Journal of Neuro-Ophthalmology, September 2013, Volume 33, Issue 3

Maculopathy and Spinocerebellar Ataxia Type 1: A New Association

Autosomal dominant cerebellar ataxia is a rare heterogeneous group of diseases characterized by cerebellar symptoms, often associated with other multisystemic signs. Mild optic neuropathy has been associated with spinocerebellar ataxia type 1 (SCA1), but macular dysfunction has been reported in only 2 cases. We report the first family with SCA1 with several members affected by visual loss related to maculopathy. Cross-sectional clinical and electrophysiological study of a family with genetically confirmed SCA1. Patients with unexplained visual loss were included. Four patients from the same family, carrying the same genetic mutation, were examined. Testing revealed an increased CAG trinucleotide repeat number within the SCA1 gene. Genetic testing results for SCA7 were negative. Visual acuities ranged between 20/20 and 20/200. Visual fields revealed central scotomas in most of the eyes, and funduscopy was unremarkable in most patients. Central retinal thinning of the retina or disorganized photoreceptor layers were found with optical coherence tomography (OCT). In one patient, multifocal electroretinography (mfERG) revealed central retinal dysfunction. A clinically subtle or even occult maculopathy can occur in association with SCA1. Macular OCT and mfERG can be abnormal even in asymptomatic patients. Unexplained visual loss in SCA1 patients should prompt evaluation of macular function, even if clinical signs of maculopathy are absent.

Maculopathy and Spinocerebellar Ataxia Type 1: A New Association? Pierre Lebranchu, MD, Guylène Le Meur, MD, PhD, Armelle Magot, MD, Albert David, MD, Christophe Verny, MD, PhD, Michel Weber, MD, PhD, Dan Milea, MD, PhD Background: Autosomal dominant cerebellar ataxia is a rare heterogeneous group of diseases characterized by cerebel-lar symptoms, often associated with other multisystemic signs. Mild optic neuropathy has been associated with spinocerebellar ataxia type 1 (SCA1), but macular dysfunc-tion has been reported in only 2 cases. We report the first family with SCA1 with several members affected by visual loss related to maculopathy. Methods: Cross-sectional clinical and electrophysiological study of a family with genetically confirmed SCA1. Patients with unexplained visual loss were included. Results: Four patients from the same family, carrying the same genetic mutation, were examined. Testing revealed an increased CAG trinucleotide repeat number within the SCA1 gene. Genetic testing results for SCA7 were nega-tive. Visual acuities ranged between 20/20 and 20/200. Visual fields revealed central scotomas in most of the eyes, and funduscopy was unremarkable in most pa-tients. Central retinal thinning of the retina or disorga-nized photoreceptor layers were found with optical coherence tomography (OCT). In one patient, multifocal electroretinography (mfERG) revealed central retinal dysfunction. Conclusions: A clinically subtle or even occult maculopathy can occur in association with SCA1. Macular OCT and mfERG can be abnormal even in asymptomatic patients. Unexplained visual loss in SCA1 patients should prompt evaluation of macular function, even if clinical signs of maculopathy are absent. Journal of Neuro-Ophthalmology 2013;33:225-231 doi: 10.1097/WNO.0b013e31828d4add © 2013 by North American Neuro-Ophthalmology Society Autosomal dominant cerebellar ataxia (ADCA) is a rare heterogeneous group of diseases characterized by cere-bellar symptoms, often associated with other neurological signs. To date, 20 associated genes have been identified, with the phenotypic spectrum ranging from isolated ataxia to multisystemic deficits. Overall, prevalence ranges from 2 to 7 per 100,000 people (1). Spinocerebellar ataxia type 1 (SCA1) usually is diagnosed in the 4th decade, with the most common neurologic signs being limb ataxia and dysarthria. Ophthalmological signs may initially include nystagmus and saccadic hypometria, eventually associated with ophthalmoparesis or mild optic neuropathy as the disease progresses. In SCA7, macular dystrophy can be associ-ated with ataxia (2). All SCA1 (3) and most of SCA7 mutations correspond to a CAG trinucleotide expansion within the