, accepted in 2013-10-15,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Mignot et al.; licensee BioMed Central Ltd.

【 图 表 】

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