the genetic nomenclature of recessive cerebellar ataxias...the genetic nomenclature of recessive...
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The Genetic Nomenclature of Recessive Cerebellar Ataxias
Malco Rossi, MD, PhD ,1 Mathieu Anheim, MD, PhD,2,3,4 Alexandra Durr, MD, PhD,5,6 Christine Klein, MD,7,8
Michel Koenig, MD, PhD,9 Matthis Synofzik, MD,10,11 Connie Marras, MD, PhD,12 and Bart P. van de Warrenburg, MD, PhD,13*on behalf of the International Parkinson and Movement Disorder Society Task Force on Classification and Nomenclature of
Genetic Movement Disorders
1Movement Disorders Section, Neuroscience Department, Raul Carrea Institute for Neurological Research, Buenos Aires, Argentina2D�epartement de Neurologie, Hopitaux Universitaires de Strasbourg, Hopital de Hautepierre, Strasbourg, France
3Institut de G�en�etique et de Biologie Mol�eculaire et Cellulaire, INSERM-U964/CNRS-UMR7104/Universit�e de Strasbourg, Illkirch, France4F�ed�eration de M�edecine Translationnelle de Strasbourg, Universit�e de Strasbourg, Strasbourg, France
5Brain and Spine Institute, Sorbonne Universit�e, Inserm U1127, CNRS UMR 7225, Piti�e-Salpetriere University Hospital, Paris, France6Department of Genetics, AP-HP, Piti�e-Salpetriere University Hospital, 7501 Paris, France
7Institute of Neurogenetics, University of Luebeck, Luebeck, Germany8Department of Neurology, University Hospital Schleswig-Holstein, Campus L€ubeck, Germany
9Laboratoire de G�en�etique de Maladies Rares, EA7402, Institut Universitaire de Recherche Clinique, Universit�e de Montpellier, CHU Montpellier,
Montpellier, France10Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of T€ubingen, T€ubingen, Germany
11German Center for Neurodegenerative Diseases, T€ubingen, Germany12Toronto Western Hospital Morton, Gloria Shulman Movement Disorders Centre, and the Edmond J. Safra Program in Parkinson’s Disease,
University of Toronto, Toronto, Canada13Department of Neurology, Donders Institute for Brain, Cognition & Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
ABSTRACT: The recessive cerebellar ataxias are alarge group of degenerative and metabolic disorders,the diagnostic management of which is difficultbecause of the enormous clinical and genetic heteroge-neity. Because of several limitations, the current classifi-cation systems provide insufficient guidance forclinicians and researchers. Here, we propose a newnomenclature for the genetically confirmed recessivecerebellar ataxias according to the principles and crite-ria laid down by the International Parkinson and Move-ment Disorder Society Task Force on Classification andNomenclature of Genetic Movement Disorders. Weapply stringent criteria for considering an associationbetween gene and phenotype to be established. Thenewly proposed list of recessively inherited cerebellarataxias includes 62 disorders that were assigned anATX prefix, followed by the gene name, because thesetypically present with ataxia as a predominant and/or
consistent feature. An additional 30 disorders that oftencombine ataxia with a predominant or consistent othermovement disorder received a double prefix (e.g., ATX/HSP). We also identified a group of 89 entities that usu-ally present with complex nonataxia phenotypes, butmay occasionally present with cerebellar ataxia. Theseare listed separately without the ATX prefix. This new,transparent and adaptable nomenclature of the reces-sive cerebellar ataxias will facilitate the clinical recogni-tion of recessive ataxias, guide diagnostic testing inataxia patients, and help in interpreting genetic findings.VC 2018 International Parkinson and Movement DisorderSociety
Key Words: genetics; recessive ataxias; movementdisorders; nomenclature
------------------------------------------------------------*Corresponding author: Dr. Bart van de Warrenburg, Expert Centre forGenetic Movement Disorders, Department of Neurology, Donders Insti-tute for Brain Cognition & Behaviour, Radboud University Medical Center,PO Box 9101, 6500 HB Nijmegen, The Netherlands;[email protected]
Relevant conflicts of interests/financial disclosures: M.S. receivedspeaker’ honoraria from Actelion Pharmaceuticals. M.A. received speakerhonoraria and travel grants from Actelion Pharmaceuticals.
Received: 24 January 2018; Revised: 15 March 2018; Accepted: 25March 2018
Published online 00 Month 2018 in Wiley Online Library(wileyonlinelibrary.com). DOI: 10.1002/mds.27415
VC 2018 International Parkinson and Movement Disorder Society
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The recessive cerebellar ataxias are a large group ofclinically and genetically heterogeneous degenerativeand metabolic disorders.1 Although cerebellar ataxiais the shared clinical theme, the phenotype is oftencomplex as other neurological features and sometimessystemic manifestations co-occur. The enormous het-erogeneity complicates clinical management, particu-larly in the diagnostic phase. The currently usedclassification systems have several limitations and aretherefore of limited use in terms of both providingguidance for clinicians in the diagnostic process andmaking understandable the field of recessive cerebellarataxias as well as its boundaries. For example, theclassification of autosomal recessive spinocerebellarataxias’s (SCAR) (for SCA-recessive) is far from com-plete, mainly consisting of relatively newer entities(the most common recessive ataxia, Friedreich ataxia,is not included) and also contains unconfirmed enti-ties. Moreover, this SCAR classification is partly par-alleled and duplicated, yet with different numbers, byanother autosomal recessive cerebellar ataxia (ARCA)classification, the ARCA classification (for a recentcriticism of these autosomal recessive ataxia nomen-clatures, see the review by Synofzik and Schule2).These problems of existing incomplete, inconsistent,and partly parallel nomenclatures are not unique torecessive ataxias, as the classifications of other geneticmovement disorders are similarly flawed.3 For this rea-son, the International Parkinson and Movement Disor-der Society Task Force on Classification andNomenclature of Genetic Movement Disorders wasinstalled to take on the task of designing a uniform,adaptable, and phenotype-first nomenclature forgenetic movement disorders. A certain genetic entity isincluded only after stringent, predefined criteria aremet.4 Although the review process and the classifica-tion procedure incorporate clinical data, the proposednomenclature does not constitute a new clinical classi-fication of the recessive ataxias. The first paper of thistask force included the proposed nomenclature forgenetic parkinsonism, dystonia, autosomal dominantcerebellar ataxia, hereditary spastic paraplegia, parox-ysmal movement disorder, neurodegeneration withbrain iron accumulation, and primary familial braincalcification.4
Here we present the proposed nomenclature for therecessive cerebellar ataxias, based on the same princi-ples, criteria, and recommendations as provided by thetask force.
Search Strategy
The search aimed to have a fully comprehensive listof all autosomal and X-linked recessive diseases thathave been reported to present with ataxia. The OnlineMendelian Inheritance in Man database was searched
using the term “recessive ataxia.” Each disease that wasidentified was then checked in PubMed, GeneReviews,OrphaNet, and the Washington University in St. Louisneuromuscular section webpage (http://neuromuscular.wustl.edu/ataxia/recatax.html). To ensure that no diseaseswere missed, the same search strategy without timerestrictions was applied in PubMed using the terms“recessive ataxia” or “cerebellar ataxia” and updated toAugust 2017. Only publications written in English werereviewed. Additional publications were identified by usingthe respective gene name as keyword, for example,SYNE1. A complete list of publications reviewed can befound in the supplementary material.
Review Process
In total, 355 recessive, genetic entities were identi-fied in which ataxia had been reported. A total of 48disorders for which a causative gene had not beenidentified were excluded from further analysis. Weapplied the following criteria that lend support to cau-sality according to the U.S. National Human GenomeResearch Institute: (1) the presence of the variant inmultiple, unrelated affected individuals; (2) evidencefor segregation or statistical association of the variantwith disease; (3) the variant should be conservedacross different species; and (4) the variant should bepredicted to alter the normal biochemical effect of agene product as supported by functional evidence inhuman tissue, well-established cellular or animal mod-els, or other biochemical or histological abnormalities,if possible. The members of the recessive ataxiasworking group (MA, AD, MK, MS and BW) eachreviewed a subset of entities assigned to them. Thereview process consisted of selecting those diseases inwhich cerebellar ataxia was associated with mutationsin the gene of interest in at least 2 independentreports. The review process was focused on cerebellarataxias and not on purely sensory ataxias or those dis-orders with mainly cerebellar hypoplasia as a cardinalfeature without the clinical presence of cerebellarataxia. Congenital ataxias, Joubert syndrome, and pri-mary metabolic diseases, such as peroxisomal andlysosomal disorders, were included if cerebellar ataxiawas documented at any disease stage.
During the early stages of the process, it was decidedto use the ataxia (ATX) prefix for both dominantly andrecessively inherited ataxias. The first paper that hadproposed a classification for the dominant ataxias4
used spinocerebellar ataxias (SCA) as the prefix. How-ever, to be consistent with the classification of othermovement disorders,4 we propose the same prefix inde-pendent of the mode of inheritance, in particular, asseveral ataxias can be inherited in both a autosomaldominant or autosomal recessive fashion (eg, SPTBN2,AFG3L2, ITPR1, OPA1; for a review, see ref. 5). As
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2 Movement Disorders, Vol. 00, No. 00, 2018
the term SCA is quite strongly associated with domi-nant ataxias, we decided to use the ATX prefix instead.In the International Parkinson and Movement DisorderSociety Genetic Mutation Online Database6
(MDSGene; available at http://www.mdsgene.org),which systematically links reported mutations to move-ment disorder phenotypes, the dominant ataxias willalso carry the ATX prefix.
According to the recommendations of the InternationalParkinson and Movement Disorder Society Task Force onClassification and Nomenclature of Genetic MovementDisorders,4 the ATX prefix was assigned to those disor-ders that included ataxia as a prominent and/or consistentfeature. When another movement disorder was also aprominent feature that generally coexisted with ataxia inseveral patients, a double prefix was assigned (e.g., ataxia(ATX)/Hereditary spastic paraplegia (HSP)). For thosegenes (eg, TPP1) that gave rise to allelic disorders (autoso-mal recessive spinocerebellar ataxia type 7 with pureataxia and without myoclonus as well as neuronal ceroidlipofuscinosis type 2 with myoclonus and ataxia) thatboth present with prominent and consistent ataxia, a dou-ble prefix was established of which the order reflects thephenotype of the more prevalent or common presentation(in this case, ATX/MYC-TPP1). However, when anotherphenotype (eg, myoclonic epilepsy in POLG mutations)was the most common presentation or if ataxia was notusually predominant, the disease would appear in the pro-posed new list for the recessive ataxias, but would notreceive the ATX prefix. To be considered for an ATX pre-fix, the association with ataxia must have been reportedby more than one group of investigators. Last, a prefixwas not assigned for complex or mixed phenotypes thatusually showed a different predominant, nonmovementdisorder clinical presentation (eg, mental retardation orepilepsy), as these probably would require a nonmove-ment disorder prefix that has not been established.