gene's coding region (,2-cm segment on 6p23 chromosome for SCA1 and 3p21.1-p12 for SCA7). Less often, SCA7 patients exhibit a large deletion within the gene. Both SCA1 and SCA7 mutations are usually caused by polyglutamine expan-sion, manifesting above a threshold of CAG repeats. There is a strong association between the clinical severity of the dis-ease, the age of first symptoms, and the number of CAG repeats (4). Anticipation, which explains the younger age of onset of symptoms in successive intrafamilial generations, results from CAG repeat expansion upon transmission. SCA7 has a specific association with retinal pathology. This degenerative retinopathy initially affects cones, before pro-gressing to cone-rod dystrophy (2). Fundus examination Department of Ophthalmology (PL, GLM, MW), Laboratoire d'explo-rations fonctionnelles (AM), Department of Genetic (AD), Nantes University Hospital, Nantes, France; Department of Neurology (CV), Department of Ophthalmology (DM), Angers University Hospital, Angers, France; Department of Ophthalmology (DM), Copenhagen University Hospital, Copenhagen, Denmark; and Singapore National Eye Centre and Singapore Eye Research Institute (DM), Singapore. Supported by a grant provided by UNADEV (Union des aveugles et deficient visuels), France. The authors report no conflicts of interest. Address correspondence to Pierre Lebranchu, MD, Service D'ophtal-mologie, CHU Hôtel Dieu, 1 Place Alexis Ricordeau, 44000 Nantes, France; E-mail: [e-mail] Lebranchu et al: J Neuro-Ophthalmol 2013; 33: 225-231 225 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. demonstrates macular pigmentary changes, sometimes associ-ated with mild temporal optic disc pallor (5). The gene enc-odes for a protein (ataxin-7), widely expressed in human retina but of unknown function (6). This protein may interact with the function of CRX (cone-rod homeobox), a known tran-scription factor implicated in human cone-rod dystrophy (7). Other maculopathies associated with SCAs are very rare. To our knowledge, only 2 single case reports (8,9) have been previously described a maculopathy in SCA1. In both cases, the retinal changes were caused by a late onset of clinically detectable pigmentary macular dystrophy, associ-ated with abnormal electroretinography (ERG), revealing rod and cone dysfunction. The aim of this study was to report the first family with genetically identified SCA1 asso-ciated with a maculopathy. METHODS Four patients from the same family (Fig. 1) were included in the study. All had a complete ophthalmological exami-nation and automated static perimetry, fundus photogra-phy, and optical coherence tomography (OCT). Patient 1 underwent additional testing, including microperimetry, visual evoked potentials (VEP), full-field ERG, and multi-focal electroretinography (mfERG). Details of previous genetic and neurological examinations were extracted from medical charts with patient's permission. After informed consent, DNA from family members was analyzed for SCA1 and SCA7 gene mutations (Table 1). RESULTS Patient 1 A 51-year-old man reported a 6-month history of bilateral, progressive painless visual loss. His medical history included surgical removal of a pituitary adenoma 9 years earlier with full recovery of visual fields. One year before vision loss, the patient was evaluated for mild ataxia and swallowing difficulties. Diagnosis of SCA1 was confirmed via molecular analysis with a 42 CAG repeat expansion in one allele. Visual acuity was 20/32, right eye, and 20/40, left eye. Lanthony desaturated 15-hue color testing was abnormal, with a green-red axis on the right side and without axis on the other side. Visual field testing disclosed bilateral central scotomas (Fig. 2). On funduscopy, there were small drusen around the fovea and mild temporal optic disc pallor (Fig. 3). Retinal autofluorescence revealed central pigment irregularities in both eyes. OCT disclosed disorganization of the macular photoreceptor layer bilaterally (Fig. 4) and thinning of the temporal retinal nerve fiber layer (RNFL) (Table 2). Microperimetry revealed a decrease of retinal sensitivity (threshold ranging from 0 to 8 dB) in the 2-mm central area, with a relative sparing of the perifoveal surrounding area (threshold ranging from 8 dB to 10 dB). Comparison