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Oculomotor Phenotypes in Autosomal Dominant Ataxias

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Oculomotor Phenotypes in Autosomal Dominant Ataxias ORIGINAL CONTRIBUTION Oculomotor Phenotypes in Autosomal Dominant Ataxias Ned Buttner, MD, PhD; Daniel Geschwind, MD, PhD; Joanna C. Jen, MD, PhD; Susan Perlman, MD; Stefan M. Pulst, MD; Robert W. Baloh, MD Objective: To quantify the oculomotor features of the SCA2, being present in 100% of patients with SCA2. Im- common spinocerebellar ataxia (SCA) syndromes. paired vestibulo-ocular reflex gain occurred with SCA3 only. Patients with SCA6 had prominent deficits in smooth Setting: University ataxia clinic. tracking but normal saccade velocities and vestibulo- ocular reflex gain. Patients: Twenty probands with documented SCA mu- tations. Conclusions: The oculomotor findings are consistent with pure cerebellar involvement in SCA6, pontine in- Methods: Electro-oculographic recordings of sac- volvement in SCA1 and SCA2, and vestibular nerve or cadic, smooth pursuit, optokinetic, vestibular, and visual- nuclei involvement in SCA3. These phenotypes can be vestibular eye movements. useful for clinical diagnosis and for investigating the mechanism of system specificity with the SCA syn- Results: Distinct phenotype and genotype patterns were dromes. identified with modest overlap between patterns. Slow- ing of saccade peak velocities occurred only in SCA1 and Arch Neurol. 1998;55:1353-1357 LASSIFICATION OF theauto- of the repeat expansion for each is roughly somal dominant cerebellar similar, with less than about 30 repeats be- ataxias (ADCAs) has long ing asymptomatic and more than about 40 been a source of confusion being symptomatic. The size of the repeat and controversy. Harding1 correlates with disease severity and age at Cseparated this collection of hereditary, late- onset.3 Repeat expansion constitutes the mo- onset, cerebellodegenerative disorders into lecular basis of anticipation, which typi- types I through III. The most common type, cally occurs with paternal transmission. ADCA I, presents with a range of findings in- SCA6 is the lone exception to these rules, cluding ataxia, pyramidal and extrapyrami- with a smaller, stable repeat expansion dal signs, and ophthalmoplegia. ADCA II is thought possibly to cause a loss of func- similarbutalsoincludesretinaldegeneration, tion or dominant negative effect.5,6 while ADCA III involves relatively pure cer- Each SCA mutation can produce a ebellar signs. The advent of molecular genet- wide range of phenotypes, but also a single ics has shown this classification to be geneti- phenotype may arise from several differ- cally heterogeneous, composed of a variety ent genotypes.6-9 Thus, although molecu- of distinct spinocerebellar ataxias (SCAs).2 lar genetic advances have raised the pros- SCAs1through4areformsofADCAI,SCA5 pect of distinct genotype-phenotype From the Department of and SCA6 are forms of ADCA III, and SCA7 correlations, progress here has been slow Neurology (Drs Buttner, so far is the only form of ADCA II. The genes to date. We now report a dissociation be- Geschwind, Jen, Perlman, Pulst, forSCA1,SCA2,SCA3/Machado-Josephdis- tween several SCAs with respect to a single and Baloh), Neurogenetics ease (MJD), SCA6, and SCA7 have been phenotype: oculomotor function. Program (Drs Geschwind, Jen, cloned and found to contain expanded CAG and Baloh), and Division of triplet repeats.3,4 The genes for SCA4 and Head and Neck Surgery RESULTS (Dr Baloh), UCLA School of SCA5 have been linked to chromosomes 16 Medicine, Los Angeles, Calif; and 11, respectively, but have not been VISUAL FIXATION 3 and Department of Neurology, cloned. Cedars-Sinai Medical Center, Most SCAs share properties typical of Gaze-evoked nystagmus was a common fea- Los Angeles (Dr Pulst). the CAG-repeat disorders.2,3 The size range ture of this population, found in every pa- ARCH NEUROL / VOL 55, OCT 1998 1353 ©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 PATIENTS AND METHODS (3°-36°) and interstep intervals (0.5-2.5 seconds). Horizon- tal smooth pursuit was induced by moving the laser dot si- nusoidally at frequencies of 0.1, 0.2, and 0.4 Hz (peak ve- PATIENTS locities of 11.3/s, 22.6/s, and 45.2/s, respectively). Spontaneous nystagmus occurred in the primary position, while gaze- We performed electro-oculography in 20 probands with di- evoked nystagmus occurred on 30° horizontal or vertical gaze agnoses of SCA1, SCA2, SCA3/MJD, or SCA6. Most have deviation. Rebound nystagmus was induced by saccades back been followed up on a regular basis in the ataxia clinic at to the primary position after a sustained gaze deviation, and the University of California, Los Angeles, Neurological Ser- always beat in a direction opposite to that of the preceding vices for many years. All had clinically obvious disease of gaze deviation.13 Fixation instability, such as square-wave jerks, duration ranging from 2 to 30 years (Table 1). was examined with eyes in the primary position for 30- second epochs. MOLECULAR GENETIC ANALYSIS Horizontal optokinetic nystagmus (OKN) was ob- tained with subjects seated in the center of a drum (diam- DNA was isolated from peripheral leukocytes or lympho- eter, 1.3 m) made of heavy black cloth with 30 wide ver- blastoid cell lines as previously described.7 The SCA1 and tical white stripes placed at 15.6° intervals. Patients were SCA3/MJD alleles were amplified and analyzed on agarose asked to watch the stripes passing by without following them and acrylamide gels by standard methods. For SCA3/MJD, to the periphery. Sinusoidal rotation of the drum at 0.05 the following primer pairs were used: MJD52 and MJDB Hz (peak velocity, 60°/s) stimulated the entire visual field. 