The Cerebellum (2019) 18:1098–1125 https://doi.org/10.1007/s12311-019-01052-2 CONSENSUS PAPER The Classification of Autosomal Recessive Cerebellar Ataxias: a Consensus Statement from the Society for Research on the Cerebellum and Ataxias Task Force Marie Beaudin 1,2 & Antoni Matilla-Dueñas 3 & Bing-Weng Soong 4,5 & Jose Luiz Pedroso 6 & Orlando G. Barsottini 6 & Hiroshi Mitoma 7 & Shoji Tsuji 8,9 & Jeremy D. Schmahmann 10 & Mario Manto 11,12 & Guy A Rouleau 13 & Christopher Klein 14 & Nicolas Dupre 1,2 Published online:: 2 July 2019 # The Author(s) 2019 Abstract There is currently no accepted classification of autosomal recessive cerebellar ataxias, a group of disorders characterized by important genetic heterogeneity and complex phenotypes. The objective of this task force was to build a consensus on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders. The work of this task force was based on a previously published systematic scoping review of the literature that identified autosomal recessive disorders characterized primarily by cerebellar motor dysfunction and cerebellar degeneration. The task force regrouped 12 international ataxia experts who decided on general orientation and specific issues. We identified 59 disorders that are classified as primary autosomal recessive cerebellar ataxias. For each of these disorders, we present geographical and ethnical specificities along with distinctive clinical and imagery features. These primary recessive ataxias were organized in a clinical and a pathophysiological classification, and we present a general clinical approach to the patient presenting with ataxia. We also identified a list of 48 complex multisystem disorders that are associated with ataxia and should be included in the differential diagnosis of autosomal recessive ataxias. This classification is the result of a consensus among a panel of international experts, and it promotes a unified understanding of autosomal recessive cerebellar disorders for clinicians and researchers. Keywords Spinocerebellar degenerations . Cerebellar ataxia . Friedreich ataxia . Ataxia telangiectasia . Genetics . Classification * Nicolas Dupre 6 Ataxia Unit, Department of Neurology, Universidade Federal de São nicolas.dupre@chudequebec.ca Paulo, São Paulo, SP, Brazil 7 1 Medical Education Promotion Center, Tokyo Medical University, Axe Neurosciences, CHU de Québec–Université Laval, Tokyo, Japan Québec, QC, Canada 8 2 The University of Tokyo, Tokyo, Japan Department of Medicine, Faculty of Medicine, Université Laval, 9 Quebec City, QC, Canada International University of Health and Welfare, Chiba, Japan 3 10 Department of Neuroscience, Health Sciences Research Institute Department of Neurology, Massachusetts General Hospital and Germans Trias i Pujol (IGTP), Universitat Autònoma de Barcelona, Harvard Medical School, Boston, MA, USA Badalona, Barcelona, Spain 11 Service de Neurologie, Médiathèque Jean Jacquy, CHU-Charleroi, 4 6000 Charleroi, Belgium Department of Neurology, Shuang Ho Hospital and Taipei Neuroscience Institute, Taipei Medical University, Taipei, Taiwan, 12 Service des Neurosciences, UMons, Mons, Belgium Republic of China 13 5 McGill University, Montreal, QC, Canada National Yang-Ming University School of Medicine, Taipei Veterans 14 General Hospital, Taipei, Taiwan, Republic of China Mayo Clinic, Rochester, MN, USA 1099 Cerebellum (2019) 18:1098 –1125 Introduction mild, found in a minority of patients, or present solely during episodes of metabolic decompensation. Hence, there remains The classification of hereditary ataxias represents a significant a need for a classification system that focuses on disorders challenge due to the large number of neurological and meta- affecting primarily the cerebellum and organizes clinical and bolic diseases that present with cerebellar dysfunction and the paraclinical information to promote an understanding of cer- phenotypic heterogeneity in known genetically defined disor- ebellar disorders useful not only to ataxia experts but also to ders. Indeed, ataxia is a presenting feature in degenerative general neurologists, learners, patients, and researchers. disorders that target mainly the cerebellum, but it may be The objective of this task force was to build a consensus on present in hereditary spastic paraplegias, inborn errors of me- the classification of autosomal recessive ataxias in order to tabolism, and various encephalopathies. Proper classification develop a general approach to a patient presenting with ataxia, and phenotypic understanding is of primary importance in this organize disorders according to clinical presentation, and de- field where the high prevalence of repeat expansion disorders, fine this field of research by identifying common pathophys- which are not adequately covered by the next-generation se- iological mechanisms in recessive disorders presenting with quencing (NGS) techniques [1, 2], precludes NGS as a first ataxia. This aims at bringing together clinicians and re- diagnostic step and requires phenotypic evaluation to perform searchers to promote a common understanding of recessive custom gene testing when applicable. Nevertheless, autoso- cerebellar disorders in order to advance research and improve mal recessive cerebellar ataxias have remained an ill-defined patient care. and disorganized group of disorders for two main reasons. First, unlike the dominant ataxias that have been organized with a numerical naming system, recessive disorders present- ing with ataxia have been named in a highly heterogeneous Materials and Methods manner according to clinical features, physicians’ surname, or regions of high prevalence. Second, several recessive The first step was to identify all recessive disorders presenting multisystemic or complex metabolic disorders present with with ataxia. Recessive cerebellar ataxias were defined as dis- ataxia, such that it is difficult to properly circumscribe this orders with autosomal recessive inheritance characterized by a group of disorders and classify it in a meaningful way for both cerebellar motor syndrome of gait ataxia, dysmetria, clinicians and researchers. Hence, the Society for Research on adiadochokinesia, nystagmus, and dysarthria associated with the Cerebellum and Ataxias (SRCA) Task Force on the cerebellar degeneration as demonstrated by imagery or pathol- Classification of Recessive Cerebellar Ataxias was created in ogy. A pathogenic mutation had to be identified in at least two 2016 to regroup a panel of international ataxia experts in order independent families for a specific gene to be included. Purely to propose a classification relevant to clinical practice and malformative disorders were excluded, and disorders with researchers. As a first step, we undertook a systematic scoping complex phenotypes where ataxia is a secondary or late fea- review of the literature to identify all recessive disorders pre- ture were also excluded. We conducted a systematic scoping senting with ataxia, select those in which cerebellar degener- review of the literature to identify relevant reports. The meth- ation was a core feature, and propose a first classification. This odology and results of this systematic review have been pub- systematic scoping review has been previously published [3] lished previously [3]. In the first publication, this review pro- and served as the basis for the current work. cess had allowed the identification of 2354 records and was Recently, the Movement Disorder Society Task Force on current as of September 2016. The literature search was up- Classification and Nomenclature of Genetic Movement dated and is current as of October 2018. Disorders proposed a revised naming system based on the The second step was to regroup a panel of 12 international gene name associated with a phenotypical prefix. They pre- ataxia experts to create a logical classification system and sented a list of 92 gene-defined recessive disorders associated build a consensus. Ataxia experts were identified from various with ataxia for which this naming system would be applied geographical regions and areas of expertise within the field of and an exhaustive list of disorders that may occasionally pres- ataxias, ensuring proper representation of regional differences ent with ataxia [4]. This represents a useful reference for in- in prevalence and clinical approach to ataxias. Discussions terpretation of NGS results. However, in a significant number spanned over 2 years, included meetings at two SRCA inter- of listed disorders, the cerebellum is only one of the many national conferences, and concerned general orientation, clin- affected organs in multisystemic and metabolic disorders. ical approach, specific disorders, classification issues, and re- For example, maple syrup urine disease, caused by gional specificities. The