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

M. Anheim, B. Monga, M. Fleury, P. Charles, C. Barbot, M. Salih, J. P. Delaunoy, M. Fritsch, L. Arning, M. Synofzik, L. Schöls, J. Sequeiros, C. Goizet, C. Marelli, I. Le Ber, J. Koht, J. Gazulla, J. De Bleecker, M. Mukhtar, N. Drouot, L. Ali-Pacha, T. Benhassine, M. Chbicheb, A. M’Zahem, A. Hamri, B. Chabrol, J. Pouget, R. Murphy, M. Watanabe, P. Coutinho, M. Tazir, A. Durr, A. Brice, C. Tranchant, M. Koenig
Brain. 2009-08-20; 132(10): 2688-2698
DOI: 10.1093/BRAIN/AWP211

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1. Brain. 2009 Oct;132(Pt 10):2688-98. doi: 10.1093/brain/awp211. Epub 2009 Aug 20.

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

Anheim M(1), Monga B, Fleury M, Charles P, Barbot C, Salih M, Delaunoy JP,
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.

Author information:
(1)Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS,
Université de Strasbourg, INSERM, Illkirch, France.

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.

DOI: 10.1093/brain/awp211
PMID: 19696032 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus