CARDAIOLI, ELENA

DOTTI, MARIA

FEDERICO, ANTONIO

FEDERIGHI, PAMELA

PRETEGIANI, ELENA

ROSINI, FRANCESCA

RUFA, ALESSANDRA

Sicurelli, Francesco

VINCIGUERRA, CLAUDIA

Archivio della Ricerca - Università degli Studi di Siena

Journal of the Neurological Sciences 350 (2015) 107–109Contents lists available at ScienceDirectJournal of the Neurological Sciencesj ourna l homepage: www.e lsev ie r .com/ locate / jnsLetter to the EditorEye movement changes inmitochondrial neurogastrointestinalencephalomyopathy (MNGIE)Keywords:Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)Eye movementsExtrinsic ocular motor muscles (EOMs)Muscular metabolism1. IntroductionMitochondrial neurogastrointestinal encephalomyopathy (MNGIE)is an autosomal recessive disease due to ECGF1 gene mutations (chro-mosome 22) causingmultiple deletions and depletion of mitochondrialDNA in skeletal muscle. The determination of the activity of the gene-product tymidine phosphorylase (TP) in leukocytes and genetic analysisare diagnostic. External ophthalmoplegia, severe gastrointestinaldysmotility, cachexia, peripheral sensory-motor neuropathy, diffusemyopathy and leukoencephalopathy are typical ﬁndings. The severedisease progression leads to death in a few years [1]. Allogeneic hema-topoietic stem cell transplantation (HSCT)may restore enzymatic levelsimproving the clinical outcome [2].Extraocular muscles (EOMs), fast and fatigue resistant, are affectedearly in MNGIE, as in other mitochondrial diseases, and their dysfunc-tion parallels the disease evolution. This vulnerability is due to theirhigher mitochondrial content and metabolic rate than limb skeletalmuscles, implying a particular dependence on oxidative phosphoryla-tion and a selective vulnerability to respiratory chain dysfunctions.Moreover, EOMs are functionally divided in the orbital and global layers,containing muscle ﬁbers with unique structural and functional proper-ties that may make them differently susceptible to the mitochondrialfailure [3].Their recruitment appear to reﬂect their fatigability, beingthe fast but low fatigue resistant ﬁbers of the orbital layer activatedmainly during saccades [4].These changes may be quantiﬁed by the analysis of the dynamicproperties of saccades, which therefore could provide a reliable andreproducible clinical assessment and follow-up in MNGIE and othermitochondrial disorders.2. Case reportWe describe the saccadic features of two patients affected byMNGIE: patient 1 (P1, 27 years old) with juvenile onset and rapid evo-lution who received HSCT at 23 years [5] and patient 2 (P2, 47 yearsold), late onset and severe course, who was waiting for transplant. P2presented with a typical phenotype and analysis for TP revealed ahomozygous A to C transition in exon 7 (A3371C). P1 instead, carryinga homozygous c.1249dupC mutation of TP, improved clinically aftertransplant and restored enzyme activity to normal levels [5]. Patient'shttp://dx.doi.org/10.1016/j.jns.2015.01.0310022-510X/© 2015 Elsevier B.V. All rights reserved.information and data acquisition were collected under the approval ofthe local ethical committee. Informant consent was obtained fromeach patient.Horizontal visually guided saccades were recorded at 10° and 18° ofeccentricity. Detailedmethods of signal processing and saccade analysishave been reported elsewhere [6]. Saccadic parameters were comparedseparately with a control group of 25 healthy subjects (11 males, 14females) of mean age 43.2 years (range 30–68 years) (see ref. [6] fordetails).Both patients showed slow and hypometric saccades (Fig. 1A–C) asdemonstrated by a signiﬁcant reduction (p b 0.001) of peak velocity(P1, 10°:241 ± 48°/s, 18°:324 ± 69°/s; P2, 10°:165 ± 56°/s,18°:213 ± 73°/s) and amplitude (P1, 10°:8.3 ± 1.7°, 18°:17.6 ± 2.1°;P2, 10°:6.7 ± 2.5°, 18°:9.8 ± 5.1°) compared to controls (10°:383 ±65°/s; 18°:498± 85°/s and 10°:10.2± 1.1°; 18°:18.1± 1.7°, respective-ly). Particularly, P1 showed fragmented trend especially in saccades tofar targets (18°), with greater speed and accuracy respect to P2, whichoften failed to reach the target and showed saccades with increasedduration and low speed. These very slow saccades often showed aninterruption of the velocity proﬁle (camel-hump proﬁle) (Fig. 1A, B).A peculiar saccadic behavior resulted from comparing adducting andabducting saccadic parameters in our patients (Fig. 1D–E). Indeed, forlarger saccades, we found faster adducting than abducting saccades inP2, with a greater loss of accuracy: peak velocity at 18° was 240 ±84°/s adducting vs 197 ± 61°/s abducting (p b 0.001); error in accuracywas 10.5± 3.3°adducting vs 8± 5.5°abducting (p b 0.001). Conversely,P1 showed faster abducting than adducting saccades: peak velocity at10° was 219 ± 42°/s adducting vs 255 ± 48°/s abducting (p b 0.001);at 18°:271 ± 45°/s adducting vs 370 ± 51°/s abducting (p b 0.005).3. DiscussionBoth patients showed hypometric and low speed saccades com-pared to controls, particularly for larger movements, reﬂecting a globalEOMs muscle weakness due to severe mitochondrial myopathy.Moreover, the saccadic proﬁle of the transplanted patient was great-er than that of the untreated patient. Indeed P1, despite slow andhypometric saccades (multi-step pattern), satisﬁed the mean sequencerelationship between speed and amplitude (Fig. 1A and C).Moreover, asreported in normal subjects [6], her abducting saccadeswere faster thanadducting.P2, instead, showed extremely slow and hypometric saccades notfulﬁlling the mean sequence, and abducting saccades were severelycompromised so adducting saccades were faster. Differences in residualenzymatic activity and disease severitymay explain the different veloc-ity and amplitude proﬁles of saccades between the two patients.However, it does not completely clarify the diverse adducting andabducting saccadic behavior.A possible explanation of this differencemay be the uneven dissem-ination of the mutated mitochondria in lateral vs medial recti ﬁbersbased on their random duplication or a diverse genetic expression [4].Fig. 1. The Fig. 1 shows an example of 18° horizontal saccade of patient 1(A) and patient 2 (B). Panels C–E illustrate themain sequence relationships of peak velocity versus amplitude. Thedata point (C) are saccades of patient 1 (light green circle) and patient 2 (red circle). Saccades of patient 1, in abduction, are represented by dark green circle and those in adduction byfuchsia circle (D). The saccades of patient 2 in abduction are depicted by circle dark green and adduction by fuchsia circle (E). The graph-bar shows the peak velocity and amplitude valuesof the MNGIE patients in respect to controls (F).108 Letter to the EditorAnother possibility is the different distribution and susceptibility to fa-tigue of ﬁber subgroups in lateral versus medial recti. EOMs containabout 90% of fast-twitch single-innervation ﬁbers (SIFs)with highmito-chondrial content and resistance to fatigue. However, while orbital layercontains only fatigue resistant SIFs, the global layer contains fast-twitchﬁbers with different degrees of fatigue resistance, and very fast butrapidly fatigable pale ﬁbers recruited during saccades [7–9]. Both layersare activated during saccades; the orbital, more fatigue resistant,109Letter to the Editorensures a more sustained contraction in larger movements [9,10]. Themedial recti, responsible of adduction, are thicker and have a higherpercentage of orbital fast-twitch ﬁbers than the lateral recti, responsibleof abduction [9,10]. These structural differences may possibly have adynamic counterpart as observed in our patients [3,7,8]. Data from alarger number of patients could