the genetic nomenclature of recessive cerebellar ataxias...the genetic nomenclature of recessive...

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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Movement Disorders, Vol. 00, No. 00, 2018 1

http://orcid.org/0000-0003-3383-8566

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

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http://neuromuscular.wustl.edu/ataxia/recatax.html

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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for

the

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A.Disordersthat

presentwith

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inantor

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feature

ATX-AB

CB71

2Sideroblastic

anem

iawith

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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


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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ities

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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


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


sensorineuraldeafness,intentiontremor,peripheral

neuropathy,seizures,shortstature,

saltcraving,

enuresis,polydipsia,polyuria,electrolyte

imbalance

612780

ARNone

ATX-KIAA0226

41Salih

ataxia

Developm


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


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


recurrentinfections,hirsutism,postaxialpolydactyly,

cysticrenaldisease,facialdysm

orphism,macrocephaly

300804

XRJBTS10

ATX-OP

HN14

9X-linkedmentalretardationwith

cerebellarhypoplasiaanddis-

tinctivefacialappearance

Developm


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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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

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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


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


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


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


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


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


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


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


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


impairm

ent,apraxia,

psychiatric

symptom

s,dysphonia,

nystag-

mus,bradykinesia,dystonia,muscleatrophyandweakness,pyramidalsigns

615157

ARNone

ATX-VLDLR8

2Cerebellarataxia,mentalretar-

dation,

anddysequilibrium

syndrometype

1

Developm


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


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


decline,

nystagmus,tremor,peripheral

neuropathy,sensationdeficits,muscleweaknessandatrophy,jointcontractures

611105

ARNone

ATX/HS

P-FOLR18

7Neurodegenerationas

aresult

ofcerebralfolate

transport

deficiency

Spastic


entalregression,

mentalretardation,

visualdisturbances,senso-

rineuralhearingloss,chorea,generalized

tonic-clonic,atonicandmyoclonicseizures

613068

ARNone

(Continued)



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



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


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



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


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



seizures,macrocephaly,

spasticity

604004

ARNone

(Continued)

R O S S I E T A L


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


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


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


retinopathy,pigm

entedmacular

degenera-

tion,

nystagmus

604360

ARSPG1

1

(Continued)



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


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


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


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


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


pyramidalsigns,esotropia,

exotropia,

strabism

us,

nystagmus,seizures

606854

ARNone

(Continued)



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

HEPACA

M159

Autosomalrecessivemegalen-

cephalicleukoencephalopathy

with

subcorticalcyststype

2A

Developm


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


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


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


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


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


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


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


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


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


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


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)



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

PRPS11

90-192

Allelic

disordersor

continuum

with

Artssyndrome,

X-linked

recessiveCharcot-Marie-

Toothdisease-5or

Rosenberg-Chutoriansyn-

drom

eandHyperuricem

ia,

mentalretardationandsenso-

rineuraldeafnesswith

PRPS1

superactivity

Developm


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


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


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


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


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

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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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the genetic nomenclature of recessive cerebellar ataxias...the genetic nomenclature of recessive...

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