Bailie, Maura

Bradshaw, Karen

Browning, Andrew C

Chinnery, Patrick F

Guthrie, Grant

Horvath, Rita

Pfeffer, Gerald

Yu-Wai-Man, Patrick

English

PubMed

Grant Guthrie

Gerald Pfeffer

Maura Bailie

Karen Bradshaw

Andrew C. Browning

Rita Horvath

Patrick F. Chinnery

Patrick Yu-Wai-Man

Springer - Publisher Connector

The neurological and ophthalmological manifestations of SPG4-related hereditary spastic paraplegia

Apollo (Cambridge)

LETTER TO THE EDITORSThe neurological and ophthalmological manifestationsof SPG4-related hereditary spastic paraplegiaGrant Guthrie • Gerald Pfeffer • Maura Bailie • Karen Bradshaw •Andrew C. Browning • Rita Horvath • Patrick F. Chinnery •Patrick Yu-Wai-ManReceived: 23 October 2012 / Accepted: 29 November 2012 / Published online: 13 December 2012 The Author(s) 2012. This article is published with open access at Springerlink.comDear Sirs,The hereditary spastic paraplegias (HSPs) are a genet-ically heterogeneous group of disorders characterisedby progressive corticospinal tract degeneration and thedevelopment of lower limb spasticity [1, 2]. Autoso-mal-dominant HSP is the most commonly inheritedform of the disease and in this group, SPG4 mutationsaccount for *40 % of cases [1]. The SPG4 gene codesfor spastin, a critical neuronal protein that maintainsorganelle axonal transport by severing and rearrangingthe microtubule network [3, 4]. Dysfunctional mutantproteins or insufficient quantities of the wild-typeprotein inhibit this dynamic shuttling process resultingin axonal swelling and progressive retrograde degen-eration that preferentially affects the long corticospinalaxons [3, 4].There is mounting evidence that the microtubule andmitochondrial networks are intrinsically linked at thecellular level [5]. This intriguing association has recentlybeen highlighted by the clinical observation that autoso-mal-dominant optic atrophy (DOA)—a classical mito-chondrial optic neuropathy caused by pathogenic OPA1mutations—can result in complicated neurological phe-notypes (DOA?) with features indistinguishable fromHSP [6]. Furthermore, subclinical corticospinal tractdysfunction also seems to be a prevalent feature amongOPA1 mutation carriers presenting with isolated visualfailure, suggesting a wider disease spectrum than origi-nally considered [7]. Interestingly, these overlappinggenotype-phenotype manifestations have been reportedpreviously in families with a rarer, autosomal-recessiveform of HSP caused by pathogenic SPG7 mutations, inwhich bilateral optic atrophy was a prominent featuresegregating with spastic paraplegia [8–10]. Given theemerging disease mechanisms linking corticospinal tractdysfunction with optic nerve degeneration, the aim of thisstudy was to determine the neurological and ophthalmo-logical manifestations of SPG4-related HSP, lookingspecifically for evidence of clinical or subclinical opticneuropathy among affected patients. The overall neuro-logical disability, including cognitive function, was alsoevaluated to provide a comprehensive assessment of theburden of disease in this group of patients.A comprehensive neurological (GP, RH, PFC) andophthalmological (PYWM) assessment (SupplementaryMethod) was carried out on ten white patients from theNorth of England harbouring confirmed pathogenicSPG4 mutations (Table 1). A broad spectrum ofElectronic supplementary material The online version of thisarticle (doi:10.1007/s00415-012-6780-3) contains supplementarymaterial, which is available to authorized users.G. Guthrie  M. Bailie  K. Bradshaw  A. C. Browning P. Yu-Wai-ManDepartment of Ophthalmology, Royal Victoria Infirmary,Newcastle upon Tyne, UKG. Guthrie  G. Pfeffer  R. Horvath  P. F. Chinnery P. Yu-Wai-ManDepartment of Neurology, Royal Victoria Infirmary,Newcastle upon Tyne, UKG. Pfeffer  R. Horvath  P. F. Chinnery  P. Yu-Wai-Man (&)Wellcome Trust Centre for Mitochondrial Research,Institute of Genetic Medicine, Newcastle University,Newcastle upon Tyne NE1 3BZ, UKe-mail: Patrick.Yu-Wai-Man@ncl.ac.ukK. BradshawDepartment of Medical Physics, Royal Victoria Infirmary,Newcastle upon Tyne, UK123J Neurol (2013) 260:906–909DOI 10.1007/s00415-012-6780-3neurological