An initial draft list was prepared along with anydoubts or queries, which were then reviewed by aworking group member who had not initially reviewedthe entity. At various stages of the process, all authorsof this work held telephone conferences to discuss thecriteria, discrepancies, and open issues. A cross-checkwith members of the chorea, myoclonus and heredi-tary spastic paraplegia working groups was done toensure that the disorders that received the ATX prefixwere referred to in a similar way with respect to theentities listed in the new nomenclature lists of theabovementioned disorders. Discrepancies wereresolved by discussion until consensus was reached.
The Proposed New List for theRecessive Cerebellar Ataxias
The newly proposed list of recessively inherited cere-bellar ataxias is shown in Table 1. This list includes
62 disorders that usually present with ataxia as a pre-dominant and/or consistent feature, which wereassigned the ATX prefix (group A, Table 1). It alsolists 30 diseases that usually combine ataxia withother predominant and/or consistent movement disor-ders (eg, spastic paraparesis) and that received amixed prefix (eg, ATX/HSP or HSP/ATX, dependingon the phenotype that is consistent with the majorityof cases; group B, Table 1). A group of 89 entitiesthat usually present with other complex and/or nona-taxia phenotypes but that may occasionally manifestcerebellar ataxia were not assigned an ATX prefix(group C, Table 1). Supplementary Table 1 lists therecessive diseases that appeared in our initial list fol-lowing the abovementioned search strategy, but thatupon review were classified as diseases with only occa-sional ataxia presentation, or diseases for which thepresence of ataxia or the genetic finding itself remainsunconfirmed. The posterior column ataxia with retini-tis pigmentosa, a purely sensory ataxia as a result ofmutations in the FLVCR1 gene, was excluded.
Discussion
Here we propose a new nomenclature of the geneti-cally confirmed recessive cerebellar ataxias accordingto the principles and criteria of the International Par-kinson and Movement Disorder Society Task Force onClassification and Nomenclature of Genetic Move-ment Disorders.
We identified and listed almost 100 different, con-firmed genetic entities that present with ataxia as adominant or relevant phenotype. We also provided alist of a similar number of entities that more com-monly have nonataxia presentations but that may pre-sent with ataxia. We believe that this resource is auseful guide for the selection and interpretation ofgenetic testing when confronted with a patient withataxia. A unique feature of our work is separating outthose entities for which the genetic association remainsunconfirmed. An important limitation of the previousnomenclature was the potential for perpetuating spuri-ous associations.3 Requiring independent confirmationof associations before assigning prefixes should mini-mize such occurrences.
There have been earlier attempts to classify recessivecerebellar ataxias, a complex task because of the largeclinical and genetic heterogeneity. Previous classifica-tions have used phenotypic precision (ie, a list of therecessive ataxia genes per phenotypic category), forexample, by separating Friedreich from non-Friedreichataxias or by distinguishing those with from thosewithout a peripheral neuropathy.1,7 However, this sys-tem does not reflect the within-genotype heterogeneityand is also difficult to update as it might not be clearwhat the consistent phenotype is for a new ataxia
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TA
BL
E1.
The
pro
po
sed
new
list
for
the
recessiv
ecere
bella
rata
xia
sa
New
desig
natio
nA
ltern
ate
nam
eM
ain
clin
ical
featu
res
OM
IM
Inherita
nce
patt
ern
Lo
cus
sym
bo
l
A.Disordersthat
presentwith
ataxiaas
apredom
inantor
consistent
feature
ATX-AB
CB71
2Sideroblastic
anem
iawith
spino-
cerebellarataxia
Intentiontremor,pyramidalsigns,hypochromic,microcytic
anem
ia,abnorm
alpigm
entation,
skinatrophy
301310
XRNone
ATX-AB
HD12
13Polyneuropathy,hearingloss,
ataxia,retinitispigm
entosa,
andcataract
(PHA
RC)
Retinopathy,cataract,hearingloss,intentiontremor,pyramidalsigns,peripheralneuropathy,
pescavus
612674
ARNone
ATX-AD
CK31
4,15
Developm
entaldelay,muscleweakness,pescavus,exercise
intolerance,
myoclonus,dystonia,
headache,stroke-like
episodes,seizures
612016
ARSC
AR9,
ARCA
2
ATX-AH
I116,17
Developm
entaldelay,morphologicalabnorm
alities,oculom
otor
apraxia,
nystagmus,retinopathy,
spasticity,scoliosis,seizures,renalfailure,respiratory
dysfunction
608629
ARJBTS3
ATX-ALDH
5A11
8Succinicsemialdehydedehydro-
genase
deficiency
Developm
entaldelay,mentalretardation,
hyperkinesis,hyporeflexia,
psychiatric
symptom
s,abnorm
aleyemovem
ents,seizures
271980
ARNone
ATX-ALG6
19Developm
entaldelay,psychiatric
symptom
s,nystagmus,strabism
us,peripheralneuropathy,
muscleweakness,seizures,skeletaldeform
ities,coagulationanom
alies
603147
ARNone
ATX-AN
O102
0Cognitive
impairm
ent,nystagmus,hyperm
etric
saccades,tortuousconjunctivalvessels,pyrami-
dalsigns,intentiontremor,proximallower
limbs
atrophy,fasciculations,seizures,pescavus
613728
ARSC
AR10,AR
CA3
ATX-APTX
21,22
Hypometric
saccades,oculom
otor
apraxia,
nystagmus,ophthalmoplegia,
peripheralneuropathy,
scoliosis,pescavus,choreoathetosis,tremor,dystonia,cognitive
decline
208920
ARAO
A1
ATX-AR
L13B
23Developm
entaldelay,oculom
otor
apraxia,
retinopathy,respiratory
dysfunction
612291
ARJBTS8
ATX-ATM24
Ataxia-telangiectasia(including
variant
ataxia-telangiectasia)
Telangiectases
andotherskinalterations,oculom
otor
apraxia,
dystonia,chorea,myoclonus,
tremor,peripheralneuropathy,distalmuscularatrophy,shortstature,
hypogonadism
,respi-
ratory
dysfunction,
immunodeficiency,predispositionto
neoplasia,
glucoseintolerance
208900
ARNone
ATX-BC
KDHB
25Maplesyrupurinedisease
Maplesyrupurineodor,life-threateningmetabolicdecompensation,
lethargy,coma,
hypoglyce-
mia,ketosis,lacticacidosis,hallucinations,seizures,mentalretardationifuntreated,vomit-
ing,
pancreatitis
248600
ARNone
ATX-BTD4
26Biotinidasedeficiency
Developm
entaldelay,optic
atrophy,vision
andhearingloss,seizures,metabolicketoacidosis,
organicaciduria,skinproblems,alopecia,hepatosplenomegaly,breathingproblems
253260
ARNone
ATX-C10orf2
27Hepatocerebraltype
ofMito-
chondrialD
NAdepletion
syndrome
Psychomotor
retardation,
psychiatric
symptom
s,ophthalmoplegia,
nystagmus,optic
atrophy,
hearingloss,peripheralneuropathy,myopathy,status
epilepticus,epilepticencephalopathy,
headaches,liver
disease,
hypergonadotrophichypogonadism
271245
ARNone
ATX-CA
8428
Cerebellarataxiaandmental
retardationwith
orwithout
quadrupedallocom
otion
type
3
Mentalretardation,
dysarthria,quadrupedalgait,tremor
613227
ARNone
ATX-CEP290
29,30
Mentalretardation,
congenitalamaurosis,oculom
otor
apraxia,
retinopathy,retinalcoloboma,
nystagmus,nephronophthisis,neonatalbreathingdysregulation
610188
ARJBTS5
ATX-CO
X203
1Mitochondrialcom
plex
IVdefi-
ciency
orcytochromecoxi-
dase
deficiency
Developm
entaldelay,mentalretardation,
pyramidalsigns,peripheralneuropathy,dystonia,lac-
ticacidosisretinopathy,optic
atrophy,respiratory
insufficiency
220110
AR/Mi
None
ATX-CW
F19L13
2Developm
entaldelay,intellectualdisability,tremor,hyperreflexiainlower
limbs
616127
ARSC
AR17
ATX-CYP27A13
3Cerebrotendinous
xanthomatosis
(CTX)
Tuberous
skinandtendon
xantom
as,xanthelasm
as,cataracts,chronicdiarrhea,cognitive
decline,
psychiatric
symptom
s,peripheralneuropathy,parkinsonism
,dystonia,myoclonus,
spastic
paraplegia,pseudobulbar
palsy,seizures
213700
ARNone
(Continued)
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4 Movement Disorders, Vol. 00, No. 00, 2018
TA
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Co
ntinued
New
desig
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nA
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nam
eM
ain
clin
ical
featu
res
OM
IM
Inherita
nce
patt
ern
Lo
cus
sym
bo
l
ATX-DN
AJC194
343-methylglutaconicaciduria,
type
VDevelopm
entaldelay,mentalretardation,
grow
thretardation,
optic