between function and anatomy confirmed the decrease of sensitivity in the area where the photoreceptor layer was laminated (Fig. 5). Full-field ERG was normal but mfERG confirmed macular dysfunction in each eye. VEP disclosed mildly increased P100 latencies and decreased P100 amplitudes. Patient 2 A 73-year-old woman had a long history of ataxia and unexplained visual loss. She had suffered a slow deteriora-tion in her ability to walk since her 50s and dysarthria since her 60s. No cognitive disabilities were reported. Visual acuity was 20/50, right eye, and 20/80, left eye. Visual field results were not reliable. Macular drusen were present bilaterally (Fig. 3), and retinal autofluorescence was sugges-tive of central atrophy. The optic discs were normal. Fluo-rescein angiography showed mild granular appearance of the perifoveal retinal pigmentary epithelium (RPE). Macular OCT revealed bilateral macular atrophy with an abnormal foveal lamination pattern between the external layers. Focal thickening of the retinal pigment epithelium complex was present in the right eye (Fig. 4). Measurement of macular and global RNFL thickness was normal (Table 2). Patient 3 A 55-year-old woman, with severe ataxia that began 13 years earlier complained of bilateral, progressive painless visual loss. Serial neurological examinations revealed slowly FIG. 1. Genealogical tree of the family. Square = male, circle = female, black = SCA1 patients. 226 Lebranchu et al: J Neuro-Ophthalmol 2013; 33: 225-231 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. progressive kinetic and static cerebellar syndrome, associ-ated with tetrapyramidal signs and speech and swallowing difficulties. Marked ponto-cerebellar atrophy was detected on magnetic resonance imaging (MRI). Visual acuity was 20/200, right eye, and 20/100, left eye. Visual fields showed bilateral central scotomas. Funduscopy revealed only mild granular appearance of the foveal RPE (Fig. 3). There was RNFL thinning on OCT (Table 2) and abnormal foveal cavitation was visible, between the outer segment layer and the layer representing the junction of the inner and outer segments. The layer corresponding to the retinal epithelium complex exhibited local foveal thickening (Fig. 4). Patient 4 A 52-year-old man, with no visual complaints, had a history of slowly progressive cerebellar-pyramidal syndrome. MRI showed marked cerebellar atrophy, and genetic analysis con-firmed SCA1 diagnosis. Other causes of genetic spinocere-bellar ataxia were excluded (SCA 2, 3, 6, 7, 12, and 17). Visual acuity was 20/20 bilaterally. Macular visual field testing revealed asymptomatic, asymmetric central scoto-mas. Funduscopy was normal (Fig. 3), but OCT revealed central alteration of the photoreceptor outer segment layer, with focal thickening (Fig. 4). RNFL thickness was normal (Table 2). DISCUSSION Optic neuropathy has been reported previously as a cause of visual impairment in SCA1. Abe et al (10) reported 6 SCA1 patients from 3 families with decreased visual acuity and optic atrophy. Using OCT, Stricker et al (11) demonstrated significant thinning of temporal retinal nerve fibers, suggesting preferential involvement of the papillomacular bundle. Abnormalities of both latency and amplitude of VEPs also have been found in SCA1 patients (12-14). In most of these studies, the retinal function was tested using full-field ERG; mfERG was not performed. Among ADCA, SCA7 has been associated with retinal disease (15), ranging from minor retinal findings (slightly attenuated retinal arteries, mild temporal disc pallor, normal fundus autofluorescence (16)) to severe visual loss (17). Macular OCT in SCA7 patients has confirmed both quan-titative macular thinning and qualitative altered foveal lam-ination of the photoreceptor layer at early stages of disease (18,19). There is an increasing evidence of macular abnor-malities occurring in ADCA patients, being 2.7 times more common in ataxic patients (20). Stricker et al (11) found decreased total macular volume with OCT in 6 SCA1 pa-tients, but this was not statistically significant. Using OCT, Pula et al (21) found a significant thinning of macular volume at 3 mm in 7 SCA1 patients, and Vaclavik et al (22) described a SCA1 patient with maculopathy and retinal dysfunction. Thurtell