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

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.

Two novel mutations of the SETX gene and ataxia with oculomotor apraxia type 2

“…The majority of the clinical presentations of our patients are in line with existing reports [2][3][4]. Although oculomotor apraxia is part of the name of the disorder, it is absent in about half of AOA2 patients [2], including our patient.…”

“…Although oculomotor apraxia is part of the name of the disorder, it is absent in about half of AOA2 patients [2], including our patient. The presence of pyramidal signs is more typical for patients with missense mutations in the helicase domain [2]. Thus, their absence in our patient is not surprising.…”

Hereditary ataxias: overview

“…[33][34][35] Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by onset between ages 10 and 22 years, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia, and elevated serum concentration of α-fetoprotein. 36,37 The diagnosis of AOA2 is based on clinical and biochemical findings, family history, and exclusion of the diagnoses of A-T and AOA1; it is confirmed by molecular genetic testing.…”

Saccharomyces cerevisiae Sen1 as a Model for the Study of Mutations in Human Senataxin That Elicit Cerebellar Ataxia

“…More detailed analysis of the effects of the AOA2 mutations in Sen1, for example, by transcriptome studies, may yield insight into the nature of the molecular defects that lead to the symptoms of AOA2. R2444H (BERNARD et al 2008;ANHEIM et al 2009;GAZULLA et al 2010) AOA2…”