Babalini, C

Carosi, L

Di Lullo, M

Gaudiello, F

Kawarai, T

Lo Giudice, T

Lombardi, F

Marfia, G

Massa, R

Orlacchio, A

Journal of Neurology Neurosurgery & Psychiatry

PubMed

Archivio della Ricerca - Università di Roma Tor vergata

LETTER
Hereditary spastic paraplegia:
a novel mutation and
expansion of the phenotype
variability in SPG10
INTRODUCTION
Hereditary spastic paraplegias (HSPs) are
a group of disorders characterised by slow
progressive weakness and spasticity of the
lower limbs. HSPs have been divided into
pure and complicated forms, depending
on the absence or presence of additional
neurological or non-neurological features.
To date, 72 loci and 55 spastic paraplegia
genes (SPGs) have been identiﬁed.1
SPG10 is caused by mutations in the
KIF5A gene encoding neuron-speciﬁc
kinesin heavy chain 5A (NK-HC5A), a
member of the kinesin-1 family of motor
proteins. In mammals, NK-HC5A is
necessary for the anterograde axonal
transport of neuroﬁlament subunits, and
it has a role in the transport of other
anterograde cargoes, such as membrane
vesicles. SPG10 is an autosomal dominant
HSP (ADHSP), accounting for about 10%
of the complicated forms. Peripheral neur-
opathy and cognitive impairment are the
most common additional clinical fea-
tures.1 This report describes a novel
KIF5A genetic defect in a large Italian
ADHSP family with exclusive clinical
features.
METHODS
The currently living family members were
examined by movement disorder specialists
(TLG, GAM, RM and AO). Neurological
assessments, including the Spastic
Paraplegia Rating Scale (SPRS)2 Mental
Deterioration Battery (MDB)3 electrophysi-
ology of peripheral nerves, and neuroima-
ging analyses, were carried out. After
informed consent was given, genomic DNA
was extracted from peripheral lymphocytes.
Genetic analyses were conducted as
described in online supplementary data,
including linkage studies at the currently
known ADHSP loci, PCR-direct sequen-
cing, PCR-restriction fragment length poly-
morphism (PCR-RFLP) assay, and in silico
analysis.
RESULTS
The RM 551 family is composed of a
three-generation kindred with AD inherit-
ance. Eleven individuals were diagnosed as
‘certainly affected’ and classiﬁed as having
complicated HSP.1 At examination, the age
range of the affected individuals was 19–
77 years (mean±SD=40.4±17.9 years).
Spastic paraparesis was the primary
symptom in the clinical course of
each patient; age at onset ranged between
12 and 55 years (mean±SD=32.2±
15.0 years). The decrease of age at onset
between successive generations ranged
from 4 to 39 years per generation. The
disease was slowly progressive and urinary
urgency was a common symptom.
Electroneurography of both motor and
sensory nerves, as well as electromyogra-
phy, were normal. MDB did not show cog-
nitive impairment. Other clinical features
associated with SPG101 were absent.
Interestingly, this variant form of HSP was
associated in all affected individuals of the
family with varicose veins (VV) of the legs,
as well as bilateral Dupuytren’s disease (DD)
at various stages, according to Clinical-
Etiology-Anatomy-Pathophysiology (CEAP)4
and Tubiana5 classiﬁcations, respectively
(table 1 and online supplementary ﬁgure
S1). DD and VV were absent in all
members of the family who did not have
gait difﬁculty. The environmental associa-
tions of DD, such as alcohol consumption,
tobacco exposure, manual activities,
retractile capsulitis, epilepsy, diabetes, HIV
and dyslipidemia,5 were absent in all
patients. Obesity and lower limb deep vein
thrombosis examined by venous ultrason-
ography were also absent, suggesting a
primary form of VV.4
Signiﬁcant logarithm of odds (LOD)
scores were obtained at the SPG10 locus
only (Zmax=4.56 at θ=0.0 at the microsat-
ellite marker D12S1724, online
supplementary table S1) and a novel het-
erozygous change in exon 6 (c.484C>T)
was found, resulting in amino acid substi-
tution of arginine to tryptophan at codon
162 (p.R162W). The PCR-RFLP analysis
demonstrated a complete cosegregation of
the mutation with the disease and the
nucleotide change is predicted to cause the
disease, as well as inﬂuence the protein
function by in silico analysis (see online
supplementary ﬁgure S2 and table S2).
DISCUSSION
To date, 21 mutations have been reported
in SPG10/KIF5A. Most of the mutations
locate within the kinesin motor domain
and are missense mutations, except from
one in-frame deletion mutation N256del.
The residues p.R204, p.N256 and p.R280
are mutational hot spots (see online
supplementary ﬁgure S3). Neither nonsense
nor frameshift mutations leading to trun-
cated proteins are reported. These data
Table 1 Clinical findings in family members with the KIF5A mutation
I:2 II:1 II:4 II:5 II:6 III:1 III:4 III:5 III:7 III:8 III:10
Sex F F M F M F M F M M M
Age at examination 77 58 54 49 43 40 31 28 25 21 19
Age at onset* 55 49 51 39 36 32 26 18 21 16 12
Disease duration (years) 22 9 3 10 7 8 5 10 4 5 7
Disability stage† 2 2 2 3 2 3 3 4 3 3 3
SPRS‡ 14 16 16 21 18 25 26 38 26 25 28
LL pyramidal weakness + + + + + ++ ++ ++ ++ ++ ++
LL hyper-reflexia + + ++ ++ + + ++ ++ ++ ++ ++
LL spasticity + + + + + ++ + ++ ++ + ++
Babinski reflex +/+ +/+ +/+ +/+ +/+ +/+ +/+ +/+ +/+ +/+ +/+
Pes cavus − − − − − − − + − − −
Sensory deficits + − + − − + − + − − −
VV R/L R/L L R/L R/L R/L L R R/L L R/L
VV stage§
(affected or worst side)
C2 C2 C4a C2 C2 C6 C4b C4a C3 C3 C2
Bilateral DD + + + + + + + + + + +
DD stage¶ (worst side) 1 1 2 N 1 3 3 2 4 3 3
Sphincter disturbances + + + − + + − + + − −
*Age at onset was calculated approximately as the time when difficulty in walking first appeared in the affected
individuals.
†Disability stages: 1, no mobility problems or slight stiffness of the legs; 2, moderate gait stiffness; 3, problems
running, but able to walk alone; 4, problems walking; 5, wheelchair user.
‡SPRS, Spastic Paraplegia Rating Scale.2
§Clinical section from CEAP classification of chronic venous disease4: C0, no visible or palpable signs of venous disease;
C1, telangiectasies or reticular veins; C2, varicose veins; C3, oedema; C4a, pigmentation or eczema; C4b,
lipodermatosclerosis or atrophie blanche; C5, healed venous ulcer; C6, active venous ulcer.
¶Tubiana classification5: 0, no lesion; N, palmar nodule without the presence of contracture; 1, TFD between 0°
and 45°; 2, TFD between 45° and 90°; 3, TFD between 90° and 135°; 4, TFD greater than 135°.
+ and −, indicate the presence and absence of a feature, respectively; DD, Dupuytren’s disease; F, female; L, left leg;
LL, lower limbs; M, male; R, right leg; TFD, total flexion deformity; VV, varicose veins.
J Neurol Neurosurg Psychiatry Month 2014 Vol 0 No 0 1
PostScript
 JNNP Online First, published on October 28, 2014 as 10.1136/jnnp-2014-308625
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suggest that SPG10 pathogenesis is not
simply due to haploinsufﬁciency. A domin-
ant negative effect has been postulated in
SPG10 pathogenesis. The novel missense
mutation, p.R162W, would lead to altering
the conformation of the kinesin-1 complex
and disrupting cargo transportation along
the axon.
Other kinesin isotypes, KIF1A and
KIF1C, have been reported as causative
genes of SPG30 and spastic ataxia 2
(SAX2 or SPG58), respectively. This indi-
cates that the underlying pathological
mechanism in spastic paraplegia caused by
mutations in the kinesin gene family
varies depending on the basis of the
isotype. Moreover, HSP-related proteins
interact with each other, including myelin
proteolipid protein 1, atlastin-1,
kinesin-HC5A, kinesin-3, REEP1, KIF1C
and reticulon proteins. Mutations in
KIF5A might further affect the biological
pathway revealed by such interactions
leading to motoneuron degeneration, as
described in the Drosophila model.6
Additional clinical features observed in
the family, such as VV and DD, might be
explained by two potential pathological
mechanisms. The genetic factor(s) for
developing VV and/or DD might exist
within the approximately 7.5 cM interval
encompassed by the two microsatellite
markers, D12S270 and D12S1601.
Developmental abnormalities, including
vessel malformation, were observed in an
individual with chromosomal deletion of
1.76-Mb comprising the SPG10 locus7
suggesting that there might be genetic pre-
disposing factor(s) for fragility of the
blood vessel within the region.
Considering the histopathology in DD,
genes involved in myoﬁbroblast regula-
tion, extracellular matrix or collagen
might be a candidate for developing the
disease. The OS-9 gene, encoding osteo-
sarcoma ampliﬁed 9, has been mapped
143-kb away from KIF5A [National
Center for Biotechnology Information
(NCBI) website at http://www.ncbi.nlm.nih.
gov/]. The gene expression was coampliﬁed
with the cyclin-dependent kinase 4 (CDK4)
gene in sarcoma tissues.8 Dysregulation of
the gene might be involved in DD observed
in the patients. The other possibility is that
the combined phenotypic features might be
due to the coexistence of the KIF5A muta-
tion and other genetic variation(s)
mapped to region(s) away from the
SPG10 locus. There is a growing body
of evidence that expression of the trans-
forming growth factor β (TGFβ) is
elevated in Dupuytren’s ﬁbroblasts.9
Further investigation of genetic variations
at the promoter region of TGFβ is needed
to conﬁrm the genetic model.
In conclusion, this study demonstrates
further allelic heterogeneity, thus expand-
ing the clinical-genetic spectrum of
SPG10.
Laura Carosi,1,2 Temistocle Lo Giudice,1,2
Martina Di Lullo,1 Federica Lombardi,1
Carla Babalini,1 Fabrizio Gaudiello,1
Girolama Alessandra Marﬁa,2 Roberto Massa,1,2
Toshitaka Kawarai,3 Antonio Orlacchio1,2
1Laboratorio di Neurogenetica, Centro Europeo di
Ricerca sul Cervello (CERC)-Istituto di Ricovero e Cura a
Carattere Scientiﬁco (IRCCS) Santa Lucia, Rome, Italy
2Dipartimento di Medicina dei Sistemi, Università di
Roma “Tor Vergata”, Rome, Italy
3Department of Clinical Neuroscience, Institute of
Health Biosciences, Graduate School of Medicine,
University of Tokushima, Tokushima, Japan
Correspondence to Prof. Antonio Orlacchio,
Laboratorio di Neurogenetica, Centro Europeo di
Ricerca sul Cervello (CERC)-Istituto di Ricovero e
Cura a Carattere Scientiﬁco (IRCCS) Santa Lucia,
64 Via del Fosso di Fiorano, Rome 00143, Italy;
a.orlacchio@hsantalucia.it
Acknowledgements The authors thank Michela
Renna, MA, for the language advice. They also thank
the patients and family members for taking part in this
study. They are extremely grateful to the Genetic Bank
of the Laboratorio di Neurogenetica, CERC-IRCCS Santa
Lucia, Rome, Italy (http://www.hsantalucia.it/neurogen/
index_en.htm) for the service provided.
Contributors GAM, RM and AO contributed to the
study concept and design of the article. LC, TLG, MDL,
FL, CB, FG, TK and AO contributed to the acquisition,
analysis and interpretation of data. LC, TLG, MDL, FL,
CB, FG, TK and AO contributed to the drafting of the
manuscript. GAM, RM, TK and AO contributed to the
critical revision of the manuscript for important
intellectual content. TLG and TK contributed to the
statistical analysis. TK and AO contributed to obtaining
funding. LC, MDL, FL, CB and FG contributed to
administrative, technical and material support. GAM,
RM and AO contributed to the study supervision. All
authors gave ﬁnal approval of the article to be
published. LC and TLG have contributed equally.
Competing interests TK received grants from the
Japan Society (for the Promotion of Science; JSPS
KAKENHI Grant no. 26461294 to TK) and the Brain
Science Foundation, Japan. TK received grant for
conducting research on rare and intractable diseases
from the Japanese Ministry of Health, Labour and
Welfare. AO received grants from the Italian Ministero
della Salute (Grant no. GR09.109) and the Comitato
Telethon Fondazione Onlus, Italy (Grant no.
GGP10121).
Patient consent Obtained.
Ethics approval Approved by the Ethics Committee
of the Istituto di Ricovero e Cura a Carattere Scientiﬁco
(IRCCS) Santa Lucia, Rome, Italy.
Provenance and peer review Not commissioned;
externally peer reviewed.
Data sharing statement This study makes use of
data generated by the DECIPHER Consortium. Data
sharing for further discussion might be available on
request in respect of the Decipher policy.
▸ Additional material is published online only. To view
please visit the journal online (http://dx.doi.org/10.
1136/jnnp-2014-308625).
Open Access This is an Open Access article
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Attribution Non Commercial (CC BY-NC 4.0) license,
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To cite Carosi L, Lo Giudice T, Di Lullo M, et al.
J Neurol Neurosurg Psychiatry Published Online First:
[please include Day Month Year] doi:10.1136/jnnp-
2014-308625
Received 22 May 2014
Revised 30 August 2014
Accepted 1 September 2014
J Neurol Neurosurg Psychiatry 2014;0:1–2.
doi:10.1136/jnnp-2014-308625
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7 Firth HV, Richards SM, Bevan AP, et al. DECIPHER:
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9 Krause C, Kloen P, Ten Dijke P. Elevated transforming
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2 J Neurol Neurosurg Psychiatry Month 2014 Vol 0 No 0
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variability in SPG10
mutation and expansion of the phenotype 
Hereditary spastic paraplegia: a novel
Marfia, Roberto Massa, Toshitaka Kawarai and Antonio Orlacchio
Lombardi, Carla Babalini, Fabrizio Gaudiello, Girolama Alessandra 
Laura Carosi, Temistocle Lo Giudice, Martina Di Lullo, Federica
 published online October 28, 2014J Neurol Neurosurg Psychiatry 
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Hereditary spastic paraplegia: a novel mutation and expansion of the phenotype variability in SPG10.

CAROSI, LAURA

Giudice, TL

Lullo, MD

GAUDIELLO, FABRIZIO

Marfia, GA

MASSA, ROBERTO

ORLACCHIO, ANTONIO

English

Hereditary spastic paraplegia:A novel mutation and expansion of the phenotype variability in SPG10

Carosi, Laura

Lo Giudice, Temistocle

Di Lullo, Martina

Lombardi, Federica

Babalini, Carla

Gaudiello, Fabrizio

Marfia, Girolama Alessandra

Massa, Roberto

Kawarai, Toshitaka

Orlacchio, Antonio

(range 0–307), with a median citation rateof 3 per year (range 0–48.3).A literature review of UK medical meet-ings during a similar time period revealedvariable rates of eventual publication.Weale et al2 found publication rates of24–54% across four surgical meetings. Astudy of emergency medicine identified apublication rate of 30%, with platformpresentations more likely to be pub-lished.3 Oral and maxillofacial surgeryabstracts from 2001 to 2007 were pub-lished in 24% of cases, with scientificversus clinical presentations more likely toachieve eventual publication.4 Urologyabstracts from 2001 to 2002 were pub-lished in 42% cases.5Strengths of our study include survey-ing a large number of abstracts, a rela-tively long follow-up time and a robustsearch methodology consistent with previ-ous work on this subject. A potential limi-tation is that we were unable to determinehow many abstracts were submitted forfull publication but eventually rejected, ornever submitted at all, as this would haverequired extensive surveying of all authorspresenting at the ABN. Our findingsemphasise the importance of collaborativework in achieving high-quality researchand publication. However, it is possiblethat this represents a surrogate of otherfactors, for example case reports may belikely to be single-centre work. Whileimpact factors are a controversial metricof research quality, the majority of eventu-ally published work following presenta-tion at the ABN contributed to thescientific literature in the form of subse-quent citations.Sola Odunsi,1 Christopher Kobylecki,2,3Matthew Jones2,31North Manchester General Hospital, Manchester, UK2Department of Neurology, Greater ManchesterNeurosciences Centre, Salford, UK3Institute of Brain, Behaviour and Mental Health,University of Manchester, Manchester, UKCorrespondence to Dr Matthew Jones, Departmentof Neurology, Greater Manchester NeurosciencesCentre, Salford, M6 8HD UK; matthew.jones@manchester.ac.ukContributors SO was involved in data acquisition andanalysis, writing of first draft and subsequent revisions.CK was involved in conception; data analysis; reviewand critical review of manuscript. MJ was involved inconception; data analysis; critical review of manuscriptand supervision.Competing interests None.Provenance and peer review Not commissioned;externally peer reviewed.To cite Odunsi S, Kobylecki C, Jones M. J NeurolNeurosurg Psychiatry 2015;86:701–702.Received 7 August 2014Revised 18 September 2014Accepted 21 September 2014Published Online First 9 October 2014J Neurol Neurosurg Psychiatry 2015;86:701–702.doi:10.1136/jnnp-2014-309183REFERENCES1 von Elm E, Costanza MC, Walder B, et al. Moreinsight into the fate of biomedical meeting abstracts: asystematic review. BMC Med Res Methodol2003;3:12.2 Weale AR, Edwards AG, Lear PA, et al. From meetingpresentation to peer-review publication—a UK review.Ann R Coll Surg Engl 2006;88:52–6.3 Macmillan CD, Moore AK, Cook RJ, et al.Abstract-to-publication ratio for papers presented atscientific meetings: a quality marker for UK emergencymedicine research. Emerg Med J 2007;24:425–6.4 Collier JM, Vig N, Hammond D. Publish or perish? Asurvey of abstracts accepted for meetings of the BritishAssociation of Oral and Maxillofacial Surgeons, andsubsequently published. Br J Oral Maxillofac Surg2010;48:540–3.5 Rao AR, Beatty JD, Laniado M, et al. Publication rateof abstracts presented at the British Association ofUrological Surgeons Annual Meeting. BJU Int2006;97:306–9.Hereditary spastic paraplegia:a novel mutation