Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients.

Hdl Handle:
http://hdl.handle.net/10147/254482
Title:
Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients.
Authors:
Anheim, M; Monga, B; Fleury, M; Charles, P; Barbot, C; Salih, M; Delaunoy, J P; Fritsch, M; Arning, L; Synofzik, M; Schöls, L; Sequeiros, J; Goizet, C; Marelli, C; Le Ber, I; Koht, J; Gazulla, J; De Bleecker, J; Mukhtar, M; Drouot, N; Ali-Pacha, L; Benhassine, T; Chbicheb, M; M'Zahem, A; Hamri, A; Chabrol, B; Pouget, J; Murphy, R; Watanabe, M; Coutinho, P; Tazir, M; Durr, A; Brice, A; Tranchant, C; Koenig, M
Affiliation:
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, Université de Strasbourg, INSERM, Illkirch, France. anheim@titus.u-strasbg.fr
Citation:
Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients. 2009, 132 (Pt 10):2688-98 Brain
Publisher:
Brain : a journal of neurology
Journal:
Brain : a journal of neurology
Issue Date:
Oct-2009
URI:
http://hdl.handle.net/10147/254482
DOI:
10.1093/brain/awp211
PubMed ID:
19696032
Abstract:
Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disease due to mutations in the senataxin gene, causing progressive cerebellar ataxia with peripheral neuropathy, cerebellar atrophy, occasional oculomotor apraxia and elevated alpha-feto-protein (AFP) serum level. We compiled a series of 67 previously reported and 58 novel ataxic patients who underwent senataxin gene sequencing because of suspected AOA2. An AOA2 diagnosis was established for 90 patients, originating from 15 countries worldwide, and 25 new senataxin gene mutations were found. In patients with AOA2, median AFP serum level was 31.0 microg/l at diagnosis, which was higher than the median AFP level of AOA2 negative patients: 13.8 microg/l, P = 0.0004; itself higher than the normal level (3.4 microg/l, range from 0.5 to 17.2 microg/l) because elevated AFP was one of the possible selection criteria. Polyneuropathy was found in 97.5% of AOA2 patients, cerebellar atrophy in 96%, occasional oculomotor apraxia in 51%, pyramidal signs in 20.5%, head tremor in 14%, dystonia in 13.5%, strabismus in 12.3% and chorea in 9.5%. No patient was lacking both peripheral neuropathy and cerebellar atrophy. The age at onset and presence of occasional oculomotor apraxia were negatively correlated to the progression rate of the disease (P = 0.03 and P = 0.009, respectively), whereas strabismus was positively correlated to the progression rate (P = 0.03). An increased AFP level as well as cerebellar atrophy seem to be stable in the course of the disease and to occur mostly at or before the onset of the disease. One of the two patients with a normal AFP level at diagnosis had high AFP levels 4 years later, while the other had borderline levels. The probability of missing AOA2 diagnosis, in case of sequencing senataxin gene only in non-Friedreich ataxia non-ataxia-telangiectasia ataxic patients with AFP level > or =7 microg/l, is 0.23% and the probability for a non-Friedreich ataxia non-ataxia-telangiectasia ataxic patient to be affected with AOA2 with AFP levels > or =7 microg/l is 46%. Therefore, selection of patients with an AFP level above 7 microg/l for senataxin gene sequencing is a good strategy for AOA2 diagnosis. Pyramidal signs and dystonia were more frequent and disease was less severe with missense mutations in the helicase domain of senataxin gene than with missense mutations out of helicase domain and deletion and nonsense mutations (P = 0.001, P = 0.008 and P = 0.01, respectively). The lack of pyramidal signs in most patients may be explained by masking due to severe motor neuropathy.
Item Type:
Article
Language:
en
MeSH:
Adult; Age of Onset; Apraxia, Ideomotor; Ataxia; Cohort Studies; Disease Progression; Female; Genotype; Humans; Magnetic Resonance Imaging; Male; Mutation, Missense; Ophthalmoplegia; Phenotype; RNA Helicases; Retrospective Studies; alpha-Fetoproteins
ISSN:
1460-2156