disability was observed among affectedpatients with scores ranging from one to nine on themodified EDSS scale (Table 2). Importantly, fourpatients had abnormal MOCA scores of less than 26points. Seven patients performed poorly on the memorycomponent of the MOCA test protocol and one patienthad abnormal visuospatial/executive performance. Theassociation between SPG4 mutations and progressivecognitive decline remains controversial [11–13] and ourstudy of a well-characterised patient cohort providesfurther evidence favouring a true causal link. Two of thepatients with abnormal MOCA scores were younger thanthe age of 30 years, clearly highlighting the need forclinical vigilance to detect early signs of cognitiveimpairment and to provide adequate level of support,especially to carers.Except for one patient who had bilateral nuclearsclerotic cataracts, all patients had best-corrected visualacuities of 20/20 bilaterally (Table 1). The ophthalmolog-ical examination was normal with full colour discrimina-tion and no detectable optic disc or retinal abnormalities.Visual fields, RNFL thickness measurements and visualelectrophysiology were within the normal range for theentire HSP patient cohort. Three patients had abnormal eyemovements with horizontal square wave jerks and saccadicsmooth pursuits. No significant ptosis or limitation of eyemovements was noted on orthoptic assessment. Based onour comprehensive clinical and electrophysiological eval-uation, visual loss secondary to optic nerve or retinaldegeneration is unlikely to be a major phenotypic mani-festation of SPG4-related disease. Affected patients and at-risk family members can therefore be reassured that unlikeother genetically-determined forms of HSP [6–10], SPG4mutations are not associated with the development of sig-nificant ophthalmological complications, in particularvisual failure.Table 1 Molecular genetic and ophthalmological features of the SPG4 patient cohortPatient Sex Age(years)SPG4 mutation BCVARE-LEOptic discs/OCTmeasurementsEyemovementsVisualelectrophysiologyExon cDNA change/consequence1 F 31 5 c.743C[G/p.S245X 20/20-20/20 Normal/no RNFLthinningNormal Normal2 M 53 5 c.743C[G/p.S245X 20/20-20/20 Normal/no RNFLthinningHorizontal SWJ/saccadic pursuitNormal3 F 50 6 c.937delG/p.D313fsX1 20/20-20/20 Normal/no RNFLthinningNormal Normal4 F 55 4–17 del exon 4-17/large-scaledeletion20/20-20/20 Normal/no RNFLthinningNormal Normal5 F 29 10 c.1253_1255delAAG/p.E418fsX19820/20-20/20 Normal/no RNFLthinningHorizontal SWJ/saccadic pursuitNormal6 F 25 11 c.1442_1443insA/p.V482fsX520/20-20/20 Normal/no RNFLthinningNormal Normal7 F 55 11 c.1442_1443insA/p.V482fsX520/20-20/20 Normal/no RNFLthinningHorizontal SWJ/saccadic pursuitNormal8 F 49 11 c.1414G[A/p.V472I 20/20-20/20 Normal/no RNFLthinningNormal Normal9 F 72 11 c.1384A[G/p.K462E 20/60-20/30 Normal/no RNFLthinningNormal Normal10 M 65 11 c.1081C[A; c.1082T[A/p.L361N20/20-20/20 Normal/no RNFLthinningNormal NormalBCVA best-corrected visual acuities, cDNA complementary DNA, LE left eye, OCT optical coherence tomography, RE right eye, RNFL retinalnerve fibre layer, SWJ square wave jerksJ Neurol (2013) 260:906–909 907123Table2NeurologicalandcognitivefeaturesoftheSPG4patientcohortPatientCognitiveassessment(MOCA)MotorexaminationVibrationsenseOtherfindingsDisabilitymeasurementsModifiedAshworthspasticityscoreDeeptendonreflexesPower(MRCscale)CoordinationScoreCommentsL/REL/RKL/RBRL/RBL/RTL/RPL/RAPRULex/flLLfl/ex10mwalkModifiedEDSS127/303pointsfrommemory0,03,33,33,33,34,42,2Ex5,54,5ATAnkles19.1s6.5227/304pointsfrommemory0,01,12,22,22,23,32,2Fl5,55,5NN8.2s1327/302pointseachfromvisuospatial/executiveandattention0,01,12,22,22,23,32,2Ex5,54,4NKnees10.1s2427/303pointsfrommemory0,02,23,33,32,23,32,2Ex5,54,3–4NKneesMarkedLLoedemaWC7523/303pointsfrommemory3,34,43,33,33,33,34,4Ex4,40,0NKneesSpasticdysarthriaWC9625/303pointsfrommemory0,01,12,22,22,23,33,3Fl5,55,5NN8.9s1725/305pointsfrommemory0,03,32,23,33,34,43,3Ex5,54,5NAnkles13.4s4829/300,03,32,22,22,24,44,4Ex5,54,4NN11.3s21025/304pointsfrommemory1,12,22,22,22,23,33,3Ex5,54,4NAnklesTwocanesneededforwalking36.6s6.5Patientninewasnotavailableforthisportionoftheassessment.AtotalMOCAscoreof26orhigherisconsiderednormal.Forsubjectswith12yearsoftotaleducationorless,anadditionalpointisadded.MOCAscoreslowerthan26aresuggestiveofcognitiveimpairment[14].Vibrationsensehasbeenreportedasthelowestnormaltestinglocation.Publishednormativerangeforthe10mwalktestprotocol:mean6.7s,95%confidenceinterval5.6–7.9s[15]AAchilles,ATactiontremor,Bbiceps,BRbrachioradialis,Eelbow,EDSSExpandedDisabilityStatusScale,Exextensor,Flflexor,Kknee,Lleft,LLlowerlimbs,mmetres,MOCAMontrealCognitiveAssessmentScale,MRCMedicalResearchCouncil,Nnormal,PRplantarresponses,Rright,sseconds,Ttriceps,ULupperlimbs,WCwheelchair-bound908 J Neurol (2013) 260:906–909123Acknowledgments This work was supported by a research grantfrom the Association of British Neurologists (ABN, UK). GP is therecipient of a Bisby Fellowship from the Canadian Institutes of HealthResearch. RH is supported by the Medical Research Council (MRC,UK). PFC is a Wellcome Trust Senior Fellow in Clinical Science anda UK National Institute of Health Research (NIHR) Senior Investi-gator who also receives funding from the MRC (UK), and the UKNIHR Biomedical Research Centre for Ageing and Age-related dis-ease award to the Newcastle upon Tyne Hospitals NHS FoundationTrust. PYWM is an MRC (UK) Clinician Scientist.Conflicts of interest All the listed authors in this manuscript reportno relevant financial disclosures or conflicts of interest.Ethical standard This study had the relevant institutional ethicalapproval and it was carried out in compliance with the Declaration ofHelsinki.Open Access This article is distributed under the terms of theCreative Commons Attribution License which permits any use, dis-tribution, and reproduction in any medium, provided the originalauthor(s) and the source are credited.References1. Salinas S, Proukakis C, Crosby A, Warner TT (2008) Hereditaryspastic paraplegia: clinical features and pathogenetic mecha-nisms. Lancet Neurol 7:1127–11382. Harding AE (1983) Classification of the hereditary ataxias andparaplegias. Lancet 1:1151–11553. McDermott CJ, Grierson AJ, Wood JD et al (2003) Hereditaryspastic paraparesis: disrupted intracellular transport associatedwith spastin mutation. Ann Neurol 54:748–7594. Lumb JH, Connell JW, Allison R, Reid E (2012) The AAAATPase spastin links microtubule severing to membrane model-ling. Biochim Biophys Acta 1823:192–1975. Schon EA, Przedborski S (2011) Mitochondria: the next(Neurode) generation. Neuron 70:1033–10536. Yu-Wai-Man P, Griffiths PG, Gorman GS et al (2010) Multi-system neurological disease is common in patients with OPA1mutations. Brain 133:771–7867. Baker MR, Fisher KM, Whittaker RG, Griffiths PG, Yu-Wai-ManP, Chinnery PF (2011) Subclinical multisystem neurologic dis-ease in ‘‘pure’’ Opa1 autosomal dominant optic atrophy. Neu-rology 77:1309–13128. Casari G, De Fusco M, Ciarmatori S et al (1998) Spastic para-plegia and OXPHOS impairment caused by mutations in para-plegin, a nuclear-encoded mitochondrial metalloprotease. Cell93:973–9839. Wilkinson PA, Crosby AH, Turner C et al (2004) A clinical,genetic and biochemical study of SPG7 mutations in hereditaryspastic paraplegia. Brain 127:973–98010. van Gassen KL, van der Heijden CD, de Bot ST et al (2012)Genotype-phenotype correlations in spastic paraplegia type 7: astudy in a large Dutch cohort. Brain 135:2994–300411. Tallaksen CME, Guichart-Gomez E, Verpillat P et al (2003)Subtle cognitive impairment but no dementia in patients withspastin mutations. Arch Neurol 60:1113–111812. McMonagle P, Byrne P, Hutchinson M (2004) Further evidenceof dementia in SPG4-linked autosomal dominant hereditaryspastic paraplegia. Neurology 62:407–41013. Murphy S, Gorman G, Beetz C et al (2009) Dementia in SPG4hereditary spastic paraplegia Clinical, genetic, and neuropatho-logic evidence. Neurology 73:378–38414. Nasreddine ZS, Phillips NA, Bedirian V et al (2005) The mon-treal cognitive assessment, MoCA: a brief screening tool for mildcognitive impairment. J Am Geriatr Soc 53:695–69915. Watson M (2002) Refining the ten-metre walking test for use withneurologically impaired people. Physiotherapy 88:386–397J Neurol (2013) 260:906–909 909123

The neurological and ophthalmological manifestations of SPG4-related hereditary spastic paraplegia.

LETTER TO THE EDITORS
The neurological and ophthalmological manifestations
of SPG4-related hereditary spastic paraplegia
Grant Guthrie • Gerald Pfeffer • Maura Bailie • Karen Bradshaw •
Andrew C. Browning • Rita Horvath • Patrick F. Chinnery •
Patrick Yu-Wai-Man
Received: 23 October 2012 / Accepted: 29 November 2012 / Published online: 13 December 2012
 The Author(s) 2012. This article is published with open access at Springerlink.com
Dear Sirs,
The hereditary spastic paraplegias (HSPs) are a genet-
ically heterogeneous group of disorders characterised
by progressive corticospinal tract degeneration and the
development of lower limb spasticity [1, 2]. Autoso-
mal-dominant HSP is the most commonly inherited
form of the disease and in this group, SPG4 mutations
account for *40 % of cases [1]. The SPG4 gene codes
for spastin, a critical neuronal protein that maintains
organelle axonal transport by severing and rearranging
the microtubule network [3, 4]. Dysfunctional mutant
proteins or insufficient quantities of the wild-type
protein inhibit this dynamic shuttling process resulting
in axonal swelling and progressive retrograde degen-
eration that preferentially affects the long corticospinal
axons [3, 4].
There is mounting evidence that the microtubule and
mitochondrial networks are intrinsically linked at the
cellular level [5]. This intriguing association has recently
been highlighted by the clinical observation that autoso-
mal-dominant optic atrophy (DOA)—a classical mito-
chondrial optic neuropathy caused by pathogenic OPA1
mutations—can result in complicated neurological phe-
notypes (DOA?) with features indistinguishable from
HSP [6]. Furthermore, subclinical corticospinal tract
dysfunction also seems to be a prevalent feature among
OPA1 mutation carriers presenting with isolated visual
failure, suggesting a wider disease spectrum than origi-
nally considered [7]. Interestingly, these overlapping
genotype-phenotype manifestations have been reported
previously in families with a rarer, autosomal-recessive
form of HSP caused by pathogenic SPG7 mutations, in
which bilateral optic atrophy was a prominent feature
segregating with spastic paraplegia [8–10]. Given the
emerging disease mechanisms linking corticospinal tract
dysfunction with optic nerve degeneration, the aim of this
study was to determine the neurological and ophthalmo-
logical manifestations of SPG4-related HSP, looking
specifically for evidence of clinical or subclinical optic
neuropathy among affected patients. The overall neuro-
logical disability, including cognitive function, was also
evaluated to provide a comprehensive assessment of the
burden of disease in this group of patients.
A comprehensive neurological (GP, RH, PFC) and
ophthalmological (PYWM) assessment (Supplementary
Method) was carried out on ten white patients from the
North of England harbouring confirmed pathogenic
SPG4 mutations (Table 1). A broad spectrum of
Electronic supplementary material The online version of this
article (doi:10.1007/s00415-012-6780-3) contains supplementary
material, which is available to authorized users.
G. Guthrie  M. Bailie  K. Bradshaw  A. C. Browning 
P. Yu-Wai-Man
Department of Ophthalmology, Royal Victoria Infirmary,
Newcastle upon Tyne, UK
G. Guthrie  G. Pfeffer  R. Horvath  P. F. Chinnery 
P. Yu-Wai-Man
Department of Neurology, Royal Victoria Infirmary,
Newcastle upon Tyne, UK
G. Pfeffer  R. Horvath  P. F. Chinnery  P. Yu-Wai-Man (&)
Wellcome Trust Centre for Mitochondrial Research,
Institute of Genetic Medicine, Newcastle University,
Newcastle upon Tyne NE1 3BZ, UK
e-mail: Patrick.Yu-Wai-Man@ncl.ac.uk
K. Bradshaw
Department of Medical Physics, Royal Victoria Infirmary,
Newcastle upon Tyne, UK
123
J Neurol (2013) 260:906–909
DOI 10.1007/s00415-012-6780-3
neurological disability was observed among affected
patients with scores ranging from one to nine on the
modified EDSS scale (Table 2). Importantly, four
patients had abnormal MOCA scores of less than 26
points. Seven patients performed poorly on the memory
component of the MOCA test protocol and one patient
had abnormal visuospatial/executive performance. The
association between SPG4 mutations and progressive
cognitive decline remains controversial [11–13] and our
study of a well-characterised patient cohort provides
further evidence favouring a true causal link. Two of the
patients with abnormal MOCA scores were younger than
the age of 30 years, clearly highlighting the need for
clinical vigilance to detect early signs of cognitive
impairment and to provide adequate level of support,
especially to carers.
Except for one patient who had bilateral nuclear
sclerotic cataracts, all patients had best-corrected visual
acuities of 20/20 bilaterally (Table 1). The ophthalmolog-
ical examination was normal with full colour discrimina-
tion and no detectable optic disc or retinal abnormalities.
Visual fields, RNFL thickness measurements and visual
electrophysiology were within the normal range for the
entire HSP patient cohort. Three patients had abnormal eye
movements with horizontal square wave jerks and saccadic
smooth pursuits. No significant ptosis or limitation of eye
movements was noted on orthoptic assessment. Based on
our comprehensive clinical and electrophysiological eval-
uation, visual loss secondary to optic nerve or retinal
degeneration is unlikely to be a major phenotypic mani-
festation of SPG4-related disease. Affected patients and at-
risk family members can therefore be reassured that unlike
other genetically-determined forms of HSP [6–10], SPG4
mutations are not associated with the development of sig-
nificant ophthalmological complications, in particular
visual failure.
Table 1 Molecular genetic and ophthalmological features of the SPG4 patient cohort
Patient Sex Age
(years)
SPG4 mutation BCVA
RE-LE
Optic discs/OCT
measurements
Eye
movements
Visual
electrophysiology
Exon cDNA change/
consequence
1 F 31 5 c.743C[G/p.S245X 20/20-20/20 Normal/no RNFL
thinning
Normal Normal
2 M 53 5 c.743C[G/p.S245X 20/20-20/20 Normal/no RNFL
thinning
Horizontal SWJ/
saccadic pursuit
Normal
3 F 50 6 c.937delG/p.D313fsX1 20/20-20/20 Normal/no RNFL
thinning
Normal Normal
4 F 55 4–17 del exon 4-17/large-scale
deletion
20/20-20/20 Normal/no RNFL
thinning
Normal Normal
5 F 29 10 c.1253_1255delAAG/
p.E418fsX198
20/20-20/20 Normal/no RNFL
thinning
Horizontal SWJ/
saccadic pursuit
Normal
6 F 25 11 c.1442_1443insA/
p.V482fsX5
20/20-20/20 Normal/no RNFL
thinning
Normal Normal
7 F 55 11 c.1442_1443insA/
p.V482fsX5
20/20-20/20 Normal/no RNFL
thinning
Horizontal SWJ/
saccadic pursuit
Normal
8 F 49 11 c.1414G[A/p.V472I 20/20-20/20 Normal/no RNFL
thinning
Normal Normal
9 F 72 11 c.1384A[G/p.K462E 20/60-20/30 Normal/no RNFL
thinning
Normal Normal
10 M 65 11 c.1081C[A; c.1082T[A/
p.L361N
20/20-20/20 Normal/no RNFL
thinning
Normal Normal
BCVA best-corrected visual acuities, cDNA complementary DNA, LE left eye, OCT optical coherence tomography, RE right eye, RNFL retinal
nerve fibre layer, SWJ square wave jerks
J Neurol (2013) 260:906–909 907
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908 J Neurol (2013) 260:906–909
123
Acknowledgments This work was supported by a research grant
from the Association of British Neurologists (ABN, UK). GP is the
recipient of a Bisby Fellowship from the Canadian Institutes of Health
Research. RH is supported by the Medical Research Council (MRC,
UK). PFC is a Wellcome Trust Senior Fellow in Clinical Science and
a UK National Institute of Health Research (NIHR) Senior Investi-
gator who also receives funding from the MRC (UK), and the UK
NIHR Biomedical Research Centre for Ageing and Age-related dis-
ease award to the Newcastle upon Tyne Hospitals NHS Foundation
Trust. PYWM is an MRC (UK) Clinician Scientist.
Conflicts of interest All the listed authors in this manuscript report
no relevant financial disclosures or conflicts of interest.
Ethical standard This study had the relevant institutional ethical
approval and it was carried out in compliance with the Declaration of
Helsinki.
Open Access This article is distributed under the terms of the
Creative Commons Attribution License which permits any use, dis-
tribution, and reproduction in any medium, provided the original
author(s) and the source are credited.
References
1. Salinas S, Proukakis C, Crosby A, Warner TT (2008) Hereditary
spastic paraplegia: clinical features and pathogenetic mecha-
nisms. Lancet Neurol 7:1127–1138
2. Harding AE (1983) Classification of the hereditary ataxias and
paraplegias. Lancet 1:1151–1155
3. McDermott CJ, Grierson AJ, Wood JD et al (2003) Hereditary
spastic paraparesis: disrupted intracellular transport associated
with spastin mutation. Ann Neurol 54:748–759
4. Lumb JH, Connell JW, Allison R, Reid E (2012) The AAA
ATPase spastin links microtubule severing to membrane model-
ling. Biochim Biophys Acta 1823:192–197
5. Schon EA, Przedborski S (2011) Mitochondria: the next
(Neurode) generation. Neuron 70:1033–1053
6. Yu-Wai-Man P, Griffiths PG, Gorman GS et al (2010) Multi-
system neurological disease is common in patients with OPA1
mutations. Brain 133:771–786
7. Baker MR, Fisher KM, Whittaker RG, Griffiths PG, Yu-Wai-Man
P, Chinnery PF (2011) Subclinical multisystem neurologic dis-
ease in ‘‘pure’’ Opa1 autosomal dominant optic atrophy. Neu-
rology 77:1309–1312
8. Casari G, De Fusco M, Ciarmatori S et al (1998) Spastic para-
plegia and OXPHOS impairment caused by mutations in para-
plegin, a nuclear-encoded mitochondrial metalloprotease. Cell
93:973–983
9. Wilkinson PA, Crosby AH, Turner C et al (2004) A clinical,
genetic and biochemical study of SPG7 mutations in hereditary
spastic paraplegia. Brain 127:973–980
10. van Gassen KL, van der Heijden CD, de Bot ST et al (2012)
Genotype-phenotype correlations in spastic paraplegia type 7: a
study in a large Dutch cohort. Brain 135:2994–3004
11. Tallaksen CME, Guichart-Gomez E, Verpillat P et al (2003)
Subtle cognitive impairment but no dementia in patients with
spastin mutations. Arch Neurol 60:1113–1118
12. McMonagle P, Byrne P, Hutchinson M (2004) Further evidence
of dementia in SPG4-linked autosomal dominant hereditary
spastic paraplegia. Neurology 62:407–410
13. Murphy S, Gorman G, Beetz C et al (2009) Dementia in SPG4
hereditary spastic paraplegia Clinical, genetic, and neuropatho-
logic evidence. Neurology 73:378–384
14. Nasreddine ZS, Phillips NA, Bedirian V et al (2005) The mon-
treal cognitive assessment, MoCA: a brief screening tool for mild
cognitive impairment. J Am Geriatr Soc 53:695–699
15. Watson M (2002) Refining the ten-metre walking test for use with
neurologically impaired people. Physiotherapy 88:386–397
J Neurol (2013) 260:906–909 909
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http://dx.doi.org/10.1007/s00415-012-6780-3

The neurological and ophthalmological manifestations of SPG4-related hereditary spastic paraplegia.

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