atrophy,muscleweakness,
dilatedcardiomyopathy,long
Q-Tsyndrome,
genitourinarydeform
ities
610198
ARNone
ATX-FXN3
5,36
Friedreich
ataxia(FRD
A)Nystagmus,square
wavejerks,optic
atrophy,hearingloss,peripheralsensory
neuropathy,pes
cavus,hammertoes,muscleweakness,am
yotrophy,extensor
plantarresponses,spasticity,
spastic
ataxia,chorea,scoliosis,hypertrophiccardiomyopathy,diabetes
229300
ARNone
ATX-GR
ID23
7Developm
entaldelay,cognitive
impairm
ent,esotropia,
nystagmus,oculom
otor
apraxia,
tonic
upgaze,paleoptic
discs,retinopathy,pyramidalsigns,muscleatrophy,jointcontractures,
scoliosis
616204
ARSC
AR18
ATX-GR
N38
Dementia,myoclonicretinopathy,optic
atrophy,seizures
614706
ARCLN1
1ATX-ITPR13
9Gillespiesyndrome
Developm
entaldelay,mentalretardation,
aniridiaor
irishypoplasia,scallopedpupillary
margins
ofiris,nystagmus,visualimpairm
ents,posturaltremor
206700
ARNone
ATX-KC
NJ10
40Seizures,sensorineuraldeaf-
ness,ataxia,mentalretarda-
tion,
andelectrolyte
imbalance(SESAM
Esyndrome)
Developm
entaldelay,mentalretardation,
sensorineuraldeafness,intentiontremor,peripheral
neuropathy,seizures,shortstature,
saltcraving,
enuresis,polydipsia,polyuria,electrolyte
imbalance
612780
ARNone
ATX-KIAA0226
41Salih
ataxia
Developm
entaldelay,mentalretardation,
nystagmus,abnorm
alsaccadiceyemovem
ents,
seizures
615705
ARSC
AR15
ATX-L2HG
DH42
L-2-hydroxyglutaric
aciduriaor
academ
iaPsychomotor
regression,mentalretardation,
cognitive
impairm
ent,hearingloss,strabism
us,
optic
atrophy,nystagmus,spastic
tetraparesis,facialdyskinesia,rigidity,dystonia,intention
tremor,action-inducednegativemyoclonus,pyramidalsigns,seizures,macrocephaly
236792
ARNone
ATX-MAN
2B14
3Alpha-mannosidosis
Developm
entaldelay,mentalretardation,
grow
thretardation,
sensorineuraldeafness,nystag-
mus,pyramidalsigns,macrocephaly,facialdysm
orphism,skeletaldeform
ities,
hepatosplenomegaly
248500
ARNone
ATX-MRE11A4
4Ataxia-telangiectasia-likedisor-
dertype
1Hypometric
saccades,oculom
otor
apraxia,
nystagmus,chorea,dystonia,myoclonus,tremor,
hyporeflexia,
distalmuscleatrophy
604391
ARNone
ATX-MSTO1
45Myopathy,developm
entaldelay,grow
thimpairm
ent,pigm
entary
retinopathy
with
papillary
pal-
lor,tremor,skeletalabnorm
alities,pescavus,dysm
oprhism
617619
ARNone
ATX-NP
C146
Niem
ann-Pick
diseasetype
C1Developm
entalregression,
cognitive
impairm
ent,psychiatric
symptom
s,loss
ofspeech,vertical
supranuclear
gaze
palsy,dystonia,intentiontremor,spasticity,seizures,hepatosplenome-
galy,cholestatic
jaundice,gelasticcataplexy
257220
ARNone
ATX-NP
C247
Niem
ann-Pick
diseasetype
C2Similarthan
ATX-NP
C1with
severe
pulmonaryinvolvem
entandrespiratory
failure
607625
ARNone
ATX-OFD1
48Developm
entaldelay,mentalretardation,
recurrentinfections,hirsutism,postaxialpolydactyly,
cysticrenaldisease,facialdysm
orphism,macrocephaly
300804
XRJBTS10
ATX-OP
HN14
9X-linkedmentalretardationwith
cerebellarhypoplasiaanddis-
tinctivefacialappearance
Developm
entaldelay,mentalretardation,
spasticity,psychiatric
symptom
s,seizures,macroce-
phaly,facialdysm
orphism,microphaly,hypoplastic
scrotum,cryptorchidism
,strabism
us300486
XRNone
ATX-OT
C50(Heterozygous
females)
Ornithinetranscarbam
ylase
deficiency
Episodicextremeirritability,episodicvomiting
andlethargy,proteinavoidance,
coma,
delayed
grow
th,developm
entaldelay,seizures
311250
XRNone
ATX-PEX7
51Peroxisomebiogenesisdisorder
9Bor
Zellw
eger
spectrum
disorder
Developm
entaldelay,cognitiveimpairm
ent,cataracts,retinopathy,anosmia,hearingloss,mus-
cleweakness,pescavus,peripheralneuropathy
614879
ARNone
ATX-PEX105
2Peroxisomebiogenesisdisorder
6Bor
Zellw
eger
spectrum
disorder
Mentalretardation,
intentiontremor,peripheralneuropathy,pyramidalsigns,distalmuscle
atrophy,pescavus,dysm
etric
saccades,impairedsm
ooth
pursuit,nystagmus,diabetes
614871
ARNone
(Continued)
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TA
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Co
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New
desig
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nam
eM
ain
clin
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featu
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OM
IM
Inherita
nce
patt
ern
Lo
cus
sym
bo
l
ATX-PH
YH53
Refsum
diseaseor
orhereditary
motor
andsensoryneuropa-
thytype
IV
Muscleweaknessandatrophy,peripheralneuropathy,sensoryimpairm
ent,pescavus,anos-
mia,sensorineuraldeafness,retinopathy,ichthyosis,shortening
ofthemetacarpalsand
metatarsals,multipleepiphysealdysplasia,
cardiomyopathy,sudden
death
266500
ARNone
ATX-PM
M25
4Congenitaldisorderof
glycosyla-
tiontype
Ia(CDG
Ia)or
Jaeken
syndrome
Developm
entaldelay,psychomotor
retardation,
cognitive
impairm
ent,strabism
us,nystagmus,
retinopathy,peripheralneuropathy,stroke-like
episodes,seizures,microcephaly,morphologi-
calabnormalities,abnorm
alsubcutaneous
fattissuedistribution,
pericardialeffusion,hepa-
tomegaly,liver
steatosis,diarrhea,renalcysts,nephrotic
syndrome,
thrombotic
events,
hypothyroidism
,hypergonadotropichypogonadism
,scoliosis,osteoporosis
212065
ARNone
ATX-PM
PCA5
5Developm
entaldelay,mentalretardation,
visuospatialdefects,nystagmus,dysm
etric
saccades,
pescavus,hyperreflexia,spasticity,tremor,shortstature
213200
ARSC
AR2
ATX-PO
LR3B
56Hypomyelinatingleukodystrophy
type
8with
orwithoutoligo-
dontiaand/or
hypogonado-
tropichypogonadism
Developm
entaldelay,cognitive
decline,
mentalretardation,
nystagmus,abnorm
alsaccades,
verticalgazepalsy,myopia,
spasticity,tremor,oligodontia,hypodontia,delayeddentition,
shortstature,
hypogonadism
614381
ARNone
ATX-PRKC
G57
Peripheralneuropathy,pyramidalsigns,cognitive
impairm
ent,depression,myoclonus,tremor
605361
ARNone
ATX-PTRH
258
Infantile-onset
multisystem
neu-
rologic,endocrine,
andpan-
creatic
disease(IM
NEPD
)
Developm
entaldelay,failure
tothrive,
poor
postnatalgrowth,poor
expressive
speech,periph-
eralneuropathy,distalmuscleweakness,foot
andhand
deform
ities,hypothyroidism
,pan-
creatic
endocrineinsufficiency,facialdysm
orphism,brachycephaly,shortstature
616263
ARNone
ATX-RN
F168
59RIDD
LEsyndrome
Learning
difficulties,immunodeficiency,dryskin,progressivepulmonaryfibrosisandfailure,
ocular
telangiectasia,shortstature,
microcephaly,dysm
orphicfeatures
611943
ARNone
ATX-RN
F216
60Gordon
Holmes
syndrome
Mentalretardation,
dementia,psychiatric
symptom
s,chorea,sensorineuraldeafness,
hypogonadism
212840
ARNone
ATX-SETX
61Saccadicpursuit,oculom
otor
apraxia,
nystagmus,strabism
us,intentiontremor,head
tremor,
dystonia,chorea,pyramidalsigns,peripheralneuropathy,distalmuscleatrophyandweak-
ness,pescavus,scoliosis
606002
ARSC
AR1,
AOA2
ATX-SIL1
62Marinesco-Sj€ ogren
syndrome
Developm
entaldelay
orregression,mentalretardation,
grow
thretardation,
microcephaly,facial
dysm
orphism,shortstature,
congenitalcataracts,nystagmus,strabism
us,spasticity,muscle
weaknessandatrophy,peripheralneuropathy,scoliosis,skeletaldeform
ities,hypogonadism
248800
ARNone
ATX-SLC17A56
3Salla
diseaseor
Finnishtype
sialuriaandthevariant
syn-
drom
eof
infantile
form
ofsialicacidstoragedisorder
Developm
entaldelay,mentalretardation,
rigidity,spasticity,seizures,viscerom
egaly,facial
dysm
orphism,hypopigm
entedskin
604369
and269920
ARNone
ATX-SLC33A16
4Congenitalcataracts,hearing
loss,andneurodegeneration
(CCH
LND)
Psychomotor
retardation,
nystagmus,congenitalcataracts,hearingloss,seizures
614482
ARNone
ATX-SLC52A26
5,66
(allelic
with
Brow
n-Vialetto-Van
Laere
syndrometype
2)
Optic
atrophy,blindness,cochlear
degeneration,
deafness
271250
ARSC
AR3
ATX-SN
X146
7Developm
entaldelay,mentalretardation,
autistic
behavior,macrocephaly,sensorineuralhear-
ingloss,nystagmus,apraxia,
spasticity,extensor
plantarresponses,hyporeflexia,
seizures,
hypertrichosis,scoliosis,distalskeletaldeform
ities,brachycamptodactyly,facial
dysm
orphism
616354
ARSC
AR20
ATX-SPTBN2
68Developm
entaldelay,cognitive
impairm
ent,speech
delay,intentiontremor,spasticity,hyperre-
flexia,
hypometric
saccades,nystagmus,abnorm
aleyemovem
entswith
convergent
squint
615386
ARSC
AR14
(Continued)
R O S S I E T A L
6 Movement Disorders, Vol. 00, No. 00, 2018
TA
BL
E1.