andexpansion of the phenotypevariability in SPG10INTRODUCTIONHereditary spastic paraplegias (HSPs) area group of disorders characterised by slowprogressive weakness and spasticity of thelower limbs. HSPs have been divided intopure and complicated forms, dependingTable 1 Publication rates of abstracts presented at the Association of British Neurologists by category of abstractVariable Category Proportion (%) published OR (95% CI)Type of presentation Platform 135/299 (45) 1.654 (1.97 to 2.286)Poster 109/328 (33) p=0.002Number of centres Single centre 126/390 (32) 0.457 (0.329 to 0.637)Collaborative 122/239 (51) p<0.0001Content Case report 32/106 (23) 0.394 (0.256 to 0.609)Other studies 212/489 (43) p<0.0001Table 1 Publication rates of abstracts presented at the Association of British Neurologists by category of abstractJournal Number of papers (%)Journal of Neurology Neurosurgery and Psychiatry 29 (11.9)Brain 21 (8.6)Neurology 17 (6.9)European Journal of Neurology 9 (3.7)Multiple Sclerosis 9 (3.7)Annals of Neurology 7 (2.9)Movement Disorders 7 (2.9)Stroke 6 (2.5)British Medical Journal 4 (1.7)Lancet Neurology 4 (1.7)Others (1–2 papers in each) 113 (54.9)The top 10 most frequent journals for publication are shown above.PostScript702 J Neurol Neurosurg Psychiatry June 2015 Vol 86 No 6on the absence or presence of additionalneurological or non-neurological features.To date, 72 loci and 55 spastic paraplegiagenes (SPGs) have been identified.1SPG10 is caused by mutations in theKIF5A gene encoding neuron-specifickinesin heavy chain 5A (NK-HC5A), amember of the kinesin-1 family of motorproteins. In mammals, NK-HC5A isnecessary for the anterograde axonaltransport of neurofilament subunits, andit has a role in the transport of otheranterograde cargoes, such as membranevesicles. SPG10 is an autosomal dominantHSP (ADHSP), accounting for about 10%of the complicated forms. Peripheral neur-opathy and cognitive impairment are themost common additional clinical fea-tures.1 This report describes a novelKIF5A genetic defect in a large ItalianADHSP family with exclusive clinicalfeatures.METHODSThe currently living family members wereexamined by movement disorder specialists(TLG, GAM, RM and AO). Neurologicalassessments, including the SpasticParaplegia Rating Scale (SPRS)2 MentalDeterioration Battery (MDB)3 electrophysi-ology of peripheral nerves, and neuroima-ging analyses, were carried out. Afterinformed consent was given, genomic DNAwas extracted from peripheral lymphocytes.Genetic analyses were conducted asdescribed in online supplementary data,including linkage studies at the currentlyknown ADHSP loci, PCR-direct sequen-cing, PCR-restriction fragment length poly-morphism (PCR-RFLP) assay, and in silicoanalysis.RESULTSThe RM 551 family is composed of athree-generation kindred with AD inherit-ance. Eleven individuals were diagnosed as‘certainly affected’ and classified as havingcomplicated HSP.1 At examination, the agerange of the affected individuals was 19–77 years (mean±SD=40.4±17.9 years).Spastic paraparesis was the primarysymptom in the clinical course ofeach patient; age at onset ranged between12 and 55 years (mean±SD=32.2±15.0 years). The decrease of age at onsetbetween successive generations rangedfrom 4 to 39 years per generation. Thedisease was slowly progressive and urinaryurgency was a common symptom.Electroneurography of both motor andsensory nerves, as well as electromyogra-phy, were normal. MDB did not show cog-nitive impairment. Other clinical featuresassociated with SPG101 were absent.Interestingly, this variant form of HSP wasassociated in all affected individuals of thefamily with varicose veins (VV) of the legs,as well as bilateral Dupuytren’s disease (DD)at various stages, according to Clinical-Etiology-Anatomy-Pathophysiology (CEAP)4and Tubiana5 classifications, respectively(table 1 and online supplementary figureS1). DD and VV were absent in allmembers of the family who