title: Phenotypic variability in ARCA2 and identification of a core ataxic phenotype with slow progression.
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.forename: Cyril
authors.initials: C
authors.lastname: Mignot
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Apartis
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.forename: Charles
authors.initials: C
authors.lastname: Marques Lourenço
authors.forename: Perrine
authors.initials: P
authors.lastname: Charles
authors.forename: David
authors.initials: D
authors.lastname: Devos
authors.forename: Caroline
authors.initials: C
authors.lastname: Moreau
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
authors.forename: Nathalie
authors.initials: N
authors.lastname: Drouot
authors.forename: Lydie
authors.initials: L
authors.lastname: Burglen
authors.forename: Nadine
authors.initials: N
authors.lastname: Kempf
authors.forename: Elsa
authors.initials: E
authors.lastname: Nourisson
authors.forename: Sandra
authors.initials: S
authors.lastname: Chantot-Bastaraud
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Lebre
authors.forename: Marlène
authors.initials: M
authors.lastname: Rio
authors.forename: Yves
authors.initials: Y
authors.lastname: Chaix
authors.forename: Eric
authors.initials: E
authors.lastname: Bieth
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Roze
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bonnet
authors.forename: Sandrine
authors.initials: S
authors.lastname: Canaple
authors.forename: Coralie
authors.initials: C
authors.lastname: Rastel
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Agnès
authors.initials: A
authors.lastname: Rötig
authors.forename: Isabelle
authors.initials: I
authors.lastname: Desguerre
authors.forename: Christine
authors.initials: C
authors.lastname: Tranchant
authors.forename: Michel
authors.initials: M
authors.lastname: Koenig
authors.affiliation: Department of Genetics and Cytogenetics, AP-HP, Hôpital de la Salpêtrière, Paris, F-75013, France. mathieu.anheim@chru-strasbourg.fr.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Anheim
mesh_terms: D000293:Adolescent; D000328:Adult; D002524:Cerebellar Ataxia / Q000175:diagnosis* / Q000473:pathology / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D010641:Phenotype; D055815:Young Adult