first author (MB) reviewed identified BCKDHB mutations, and congenital disorders of glycosyla- records for inclusion, extracted clinical, epidemiological, and tion 1a, 1c, and 1q have been included. These disorders are molecular data to build the classifications and wrote the text inborn errors of metabolism characterized by developmental integrating all authors’ input and comments. All authors ap- delay, hypotonia, and metabolic defects, and ataxia is only proved the final manuscript and list of included disorders. Cerebellum (2019) 18:1098 –1125 1100 Results lesions. Electromyography and nerve conduction studies can prove the presence of clinically suspected or subclin- The final list of included autosomal recessive cerebellar ical neuropathy and provide evidence of associated ataxias is presented in Table 1 and includes 59 primary reces- myopathy. sive ataxias, which regroup 15 disorders that are more preva- lent and widely distributed and 44 disorders that are less fre- 2. Following the clinical assessment, one should verify that quent and reported only in certain populations or few families. acquired and treatable causes for ataxia have been exclud- Because ethnic and regional specificities are an essential ele- ed. These include vascular disease, trauma, infection, pri- ment to consider in the appraisal of a patient with a recessive mary or metastatic tumor, excess alcohol consumption, ataxia, areas where the disorder has been reported to date are vitamin deficiency, Creutzfeldt-Jakob disease, and listed. Metabolic or mitochondrial disorders where ataxia is immune-mediated cerebellar ataxias such as multiple scle- only a secondary nonspecific finding in a multisystemic phe- rosis, gluten ataxia, anti-GAD (glutamic acid decarboxyl- notype were excluded, as cerebellar pathology is not central in ase) ataxia, and paraneoplastic cerebellar degenerations. these disorders. However, clinicians must bear in mind that Clinical evaluation should reveal previous exposure to some of these disorders may present with a milder juvenile or toxins or traumatic injuries, along with specific signs adult onset phenotype where cerebellar ataxia may predomi- and symptoms suggestive of infectious, vascular, or met- nate, for example, in Niemann-Pick disease type C, Tay-Sachs astatic disease. Laboratory tests are useful to identify vi- disease, sialic acid storage disorders, congenital disorders of tamin deficiencies or autoimmune conditions. glycosylation, and Zellweger spectrum disorders. As some of Specifically, testing for antibodies involved in these metabolic disorders may benefit from early treatment, paraneoplastic or autoimmune cerebellar degeneration clinicians must keep a high index of suspicion to test for these may be particularly useful for patients with a subacute disorders, and they should be included in large NGS gene progression, older age at onset, and absence of family panels for ataxia. These and other complex disorders that history. The paraneoplastic antibodies most associated may occasionally present with ataxia are presented in with cerebellar degeneration are anti-Yo, anti-Hu, anti- Table 2. This second list is not exhaustive and presents only Tr, and anti-mGluR1 antibodies; the tumors most often the main or most frequent disorders occasionally associated involved are breast and gynecological tumors, Hodgkin with ataxia. Disorders in which the cerebellar phenotype is not lymphoma, and small-cell lung carcinoma [218]. Large clearly established have been excluded. paraneoplastic autoantibody panels are now available and may reduce the delay associated with serial testing. Clinical Approach to a Patient Presenting with Ataxia 3. Once acquired causes have been ruled out, a genetic eti- 1. The first step in evaluating a patient with ataxia is to ology may be considered, especially in the presence of a perform a detailed clinical evaluation that includes a clin- positive family history, early onset, chronic progressive ical history, a family history, a targeted neurological and course, or with a set of clinical signs and symptoms that systemic physical evaluation, and relevant paraclinical is reminiscent of a well-described genetic disorder. One tests. The temporal course is a central element in deter- should bear in mind that a negative family history does mining the underlying etiology. Indeed, a chronic pro- not rule out a genetic cause, and sporadic cases may be gressive evolution over months to years, without trauma due to recessive or mitochondrial inheritance, de novo or toxin exposure, is suggestive of a hereditary disorder, mutations, genetic anticipation, incomplete penetrance, whereas acute or subacute onset points towards an ac- variability in disease expression, paternity error, gonadic quired etiology. A clinical history and physical examina- mosaicism, or incomplete phenotyping of family mem- tion are essential to assess the severity of the cerebellar bers. Indeed, recessive disorders may appear as sporadic syndrome and the presence of associated neurological in small kindred or with incomplete family history. In features or systemic involvement. Headache, fever, or an other cases, a complete family history should allow iden- associated autoimmune disorder should prompt the con- tification of the mode of transmission. sideration of acquired etiologies. A detailed family history should be obtained to search for relatives with similar 4. If autosomal recessive inheritance is suspected, the next symptomatology. Laboratory tests may be useful to rule step in clinical evaluation is to consider age at onset and out acquired causes or as biomarkers for certain disorders. clinical signs and symptoms to evaluate if the clinical Neuroimaging, preferably with magnetic resonance imag- picture is reminiscent of a well-described disorder. ing, is an essential tool to evaluate the presence of cere- Presentation in infancy suggests ataxia telangiectasia or bellar atrophy or signal anomalies, to search for associat- autosomal recessive ataxia of Charlevoix-Saguenay. ed pontine atrophy, and to rule out space-occupying Childhood or teenage onset should raise the suspicion 1101 Cerebellum (2019) 18:1098 –1125 Table 1 Primary autosomal recessive cerebellar ataxias MDS nomenclature1 Alternate nomenclature2 OMIM Geographic specificities Additional clinical clues and References or gene name neuroimaging findings Most prevalent ataxias ATX-FXN FRDA 229300 Most prevalent in populations Bilateral Babinski sign, square-wave [5, 6] of European descent, Middle jerks, scoliosis, hypertrophic East, and North Africa; cardiomyopathy, sensory involvement, absent in Far East teenage onset, spinal cord atrophy, ab- populations sence of cerebellar atrophy ATX-ATM AT 208900 Second most common cause of Telangiectasias, oculomotor apraxia, [7–9] recessive ataxia worldwide, photosensitivity, immunodeficiency, especially in regions with predisposition for cancer, dystonia, low inbreeding myoclonus, choreoathetosis, tremor, elevation of α-fetoprotein, infantile onset, cerebellar atrophy ATX-APTX AOA1/EAOH 208920 Most prevalent in Japan; Oculomotor apraxia, cognitive [10–12] second most prevalent ataxia impairment, axonal motor in Portugal polyneuropathy, late onset of hypoalbuminemia, elevated α-fetoprotein and hypercholesterolemia, childhood onset, cerebellar atrophy ATX-SETX AOA2 606002 Worldwide, second most Axonal sensorimotor polyneuropathy, [13–15] prevalent in Eastern France pyramidal signs, oculomotor apraxia, head tremor, chorea, dystonia, elevation of α-fetoprotein, teenage onset, cerebellar atrophy ATX/HSP-SACS ARSACS 270550 Worldwide Spastic paraparesis, retinal striation with [16, 17] thickened retinal nerve fibers, sensorimotor neuropathy, pes cavus, infantile or childhood onset, anterior superior cerebellar atrophy, occasional T2-weighted linear hypointensities in pons POLG MIRAS, SANDO, SCAE 607459 Prevalent in populations of Cerebellar and sensory ataxia, dysarthria, [18–20] European descent, especially progressive external ophthalmoplegia, Scandinavia, UK, and myoclonus, epilepsy, myopathy, Belgium migraine, variable age at onset, signal abnormalities in the cerebellum and thalamus ATX-SYNE1 ARCA1 610743 Worldwide Pure cerebellar ataxia with occasional [21–23] upper and/or lower motor neuron involvement, cognitive impairment, late onset, cerebellar atrophy HSP/ATX-SPG7 SPG7 607259 Described worldwide, frequent Spasticity, pyramidal signs, optic [24, 25] in Europe neuropathy, ptosis, ophthalmoparesis, bladder dysfunction, adult onset, cerebellar atrophy COQ8A ARCA2 612016 European descent, Algeria, Exercise intolerance, epilepsy, [26, 27] (ATX-ADCK3) Middle East myoclonus, developmental delay, intellectual disability, childhood onset, cerebellar atrophy, occasional stroke-like cerebral lesions ATX-ANO10 ARCA3 613728 