Chinnery, Patrick F

Griffin, Helen

Horvath, Rita

Pyle, Angela

Santibanez-Korev, Mauro

Yu-Wai-Man, Patrick

British Journal of Ophthalmology

English

PubMed

Apollo (Cambridge)

LETTERAbnormal retinal thickening isa common feature amongpatients with ARSACS-relatedphenotypesAutosomal-recessive spastic ataxia ofCharlevoix-Saguenay (ARSACS) was firstdescribed among French Canadian patientsfrom Québec presenting with a stereotyp-ical triad of early-onset cerebellar ataxia,spastic paraplegia and peripheral neur-opathy. Two recurring pathogenic muta-tions in the SACS gene were subsequentlyidentified in these families in keeping with amutational founder event in a geographic-ally isolated population.1 However,ARSACS is being increasingly recognisedworldwide as an important cause of inher-ited ataxia.2 Interestingly, non-Québecpatients can show strikingly variable fea-tures marked by a lack of spasticity, cogni-tive impairment and a delayed age ofonset.2 Given the heterogeneous clinicalpicture that can be associated with SACSmutations, the identification of ancillaryfeatures linked with these genetic defectscould prove particularly useful in prioritis-ing the most appropriate lines of investiga-tions when confronted with a suspectedcase of ARSACS. Although prominentretinal hypermyelination is thought to be acharacteristic manifestation of classicalARSACS among Québec patients, this oph-thalmological finding has only beendescribed infrequently in patients fromEurope, Asia and the Middle East.2 Arecent case report has even further arguedthat retinal ‘hypermyelination’ in ARSACSis a pathologically misleading term thatshould be abandoned in favour of retinalnerve fibre layer (RNFL) hypertrophy.3To more accurately define the nature ofthe retinal findings in ARSACS and its pos-sible practical relevance as a screening toolin routine clinical practice, we carried out acomprehensive neuro-ophthalmologicalexamination of five patients from the Northof England with molecularly confirmedARSACS (table 1).4 5 Topographic analysisof the optic disc was performed with theSpectralis optical coherence tomography(OCT) platform (Heidelberg Engineering,Heidelberg, Germany).No patient had evidence of retinalhypermyelination. Retinal striations wereobserved around the optic discs in fourpatients (A, B, C and D) and OCT mea-surements showed significant generalisedperipapillary RNFL thickening (see onlinesupplementary figures S1–S4). Patient Ehad no fundus abnormalities, and theperipapillary RNFL thickness was withinthe normal range for healthy controls (seeonline supplementary figure S5).Our case series has provided convincingevidence that abnormal retinal thickeningis a common, although not universal,feature among patients withARSACS-related phenotypes secondary topathogenic SACS mutations. Significantperipapillary RNFL thickening has alsobeen previously reported in eight patientsharbouring confirmed pathogenic SACSmutations with different OCT imagingplatforms to the one used in our study.6–8Classical myelinated retinal nerve fibreswere not observed, and the current bodyof evidence, at least among non-Québecpatients, suggests that retinal ‘hypermyeli-nation’ has been used inappropriately todescribe the striated appearance of athickened RNFL around the optic discs.The pathophysiological basis for thisobservation remains to be determined, butit is rather revealing that the sacsinprotein localises to mitochondria. In atransgenic knock-out mouse model, deple-tion of the sacsin protein resulted in dis-ruption of mitochondrial axonal transportand cerebellar neurones with aberrantdendritic morphologies.9 Although specu-lative, RNFL thickening in ARSACS couldtherefore be related to axoplasmic stasiswithin the long axons of the retinal gan-glion cells as they converge to form theoptic nerve in the anatomically con-strained region of the