did not havegait difficulty. The environmental associa-tions of DD, such as alcohol consumption,tobacco exposure, manual activities,retractile capsulitis, epilepsy, diabetes, HIVand dyslipidemia,5 were absent in allpatients. Obesity and lower limb deep veinthrombosis examined by venous ultrason-ography were also absent, suggesting aprimary form of VV.4Significant logarithm of odds (LOD)scores were obtained at the SPG10 locusonly (Zmax=4.56 at θ=0.0 at the microsat-ellite marker D12S1724, onlinesupplementary table S1) and a novel het-erozygous change in exon 6 (c.484C>T)was found, resulting in amino acid substi-tution of arginine to tryptophan at codon162 (p.R162W). The PCR-RFLP analysisdemonstrated a complete cosegregation ofthe mutation with the disease and thenucleotide change is predicted to cause thedisease, as well as influence the proteinfunction by in silico analysis (see onlinesupplementary figure S2 and table S2).DISCUSSIONTo date, 21 mutations have been reportedin SPG10/KIF5A. Most of the mutationslocate within the kinesin motor domainand are missense mutations, except fromone in-frame deletion mutation N256del.The residues p.R204, p.N256 and p.R280are mutational hot spots (see onlinesupplementary figure S3). Neither nonsensenor frameshift mutations leading to trun-cated proteins are reported. These datasuggest that SPG10 pathogenesis is notsimply due to haploinsufficiency. A domin-ant negative effect has been postulated inSPG10 pathogenesis. The novel missensemutation, p.R162W, would lead to alteringthe conformation of the kinesin-1 complexand disrupting cargo transportation alongthe axon.Other kinesin isotypes, KIF1A andKIF1C, have been reported as causativegenes of SPG30 and spastic ataxia 2(SAX2 or SPG58), respectively. This indi-cates that the underlying pathologicalmechanism in spastic paraplegia caused byTable 1 Clinical findings in family members with the KIF5A mutationI:2 II:1 II:4 II:5 II:6 III:1 III:4 III:5 III:7 III:8 III:10Sex F F M F M F M F M M MAge at examination 77 58 54 49 43 40 31 28 25 21 19Age at onset* 55 49 51 39 36 32 26 18 21 16 12Disease duration (years) 22 9 3 10 7 8 5 10 4 5 7Disability stage† 2 2 2 3 2 3 3 4 3 3 3SPRS‡ 14 16 16 21 18 25 26 38 26 25 28LL pyramidal weakness + + + + + ++ ++ ++ ++ ++ ++LL hyper-reflexia + + ++ ++ + + ++ ++ ++ ++ ++LL spasticity + + + + + ++ + ++ ++ + ++Babinski reflex +/+ +/+ +/+ +/+ +/+ +/+ +/+ +/+ +/+ +/+ +/+Pes cavus − − − − − − − + − − −Sensory deficits + − + − − + − + − − −VV R/L R/L L R/L R/L R/L L R R/L L R/LVV stage§(affected or worst side)C2 C2 C4a C2 C2 C6 C4b C4a C3 C3 C2Bilateral DD + + + + + + + + + + +DD stage¶ (worst side) 1 1 2 N 1 3 3 2 4 3 3Sphincter disturbances + + + − + + − + + − −*Age at onset was calculated approximately as the time when difficulty in walking first appeared in the affectedindividuals.†Disability stages: 1, no mobility problems or slight stiffness of the legs; 2, moderate gait stiffness; 3, problemsrunning, but able to walk alone; 4, problems walking; 5, wheelchair user.‡SPRS, Spastic Paraplegia Rating Scale.2§Clinical section from CEAP classification of chronic venous disease4: C0, no visible or palpable signs of venous disease;C1, telangiectasies or reticular veins; C2, varicose veins; C3, oedema; C4a, pigmentation or eczema; C4b,lipodermatosclerosis or atrophie blanche; C5, healed venous ulcer; C6, active venous ulcer.¶Tubiana classification5: 0, no lesion; N, palmar nodule without the presence of contracture; 1, TFD between 0°and 45°; 2, TFD between 45° and 90°; 3, TFD between 90° and 135°; 4, TFD greater than 135°.