et al (9) reported a case of a genetically proven SCA1 patient with visual loss also secondary to rod- cone dystrophy, whose clinical findings were very similar to those of our patients: bilateral, progressive painless visual loss with macular drusen and mild pigmentary alterations on fundus examination. Other members of this reported FIG. 2. Central scotomas, visible on the visual field re-cordings of SCA1 patients, using central (P1 and P4) or 24-2 tests (P3). The recordings were performed with the Octopus 101 perimeter (P1) or the Humphrey Field Analyser (P3 and P4). Only pattern deviations are shown. TABLE 1. Demographic and genetic data of SCA1 patients Patient Age, yr Gender Number of CAG Repeats P1 51 Male 42-30 P2 73 Female 41-28 P3 55 Female * P4 52 Male 44-28 SCA1 gene given for both alleles. *Because of typical neurological findings, no genetic analysis was performed on patient 3 (sister of P4). Lebranchu et al: J Neuro-Ophthalmol 2013; 33: 225-231 227 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. family (9) exhibiting the SCA1 mutation also complained of visual loss, but no details of their fundus examination were reported. We can only speculate why several related patients exhibiting the same SCA1 mutation were affected by a mac-ulopathy, with heterogeneous intrafamilial expression. A common finding in SCA1 patients is phenotypic variability because of the number of CAG repeats among affected patients (23). To explain the occurrence of both neurolog-ical and ophthalmological diseases in this family, the hypothesis of 2 independently segregated traits cannot be excluded, but the evidence is weak. The probability of an FIG. 3. Fundus appearance of SCA1 patients (P1, P2, and P3) shows mild granular appearance of the perifoveal retinal pigment epithelium and small drusen around the foveola. Funduscopy was normal in P4. FIG. 4. OCT in patients with SCA1 (P1, P2, P3, and P4) reveals altered foveal lamination and abnormal space between the retinal pigment epithelium and external limiting membrane. 228 Lebranchu et al: J Neuro-Ophthalmol 2013; 33: 225-231 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. SCA1 family exhibiting an hereditary macular disease is equal to that of the general population, less than 1/40,000 (24). The probability of 4 relatives harboring 2 separate autosomal dominant diseases is even lower. It is more likely that both diseases are genetically linked, either with 2 independent mutations nearby on the same chromo-some or because of a "local effect" of one mutation on another gene nearby. TABLE 2. Visual acuity and measurement of retinal nerve fiber layer thickness in SCA1 patients Patient Side Visual acuity Macular (mm) Average RNFL (mm) Temporal RNFL (mm) P1 R 20/32 220 (H) 174 (N) 71 (H) 34 (H) L 20/40 226 (H) 183 (N) 77 (H) 43 (H) P2 R 20/50 181 (C) 97 (C) NA L 20/80 188 (C) 97 (C) NA P3 R 20/200 173 (C) 96 (C) 59 (C) L 20/100 156 (C) 94 (C) 58 (C) P4 R 20/20 188 (C) 90 (C) 61 (C) L 20/20 187 (C) 99 (C) 64 (C) Measurement done with spectral-domain optical coherence tomography Heidelberg (H), Nidek MP1 microperimeter (N), and Cirrus HD-OCT (C). Normal RNFL thickness (in micrometer): macular, H = 248-292, N = 219-269, and C = 220-294; temporal, H = 64-92, C = 45-82; and average, H = 94-115 and C = 75-107. L, left; NA, not available; R, right; RNFL, retinal nerve fiber layer. FIG. 5. Microperimetry recordings in P1. Right (A) and left (B) macular sensitivity, tested in 29 different points. The number above each point represents the sensitivity (in decibels) found in each portion of the retina. Color scale: green = sensitivity threshold found in 95% of the population; yellow = deficit of sensitivity found in less than 5% of the population; red = deficit of sensitivity found in less than 1% of the population. Right (C) and left (D) macular thickness. Macula is divided in 9 regions, and the average thickness (in micrometer) of each is indicated numerically. Color scale: green = thickness observed in 95% of a normal population; yellow = abnormal thickness observed in less than 5%; and red = abnormal thickness observed in less than 1%. Lebranchu et al: J Neuro-Ophthalmol 2013; 33: 225-231 229 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Pathogenesis of SCA1 is due partly to direct mutation