conﬁrm and better elucidate this specif-ic behavior.In conclusion, the saccadic proﬁle may provide a reliable measure ofmuscle dysfunction. Low-speed and short saccades, particularly inabduction, reﬂect a clinically severe mitochondrial involvement, whilemultistep, normal speed saccades with well-preserved abduction indi-cate a more efﬁcient aerobic muscle activity. In this respect, analysis ofadducting and abducting saccades may have a clinical relevance in thedifferential diagnosis with other ophthalmoparesis or myastheniausually affecting adduction more than abduction and adding furtherinsight into pathophysiology of EOMs susceptibility to energy depriva-tion due to muscle damage.Eye movements recorded through an eye-tracking technique is aneasily repeatable and noninvasive tool that can help in diagnosis,follow-up and evaluation of the response to treatment in variousmitochondrial myopathies, such as MNGIE.Conﬂict of interestAll authors declare no conﬂict of interest.AcknowledgmentsStudy in part funded by EC FP7-PEOPLE-IRSES-CERVISO 269263.References[1] Nishino I, Spinazzola A, Hirano M. Thymidine phosphorylase gene mutations inMNGIE, a human mitochondrial disorder. Science 1999;283:689–92.[2] Hirano M, Martí R, Casali C, Tadesse S, Uldrick T, Fine B, et al. Allogeneic stem celltransplantation corrects biochemical derangements in MNGIE. Neurology 2006;67(8):1458–60.[3] Porter JD. Extraocular muscle: cellular adaptations for a diverse functional reper-toire. Ann N Y Acad Sci 2002;956:7–16.[4] Shall MS, Goldberg SJ. Extraocular motor units: type classiﬁcation and motoneuronstimulation frequency-muscle unit force relationship. Brain Res 1992;587:291–300.[5] Sicurelli F, Carluccio MA, Toraldo F, Tozzi M, Bucalossi A, Lenoci M, et al. Clinical andbiochemical improvement followingHSCT in a patientwithMNGIE: 1-year follow-up.J Neurol 2012;259(9):1985–7.[6] Federighi P, Cevenini G, Dotti MT, Rosini F, Pretegiani E, Federico A, et al. Differencesin saccade dynamics between spinocerebellar ataxia 2 and late-onset cerebellarataxias. Brain 2011;134:879–91.[7] McLoon LK, Christiansen SP. Extraocular muscles: extraocular muscle anatomy. In:Dartt Darlene A, editor. Encyclopedia of the Eye, vol 2. Oxford: Academic Press;2010. p. 89–98.[8] Leigh RJ, Zee DS. The Neurology of Eye Movements (Book/DVD). 4th ed. New York:Oxford University Press; 2006 327–9.[9] Spencer RF, Porter D. Biological organization of the extraocular muscles. Prog BrainRes 2006;151:43–80.[10] Scott AB, Collins CC. Division of labor in human extraocular muscle. ArchOphthalmol 1973;90(4):319–22.Claudia VinciguerraEye-tracking and Visual Application Lab (EVALab), University of Siena, ItalyNeurometabolic Unit Department of Medicine, Surgery and Neurosciences,University of Siena, ItalyPamela FederighiEye-tracking and Visual Application Lab (EVALab), University of Siena, ItalyFrancesca RosiniElena PretegianiEye-tracking and Visual Application Lab (EVALab), University of Siena, ItalyNeurometabolic Unit Department of Medicine, Surgery and Neurosciences,University of Siena, ItalyElena CardaioliMaria T. DottiFrancesco SicurelliAntonio FedericoNeurometabolic Unit Department of Medicine, Surgery and Neurosciences,University of Siena, ItalyAlessandra RufaEye-tracking and Visual Application Lab (EVALab), University of Siena, ItalyNeurometabolic Unit Department of Medicine, Surgery and Neurosciences,University of Siena, ItalyCorresponding author at: University of Siena, viale Bracci 2, PoliclinicoSanta Maria alle Scotte, Siena, Italy.Tel.: +39 0577233136; fax: +39 057740327.E-mail address: rufa@unisi.it.22 November 2014

Eye movement changes in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

Eye movement changes in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

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