Full metadata record

DC FieldValue Language
dc.contributor.authorAnheim, Men_GB
dc.contributor.authorMonga, Ben_GB
dc.contributor.authorFleury, Men_GB
dc.contributor.authorCharles, Pen_GB
dc.contributor.authorBarbot, Cen_GB
dc.contributor.authorSalih, Men_GB
dc.contributor.authorDelaunoy, J Pen_GB
dc.contributor.authorFritsch, Men_GB
dc.contributor.authorArning, Len_GB
dc.contributor.authorSynofzik, Men_GB
dc.contributor.authorSchöls, Len_GB
dc.contributor.authorSequeiros, Jen_GB
dc.contributor.authorGoizet, Cen_GB
dc.contributor.authorMarelli, Cen_GB
dc.contributor.authorLe Ber, Ien_GB
dc.contributor.authorKoht, Jen_GB
dc.contributor.authorGazulla, Jen_GB
dc.contributor.authorDe Bleecker, Jen_GB
dc.contributor.authorMukhtar, Men_GB
dc.contributor.authorDrouot, Nen_GB
dc.contributor.authorAli-Pacha, Len_GB
dc.contributor.authorBenhassine, Ten_GB
dc.contributor.authorChbicheb, Men_GB
dc.contributor.authorM'Zahem, Aen_GB
dc.contributor.authorHamri, Aen_GB
dc.contributor.authorChabrol, Ben_GB
dc.contributor.authorPouget, Jen_GB
dc.contributor.authorMurphy, Ren_GB
dc.contributor.authorWatanabe, Men_GB
dc.contributor.authorCoutinho, Pen_GB
dc.contributor.authorTazir, Men_GB
dc.contributor.authorDurr, Aen_GB
dc.contributor.authorBrice, Aen_GB
dc.contributor.authorTranchant, Cen_GB
dc.contributor.authorKoenig, Men_GB
dc.date.accessioned2012-12-04T15:56:05Z-
dc.date.available2012-12-04T15:56:05Z-
dc.date.issued2009-10-
dc.identifier.citationAtaxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients. 2009, 132 (Pt 10):2688-98 Brainen_GB
dc.identifier.issn1460-2156-
dc.identifier.pmid19696032-
dc.identifier.doi10.1093/brain/awp211-
dc.identifier.urihttp://hdl.handle.net/10147/254482-
dc.description.abstractAtaxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disease due to mutations in the senataxin gene, causing progressive cerebellar ataxia with peripheral neuropathy, cerebellar atrophy, occasional oculomotor apraxia and elevated alpha-feto-protein (AFP) serum level. We compiled a series of 67 previously reported and 58 novel ataxic patients who underwent senataxin gene sequencing because of suspected AOA2. An AOA2 diagnosis was established for 90 patients, originating from 15 countries worldwide, and 25 new senataxin gene mutations were found. In patients with AOA2, median AFP serum level was 31.0 microg/l at diagnosis, which was higher than the median AFP level of AOA2 negative patients: 13.8 microg/l, P = 0.0004; itself higher than the normal level (3.4 microg/l, range from 0.5 to 17.2 microg/l) because elevated AFP was one of the possible selection criteria. Polyneuropathy was found in 97.5% of AOA2 patients, cerebellar atrophy in 96%, occasional oculomotor apraxia in 51%, pyramidal signs in 20.5%, head tremor in 14%, dystonia in 13.5%, strabismus in 12.3% and chorea in 9.5%. No patient was lacking both peripheral neuropathy and cerebellar atrophy. The age at onset and presence of occasional oculomotor apraxia were negatively correlated to the progression rate of the disease (P = 0.03 and P = 0.009, respectively), whereas strabismus was positively correlated to the progression rate (P = 0.03). An increased AFP level as well as cerebellar atrophy seem to be stable in the course of the disease and to occur mostly at or before the onset of the disease. One of the two patients with a normal AFP level at diagnosis had high AFP levels 4 years later, while the other had borderline levels. The probability of missing AOA2 diagnosis, in case of sequencing senataxin gene only in non-Friedreich ataxia non-ataxia-telangiectasia ataxic patients with AFP level > or =7 microg/l, is 0.23% and the probability for a non-Friedreich ataxia non-ataxia-telangiectasia ataxic patient to be affected with AOA2 with AFP levels > or =7 microg/l is 46%. Therefore, selection of patients with an AFP level above 7 microg/l for senataxin gene sequencing is a good strategy for AOA2 diagnosis. Pyramidal signs and dystonia were more frequent and disease was less severe with missense mutations in the helicase domain of senataxin gene than with missense mutations out of helicase domain and deletion and nonsense mutations (P = 0.001, P = 0.008 and P = 0.01, respectively). The lack of pyramidal signs in most patients may be explained by masking due to severe motor neuropathy.en_GB
dc.language.isoenen
dc.publisherBrain : a journal of neurologyen_GB
dc.rightsArchived with thanks to Brain : a journal of neurologyen_GB
dc.subject.meshAdult-
dc.subject.meshAge of Onset-
dc.subject.meshApraxia, Ideomotor-
dc.subject.meshAtaxia-
dc.subject.meshCohort Studies-
dc.subject.meshDisease Progression-
dc.subject.meshFemale-
dc.subject.meshGenotype-
dc.subject.meshHumans-
dc.subject.meshMagnetic Resonance Imaging-
dc.subject.meshMale-
dc.subject.meshMutation, Missense-
dc.subject.meshOphthalmoplegia-
dc.subject.meshPhenotype-
dc.subject.meshRNA Helicases-
dc.subject.meshRetrospective Studies-
dc.subject.meshalpha-Fetoproteins-
dc.titleAtaxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients.en_GB
dc.typeArticleen
dc.contributor.departmentInstitut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, Université de Strasbourg, INSERM, Illkirch, France. anheim@titus.u-strasbg.fren_GB
dc.identifier.journalBrain : a journal of neurologyen_GB
dc.description.provinceLeinsteren

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