The Clinical Spectrum of Ataxia with Oculomotor Apraxia Type 2
- Relevant disclosures and conflicts of interest are listed at the end of this article.
Ataxia with oculomotor apraxia type 2 (AOA2) is an inherited disorder caused by mutations within both alleles of the senataxin gene. First symptoms are usually recognized before the age of 30. Unlike several other autosomal recessive cerebellar ataxia syndromes, levels of alpha-fetoprotein are nearly always elevated in AOA2 and thus narrowing down the differential diagnosis list. We present 3 video cases illustrating and expanding the clinical spectrum of AOA2, with 1 case bearing a novel mutation with cervical dystonia as the first symptom, the absence of neuropathy, and a disease onset beyond the age of 40. Furthermore, all patients were assessed by oculographic analysis, which revealed distinct patterns of oculomotor abnormalities. The clinical spectrum of AOA2 might be even broader than previously described in larger series. Oculography might be a useful tool to detect subclinical oculomotor apraxia in this disorder.
With a prevalence of ~8%, ataxia with oculomotor apraxia type 2 (AOA2) may be the third-most common non-Friedreich autosomal recessive cerebellar ataxia in the European population.[1, 2] Disease-causing mutations lie in the SETX gene (9q34) coding for senataxin, which is thought to be involved as a helicase in DNA transcription and RNA processing.[3, 4] The clinical spectrum of AOA2 includes cerebellar ataxia, sensorimotor neuropathy, oculomotor apraxia, pyramidal signs, mild cognitive impairment, skeletal deformities, and hyperkinetic movement disorders, including head tremor, dystonia, chorea, and myoclonus. Cerebellar atrophy and elevated alpha-fetoprotein (AFP; 99%) are usually present from early on.[5, 6] The absence of both peripheral neuropathy and cerebellar atrophy is nearly exclusive for AOA2.
Clinically, oculomotor apraxia is characterized by an initial head thrust, which is followed by eye movements to the intended side. The name of the disease can be misleading because oculomotor apraxia is absent in half of the patients with AOA2. The term “apraxia” is also considered to be a misnomer in this context because it usually refers to the inability to properly execute skilled voluntary movements, despite normal elementary sensorimotor function.
We report on 3 illustrative video cases of genetically confirmed AOA2, which show the wide clinical spectrum of the disease and describe new clinical features and a new mutation.
Illustrative Cases: Clinical Presentation
This 24-year-old Macedonian female with known Sturge-Weber syndrome first complained about unsteadiness at the age of 11. At initial evaluation, she presented with gait ataxia, increased left-sided muscle tone, reduced tendon reflexes, and oculomotor apraxia. Family history was unremarkable, and the brain MRI was normal. However, cerebellar atrophy was observed on a subsequent scan 5 years later. At the age of 16, the AFP was slightly elevated (6.7 ng/mL; N < 5.8 ng/mL). Over the next 8 years, the disease progressed to an advanced cerebellar syndrome with sensorimotor polyneuropathy, scoliosis, and pes cavus. Oculomotor examination revealed convergent strabismus, gaze-evoked nystagmus, and slowing of saccades, but without clear-cut oculomotor apraxia (see Video, Segment 1). The AFP level at this time was normal (11.3 ng/mL; N < 13 ng/mL). Subsequent genetic testing revealed compound heterozygous mutations of the SETX gene (Table 1).
Table 1. Case synopsis
|Age at onset||11 years||~40 years||Early adolescence|
|Age at referral||24 years||56 years||35 years|
(frameshift mutation → p.Gln1864ArgfsX34)
(missense mutation → p.Asn2316Lys)
(missense mutation → p.Ile1942Thr)
(missense mutation →p.Arg2287Gln)
(missense mutation →p.Arg2444His)
|Neuropathy||++||−||− (subclinical sensory)|
|Disease progression||Rapid||Slow||Very slow|
|Time onset to wheelchair||~5 years||~15 years||Not applicable|
|Elevated AFP levels||−||+||+|
|DaTSCAN||Not done||Not done||Normal|
|Formal oculographic testing||Reduced number of saccades; markedly reduced amplitude of horizontal saccades; decreased velocity of upward saccades||Markedly reduced number of saccades (vertical > horizontal); severely decreased amplitude of saccades of all axes; saccade velocity cannot reliably be evaluated as a result of the paucity of generated saccades.|| |
Initial testing: rare and slowed downward saccades
Follow-up (+2 years): further decrease of saccade velocity downward
|Electrophysiology||Axonal sensorimotor neuropathy||No evidence of neuropathy||Axonal sensory neuropathy (subclinical)|
This 56-year-old Macedonian female first came to medical attention at the age of 42 because of involuntary head movements with impaired oculomotor control that occurred only a few months before. Family history was unremarkable and without evidence of parental consanguinity. At that time, the CT scan of the brain was normal and she was diagnosed with “cervical dystonia.” After another 14 years, she was referred again because her gait and “eye movements” had further deteriorated, making her wheelchair bound shortly before referral. On clinical examination, she displayed severe gait ataxia, right-sided hemidystonia, gaze-evoked nystagmus, and severe oculomotor apraxia. Vestibulo-ocular reflex (VOR) suppression was absent (see Video, Segment 2). There was no evidence (neither clinically nor electrophysiologically) of polyneuropathy. The brain MRI showed vermis atrophy. Laboratory testing showed elevated AFP levels (44.1 ng/mL; N < 13.9 ng/mL). Genetic testing revealed a novel homozygous missense mutation of the SETX gene, leading to a p.Ile1942Thr change (Table 1). This mutation is predicted to be pathogenic with a score of 0.993 (range, 0–1) by the PolyPhen-2 program and from sequence conservation analysis (position homologous to p.Ile1942 is always an isoleucine or valine, in any investigated eukaryotic species).