Co
ntinued
New
desig
natio
nA
ltern
ate
nam
eM
ain
clin
ical
featu
res
OM
IM
Inherita
nce
patt
ern
Lo
cus
sym
bo
l
ATX-SR
D5A3
69Congenitaldisorderof
glycosyla-
tion,
type
IqDevelopm
entaldelay,mentalretardation,
coloboma,
nystagmus,facialdysm
orphism,hypertri-
chosis,skinabnorm
alities,coagulationdefects,microcytic
anem
ia612379
ARNone
ATX-STUB
170
Nystagmus,externalophthalmoplegia,
pyramidalsigns,tremor,myoclonus,cognitive
impair-
ment,peripheralneuropathy,reducedvibrationsenseinlower
limbs,hypogonadism
615768
ARSC
AR16
ATX-SYNE
171
Nystagmus,abnorm
alsaccades
andslow
orjerkypursuit,hyperreflexiainlower
limbs,motor
neuron
involvem
ent,respiratory
dysfunctiondueto
multisystemicneurom
uscularcompro-
mise,
mentalretardation
610743
ARSC
AR8,
ARCA
1
ATX-TTPA
72Ataxiawith
vitaminEdeficiency
Nystagmus,retinopathy,propioceptionloss,areflexiainlower
limbs,peripheralneuropathy,
extensor
plantarresponse,head
titubationor
tremor,dystonia,hypoacusia,tendon
xantho-
mas,pescavus,hammer
toes,kyphoscoliosis
277460
ARNone
ATX-TM
EM2167
3Developm
entaldelay,failure
tothrive,
mentalretardation,
impairedsaccades,oculom
otor
apraxia,
nystagmus,optic
nervecoloboma,
chorioretinalcoloboma,
retinopathy,esotropia,
polydactyly,nephronophthisis,renalcysts,hypoplastic
genitalia,episodichyperpneaor
apnea,
facialdysm
orphism,macrocephaly
608091
ARJBTS2
ATX-TM
EM67
74,75 ,ATX-
RPGR
IP1L
76-78
ATX-CC
2D2A
79
COAC
Hsyndrome(cerebellar
verm
ishypo/aplasia,oligo-
phrenia,
ataxia,ocular
colo-
boma,
andhepatic
fibrosis)
andallelic
disorders
Developm
entaldelay,mentalretardation,
oculom
otor
apraxia,
ocular
coloboma,
retinopathy,
nystagmus,facialdysm
orphism,polydactyly,pyramidalsigns,seizures,splenomegaly,renal
failure,liver
disease,
breathingdysregulation
216360,611560,
610688
ARJBTS6,
JBTS7
ATX-TM
EM2318
0Developm
entaldelay,oculom
otor
apraxia,
psychiatric
symptom
s,polydactyly,syndactyly,renal
cysts,retinopathy
614970
ARJBTS20
ATX-TTC198
1Mitochondrialcom
plex
IIIdefi-
ciency
nucleartype
2Developm
entaldelay,cognitive
impairm
ent,apraxia,
psychiatric
symptom
s,dysphonia,
nystag-
mus,bradykinesia,dystonia,muscleatrophyandweakness,pyramidalsigns
615157
ARNone
ATX-VLDLR8
2Cerebellarataxia,mentalretar-
dation,
anddysequilibrium
syndrometype
1
Developm
entaldelay,mentalretardation,
lack
ofspeech
developm
ent,strabism
us,postnatal
cataracts,nystagmus,saccadicvisualpursuit,quadrupedalgait,intentiontremor,hyperre-
fexia,
seizures,pesplanus,shortstature
224050
ARNone
ATX-WDR
7383
Galloway-M
owat
syndrome
Delayedpsychomotor
developm
ent,mentalretardation,
oculom
otor
apraxia,
optic
atrophy,reti-
nopathy,seizures,spastic
quadriplegia,
dystonia,hyperreflexia,skinabnorm
alities
(osm
io-
philicskinvessels),skeletaldeform
ities,genitourinaryaffectation,
facialdysm
orphias,
microcephaly,shortstature,
intrauterinegrow
thretardation
251300
ARSC
AR5
ATX-WDR
8184
Cerebellarataxia,mentalretar-
dation,
anddysequilibrium
syndrometype
2
Developm
entaldelay,mentalretardation,
strabism
us,facialdysm
orphism,quadrupedalloco-
motion,
poor
orabsencelanguage
developm
ent,tremor,h
yporeflexia,hirsutism,sm
allhands
andfeet,thoracickyphosis,shortstature
610185
ARNone
B.Combinedataxias(disorders
where
ataxiafrequently
coexistswith
otherpredom
inantor
consistent
movem
entdisorders)
ATX/HS
P-AFG3
L285
Spastic
paraparesis,oculom
otor
apraxia,
dystonia,myoclonus,myoclonicepilepsy,generalized
tonic-clonicseizures,distalmuscleatrophy,peripheralneuropathy
614487
ARSPAX5
ATX/HS
P-DA
RS28
6Leukoencephalopathywith
brain
stem
andspinalcord
involve-
mentandlactateelevation
Spastic
paraparesis,developm
entaldelay,cognitive
decline,
nystagmus,tremor,peripheral
neuropathy,sensationdeficits,muscleweaknessandatrophy,jointcontractures
611105
ARNone
ATX/HS
P-FOLR18
7Neurodegenerationas
aresult
ofcerebralfolate
transport
deficiency
Spastic
paraparesis,developm
entalregression,
mentalretardation,
visualdisturbances,senso-
rineuralhearingloss,chorea,generalized
tonic-clonic,atonicandmyoclonicseizures
613068
ARNone
(Continued)
G E N E T I C N O M E N C L A T U R E O F R E C E S S I V E A T A X I A S
Movement Disorders, Vol. 00, No. 00, 2018 7
TA
BL
E1.
Co
ntinued
New
desig
natio
nA
ltern
ate
nam
eM
ain
clin
ical
featu
res
OM
IM
Inherita
nce
patt
ern
Lo
cus
sym
bo
l
ATX/HS
P-GJC2
88Hypomyelinatingleukodystrophy-
2or
Pelizaeus-M
erzbacher-
likedisease
Spastic
paraparesis,developm
entaldelay,mentalretardation,
lack
ofindependentam
bulation,
poor
head
andtrunk
controlininfancy,optic
atrophy,rotary
nystagmus,myopia,
facial
weakness,tremor,head
titubation,
dystonia,spasticity,seizures,peripheralneuropathy
608804
ARNone
ATX/HS
P-HEXA
89Tay-Sachsdiseaseor
GM2-
gangliosidosistype
ISpastic
paraparesis,cognitive
decline,
psychiatric
symptom
s,late
spasticity,dystonia,periph-
eralneuropathy,macular
pallorwith
prom
inence
offoveacentralis
(cherryredspot),blind-
ness,muscularweaknessandatrophy,seizures
272800
ARNone
ATX/HS
P-HEXB
90Sandhoffdiseaseor
GM2-
Gangliosidosistype
IISpastic
paraparesis,progressivementaland
motor
deterioration,
macrocephaly,macular
pallor
with
prom
inence
offoveacentralis
(cherryredspot),blindness,dysm
orphicfeatures,startle
reaction,
hyperreflexia,muscularatrophy,fasciculations,cardiomegaly,episodicabdominal
pain,chronicdiarrhea,hepatosplenomegaly,macroglossia,
high
lumbargibbus
268800
ARNone
ATX/HS
P-PN
PLA6
91-95
PNPLA6-related
disorders:
Boucher-Neuhausersyn-
drom
e,Laurence-M
oonsyn-
drom
eandOliver-M
cFarlane
syndrome
Visualimpairm
entdueto
chorioretinaldystrophy,nystagmus,distalmuscleatrophy,intention
tremor,spastic
paraparesis,cognitive
impairm
ent,peripheralneuropathy,hypogonadism
,tri-
chom
egaly,shortstature
215470,
215470,245800,
275400,612020
ARSPG3
9
ATX/HS
P-PO
LR3A
96Hypomyelinatingleukodystrophy
type
7with
orwithoutoligo-
dontiaand/or
hypogonado-
tropichypogonadism
or4H
syndrome
Spastic
paraparesis,developm
entaldelay,cognitive
decline,
mentalretardation,
optic
atrophy,
nystagmus,abnorm
alsaccades,verticalgazepalsy,pyramidalsigns,posturaltremor,dysto-
nia,
seizures,peripheralneuropathy,oligodontia,hypodontia,delayeddentition,hypogonado-
tropichypogonadism
,shortstature
607694
ARNone
ATX/HS
P-SACS
97Autosomalrecessivespastic
ataxiaof
Charlevoix-Saguenay
(ARS
ACS)
orautosomal
recessivespastic
ataxiatype
6
Spastic
paraparesis,delayedwalking
developm
ent,retinalstriation,
nystagmus,impaired
smooth
pursuit,pescavus,hammertoes,fingerdeform
ities,hyperreflexia,ankleareflexia,
spasticity,extensor
plantarresponses,scoliosis,distalmuscleweaknessandatrophy,
peripheralneuropathy,dystonia,erectiledysfunction
270550
ARSPAX6
HSP/ATX-B4GA
LNT1
98Spastic
paraparesis,distalam
yotrophy,nonprogressive
cognitive
impairm
ent,sensorypolyneur-
opathy,pescavus,stereotypies,em
otionallability,psychiatric
symptom
s,seizures
609195
ARSPG2
6
HSP/ATX-CA
PN19
9Spasticity
inlower
andupperlim
bs,otherpyramidalsigns,peripheralneuropathy,pescavus,
pesvalgus,nystagmus
616907
ARSPG7
6
HSP/ATX-CLCN
2100
Leukoencephalopathywith
ataxia
Spastic
paraparesis,learning
disabilities,headache,optic
neuropathy,chorioretinopathy,visual
fielddefects
615651
ARNone
HSP/ATX-CYP7B1
101
Spastic
paraparesis,otherpyramidalsignsbesidesspasticity,cognitive
impairm
ent,nystag-
mus,optic
atrophy,cataracts,alteredsaccadiceyemovem
ents,pescavus,sensation
deficits
270800
ARSPG5
A
HSP/ATX-GA
N102
Spastic
paraparesis,distallim
bmuscleweaknessandatrophyas
aresultof
peripheralneu-
ropathy,distalsensoryimpairm
ent,kinkyor
curly
hair,
foot
orhand
deform
ities,scoliosis,
nystagmus,facialweakness
256850
ARNone
HSP/ATX-GB
A2103
Spastic
paraparesis,otherpyramidalsigns,muscleweakness,pseudobulbar
dysarthria,cogni-
tiveimpairm
ent,mentalretardation,
congenitalcataracts,nystagmus,hearingloss,head
tremor,peripheralneuropathy,pescavus,scoliosis,infertility,sm
alltesticles,hypogonadism
inmales
614409
ARSPG4
6
HSP/ATX-KIF1C1
04,105
Spastic
paraparesis,chorea,myoclonus,dystonia,developm
entaldelay,mild
mentalretarda-
tion,
hypodontia,ptosis,shortstature,
sensorineuraldeafness,pesplanus
611302
ARSPAX2,
SPG5
8
HSP/ATX-MLC11
06Megalencephalicleukoencephal-
opathy
with
subcorticalcysts
Spastic
paraparesis,developm
entaldelay,mentalretardation,
seizures,macrocephaly,
spasticity
604004
ARNone
(Continued)
R O S S I E T A L
8 Movement Disorders, Vol. 00, No. 00, 2018
TA
BL
E1.