European descent, Middle East, Pure cerebellar ataxia with occasional [28–30] West Indies, Japan upper motor neuron signs, cognitive impairment, epilepsy, nystagmus, teenage or adult onset, cerebellar atrophy ATX-TTPA AVED 277460 Worldwide, high prevalence Dorsal column involvement, areflexia, [31–33] around Mediterranean sea retinitis pigmentosa, head titubation, low serum vitamin E, skeletal deformities, teenage onset, spinal cord atrophy, occasional cerebellar atrophy Cerebellum (2019) 18:1098 –1125 1102 Table 1 (continued) MDS nomenclature1 Alternate nomenclature2 OMIM Geographic specificities Additional clinical clues and References or gene name neuroimaging findings ATX-CYP27A1 CTX 213700 Worldwide Dementia, pyramidal signs, epilepsy, [34–36] tendon xanthomas, atherosclerosis, cataracts, diarrhea, elevated serum cholestanol, polyneuropathy, childhood to adult onset, variable cerebellar atrophy, cerebellar or cerebral white matter anomalies ATX-SIL1 MSS 248800 Worldwide Cataracts, intellectual disability, [37, 38] myopathy, short stature, childhood onset, cerebellar atrophy TWNK IOSCA/MTDPS7 271245 Described worldwide, highly Athetosis, sensory axonal neuropathy, [39, 40] (ATX-C10orf2) prevalent in Finland hypotonia, optic atrophy, ophthalmoplegia, sensorineural deafness, epilepsy, hypogonadism, liver involvement, infantile onset, atrophy of the brainstem and cerebellum Rare ataxias or described only in few families ATX-ABHD12 PHARC 612674 Europe, USA, Middle East, Demyelinating sensorimotor neuropathy, [41, 42] Algeria pes cavus, cataracts, hearing loss, retinitis pigmentosa, teenage onset, cerebellar atrophy ATX/HSP-AFG3L2 SPAX5 614487 Colombia, Saudi Arabia Ataxia, spasticity, oculomotor apraxia, [43, 44] myoclonic epilepsy, neuropathy, extrapyramidal involvement, optic atrophy, severe cases with developmental regression, microcephaly, hypsarrhythmia and intractable epilepsy, infantile to childhood onset, cerebellar atrophy ATCAY Cayman ataxia 601238 Grand Cayman Islands, Psychomotor retardation, hypotonia, [45, 46] Pakistan strabismus, bradykinesia, occasional dystonia, neonatal or infantile onset, cerebellar hypoplasia ATX-CA8 CAMRQ3 613227 Iran, Saudi Arabia, Syria Mild intellectual disability, occasional [47, 48] quadrupedal gait, tremor, hyperreflexia, congenital onset, cerebellar atrophy, periventricular white matter anomalies HSP/ATX-CAPN1 SPG76 616907 Europe, Middle East, Brazil, Pyramidal signs, pes cavus, dysarthria, [49, 50] Japan, Punjab ataxia, slow saccades, cognitive impairment, teenage to adult onset, cerebellar vermian atrophy HSP/ATX-CLCN2 Leucoencephalopathy 615651 Europe, North Africa, Turkey, Chorioretinopathy, optic neuropathy, [51, 52] with ataxia Japan learning disability, headaches, occasional mild spasticity, childhood to adult onset, T2 hypersignal in cerebellar and cerebral peduncles with internal capsule, myelin microvacuolation COA7 MC4D, SCAN3 220110 Italy, Japan Sensorimotor neuropathy, hyporeflexia, [53, 54] mild cognitive impairment, elevated serum creatine kinase, elevated lactate and pyruvate, ragged red fibers, infantile to childhood onset, cerebellar atrophy, supratentorial leucopathy, spinal cord atrophy ATX-COX20 Mitochondrial complex 220110 Turkey Growth retardation, pyramidal signs, [55, 56] IV deficiency sensory neuropathy, extrapyramidal 1103 Cerebellum (2019) 18:1098 –1125 Table 1 (continued) MDS nomenclature1 Alternate nomenclature2 OMIM Geographic specificities Additional clinical clues and References or gene name neuroimaging findings features, elevation of blood lactate, childhood or teenage onset, cerebellar atrophy ATX-CWF19L1 SCAR17 616127 Turkey, Netherlands Intellectual disability, congenital to [57, 58] infantile onset, cerebellar atrophy HSP/ATX-CYP7B1 SPG5A 270800 Worldwide, prevalent in Pyramidal signs, dorsal column sensory [59, 60] Europe deficits, urge incontinence or voiding, childhood or teenage onset, white matter lesions ATX/HSP-DARS2 LBSL 611105 Worldwide, high carrier rate in Pyramidal signs, dorsal column [61, 62] Finland dysfunction, axonal neuropathy, tremor, cerebral lactic acidosis, seizures, infantile to adult onset, signal abnormalities in cerebral white matter and specific brainstem and spinal cord tracts ATX-DNAJC19 DCMA/MGCA5 610198 Canadian Hutterite population, Dilated cardiomyopathy, nonprogressive [63–65] Finland, Turkey cerebellar ataxia, intellectual disability, testicular