This 35-year-old Swiss male was referred because of progressive gait problems. During early adolescence, he experienced some “clumsiness.” In the third decade, he gradually developed impairment of gait and mild dysarthria; however, these symptoms remained mild upon referral. Family history was negative, and parental consanguinity was denied by the patient. At first referral, he showed mild gait ataxia, square wave jerks, nystagmus, dysmetric saccades, right-sided brady-/hypokinesia, and slightly increased muscle tone (see Video, Segment 3). Electrophysiological testing detected subclinical sensory axonal polyneuropathy. The brain MRI showed vermis atrophy, and AFP was elevated (35.6 ng/mL; N < 8.0 ng/mL). A dopaminergic deficit was suspected because of the akinetic-rigid signs, but a DaTSCAN was normal. Subsequent genetic testing revealed a compound heterozygous mutation in the SETX gene (Table 1). The patient engages in regular coordinative physical therapy and, until present, remains physically independent.
Video oculography was performed using a head-mounted, video-based monocular eye tracker (Eyelink II). Subjects were seated in front of a monitor in an optically and acoustically shielded room with their heads stabilized by a chin rest. Four sessions with 15 pictures each were presented on a monitor. The patients were instructed to freely and actively explore the pictures. In case 1, only a few saccades were recorded. The horizontal saccades showed reduced amplitudes, whereas the saccade velocity was decreased for vertical saccades. In case 2, the paucity of generated saccades with reduced amplitudes was the most prominent finding. In case 3, video oculography revealed a decreased number of downward saccades with reduced velocity. The horizontal saccades were, however, largely normal.
During diagnostic workup of autosomal recessive ataxias with oculomotor apraxia and/or sensorimotor neuropathy, the assessment of serum AFP might be useful because, if elevated, it narrows down the differential diagnosis list to AOA2 and ataxia telangiectasia. Elevated AFP levels, the absence of telangiectasia, the absence of recurrent infections and susceptibility for neoplasms as well as disease onset after the age of 10 should favor genetic testing for AOA2. However, normal AFP is not strictly exclusive for AOA2, especially if measured just once. AFP usually remains stable throughout the disease, but the level can change as the disease progresses. It has been shown that the AFP level has an inverse correlation with the occurrence of strabismus, and that strabismus is associated with faster disease progression, which is in line with case 1. Another interesting point of case 1 is that oculomotor apraxia was described at initial clinical workup and had disappeared by the age of 24, which fits to the description of one Algerian family.
Case 2 presented with an unusual late disease onset beyond the age of 40 years, with a rather slow progression over two decades to a severe phenotype. Of all our cases, oculomotor apraxia was most prominent in this case. This individual observation underpins what Anheim et al. found on the basis of a larger population, showing that disease progression has an inverse correlation with age of onset and with the occurrence of oculomotor apraxia. Notably, torticollis was the first symptom recognized by the patient. Usually, disease starts with slowly progressive gait ataxia, but head tremor, dysarthria, or even writer's cramp may also be the presenting symptoms.[9, 10] Because the vast majority of AOA2 cases display signs of polyneuropathy, the absence of neuropathy in this case is unusual. These atypical features of case 2 may be related to a new homozygous missense mutation (p.Ile1942Thr), which affects an amino acid upstream of the helicase domain. Isoleucine, at this position, is highly conserved through evolution because there is always an isoleucine or a valine, another short hydrophobic amino acid, at the equivalent position of any eukaryotic SETX ortholog. Nevertheless, some caution must be paid to the fact that genotyping of parents and other siblings was not performed. Therefore, the possibility of compound heterozygosity (exon or gene deletion on the other allele) has not been ruled out.