of the gene (6p22,3), translated into an abnormal protein (ataxin-1) that has an abnormally long stretch of glutamine. This leads to polyQ protein aggregation in the cell and aberrant protein interactions, with specific transcriptional complexes in the nucleus (25). Trinucleotide repeat disorder could exhibit other pathogenic manifestations, sec-ondary to direct accumulation of the mutant messenger RNA in the nucleus, indirect gain of function (26), or inhibition of adjacent gene (27). In our patients, OCT demonstrated alterations of the external layers of the fovea, suggesting a loss of the structural integrity of the photo-receptors. Clinically, this foveolar lamination is compatible with an adult-onset vitelliform maculopathy, but the thin-ning of the whole macular area (including the surrounding perifoveolar retina) could be related to a cone dystrophy. Cone dystrophy is a clinically and genetically heterogeneous group, and no standard screening test has been developed. More than 10 different genes and loci have been identified in autosomal dominant cone dystrophy (https://sph.uth. edu/Retnet/sum-dis.htm#A-genes). Interestingly, a cluster of genes (GUCA1A, PRPH2) implicated in a spectrum of macular disease is located in 6p21.1, nearby SCA1 mutation. The gene GUCA1A (guanylate cyclase activator 1A) is implicated in cone dystrophy (COD3), which has phenotypic variability, even in the same family (28,29). The gene PRPH2 (Peripherin 2) has been also identified in adult-onset vitelliform macular dystrophy (30) or adult-onset foveomacular dystrophy (31). On inhibiting one of its promoters, CAG trinucleotide repeat could interfere with the regulation of one of these genes. Establishing a definite association of a maculopathy with SCA1 is limited, in part, by our small patient sample size. More extensive study of relatives, especially those who do not have the SCA1 mutation, would be very informative. Other family members declined evaluation because most were free of symptoms and did not want genetic testing. However, none of them complained of neurological or visual symptoms. Whether there is truly a macular disorder associated with SCA1 awaits further study. REFERENCES 1. Whaley NR, Fujioka S, Wszolek ZK. Autosomal dominant cerebellar ataxia type I: a review of the phenotypic and genotypic characteristics. Orphanet J Rare Dis. 2011;6:33. 2. Aleman TS, Cideciyan AV, Volpe NJ, Stevanin G, Brice A, Jacobson SG. Spinocerebellar ataxia type 7 (SCA7) shows a cone-rod dystrophy phenotype. Exp Eye Res. 2002;74:737-745. 3. Orr HT, Chung MY, Banfi S, Kwiatkowski TJ Jr, Servadio A, Beaudet AL, McCall AE, Duvick LA, Ranum LP, Zoghbi HY. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet. 1993;4:221-226. 4. Stevanin G, Durr A, Brice A. Clinical and molecular advances in autosomal dominant cerebellar ataxias: from genotype to phenotype and physiopathology. Eur J Hum Genet. 2000;8:4-18. 5. Gouw LG, Digre KB, Harris CP, Haines JH, Ptacek LJ. Autosomal dominant cerebellar ataxia with retinal degeneration: clinical, neuropathologic, and genetic analysis of a large kindred. Neurology. 1994;44:1441-1447. 6. Cancel G, Duyckaerts C, Holmberg M, Zander C, Yvert G, Lebre AS, Ruberg M, Faucheux B, Agid Y, Hirsch E, Brice A. Distribution of ataxin-7 in normal human brain and retina. Brain. 2000;123(pt 12):2519-2530. 7. La Spada AR, Fu YH, Sopher BL, Libby RT, Wang X, Li LY, Einum DD, Huang J, Possin DE, Smith AC, Martinez RA, Koszdin KL, Treuting PM, Ware CB, Hurley JB, Ptacek LJ, Chen S. Polyglutamine-expanded ataxin-7 antagonizes CRX function and induces cone-rod dystrophy in a mouse model of SCA7. Neuron. 2001;31:913-927. 8. Saito Y, Matsumura K, Shimizu S, Ichikawa Y, Ochiai K, Goto J, Tsuji S, Shimizu T. Pigmentary macular dystrophy in spinocerebellar ataxia type 1. J Neurol Neurosurg Psychiatry. 2006;77:1293. 9. Thurtell MJ, Biousse V, Newman NJ. Rod-cone dystrophy in spinocerebellar ataxia type 1. Arch Ophthalmol. 2011;129:956-958. 10. Abe T, Abe K, Aoki M, Itoyama Y, Tamai M. Ocular changes in patients with spinocerebellar degeneration and repeated trinucleotide expansion of spinocerebellar ataxia type 1 gene. Arch Ophthalmol. 1997;115:231-236. 11. Stricker S, Oberwahrenbrock T, Zimmermann H, Schroeter J, Endres M, Brandt AU, Paul F. Temporal retinal nerve fiber loss in patients with spinocerebellar ataxia type 1. PLoS One. 2011;6:e23024. 