Co
ntinued
New
desig
natio
nA
ltern
ate
nam
eM
ain
clin
ical
featu
res
OM
IM
Inherita
nce
patt
ern
Lo
cus
sym
bo
l
HSP/ATX-PLP1
107
Spastic
paraparesis,lower
limbweakness,otherpyramidalsigns,mentalretardation,
upper
limbspasticity,pescavus,jointcontractures,nystagmus,optic
atrophy,tremor
312920
XRNone
HSP/ATX-SPG7
108
Spastic
paraparesis,optic
atrophy,chronicexternalophthalmoplegia-likephenotype,
nystag-
mus,decreasedvibratorysenseinthelower
limbs,pescavus,scoliosis
607259
AR/AD
SPG7
HSP/ATX-UC
HL11
09Childhood-onset
neurodegenera-
tionwith
optic
atrophy
Spastic
paraparesis,otherpyramidalsigns,myotonia,
myokymia,head
titubation,
intellectual
impairm
ent,impaireddistalsensationto
vibrationandposition,
optic
atrophy,nystagmus
615491
ARNone
HSP/ATX/NB
IA-FA2H1
10Fatty
acidhydroxylase-
associated
neurodegeneration
(FAH
N)
Spastic
paraparesis,cognitive
decline,
optic
nerveatrophy,seizures,dystonia,parkinsonism
612319
ARSPG3
5
ATX/MYC-TPP11
11,112
(allelic
disorders:Neuronalceroid
lipofuscinosistype
2and
autosomalrecessivespino-
cerebellarataxiatype
7)
Myoclonus,developm
entalregression,
speech
andlanguage
difficulties,nystagmus,diplopia,
hyperm
etric
saccades,progressivevision
loss,retinopathy,posturaltremor,pyramidalsigns,
spastic
paraparesis,decreasedvibrationsense,
fasciculations,seizures
609270,204500
ARSC
AR7,
CLN2
MYC/ATX-CSTB1
13Myoclonicepilepsyof
Unverricht
andLundborg
Myoclonicepilepsy,stimulus
sensitive
segm
entalorgeneralized
myoclonus,actionmyoclonus,
generalized
tonic-clonicor
absenceseizures,mentaland
motor
deterioration
254800
ARNone
MYC/ATX-EPM
2A114
Lafora
disease
Myoclonicor
othertypesof
seizures,focalvisualseizures,drop
attackscognitive
decline,
psy-
chosis,myoclonus
607566
ARNone
MYC/ATX-GOS
R2115
Myoclonic,absenceandtonic-clonicseizures,drop
attacks,actionmyoclonus,tremor,are-
flexia,
scoliosis,pescavus,syndactyly
614018
ARNone
MYC/ATX-KCTD7
116
Progressivemyoclonicepilepsy
type
3with
orwithoutintra-
cellularinclusions
Myoclonicepilepsy,secondarygeneralizationseizures,neurologicregression
followingseizure
onset,mentalretardation,
hyperreflexia,opsoclonus,optic
atrophy,visualloss,microcephaly
611726
ARNone
MYC/ATX-NEU11
17Neuram
inidasedeficiencyor
sialidosistype
Iand
IIMyoclonus,mentalretardation,
seizures,hyperreflexia,muscleatrophy,skeletalmalform
ations,
hepatosplenomegaly,cardiomyopathy,progressivevision
loss,cherry-red
spots,cataracts,
nystagmus,sensorineuralhearingloss,shortstature,
dysm
orphicfeatures
256550
ARNone
MYC/ATX-NHLRC
1118
Lafora
disease
Myoclonicor
othertypesof
seizures,focalvisualseizures,drop
attackscognitive
decline,
psy-
chosis,myoclonus
608072
ARNone
DYT/ATX-ATP7B1
19Wilson
disease
Dystonia,occasionallyparkinsonism
,chorea,flappingtremor,rest,action,
andintentiontremor,
orofacialdyskinesias,liver
disease,
Kayser
Fleischerrings,psychiatric
symptom
s277900
ARNone
PxMD-DY
T-ATX-PRRT21
20
(Biallelic
mutations)
Paroxysm
alnon-kinesigenicdyskinesia,prolongedepisodes
ofataxia,motor
tics,seizures,
hemiplegicmigraine,
learning
difficulties,psychiatric
symptom
s614386
ARNone
C.Disordersthat
usually
presentwith
otherphenotypes
butcanhave
occasionallyataxia(noATXprefix)
HSP-AC
P331
21Spastic
paraparesis,otherpyramidalsigns,apraxia,
bulbar
dysfunction,
developm
entaldelay,
cognitive
impairm
ent,akineticmutism,dykinesias,peripheralneuropathy
248900
ARSPG2
1
HSP-DD
HD21
22Spastic
paraparesis,otherpyramidalsigns,developm
entaldelay,mentalretardation,
lower
limbs
weakness,strabism
us,facialdysm
orphism,shortstature,
optic
nervehypoplasia
615033
ARSPG5
4
HSP-KIAA0415
123
Spastic
paraparesis,lower
limbweakness,dystonia,myoclonus,parkinsonism
,peripheral
neuropathy
613647
ARSPG4
8
HSP-
KIAA1840
124
Spastic
paraparesis,lower
limbatrophy,weakness,peripheralneuropathy,pescavus,parkin-
sonism
,cognitive
impairm
ent,mentalretardation,
retinopathy,pigm
entedmacular
degenera-
tion,
nystagmus
604360
ARSPG1
1
(Continued)
G E N E T I C N O M E N C L A T U R E O F R E C E S S I V E A T A X I A S
Movement Disorders, Vol. 00, No. 00, 2018 9
TA
BL
E1.
Co
ntinued
New
desig
natio
nA
ltern
ate
nam
eM
ain
clin
ical
featu
res
OM
IM
Inherita
nce
patt
ern
Lo
cus
sym
bo
l
HSP-KIF1A1
25Spastic
paraparesis,lower
limbatrophyandweakness,peripheralneuropathy,saccadicocular
pursuit
610357
ARSPG3
0
HSP-SPAR
TIN1
24Spastic
paraplegiaandupperlim
bspasticity,distalmuscleatrophy,pescavus,hammertoes,
shortstature,
dysm
orphism,developm
entaldelay
275900
ARSPG2
0
HSP-ZFYVE261
26Spastic
paraparesis,mentalretardation,
cognitive
impairm
ent,psychiatric
symptom
s,parkin-
sonism
,distalam
yotrophy,pescavus,peripheralneuropathy,retinopathy,hearingloss,pig-
mentary
maculopathy
270700
ARSPG1
5
MYC-CLN51
27Myoclonus,tremor,mentalretardation,
cognitive
decline,
visualloss,glaucoma,
retinopathy,
nystagmus,hyperreflexia,seizures
256731
ARCLN5
MYC-CLN61
28Myoclonus,dystonia,bradykinesia,myoclonicepilepsy,dementia,mentalretardation,
psychiat-
ricsymptom
s,blindness
204300
ARCLN6
MYC-SCA
RB21
29Progressivemyoclonicepilepsy
type
4with
orwithoutrenal
failure
Actionandrestingmyoclonus,intentionandposturaltremor,horizontalsaccades,seizures,
nephrotic
syndrome,
renalfailure
254900
ARNone
DYT/PARK
-GLB11
30Dystonia,parkinsonism
,pyramidalsigns,cognitive
deficits,skeletalabnorm
alities,shortstat-
ure,
cornealclouding,
cardiomyopathy
230600
ARNone
DYT/PARK
-SPR
131
Sepiapterin
reductasedeficiencyDystonia,parkinsonism
,motor
andspeech
delay,truncalhypotonia,
limbhypertoniaandhyper-
reflexia,
oculogyriccrises,psychiatric
symptom
s,autonomicdysfunction,
diurnalfluctuation
612716
ARNone
NBIA/DYT/PAR
K-CP
132
Aceruloplasm
inem
iaDystonia,parkinsonism
,chorea,cognitive
impairm
ent,retinopathy,blepharospasm,system
ichemosiderosis,diabetes,anem
ia604290
ARNone
NBIA/DYT-PAN
K2133
Pantothenate
kinase-associated
neurodegeneration(PKAN)
Dystonia,parkinsonism
,chorea,tremor,spasticity,cognitive
decline,
apraxiaof
eyelidopening,
retinopathy,optic
atrophy,psychiatric
symptom
s,muscleatrophy
234200
ARNB
IA1
NBIA/DYT/PAR
K-PLA2G6
134
PLA2G6
-associatedneurodegen-
erationor
Infantile
neuroaxo-
naldystrophytype
1
Dystonia,parkinsonism
,cognitive
decline,
pyramidalsigns,psychiatric
symptom
s(adultpheno-
type),ataxia(childhood
phenotype)
256600/610217
ARNB
IA2,
PARK
14
AAAS
135
Achalasia-addisonianism-alacri-
miasyndromeor
Triple-A
syndromeor
Allgrove
syndrome
Developm
entaldelay,mentalretardation,
pyramidalsigns,distalmuscleweaknessandatro-
phy,achalasia,
autonomicdysfunction,
anisocoria,peripheralneuropathy,adrenalinsuffi-
ciency,alacrim
a,optic
atrophy,shortstature,
hyperpigmentation,
hyperkeratosisof
the
palmsandsoles
231550
ARNone
AARS
2136
Progressiveleukoencephalop-
athy
with
ovarianfailure
Dystonia,tremor,developm
entaldelay,cognitive
decline,
apraxia,
psychiatric
symptom
s,nys-
tagm
us,spasticity,prem
atureovarianfailure
615889
ARNone
ABCD
1137
X-linkedadrenoleukodystrophy
Visualdisturbances,sensationdeficits,spastic
paraplegia,autonomicfailure,adrenal
dysfunction
300100
XRNone
ARX1
38Partingtonsyndrome
Dystonia,mentalretardation,
spasticity,seizures,morphologicalabnorm
alities
309510
XRNone
ATAD
3A139,140
Harel-Yoonsyndrome
Developm
entaldelay,intellectualdisability,optic
atrophy,nystagmus,spasticity,distallim
bmuscleatrophy,peripheralneuropathy,scoliosis,dysm
orphism,hypertrophiccardiomyopathy
617183
AR/AD
None
AUH1
413-methylglutaconicaciduriatype
IDystonia,developm
entaldelay,failure
tothrive,
mentalretardation,
spastic
quadriplegia,
cogni-
tiveimpairm
ent,hyperreflexia,metabolicacidosis,febrile
seizures,optic
atrophy
250950
ARNone
BCS1L,
COX10,
COX15,
FOXRED
1,ND
UFAF2,
NDUFS3,ND
UFS4,ND
UFAF6,
NDUFS7,ND
UFS8,ND
UFA10,
SDHA
,SU
RF1)
142
Leighsyndrome
Dystonia,failure
tothrive,
psychomotor
retardation,
mentalretardation,
pyramidalsigns,seiz-
ures,psychiatric
symptom
s,lacticacidosis,hypertrochosis,respiratory
failure,pigm
entary
retinopathy,ptosis,strabism
us,nystagmus,optic
atrophy,ophthalmoplegia
256000
Mi/AR
None
C5orf421
43Developm
entaldelay,oculom
otor
apraxia,
polydactyly,syndactyly,abnorm
albreathingpattern
614615
ARJBTS17
(Continued)
R O S S I E T A L
10 Movement Disorders, Vol. 00, No. 00, 2018
TA
BL
E1.