dysgenesis, anemia, increased urinary 3-methylglutaconic acid, infantile onset, progressive cere- bellar atrophy HSP/ATX-GBA2 SPG46 614409 Tunisia, Cyprus, Italy, Norway Pyramidal signs, spastic dysarthria, [66, 67] cognitive impairment, hearing loss, cataracts, urge incontinence, axonal sensorimotor neuropathy, childhood onset, cerebellar and cerebral atrophy, thin corpus callosum GDAP2 – – Belgium, Dutchland, Egypt Pyramidal signs, cognitive impairment, [68] adult onset, cerebellar atrophy ATX/HSP-GJC2 HLD2 or 608804 Worldwide Nystagmus, hypotonia progressing to [69, 70] Pelizaeus-Merzbacher-l- spastic tetraparesis, developmental ike disease delay, dystonia, chorea, neonatal to infantile onset, diffuse hypomyelination MYC/ATX-GOSR2 Progressive myoclonic 614018 North Sea region Areflexia, myoclonic seizures, scoliosis, [71, 72] epilepsy 6 late cognitive impairment, axonal sensory neuropathy and anterior horn cell involvement, raised creatine kinase, infantile onset, occasional cerebellar atrophy ATX-GRID2 SCAR18 616204 Middle East, Mexico, Morocco Tonic upgaze, vertical nystagmus, [73, 74] oculomotor apraxia, intellectual disability, developmental delay, hypotonia, infantile onset, cerebellar atrophy; possible autosomal dominant transmission GRM1 SCAR13 614831 Roma ethnic group in Bulgaria Developmental delay, intellectual [75, 76] disability, occasional pyramidal signs, short stature, seizures, congenital onset, cerebellar atrophy; allelic with SCA44 ATX-GRN CLN11 614706 Italy, Portugal, Brazil Myoclonic epilepsy, retinopathy, [77, 78] dementia, adult onset, cerebellar atrophy ATX-ITPR1 Gillespie syndrome 206700 Brazil, Europe, North Africa, Autosomal recessive and dominant [79, 80] Middle East, Asia, transmission. Nonprogressive Caribbean Islands cerebellar ataxia, iris hypoplasia, hypotonia, intellectual disability, facial dysmorphism, neonatal onset, progressive cerebellar atrophy; allelic with SCA15 and SCA29 Cerebellum (2019) 18:1098 –1125 1104 Table 1 (continued) MDS nomenclature1 Alternate nomenclature2 OMIM Geographic specificities Additional clinical clues and References or gene name neuroimaging findings HSP/ATX-KIF1C SPAX2/SPG58 611302 Palestine, Morocco, Turkey, Spastic paraparesis with pyramidal signs, [81, 82] Germany tremor, childhood or teenage onset, T2 hyperintensity in internal capsules, parietal and occipital white matter, cerebellar peduncles, and pyramidal tracts ATX-KCNJ10 EAST/SeSAME 612780 Africa, Middle East, India, Epilepsy, sensorineural deafness, [83–85] syndrome Caucasian, Afro-Caribbean intellectual disability, tubulopathy and population electrolyte imbalance, hypotonia progressing to spasticity, infantile onset, cerebellar hypoplasia, signal anomaly in dentate nuclei ATX-L2HGDH L-2-hydroxyglutaric 236792 Worldwide Developmental delay, macrocephaly, [86, 87] aciduria hypotonia, elevated levels of L-2-hydroxyglutaric acid, infantile to adult onset, subcortical white matter, dentate nucleus and basal ganglia sig- nal anomalies, cerebellar atrophy ATX-MRE11A ATLD 604391 Described in Europe, Saudi Oculomotor apraxia, extrapyramidal [88, 89] Arabia, Canada, Pakistan movement disorders, occasional and Japan myoclonus, childhood onset, cerebellar atrophy MTPAP SPAX4 613672 Amish families Pyramidal signs, optic atrophy, sensibility [90, 91] to ionizing radiations, developmental delay, cognitive impairment, growth failure, infantile onset ATX-PEX10 PBD 6B or ZSD 614871 Caucasians, Japan Axonal motor or sensorimotor [92, 93] neuropathy, variable cognitive impairment, nystagmus, hypo or hyperreflexia, childhood to adolescent onset, cerebellar atrophy ATX-PMPCA SCAR2 213200 Lebanon, France, French Intellectual disability, hypotonia, short [94–96] Canadians stature, severe phenotype with lactic academia and ophthalmoplegia, congenital or infantile onset, cerebellar atrophy PNKP AOA4 616267 European descent Dystonia, oculomotor apraxia, [97–99] sensorimotor polyneuropathy, cognitive impairment, childhood onset, cerebellar atrophy ATX/HSP-PNPLA6 BNS/GHS/OMCS 215470, Worldwide Hypogonadotropic hypogonadism, [100, 101] 2754- chorioretinal dystrophy, pyramidal 00 signs, childhood onset, atrophy of the cerebellum and pons; allelic to HSP39 ATX/HSP-POLR3A HLD7, 4H syndrome 607694 Worldwide Tremor, variable cognitive impairment, [102, 103] spasticity, hyperreflexia, variable hypodontia and dysmorphism, hypogonadotropic hypogonadism, myopia, short