12. Perretti A, Santoro L, Lanzillo B, Filla A, De MG, Barbieri F, Martino G, Ragno M, Cocozza S, Caruso G. Autosomal dominant cerebellar ataxia type I: multimodal electrophysiological study and comparison between SCA1 and SCA2 patients. J Neurol Sci. 1996;142:45-53. 13. Abele M, Burk K, Andres F, Topka H, Laccone F, Bosch S, Brice A, Cancel G, Dichgans J, Klockgether T. Autosomal dominant cerebellar ataxia type I. Nerve conduction and evoked potential studies in families with SCA1, SCA2 and SCA3. Brain. 1997;120(pt 12):2141-2148. 14. Schols L, Linnemann C, Globas C. Electrophysiology in spinocerebellar ataxias: spread of disease and characteristic findings. Cerebellum. 2008;7:198-203. 15. Marelli C, Cazenevve C, Brice A, Stevanin G, Curr A. Autosomal dominant cerebellar ataxias. Rev Neurol (Paris). 2011;167:385-400. 16. Gouw LG, Digre KB, Harris CP, Haines JH, Ptacek LJ. Autosomal dominant cerebellar ataxia with retinal degeneration: clinical, neuropathologic, and genetic analysis of a large kindred. Neurology. 1994;44:1441-1447. 17. Thurtell MJ, Fraser JA, Bala E, Tomsak RL, Biousse V, Leigh RJ, Newman NJ. Two patients with spinocerebellar ataxia type 7 presenting with profound binocular visual loss yet minimal ophthalmoscopic findings. J Neuroophthalmol. 2009;29:187-191. 18. Manrique RK, Noval S, Guilar-Amat MJ, Arpa J, Rosa I, Contreras I. Ophthalmic features of spinocerebellar ataxia type 7. J Neuroophthalmol. 2009;29:174-179. 19. Kumar N, Pulido JS. High-definition spectral domain optical coherence tomography in the evaluation of ataxia with visual impairment. Br J Ophthalmol. 2011;95:591, 598. 20. Kahle JJ, Gulbahce N, Shaw CA, Lim J, Hill DE, Barabasi AL, Zoghbi HY. Comparison of an expanded ataxia interactome with patient medical records reveals a relationship between macular degeneration and ataxia. Hum Mol Genet. 2011;20:510-527. 21. Pula JH, Towle VL, Staszak VM, Cao D, Bernard JT, Gomez CM. Retinal nerve fibre layer and macular thinning in spinocerebellar ataxia and cerebellar multisystem atrophy. Neuroophthalmology. 2011;35:108-114. 22. Vaclavik V, Munier FL, Schorderet DF, Borruat FX. Autofluorescence findings of a novel maculopathy in patient with spinocerebellar ataxia type 1 and of a cone-rod type retinal dysfunction in three generation family with spinocerebellar ataxia type 7. Abstract. Annual ARVO meeting, Ft Lauderdale, FL, May 1-5, 2011. 230 Lebranchu et al: J Neuro-Ophthalmol 2013; 33: 225-231 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. 23. Paulson HL. The spinocerebellar ataxias. J Neuroophthalmol. 2009;29:227-237. 24. Hamel CP. Cone rod dystrophies. Orphanet J Rare Dis. 2007;2:7. 25. Lam YC, Bowman AB, Jafar-Nejad P, Lim J, Richman R, Fryer JD, Hyun ED, Duvick LA, Orr HT, Botas J, Zoghbi HY. ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology. Cell. 2006;127:1335-1347. 26. Tapscott SJ, Thornton CA. Biomedicine. Reconstructing myotonic dystrophy. Science. 2001;293:816-817. 27. Rhodes JD, Monckton DG, McAbney JP, Prescott AR, Duncan G. Increased SK3 expression in DM1 lens cells leads to impaired growth through a greater calcium-induced fragility. Hum Mol Genet. 2006;15:3559-3568. 28. Michaelides M, Wilkie SE, Jenkins S, Holder GE, Hunt DM, Moore AT, Webster AR. Mutation in the gene GUCA1A, encoding guanylate cyclase-activating protein 1, causes cone, cone-rod, and macular dystrophy. Ophthalmology. 2005;112: 1442-1447. 29. Downes SM, Holder GE, Fitzke FW, Payne AM, Warren MJ, Bhattacharya SS, Bird AC. Autosomal dominant cone and cone-rod dystrophy with mutations in the guanylate cyclase activator 1A gene-encoding guanylate cyclase activating protein-1. Arch Ophthalmol. 2001;119:96-105. 30. Felbor U, Schilling H, Weber BH. Adult vitelliform macular dystrophy is frequently associated with mutations in the peripherin/RDS gene. Hum Mutat. 1997;10:301-309. 31. Yang Z, Lin W, Moshfeghi DM, Thirumalaichary S, Li X, Jiang L, Zhang H, Zhang S, Kaiser PK, Traboulsi EI, Zhang K. A novel mutation in the RDS/Peripherin gene causes adult-onset foveomacular dystrophy. Am J Ophthalmol. 2003;135:213- 218. Lebranchu et al: J Neuro-Ophthalmol 2013; 33: 225-231 231 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.