lamina cribosa.The investigation of a large multicentrecohort of patients with ARSACS will beneeded to determine whether the degree ofRNFL thickening correlates with diseaseseverity and progression or whether thereare any specific genotype–OCTcorrelations.The molecular genetic basis of inheritedataxia and spastic paraplegia syndromes ishighly heterogeneous—a situation thatposes a number of diagnostic challenges inneurology clinics. In Friedreich’s ataxia,which is the most common form of auto-somal recessive ataxia, variable reduction inRNFL thickness has been reported amongvisually asymptomatic patients.10 In a recentOCT study, we found a normal RNFLprofile among patients harbouring SPG4mutations, which account for ∼40% of allautosomal-dominant cases of hereditaryspastic paraplegia.11 A dilated fundus exam-ination and OCT imaging should thereforebe considered in patients with unexplainedmultisystem neurological disease. Whenpresent, retinal striations and RNFL thick-ening raise the distinct possibility ofTable 1 Clinical features and retinal nerve fibre layer measurements in patients with pathogenic SACS mutationsPatientAge(years) SexOnset(years) Clinical features SACS mutationsAverage RNFLThicknessOD (μm) OS (μm)A 48 F 26 Gait ataxia, dysarthria, spastic paraplegia andperipheral neuropathyc.2076delG (p.Thr692ThrfsX713);c.3965_3966delAC (p.Gly1322ValfsX1343)174 175B 45 M 19 Gait ataxia, dysarthria, spastic paraplegia andperipheral neuropathy162 140C 43 M Late-teens Gait ataxia, dysarthria, proximal myopathy andperipheral neuropathyc.13048G>T (p.Glu4350X); 0.7Mb deletion(13q12.12)138 122D 46 M Mid-teens Gait ataxia, dysarthria, proximal myopathy andperipheral neuropathy152 169E 69 M Late-teens Gait ataxia, spastic paraplegia and peripheralneuropathyc.1580C>G (p.Ser527X); c.6781C>A (p.Leu2261Ile)111 86Patients A and B, and patients C and D, are two pairs of siblings. The molecular genetic characterisation of these four patients with next-generation whole exome sequencing has beenpreviously reported.4 5 All the patients presented with progressive gait ataxia and they were severely disabled, requiring the use of a wheelchair for ambulation. Four patients (A, B, Cand D) had significant peripapillary RNFL thickening outside the normal range for healthy controls (mean average thickness=100.3 μm, SD=1.8 μm). No patient had a significantrefractive error that could be a confounding variable in the analysis of peripapillary RNFL thickness.OD, right eye; OS, left eye; RNFL, retinal nerve fibre layer.Br J Ophthalmol Month 2014 Vol 98 No 5 711PostScriptARSACS, and SACS genetic screeningshould be considered.Patrick Yu-Wai-Man,1,2 Angela Pyle,1Helen Griffin,1 Mauro Santibanez-Korev,1Rita Horvath,1,3 Patrick F Chinnery1,31Wellcome Trust Centre for Mitochondrial Research,Institute of Genetic Medicine, Newcastle University,Newcastle upon Tyne, Tyne and Wear, UK2Department of Ophthalmology, Royal VictoriaInfirmary, Newcastle upon Tyne, Tyne and Wear, UK3Department of Neurology, Royal Victoria Infirmary,Newcastle upon Tyne, Tyne and Wear, UKCorrespondence to Dr Patrick Yu-Wai-Man,Wellcome Trust Centre for Mitochondrial Research,Institute of Genetic Medicine, Newcastle University,Newcastle upon Tyne NE1 3BZ, UK;Patrick.Yu-Wai-Man@ncl.ac.ukCorrection notice The license of this article has alsochanged since publication to CC BY 4.0.Contributors PY-W-M was responsible for drafting/revising the manuscript for content, including medicalwriting for content, analysis or interpretation of data,acquisition of data; study supervision or coordination.AP, HG, MS-K and RH were responsible for drafting/revising the manuscript for content, including medicalwriting for content, analysis or interpretation of data.PFC was responsible for drafting/revising themanuscript for content, including medical writing forcontent, analysis or interpretation