stature, infantile to childhood onset, diffuse cerebral hypomyelination, cerebellar atrophy, thin corpus callosum, T2 hypointense thalamus ATX-POLR3B HLD8 614381 Japan, Caucasians, Syria, Intellectual disability, vertical gaze [104, 105] African American, limitation, hypodontia, Mediterranean hypogonadotropic hypogonadism, myopia, mild hyperreflexia, short stature, infantile to childhood onset, diffuse cerebral hypomyelination with partly myelinated internal capsule, 1105 Cerebellum (2019) 18:1098 –1125 Table 1 (continued) MDS nomenclature1 Alternate nomenclature2 OMIM Geographic specificities Additional clinical clues and References or gene name neuroimaging findings cerebellar atrophy, thin corpus callosum, T2 hypointense thalamus ATX-RNF216 Ataxia and 212840 Middle East, Caucasians Hypogonadotropic hypogonadism, [106, 107] hypogonadotropism/- dementia, occasional chorea, GHS childhood to young adult onset, cerebellar atrophy, cerebral white matter anomalies SCYL1 SCAR21 616719 European, Middle East, Cuba, Transient episodes of liver failure, [108, 109] Ashkenazi Jews intention tremor, peripheral sensorimotor neuropathy, mild cognitive impairment, occasional short stature, infantile to childhood onset, cerebellar vermis atrophy ATX-SNX14 SCAR20 616354 Portugal, Middle East, North Intellectual disability, developmental [110, 111] Africa, Central Asia delay, macrocephaly, dysmorphism, hypotonia, skeletal anomalies, occasional sensorineural hearing loss, infantile onset, cerebellar atrophy SLC9A1 LIKNS/SCAR19 616291 Turkey, Han Chinese Occasional sensorineural hearing loss, [112, 113] mild psychomotor delay, infantile to childhood onset, progressive cerebellar atrophy ATX-SPTBN2 SCAR14/SPARCA1 615386 Middle East, Egypt, North Cognitive impairment, developmental [114, 115] America delay, nystagmus, hypotonia, occasional tremor, infantile to childhood onset, cerebellar atrophy; allelic to SCA5 ATX-STUB1 SCAR16 615768 China, Middle East, Caucasians Pyramidal signs, variable cognitive [116, 117] impairment, occasional hypogonadism, variable age at onset, cerebellar atrophy; allelic to SCA48 TDP2 SCAR23 616949 Ireland, USA Seizures, developmental delay, [118, 119] dysmorphism, hypotonia, hypersomnia, failure to thrive, infantile to childhood onset, absence of cerebellar atrophy ATX-TPP1 SCAR7 609270 The Netherlands, African Occasional pyramidal signs, posterior [120, 121] American population column involvement, tremor, square-wave jerks, nystagmus, child- hood to adolescent onset, pontocerebellar atrophy; allelic to CLN2 HSP/ATX-UCHL1 SPG79 615491 Norway, Turkey Optic atrophy, nystagmus, intention [122, 123] tremor, pyramidal signs, dorsal column involvement, mild cognitive impairment, childhood onset, cerebellar atrophy ATX-VLDLR CAMRQ1/DES 224050 North American Hutterite Nonprogressive cerebellar ataxia, [124, 125] population, Middle East, moderate to severe intellectual Europe disability, hypotonia, strabismus, delayed ambulation with occasional quadripedal gait, seizures, congenital to infantile onset, inferior cerebellar hypoplasia, pontine hypoplasia, cortical gyral simplification VPS13D SCAR4 607317 Europe, USA, French Pyramidal signs, axial hypotonia, [126, 127] Canadian, Egyptian, oculomotor abnormalities, chorea or Javanese dystonia, cognitive impairment, infantile to adult onset, cerebellar atrophy, basal ganglia T2/F hyperintensity Cerebellum (2019) 18:1098 –1125 1106 Table 1 (continued) MDS nomenclature1 Alternate nomenclature2 OMIM Geographic specificities Additional clinical clues and References or gene name neuroimaging findings ATX-WDR81 CAMRQ2/DES2 610185 Turkey, Yemen Occasional quadrupedal gait, intellectual [128, 129] disability, congenital onset, cerebellar hypoplasia; allelic with Congenital hydrocephalus type 3 with brain anomalies XRCC1 SCAR26 617633 India, Pakistan Oculomotor apraxia with nystagmus, [130, 131] peripheral sensorimotor axonal neuropathy, cognitive impairment, childhood to adult onset, progressive cerebellar atrophy In part inspired from [3] 1 MDS nomenclature: nomenclature proposed by the Movement Disorder Society Task Force on Classification and Nomenclature of Genetic Movement Disorders [4] with a phenotypical prefix followed by the gene name. ATX ataxia, HSP hereditary spastic paraplegia, MYC myoclonus 2 AOA ataxia with oculomotor apraxia, ARCA autosomal recessive cerebellar ataxia, ARSACS autosomal recessive