Case 3 represents a rather classical phenotype of AOA2, but without evidence of oculomotor apraxia. The mutation, c.7331G>A (p.Arg2444His), has been described by Anheim et al. and by Gazulla et al., who reported neuropathy in patients carrying this mutation homozygously.[11, 12] Whereas Anheim et al. found mild sensorimotor axonal neuropathy in their patients, Gazulla et al. found a clinically progressive pure sensory neuropathy with preserved motor fibers, which is in contrast with previous reports of a sensorimotor pattern. In our case, with the aforementioned mutation on one allele, subclinical pure sensory neuropathy was found.
Cerebellar oculomotor signs were observed in all patients. Furthermore, video oculography showed saccadic abnormalities in all cases; however, there were substantial differences regarding generation and accuracy of saccadic movements. Increased latencies and reduced range of saccades are the hallmark of oculomotor apraxia. Clinically, oculomotor apraxia was established in case 2, but only variably present in case 1. On oculography, cases 1 and 2 generated only few saccades or saccades with low amplitudes. A low number of acquired saccades represents (1) the inability to perform saccades and (2) the very slow velocity of these eye movements, which were not registered as saccades by the device. We consider that several aspects of the oculography are likely explained by oculomotor apraxia. Although we were aware of oculomotor abnormalities in case 1, we were surprised about the extent of saccadic abnormalities on oculography. We therefore suggest that video oculography might be a useful tool to detect subclinical oculomotor apraxia.
In conclusion, case 2, with a novel SETX mutation, extends the spectrum of AOA2 by three unusual features: (1) disease onset beyond the age of 40; (2) cervical dystonia as the first symptom; and (3) absence of neuropathy. This report suggests that AFP testing should be recommended in patients with an unexplained ataxia even beyond the age of 40. Additionally, apparative assessments might be useful to detect subclinical neuropathy or oculomotor apraxia in AOA2.
(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.
F.B.: 1C, 3A
M.S: 1C, 3B
M.K.: 1C, 3B
R.M.: 1C, 3B
S.B.: 1C, 3B
A.K.-L.: 1C, 3B
C.P.K.: 1C, 3B
G.K.: 1C, 3B
The authors acknowledge Dr. J.P. Delaunoy for his support during genetic testing and Anna Müller for her English proofreading of the manuscript.
Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest.
Financial Disclosures for previous 12 months: F.B. has served on the advisory boards of Merck Serono and Biogen Idec; has received honoraria from Merck Serono (travel expenses); and has been employed by Kantonsspital St. Gallen. M.S. has held consultancies with Medtronic and Lundbeck; has received travel reimbursement and speaker's honoraria from Medtronic, Lundbeck, and Actelion; has been employed by University Hospital Berne; and is the CEO of KGMed Ltd.
M.K. has been awarded grants from Agence Nationale pour la Recherche-Maladies Rares and Maladies Neurologiques et Psychiatriques (ANR-09-MNPS-001-01) and ANR/E-rare JTC 2011 “Euro-SCAR” (2011-RARE-004-01) and has been employed by University of Strasbourg (Faculty of Medicine), University Hospital–Strasbourg. R.M. has been awarded grants from the Swiss National Foundation and has been employed by the Department of Neurology, University Hospital Bern. S.B. has served on the advisory board of UCB Pharma; has received honoraria from Abbott (travel expenses); Has been awarded grants from the Swiss National Foundation and Parkinson Switzerland; and has been employed by Luzerner Kantonsspital. A. K.-L. has served on the advisory boards of UCB Pharma and Boehringer Ingelheim; has received honoraria from Lundbeck and Allergan; has been awarded grants from Parkinson Switzerland, the Baasch-Medicus Foundation, and the Gloria and Jacques Gossweiler Foundation; has been employed by the Department of Neurology, University Hospital Bern; and has held contracts with Novartis (clinical trial agreement). C.P.K. has held consultancies with Bayer Schering, TEVA, Genzyme, Merck-Serono, and Biogen Idec; has served on the advisory boards of Bayer Schering, TEVA, Genzyme, Merck-Serono, and Biogen Idec; and has been employed by the Department of Neurology, University Hospital Bern. G.K. has served on the advisory boards of Boehringer-Ingelheim and Lundbeck; has received honoraria (to attend meetings) from Bayer and Lundbeck; has been awarded grants from Parkinson Switzerland, Swiss Heart Foundation, Medical Research Center of the Kantonsspital St. Gallen; and has been employed by Kantonsspital St. Gallen.