Co
ntinued
New
desig
natio
nA
ltern
ate
nam
eM
ain
clin
ical
featu
res
OM
IM
Inherita
nce
patt
ern
Lo
cus
sym
bo
l
CTC1
144
Cerebroretinalmicroangiopathy
with
calcifications
andcysts
orCoatsplus
syndrome
Dystonia,tremor,intrauterinegrow
thretardation,
grow
thretardation,
seizures,spasticity,hemi-
plegia,cognitive
decline,
pyramidalsigns,bone
marrowfailure,skinandhairabnorm
alities,
intracranialcalcifications,skeletaldeform
ities,intestinalbleeding,retinopathy,optic
atrophy,
blindness
612199
ARNone
CTDP
1145
Congenitalcataractswith
facial
dysm
orphism
andneuropathy
Chorea,developm
entaldelay,congenitalcataracts,nystagmus,cognitive
impairm
ent,pyramidal
signs,peripheralneuropathy,hypo-or
hypergonadotrophichypogonadism
,acuterhabdomy-
olysis,pescavus,talipes
equinovarus,skeletaldeform
ities,facialdysm
orphism
604168
ARNone
CTSA
146
Galactosialidosis
Myoclonus,mentalretardation,
seizures,angiokeratom
a,facialdysm
orphism,conjunctivaltel-
angiectases,macular
cherry
redspot,hearingloss,hemangiom
as,hepatosplenomegaly,
dysostosismultiplex,cardiacvalvular
disease
256540
ARNone
CTSF
147
Myoclonus,tremor,dementia,perioraldyskinesias,pyramidalsigns,seizures,psychiatric
symptom
s615362
ARCLN1
3
CUL4B1
48Cabezastype
ofX-linkedsyn-
drom
icmentalretardation
Trem
or,mentalretardation,
speech
delay,hypogonadism
,shortstature,
facialdysm
orphism,
skeletalabnorm
alities,seizures,psychiatric
symptom
s,centralobesity,macrocephaly
300354
XRNone
DKC1
149
X-linkeddyskeratosiscongenital
(ataxiareportedinthesevere
variant:Hoyeraal-Hreidarsson
syndrome)
Intrauterinegrow
thretardation,
developm
entaldelay,mentalretardation,
microcephaly,multi-
system
involvem
ent,bone
marrowfailure
resulting
inimmunodeficiency,enteropathy,stra-
bism
us,cataracts,optic
atrophy,sparse
eyelashes,conjunctivalleukoplakia,
shortstature,
pulmonaryfibrosis,liver
failure,skinatrophy,naildystrophy,carcinom
as,leukem
ia
305000
XRNone
DLD1
50Dihydrolipoamidedehydrogenase
deficiencyor
Maplesyrup
urinediseasetype
II
Dystonia,developm
entaldelay,episodicencephalopathy,seizures,lacticor
metabolicacidosis,
recurrentvomiting,hepatomegaly,liver
dysfunction,
hypertrophiccardiomyopathy,
microcephaly
246900
ARNone
EIF2B1,EIF2B2,EIF2B3,
EIF2B4,EIF2B5
151
Leukoencephalopathieswith
vanishingwhite
matter
Mentaland
motor
retardationor
regression,cognitive
impairm
ent,psychiatric
symptom
s,optic
atrophy,pyramidalsigns,seizures,ovarianfailure,clinicalfeatures
worsenedby
head
traum
aor
fever,macrocephaly,lethargy
603896
ARNone
ERCC
4152,153
XFEprogeroidsyndromeand
theallelic
entityXeroderm
apigm
entosum
complem
enta-
tiongroupF/Cockayne
syndrome
Dwarfism,cachexia,microcephaly,photosensitivity,wizened
appearance,scoliosis,delayed
sexualmaturity,chorea,tremor,mentalretardation,
cognitive
decline,
nystagmus,astigma-
tism,deep-set
eyes,hearingimpairm
ent,shortstature,
seborrheickeratosis-likepapules,
abnorm
alpigm
entation,
skincancer
susceptibility,plantarwarts
610965,278760
ARNone
EXOS
C3154
Pontocerebellarhypoplasiatype
1BTrem
or,developm
entaldelay,poor
grow
th,axialhypotonia,spasticity,hyperreflexia,lack
ofspeech,seizures,peripheralneuropathy,muscleatrophyandweakness,tongue
atrophyand
fasciculations,foot
deform
ities,jointcontractures,respiratory
insufficiency,oculom
otor
apraxia,
nystagmus,strabism
us,retinopathy,microcephaly
614678
ARNone
GALC
155
Krabbe
diseaseor
galacto-
cerebrosidasedeficiency
Failure
tothrive,
developm
entaldelay
orregression,d
eafness,blindness,optic
atrophy,nystag-
mus,hypersensitiveto
stimuli,irritability,spastic
tetraparesis,seizures,muscular,decere-
brateposturing,
peripheralneuropathy,pescavus,tongue
atrophy,episodicfever
245200
ARNone
GBA1
56Gaucherdiseasetype
IIIor
sub-
acuteneuronopathictype
Myoclonus,developm
entaldelay,dementia,psychiatric
symptom
s,spastic
paraparesis,hori-
zontalsupranuclear
gaze
palsy,abnorm
alsaccadeeyemovem
ents,strabism
us,seizures,
shortstature,
hepatosplenomegaly,pancytopenia
231000
ARNone
GJC2
157
Trem
or,slow
saccades,sensorineuralhearingloss,strabism
us,spastic
paraparesis,other
pyramidalsigns,pescavus,scoliosis,seizures,cognitive
impairm
ent
613206
ARSPG4
4
GPR56or
ADGR
G1158
Bilateralfrontoparietal
polymicrogyria
Developm
entaldelay,mentalretardation,
pyramidalsigns,esotropia,
exotropia,
strabism
us,
nystagmus,seizures
606854
ARNone
(Continued)
G E N E T I C N O M E N C L A T U R E O F R E C E S S I V E A T A X I A S
Movement Disorders, Vol. 00, No. 00, 2018 11
TA
BL
E1.