of data, andobtaining funding.Competing interests PY-W-M is a Medical ResearchCouncil (MRC, UK) Clinician Scientist. PY-W-M alsoreceives funding from Fight for Sight (UK) and the UKNational Institute of Health Research (NIHR) as part ofthe Rare Diseases Translational Research Collaboration.RH is funded by the MRC (UK) and the EuropeanResearch Council. PFC is a Wellcome Trust SeniorFellow in Clinical Science and a UK NIHR SeniorInvestigator. PFC also receives funding from the MRC(UK), Parkinson’s UK, and the UK NIHR BiomedicalResearch Centre for Ageing and Age-Related Diseaseaward to the Newcastle upon Tyne Hospitals NHSFoundation Trust.Ethics approval This study had the relevantinstitutional ethical approval and it complied with theDeclaration of Helsinki.Provenance and peer review Not commissioned;externally peer reviewed.Data sharing statement There are no additionalunpublished data relating to this study.▸ Additional material is published online only. To viewplease visit the journal online (http://dx.doi.org/10.1136/bjophthalmol-2013-304534).Open Access This is an Open Access articledistributed in accordance with the terms of the CreativeCommons Attribution (CC BY 4.0) license, whichpermits others to distribute, remix, adapt and buildupon this work, for commercial use, provided theoriginal work is properly cited. See: http://creativecommons.org/licenses/by/4.0/To cite Yu-Wai-Man P, Pyle A, Griffin H, et al. Br JOphthalmol 2014;98:711–712.Accepted 23 December 2013Br J Ophthalmol 2014;98:711–712.doi:10.1136/bjophthalmol-2013-304534REFERENCES1 Engert JC, Berube P, Mercier J, et al. ARSACS, aspastic ataxia common in northeastern Quebec, iscaused by mutations in a new gene encoding an11.5-kb ORF. Nat Genet 2000;24:120–5.2 Takiyama Y. Sacsinopathies: sacsin-related ataxia.Cerebellum 2007;6:353–9.3 Garcia-Martin E, Pablo LE, Gazulla J, et al. Retinalnerve fibre layer thickness in ARSACS: myelination orhypertrophy? Br J Ophthalmol 2013;97:238–41.4 Pyle A, Griffin H, Yu-Wai-Man P, et al. Prominentsensorimotor neuropathy due to SACS mutationsrevealed by whole-exome sequencing. Arch Neurol2012;69:1351–4.5 Pyle A, Griffin H, Duff J, et al. Late-onsetsacsinopathy diagnosed by exome sequencing andcomparative genomic hybridization. J Neurogenet2013;27:176–82.6 Pablo LE, Garcia-Martin E, Gazulla J, et al. Retinal nervefiber hypertrophy in ataxia of Charlevoix-Saguenaypatients. Mol Vis 2011;17:1871–6.7 Desserre J, Devos D, Sautiere BG, et al. Thickening ofperipapillar retinal fibers for the diagnosis ofautosomal recessive spastic ataxia ofCharlevoix-Saguenay. Cerebellum 2011;10:758–62.8 Nethisinghe S, Clayton L, Vermeer S, et al. Retinalimaging in autosomal recessive spastic ataxia ofCharlevoix-Saguenay. Neuro-Ophthalmology2011;35:197–201.9 Girard M, Lariviere R, Parfitt DA, et al. Mitochondrialdysfunction and Purkinje cell loss in autosomalrecessive spastic ataxia of Charlevoix-Saguenay(ARSACS). Proc Natl Acad Sci USA 2012;109:1661–6.10 Fortuna F, Barboni P, Liguori R, et al. Visual systeminvolvement in patients with Friedreichs ataxia. Brain2009;132:116–23.11 Guthrie G, Pfeffer G, Bailie M, et al. The neurologicaland ophthalmological manifestations of SPG4-relatedhereditary spastic paraplegia. J Neurol 2012;260:906–9.712 Br J Ophthalmol Month 2014 Vol 98 No 5PostScript

Abnormal retinal thickening is a common feature among patients with ARSACS-related phenotypes.

Patrick Yu-Wai-Man

Angela Pyle

Helen Griffin

Mauro Santibanez-Korev

Rita Horvath

Patrick F Chinnery

Crossref

Abnormal retinal thickening is a common feature among patients with ARSACS-related phenotypes: Table 1

http://dx.doi.org/10.1136/bjophthalmol-2013-304534

Abnormal retinal thickening is a common feature among patients with ARSACS-related phenotypes.

Abstract

Similar works

Full text

Available Versions

Apollo (Cambridge)

Crossref