+ and −, indicate the presence and absence of a feature, respectively; DD, Dupuytren’s disease; F, female; L, left leg;LL, lower limbs; M, male; R, right leg; TFD, total flexion deformity; VV, varicose veins.PostScriptJ Neurol Neurosurg Psychiatry June 2015 Vol 86 No 6 703mutations in the kinesin gene familyvaries depending on the basis of theisotype. Moreover, HSP-related proteinsinteract with each other, including myelinproteolipid protein 1, atlastin-1,kinesin-HC5A, kinesin-3, REEP1, KIF1Cand reticulon proteins. Mutations inKIF5A might further affect the biologicalpathway revealed by such interactionsleading to motoneuron degeneration, asdescribed in the Drosophila model.6Additional clinical features observed inthe family, such as VV and DD, might beexplained by two potential pathologicalmechanisms. The genetic factor(s) fordeveloping VV and/or DD might existwithin the approximately 7.5 cM intervalencompassed by the two microsatellitemarkers, D12S270 and D12S1601.Developmental abnormalities, includingvessel malformation, were observed in anindividual with chromosomal deletion of1.76-Mb comprising the SPG10 locus7suggesting that there might be genetic pre-disposing factor(s) for fragility of theblood vessel within the region.Considering the histopathology in DD,genes involved in myofibroblast regula-tion, extracellular matrix or collagenmight be a candidate for developing thedisease. The OS-9 gene, encoding osteo-sarcoma amplified 9, has been mapped143-kb away from KIF5A [NationalCenter for Biotechnology Information(NCBI) website at http://www.ncbi.nlm.nih.gov/]. The gene expression was coamplifiedwith the cyclin-dependent kinase 4 (CDK4)gene in sarcoma tissues.8 Dysregulation ofthe gene might be involved in DD observedin the patients. The other possibility is thatthe combined phenotypic features might bedue to the coexistence of the KIF5A muta-tion and other genetic variation(s)mapped to region(s) away from theSPG10 locus. There is a growing bodyof evidence that expression of the trans-forming growth factor β (TGFβ) is ele-vated in Dupuytren’s fibroblasts.9 Furtherinvestigation of genetic variations at thepromoter region of TGFβ is needed toconfirm the genetic model.In conclusion, this study demonstratesfurther allelic heterogeneity, thus expandingthe clinical-genetic spectrum of SPG10.Laura Carosi,1,2 Temistocle Lo Giudice,1,2Martina Di Lullo,1 Federica Lombardi,1Carla Babalini,1 Fabrizio Gaudiello,1Girolama Alessandra Marfia,2 Roberto Massa,1,2Toshitaka Kawarai,3 Antonio Orlacchio1,21Laboratorio di Neurogenetica, Centro Europeo diRicerca sul Cervello (CERC)-Istituto di Ricovero e Cura aCarattere Scientifico (IRCCS) Santa Lucia, Rome, Italy2Dipartimento di Medicina dei Sistemi, Università diRoma “Tor Vergata”, Rome, Italy3Department of Clinical Neuroscience, Institute ofHealth Biosciences, Graduate School of Medicine,University of Tokushima, Tokushima, JapanCorrespondence to Prof. Antonio Orlacchio,Laboratorio di Neurogenetica, Centro Europeo diRicerca sul Cervello (CERC)-Istituto di Ricovero eCura a Carattere Scientifico (IRCCS) Santa Lucia,64 Via del Fosso di Fiorano, Rome 00143, Italy;a.orlacchio@hsantalucia.itAcknowledgements The authors thank MichelaRenna, MA, for the language advice. They also thankthe patients and family members for taking part in thisstudy. They are extremely grateful to the Genetic Bankof the Laboratorio di Neurogenetica, CERC-IRCCS SantaLucia, Rome, Italy (http://www.hsantalucia.it/neurogen/index_en.htm) for the service provided.Contributors GAM, RM and AO contributed to thestudy concept and design of the article. LC, TLG, MDL,FL, CB, FG, TK and AO contributed to the acquisition,analysis and interpretation of data. LC, TLG, MDL, FL,CB, FG, TK and AO contributed to the drafting of themanuscript. GAM, RM, TK and AO contributed to thecritical revision of the manuscript for importantintellectual content. TLG and TK contributed to thestatistical analysis. TK and AO contributed to obtainingfunding. LC, MDL, FL, CB and FG contributed toadministrative, technical and material support. GAM,RM and AO contributed to the study supervision. Allauthors gave final approval of the article to bepublished. LC and TLG have contributed equally.Competing interests TK received grants from theJapan Society (for the Promotion