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ntinued
New
desig
natio
nA
ltern
ate
nam
eM
ain
clin
ical
featu
res
OM
IM
Inherita
nce
patt
ern
Lo
cus
sym
bo
l
HEPACA
M159
Autosomalrecessivemegalen-
cephalicleukoencephalopathy
with
subcorticalcyststype
2A
Developm
entaldelay,mentalretardation,
cognitive
decline,
spasticity,seizures,macrocephaly
613925
ARNone
HIBC
H160
3-hydroxyisobutyrl-CoAhydro-
lase
deficiency
Dystonia,myoclonus,developm
entaldelay
orregression,seizures,nystagmus,strabism
us,
facialdysm
orphism,head
titubation,
persistent
vomiting
250620
ARNone
HSD1
7B41
61Perraultsyndrometype
1(allelic
with
PeroxisomalD-
bifunctionalprotein
deficiency)
Sensorineuraldeafness,ovariandysgenesis,primaryam
enorrhea,developm
entaldelay,mental
retardation,
spastic
diplegia,pescavus,pesequinovarus,peripheralneuropathy,nystagmus,
shortstature,
scoliosis
233400
ARNone
LRPPRC
162
French
Canadian
type
ofLeigh
syndrome
Trem
or,developm
entaldelay,mentalretardation,
failure
tothrive,
language
delay,seizures,
lacticacidosis,metaboliccrises,strabism
us,facialdysm
orphism,liver
dysfunction
220111
ARNone
LYST
163
Chediak-Higashisyndrom
eParkinsonism
,tremor,mentalretardation,
cranialnerve
palsies,spastic
paraparesis,peripheral
neuropathy,foot
drop,seizures,anem
ia,recurrentcutaneousandsystem
icpyogenicinfec-
tions,severe
immunedeficiency,hairhypopigm
entation,
reducedvisualacuity,nystagmus,
strabism
us,reducedirispigm
entation,
macular
hypoplasia,hepatosplenomegaly,jaundice
214500
ARNone
MAG
164
Developm
entaldelay,cognitive
impairm
ent,impaireddistalvibrationsense,
peripheralneurop-
athy,distalmuscleatrophyinlower
limbs,spastic
paraplegia,optic
atrophy,nystagmus,
visualimpairm
ent
616680
ARSPG7
5
MECP2
165
Lubs
X-linkedmentalretardation
syndrome
Chorea,psychomotor
retardation,
macro-or
microcephaly,facialdysm
oprhism,seizures,spas-
ticity,recurrentrespiratory
infections,cryptorchidism
,asym
metric
skull,stereotypichand
movem
ents,autistic
features,depression,compulsions,psychosis
300260
XRNone
MFSD8
166
Developm
entalregression,
mentalretardation,
cognitive
impairm
ent,optic
atrophy,retinopathy,
blindness,seizures,myoclonus
610951
ARCLN7
MKS11
67Developm
entaldelay,intellectualdisability,nystagmus,oculom
otor
apraxia,
retinopathy
617121
ARJBTS28
MMAC
HC168
cblC
type
ofcombinedmethyl-
malonicaciduriaand
homocystinuria
Trem
or,failure
tothrive,
developm
entaldelay,mentalretardation,
dementia,retinopathy,visual
deficits,nystagmus,facialdysm
orphism,seizures,hypergonadotropichypogonadism
,ane-
mia,renalfailure,microcephaly
277400
ARNone
MPV17
169
MitochondrialD
NAdepletion
syndrome-6or
Navajo
neurohepatopathy
Dystonia,neonataljaundice,failure
tothrive,
developm
entaldelay,peripheralneuropathy,
hypo-areflexia,
paininsensitivity,acralulcerationandosteom
yelitisleadingto
autoam
puta-
tion,
painless
fractures
dueto
injury,distalmuscleweakness,lacticacidosis,system
icinfections,liver
dysfunction,
Reye
syndrome-likeepisodes,shortstature
256810
ARNone
MTFMT1
70Combinedoxidativephosphory-
lationdeficiencytype
15Trem
or,developm
entaldelay,cognitive
impairm
ent,pyramidalsigns,seizures,strabism
us,
nystagmus,optic
atrophy,shortstature,
obesity,cardiopathy
614947
ARNone
MTTP1
71Abetalipoproteinem
iaPeripheralneuropathy,retinopathy,acanthocytosis,steatorrhea(celiac-likesyndrome),hepatic
steatosis
200100
ARNone
MVK
172
Mevalonicaciduria
Developm
entaldelay,psychomotor
retardation,
failure
tothrive,
recurrentfebrile
crises
with
lymphadenopathy,hepatosplenomegaly,anem
ia,morbilliform
rash,kyphoscoliosis,arthral-
gias,facialdysm
orphism,nystagmus,centralcataracts,retinaldystrophy,microcephaly
610377
ARNone
NPHP
1173
Developm
entaldelay,mentalretardation,
congenitalheadtilt,abnorm
aleyemovem
ents,nys-
tagm
us,oculom
otor
apraxia,
hypometric
saccades,tubulointerstitialm
edullary
cystickidney
disease,
nephronophthisis,renalfailures
609583
ARJBTS4
NUBPL1
74Mitochondrialcom
plex
Ideficiency
Developm
entaldelay,strabism
us,nystagmus,contractures,spasticity,cognitive
decline
252010
AR/Mi/AD
None
(Continued)
R O S S I E T A L
12 Movement Disorders, Vol. 00, No. 00, 2018
TA
BL
E1.
Co
ntinued
New
desig
natio
nA
ltern
ate
nam
eM
ain
clin
ical
featu
res
OM
IM
Inherita
nce
patt
ern
Lo
cus
sym
bo
l
OPA1
175
Behr
syndromeor
infantile
hereditary
optic
atrophywith
neurologicabnorm
alities
Trem
or,developm
entaldelay,mentalretardation,
optic
atrophy,progressivevisualloss,nystag-
mus,spasticity,pyramidalsigns,myopathy,posteriorcolumnsensoryloss,peripheralneu-
ropathy,tendon
andmuscularcontractures
210000
ARNone
OPA3
176
3-methylglutaconicaciduriatype
IIIor
Costeffsyndrome
Chorea,cognitive
impairm
ent,optic
atrophy,visualloss,cataracts,nystagmus,pyramidalsigns
258501
ARNone
PDHX
orPD
X1177
Lacticacidem
iadueto
PDX1
deficiency
Dystonia,developm
entaldelay,mentalretardation,
microcephaly,optic
atrophy,hypertelorism,
facialdysm
orphism,spastic
quadriplegia,
seizures,lacticor
metabolicacidosis
245349
ARNone
PEX2
178
Peroxisom
ebiogenesisdisorder
5Bor
Zellweger
spectrum
disorders
Trem
or,developm
entaldelay,peripheralneuropathy,pescavus,hypoacusia,slow
saccades,
oculom
otor
apraxia,
nystagmus,retinopathy,strabism
us614867
ARNone
PEX6
25Op
ticatrophy,blindness,cochlear
degeneration,
deafness
271250
ARSC
AR3
PNKP
179-181
Microcephaly,seizures,and
developm
entaldelay
andalle-
licdisorders(eg,
autosomal
recessiveaxonalCharcot-
Marie-Tooth)
Dystonia,developm
entaldelay,mentalretardation,
cognitive
impairm
ent,oculom
otor
apraxia,
tetraplegia,impairedvibrationsense,
peripheralneuropathy,pescavus,hammertoes,distal
muscleweaknessandatrophy,seizures,microcephaly
616267,613402,
605610
ARAO
A4
PNP1
82Purinenucleoside
phosphorylase
deficiencyor
Nucleoside
phosphorylasedeficiency
Trem
or,developm
entaldelay,failure
tothrive,
mentalretardation,
spastic
diplegia,tetraparesis,
behavioraldisorder,autoimmunehemolyticanem
ia,frequentinfections,splenomegaly,
pneumonia
613179
ARNone
POLG
183-186
Allelic
disorders:Mitochondrial
recessiveataxiasyndrome
(MIRAS)or
sensoryataxic
neuropathy,dysarthria,and
ophthalmoparesis(SAN
DO),
Autosomalrecessiveprogres-
sive
externalophthalmoplegia
with
mitochondrialD
NAdele-
tions
type
1andMitochon-
drialD
NAdepletionsyndrome
4A(Alpers-Huttenlochersyn-
drom
e)and4B
(MNG
IEtype)
Myoclonus,parkinsonism
,dystonia,tremor,developm
entaldelay,cognitive
impairm
ent,psychi-
atric
symptom
s,dysarthria,nystagmus,upwardgaze
paresis,blepharoptosis,ophthalmopa-
resis,cataracts,progressiveexternalophthalmoplegia,
optic
atrophy,dyschrom
atopsia,
corticalblindness,migraine,
seizures,peripheralneuropathy,muscleweaknessandatrophy,
hypogonadism
,seizures,stroke-like
episodes,gastroparesis,intestinalpseudo-obstruction,
cardiomyopathy,hepatic
dysfunction
607459,258450,
203700,613662
ARNone
POLR1C
187
Hypomyelinatingleukodystrophy
type
11(allelic
with
Treacher
Collin
ssyndrometype
3)
Trem
or,developm
entaldelay,intellectualdisability,spasticity,myopia,
dentalabnorm
alities,
head
titubation
616494
ARNone
PRF1
188,189
Familialhemophagocytic
lym-
phohistiocytosistype
2and
theallelic
disorder
ofrecur-
rent
immune-mediated
neurodegeneration
Developm
entaldelay,failure
tothrive,
meningitis,encephalitis,hemiplegia,
tetraplegia,seiz-
ures,coma,
pancytopenia,coagulationabnorm
alities,lymphadenopathy,fever,edem
a,liver
dysfunctionNeurodegenerationtriggered
byinfections,recurrentsubacute
post-viralonset
ofataxia,primaryimmunodeficiency
603553,
170280
ARNone
(Continued)
G E N E T I C N O M E N C L A T U R E O F R E C E S S I V E A T A X I A S
Movement Disorders, Vol. 00, No. 00, 2018 13
TA
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New
desig
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nA
ltern
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nam
eM
ain
clin
ical
featu
res
OM
IM
Inherita
nce
patt
ern
Lo
cus
sym
bo
l
PRPS11
90-192
Allelic
disordersor
continuum
with
Artssyndrome,
X-linked
recessiveCharcot-Marie-
Toothdisease-5or
Rosenberg-Chutoriansyn-
drom
eandHyperuricem
ia,
mentalretardationandsenso-
rineuraldeafnesswith
PRPS1
superactivity
Developm
entaldelay,mentalretardation,
poor
grow
th,sensorineuralhearingloss,optic
atro-
phy,retinopathy,nystagmus,muscleweakness,hyperreflexia,peripheralneuropathy,distal
muscleweaknessandatrophy,distalsensoryimpairm
ent,pescavus,flaccidtetraplegia,
immunedeficiency,recurrentrespiratory
tract
infections,uricacidurolithiasis,secondary
renalinsufficiency,gout,goutyarthritis
301835,300661,
311070
XRNone
PRX1
93Distalandproximallower
limbmuscleweaknessandatrophy,peripheralneuropathy,pes
cavus,scoliosis,delayedmotor
developm
ent
614895
ARNone
RARS
194
Trem
or,developm
entaldelay,mentalretardation,
pyramidalsigns,nystagmus,alteredsm
ooth
pursuit,microcephaly
616140
ARNone
RELN
195
Norm
an-Robertstype
ofLissencephaly
Microcephaly,facialdysm
orphism,mentalretardation,
nystagmus,seizures,congenital
lymphedem
a257320
ARNone
ROGD
I196
Kohlschutter-Tonz
syndrome
Developm
entaldelay,mentalretardation,
cognitive
impairm
ent,spasticity,seizures,am
elogen-
esisimperfecta,
enam
elhypoplasia,discolored
teeth
226750
ARNone
RRM2B
197
MitochondrialD
NAdepletion
syndrome8B
(MNG
IEtype)
Failure
tothrive,
lacticacidosis,proximalrenaltubulopathy,seizures,externalophthalmoplegia,
ptosis,gastrointestinaldysm
otility,cachexia,peripheralneuropathy
612075
ARNone
RTN4
IP11
98Op
ticatrophytype
10with
orwithoutataxia,mentalretar-
dation,
andseizures
Mentalretardation,
photophobia,
nystagmus,reducedvisualacuity,colorvision
impairm
entof
red/greenaxis,optic
atrophy,centralscotomaseizures
616732
ARNone
SLC2A1
199
Dystonia,developm
entaldelay,seizures,myoclonicepilepsy,spasticity
606777
AR/AD
None
SLC6A192
00Hartnup
disease
Delayedcognitive
developm
ent,psychiatric
symptom
s,seizures,hypertonia,
light-sensitiveder-
matitis,atrophicglossitis
234500
ARNone
SLC16A22
01Allan-Herndon-Du
dley
syndrome
ormonocarboxylate
trans-
portertype
8deficiency
Dystonia,developm
entaldelay,mentalretardation,
pyramidalsigns,am
yotrophy,behavior
dis-
orders,scoliosis,nystagmus,facialdysm
orphism,microcephaly,pectus
excavatum
300523
XRNone
SLC19A32
02Thiaminemetabolism
dysfunc-
tionsyndrometype
2or
biotin-thiam
ine-responsive
basalgangliadisease
Dystonia,psychomotor
retardation,
encephalopathy,coma,
psychiatric
symptom
s,externaloph-
thalmoplegia,
nystagmus,ptosis,gaze
palsy,seizures,pyramidalsigns,paraparesis,rigidity
607483
ARNone
SLC25A15
203
Hyperornithinem
ia-hyperam
mo-
nemia-hom
ocitrullinuria(HHH
)syndrome
Psychomotor
retardation,
failuresto
thrive,
mentalretardation,
lethargy,episodicconfusion,
acuteencephalopathy,coma,
pyramidalsigns,myoclonicepilepsy,decreasedvibration
sense,
coagulopathy
asaresultof
liver
dysfunction
238970
ARNone
SLC25A46
204
Hereditary
motor
andsensory
neuropathy
type
VIBor
Charcot-Marie-Tooth
disease
type
6B
Myoclonus,delayeddevelopm
ent,optic
atrophy,pyramidalsigns,peripheralneuropathy,distal
sensoryimpairm
ent,pescavus,morphologicalabnorm
alities
616505
ARNone
SLC52A22
05Brow
n-Vialetto-Van
Laeresyn-
drom
etype
2Cranialnerve
palsies,bulbar
palsy,optic
atrophy,nystagmus,visualloss,absent
pupillary
reflex,sensorineuralhearingloss,peripheralneuropathy,muscleweaknessandatrophy,
tongue
fasciculations,psychiatric
symptom
s,claw
hands,scoliosis,respiratory
insufficiency
614707
ARNone
SNOR
D118
206
Leukoencephalopathy,braincal-
cifications,andcysts
Dystonia,tremor,seizures,spasticity,hemiplegia,
cognitive
decline,
pyramidalsigns
614561
ARNone
(Continued)
R O S S I E T A L
14 Movement Disorders, Vol. 00, No. 00, 2018
TA
BL
E1.