59-GTAACCTTGCTCCTTAATCC-39. For SCA2 allele ana- The vestibulo-ocular reflex (VOR) was tested with passive lysis, primers SCA2-A (59-GGGCCCCTCACCATGTCG-39) sinusoidal rotation of the subject at 0.05 and 0.4 Hz (peak and SCA2-B (59-CGGGCTTGCGGACATTGG-39) were velocity, 60°/s and 30°/s, respectively). Both VOR tests were used to amplify the SCA2 repeat.7,11 performed in darkness with the subject’s eyes open. Vi- For SCA6, primers F1 and R15,6 were added to 20 to sual vestibular interaction was tested in 2 ways. First, the 40 ng of human genomic DNA with standard buffer and visual VOR was tested by rotating the subject in the light nucleotide concentrations, in a final volume of 20 µL. Af- with the optokinetic drum stationary. Second, ability to ter an initial 5-minute denaturation at 95°C, 35 cycles of suppress the VOR with fixation (VOR-fix) was assessed 95°C denaturation (90 seconds), 62°C annealing (30 sec- by having the patient fixate a light-emitting diode that onds), and 72°C extension (60 seconds), followed by a fi- was attached to the sinusoidally rotating chair (0.05 Hz, nal extension of 72°C for 5 minutes were performed. Ex- 60°/s).10,12 Informed consent was given by all patients. panded alleles were reamplified with the use of phosphorus 32 end-labeled primer R1 and separated by electrophore- EYE MOVEMENT DATA ANALYSIS sis through 6% polyacrylamide sequencing gels and analyzed.11 The methods for our online computer data analysis have been reported previously.10,12 Briefly, eye position signals EYE MOVEMENT RECORDINGS were differentiated, and saccades were identified on the ba- sis of their characteristic velocity profile. Peak velocity was Direct-current electro-oculogram recordings were per- averaged for saccade amplitudes of 10°, 20°, and 30° (bin formed in accordance with established protocols.10,12 width, ±2°). Saccade latency (time from target displace- Briefly, surface electrodes were placed at the inner and ment to eye movement) and saccade accuracy ([saccade am- outer canthi of each eye for recording horizontal eye plitude/target amplitude] 3 100) were determined for each movements. Vertical nystagmus and blink artifact were identified saccade. We then calculated the average sac- monitored with electrodes attached above the eyebrow cade latency and the number of hypermetric saccades and below the lower lid. Calibration was performed (.100% accuracy) for the entire test. before each subtest by having the patient look at targets Gain measurements of VOR, OKN, and smooth pur- in primary position and at 15° horizontally. The record- suit were computed as follows. The fast components were ing signal was amplified and filtered (cutoff frequency at removed, and the resulting gaps in the slow eye velocity 42 Hz, −3 dB), then digitized for online analysis (sam- record were filled by connecting the points at each end of pling rate, 200 Hz). a missing segment with a quadratic regression line. A fast To monitor saccades, smooth pursuit, spontaneous and Fourier analysis was then performed, giving the ampli- gaze-evoked nystagmus, and fixation instability, we asked the tude of the fundamental and first 5 harmonics. The ampli- subject to fixate a red laser dot projected on a white screen. tude of the fundamental was then compared with stimu- Horizontal saccades were induced by moving the laser lus velocity for computation of gain. Normative data have dot in a stepwise pattern with pseudorandom amplitudes been previously reported.10 tient with SCA1, SCA3, and SCA6 examined. Three patients tients with SCA2. Spontaneous downbeat nystagmus was with SCA2 did not have gaze-evoked nystagmus, probably even more specific, occurring in 60% (3/5) of the patients because they could not generate corrective fast components. with SCA6 but in none of the other groups. Rebound and downbeat nystagmus were more specific. Re- Square-wave jerks were the only saccadic intru- bound nystagmus was a prominent feature of SCA3, occur- sions identified. They occurred in 43% (3/7) of patients ring in 100% (7/7) of patients. In comparison, rebound nys- with SCA3, 33% (1/3) of patients with SCA1, and 20% tagmus was observed in 40% (2/5) of the patients with SCA6, (1/5) of patients with SCA2. Ocular flutter was not 33% (1/3) of the patients with SCA1, and none of the pa- seen.
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