of Science; JSPSKAKENHI Grant no. 26461294 to TK) and the BrainScience Foundation, Japan. TK received grant forconducting research on rare and intractable diseasesfrom the Japanese Ministry of Health, Labour andWelfare. AO received grants from the Italian Ministerodella Salute (Grant no. GR09.109) and the ComitatoTelethon Fondazione Onlus, Italy (Grant no.GGP10121).Patient consent Obtained.Ethics approval Approved by the Ethics Committeeof the Istituto di Ricovero e Cura a Carattere Scientifico(IRCCS) Santa Lucia, Rome, Italy.Provenance and peer review Not commissioned;externally peer reviewed.Data sharing statement This study makes use ofdata generated by the DECIPHER Consortium. Datasharing for further discussion might be available onrequest in respect of the Decipher policy.▸ Additional material is published online only. To viewplease visit the journal online (http://dx.doi.org/10.1136/jnnp-2014-308625).Open Access This is an Open Access article distributedin accordance with the Creative Commons AttributionNon Commercial (CC BY-NC 4.0) license, which permitsothers to distribute, remix, adapt, build upon this worknon-commercially, and license their derivative works ondifferent terms, provided the original work is properlycited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/To cite Carosi L, Lo Giudice T, Di Lullo M, et al.J Neurol Neurosurg Psychiatry 2015;86:702–704.Received 22 May 2014Revised 30 August 2014Accepted 1 September 2014Published Online First 28 October 2014J Neurol Neurosurg Psychiatry 2015;86:702–704.doi:10.1136/jnnp-2014-308625REFERENCES1 Lo Giudice T, Lombardi F, Santorelli FM, et al.Hereditary spastic paraplegia: clinical-geneticcharacteristics and evolving molecular mechanisms.Exp Neurol 2014;261C:518–39.2 Schüle R, Holland-Letz T, Klimpe S. The SpasticParaplegia Rating Scale (SPRS): a reliable and validmeasure of disease severity. Neurology2006;67:430–4.3 Carlesimo GA, Caltagirone C, Gainotti G. The mentaldeterioration battery: normative data, diagnosticreliability and qualitative analyses of cognitiveimpairment. The group for the standardization of themental deterioration battery. Eur Neurol1996;36:378–84.4 Meissner MH, Gloviczki P, Bergan J, et al. Primarychronic venous disorders. J Vasc Surg2007;46:54S–67S.5 Hindocha S, John S, Stanley JK, et al. The heritabilityof Dupuytren’s disease: familial aggregation and itsclinical significance. J Hand Surg Am2006;31:204–10.6 Bayat V, Jaiswal M, Bellen HJ. The BMP signalingpathway at the Drosophila neuromuscular junction andits links to neurodegenerative diseases. Curr OpinNeurobiol 2011;21:182–8.7 Firth HV, Richards SM, Bevan AP, et al. DECIPHER:database of chromosomal imbalance and phenotype inhumans using ensembl resources. Am J Hum Genet2009;84:524–33.8 Su YA, Hutter CM, Trent JM, et al. Complete sequenceanalysis of a gene (OS-9) ubiquitously expressed inhuman tissues and amplified in sarcomas. MolCarcinog 1996;15:270–5.9 Krause C, Kloen P, Ten Dijke P. Elevated transforminggrowth factor β and mitogen-activated protein kinasepathways mediate fibrotic traits of Dupuytren’s diseasefibroblasts. Fibrogenesis Tissue Repair 2011;4:14.Open AccessScan to access morefree contentPostScript704 J Neurol Neurosurg Psychiatry June 2015 Vol 86 No 6

Hereditary spastic paraplegia: a novel mutation and expansion of the phenotype variability in SPG10

Laura Carosi

Temistocle Lo Giudice

Martina Di Lullo

Federica Lombardi

Carla Babalini

Fabrizio Gaudiello

Girolama Alessandra Marfia

Roberto Massa

Toshitaka Kawarai

Antonio Orlacchio

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Hereditary spastic paraplegia: a novel mutation and expansion of the phenotype variability in SPG10: Table 1

https://art.torvergata.it/bitstream/2108/312689/1/jnnp-2014-308625.pdf

Hereditary spastic paraplegia: a novel mutation and expansion of the phenotype variability in SPG10.

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