Co
ntinued
New
desig
natio
nA
ltern
ate
nam
eM
ain
clin
ical
featu
res
OM
IM
Inherita
nce
patt
ern
Lo
cus
sym
bo
l
SUOX
207
Sulfocysteinuria
orsulfite
oxi-
dase
deficiency
Dystonia,developm
entaldelay,infantile
hemiplegia,
seizures,behavior
disorders,finehair,
eczema,
delayedteething,ectopialentis
272300
ARNone
SURF12
08Peripheralneuropathy,distalmuscleweaknessandatrophy,kyphoscoliosis,nystagmus,senso-
rineuralhearingloss
616684
ARNone
TCTN
1209
Cognitive
impairm
ent,lim
babnorm
alities
614173
ARJBTS13
TCTN
2210
Developm
entaldelay,absent
speech,pyramidalsigns,nystagmus,hyperopia,
polydactyly,tali-
pesequinovarus
616654
ARJBTS24
TCTN
3211
Mentalretardation,
abnorm
aleyemovem
ents,facialdysm
orphism,scoliosis,polydactyly,
camptodactyly,breathinganom
alies,ventricular
septaldefect,horseshoekidney
614815
ARJBTS18
TRAPPC11
212
Limb-girdlemusculardystrophy
type
2SDystonia,chorea,tremor,developm
entaldelay,proximalmuscleweakness,musclecram
ps,
scapular
winging,scoliosis,hipdysplasia,
cataracts,strabism
us,myopia,
microcephaly,
shortstature
615356
ARNone
TRNT
1213
Congenitalsideroblasticanem
iawith
B-cellimmunodeficiency,
periodicfevers,anddevelop-
mentaldelay
Severe
sideroblastic
anem
ia,developm
entaldelay,grow
thretardation,
lacticacidosis,recurrent
fevers,brittlehair,
nephrocalcinosis,cardiomyopathy,retinopathy,sensorineuralhearingloss
seizures
616084
ARNone
VARS
2214
Combinedoxidativephosphory-
lationdeficiencytype
20Developm
entaldelay,ptosis,progressiveexternalophthalmoplegia,
seizures,facialdysm
or-
phism,microcephaly
615917
ARNone
VRK1
215
Psychomotor
retardation,
mentalretardation,
microcephaly,nystagmus,muscleweakness,dis-
talspinalm
uscularatrophy,fasciculations,peripheralneuropathy,hyperreflexia,foot
defor-
mities,skeletalcontractures,arthrogryposis,scoliosis,respiratory
insufficiency
607596
ARNone
WFS12
16Wolfram
syndrome-1or
Diabe-
tesinsipidusandmellitus
with
optic
atrophyand
deafness
Parkinsonism
,tremor,myoclonus,mentalretardationor
dementia,poor
grow
th,optic
atrophy,
retinopathy,ptosis,nystagmus,sensorineuralhearingloss,hyposm
ia,seizures,peripheral
neuropathy,stroke-like
episodes,psychiatric
symptom
s,diabetes
mellitus
anddiabetes
insipidus,hypothyroidism
,hydronephrosis,testicular
atrophy,cardiomiopathy
222300
ARNone
XRCC
4217
Shortstature,
microcephaly,and
endocrinedysfunction
syndrome
Intrauterinegrow
thfailure,developm
entaldelay,cognitive
impairm
ent,apraxia,
pyramidal
signs,peripheralneuropathy,dyslipidem
ia,diabetes
mellitus,hypothyroidism
,anem
ia,acan-
thosisnigricans,cryptorchidism
,renaldysgenesis,malpositionedteeth,
facialdysm
orphism,
shortstature,
microcephaly
616541
ARNone
AR
,auto
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cessiv
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G E N E T I C N O M E N C L A T U R E O F R E C E S S I V E A T A X I A S
Movement Disorders, Vol. 00, No. 00, 2018 15
gene. Recessive cerebellar ataxias have also been clas-sified according to their presumed molecular patho-genesis, such as metabolic alterations, mitochondrialdysfunction, altered calcium signaling, defective DNArepair, abnormal protein folding, and chaperone dys-function.2,8,9 This is a useful approach for ataxiaresearchers and for future therapeutic targeting but isof limited value to clinicians. Last, more recently thefield has begun to refer to recessive ataxias as SCAR’s(for SCA recessive). However, this list is incomplete(only 26 entities so far) and also contains unconfirmedentities, such as SCAR11 (SYT14), SCAR12(WWOX), SCAR19 (SLC9A1), SCAR21 (SCYL1),SCAR22 (VWA3B), SCAR23 (TDP2) and SCAR24(UBA5), which did not meet our criteria to be part ofthe final list (Table 1). Moreover, this SCAR classifica-tion partly parallels and duplicates the ARCA classifi-cation, yet with different numbers. For example,ATX-SYNE1 is dubbed ARCA1 in 1 nomenclaturesystem, but SCAR8 in the other.
A recently conducted systematic review of autoso-mal recessive ataxias conducted by Beaudin and col-leagues10 identified 45 genetically confirmed disordersthat have ataxia as a core feature. An important dif-ference from their approach is that we includedgenetic entities that present with ataxia as part of amore complex phenotype. Recently, the comprehen-sive features of 67 recessively inherited entities thatmay present with ataxia were gathered within aknowledgebase that was the basis of an automatedalgorithm for the diagnosis of recessive cerebellarataxias.11 During the review process of our workinggroup, we have applied strict criteria. In part relatedto this inclusive principle, we encountered classifica-tion difficulties for certain entries, for example, inrelation to the criteria of prominent or consistentataxia. Also, in some cases, it was difficult to distin-guish purely sensory ataxias (eg, the posterior columnataxia with retinitis pigmentosa as a result of muta-tions in the FLVCR1 gene) from disorders that com-bine sensory and cerebellar ataxia, such as Friedreichataxia, ataxia with vitamin E deficiency, or ataxia as aresult of mutations in the MTTP gene (also known asabetalipoproteinemia) or in the POLG gene (sensoryataxic neuropathy, dysarthria, and ophthalmoparesis).If there was a clear cerebellar contribution to the clini-cal manifestation of ataxia, such an entity wasincluded in the final list.
Prefix designation is work in progress, as prefixes maychange over time when further clinical descriptions orcase reports have been published. Also, for the system tobe fully comprehensive, prefixes need to be defined fornonmovement disorder phenotypes. This requires othersubspecialties within neurology and neurogenetics toadopt this system. We specifically designed our systemwith adaptability in mind. This also requires periodic
updating, which is facilitated by the availability of anonline tool, the International Parkinson and MovementDisorder Society genetic mutation database (http://www.mdsgene.org), which is a more suitable medium thanstatic publications of this new genetic nomenclature ofthe recessive cerebellar ataxias. The updated lists willalso be accessible on the Task Forces section of theMDS website (https://www.movementdisorders.org/MDS/About/Committees–Other-Groups/MDS-Task-Forces/Task-Force-on-Nomenclature-in-Movement-Disorders.htm).
We encourage all neurologists, particularly move-ment disorders specialists and pediatric neurologists,and researchers in the field of ataxia to adopt and usethis newly transparent and adaptable nomenclaturesystem of the recessive cerebellar ataxias as it willfacilitate the clinical recognition of numerous recessiveataxias, guide diagnostic testing in ataxia patients, andhelp in interpreting genetic findings.
Acknowledgments: MA, AD, MK, MS and BvW were supported inthe frame of the E-Rare-3 network PREPARE (BMBF 01GM1607) bythe European Union’s Horizon 2020 research and innovation programunder the ERA-NET Cofund action N8 643578.
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