spastic ataxia of Charlevoix- Saguenay, AT ataxia telangiectasia, ATLD ataxia telangiectasia-like disorder, AVED ataxia with vitamin E deficiency, BNS Boucher-Neuhäuser syn- drome, CA Cayman ataxia, CAMRQ cerebellar ataxia mental retardation with or without quadrupedal locomotion, DCMA dilated cardiomyopathy with ataxia, DES disequilibrium syndrome, EAOH early-onset ataxia with oculomotor apraxia and hypoalbuminemia, FRDA Friedreich ataxia, GHS Gordon Holmes syndrome, HLD hypomyelinating leukodystrophy, IOSCA infantile onset spinocerebellar ataxia, LIKNS Lichtenstein-Knorr syndrome, MGCA5 3-methyglutaconic aciduria type 5, MIRAS mitochondrial recessive ataxia syndrome, MC4D mitochondrial complex 4 deficiency, MSS Marinesco- Sjogren syndrome, MTDPS7 mitochondrial DNA depletion syndrome 7, NBIA neurodegeneration with brain iron accumulation, OMCS Oliver McFarlane syndrome, PBD peroxisome biogenesis disorder, PEOA3 progressive external ophthalmoplegia with mitochondrial DNA deletions, auto- somal dominant 3, PHARC polyneuropathy hearing loss ataxia retinitis pigmentosa and cataract, SANDO sensory ataxic neuropathy with dysarthria and ophthalmoparesis, SCAE spinocerebellar ataxia with epilepsy, SCAN1 spinocerebellar ataxia with axonal neuropathy 1, SCAR spinocerebellar ataxia autosomal recessive, SeSAME seizures sensorineural deafness ataxia mental retardation and electrolyte imbalance, SPAX spastic ataxia, SPG spastic paraplegia, UMN upper motor neuron, ZSD Zellweger spectrum disorder for Friedreich ataxia, ataxia with oculomotor apraxia 1 towards a particular diagnosis. Some clinical syndromes and 2, and POLG-related disorders. Finally, recessive are particularly evocative of specific disorders. ataxia with onset in adulthood is evocative of autosomal Multisystemic involvement with sensory loss, muscle recessive cerebellar ataxia 1 and 3 and spastic paraplegia weakness, cardiomyopathy, diabetes, optic atrophy, and 7. However, there are large variations in the age at onset of sensorineuronal hearing loss is characteristic of most of the presented disorders, and Friedreich ataxia is Friedreich ataxia, which is the prototype of a disorder one of the best examples with some patients presenting associated with mitochondrial dysfunction. Other associ- with late-onset (> 25 years of age) or very-late-onset ated disorders present with similar features and occasion- Friedreich ataxia (> 40 years of age). Clinical signs and ally epilepsy, retinal involvement, or ophthalmoplegia, symptoms may provide clues to identify the mutated such as POLG-related disorders, autosomal recessive cer- gene. Indeed, certain discriminating clinical features or ebellar ataxia 2, and Marinesco-Sjogren syndrome. combinations of neurological symptoms may be helpful Extrapyramidal involvement with oculomotor apraxia, el- to guide the clinician towards specific genes (Fig. 1 and evated α-fetoprotein, and occasional polyneuropathy are Table 1). As one may observe in Fig. 1, none of the auto- typical findings of ataxia telangiectasia, ataxia somal recessive ataxias reported up to now presents with a telangiectasia-like disorder, spinocerebellar ataxia reces- pure cerebellar phenotype. Even SYNE1-related autoso- sive 26, and ataxia with oculomotor apraxia types 1, 2, mal recessive cerebellar ataxia 1, which used to be the and 4. Nevertheless, autosomal recessive ataxias are char- prototype of a pure cerebellar phenotype [21], has recent- acterized by important phenotypic variability and signifi- ly been reported to be associated with upper and/or lower cant clinical overlap between different pathologies, such motor neuron involvement in 58% of cases, with some that predicting the mutated gene according to the clinical rare patients presenting with a very severe early-onset phenotype is prone to errors even for ataxia experts [219]. neuromuscular phenotype [22]. The presence of motor Some laboratory tests may serve as useful biomarkers for neuron involvement, polyneuropathy, extrapyramidal recessive ataxias. Altered levels of vitamin E, α-fetopro- movement disorders, eye movement abnormalities such tein, albumin, coenzyme Q10, cholesterol, cholestanol, as oculomotor apraxia, intellectual impairment, and asso- lactate, sex hormones, and gonadotropins have been asso- ciated multisystemic involvement may guide the clinician ciated with specific disorders (see Table 1). Dosing of 1107 Cerebellum (2019) 18:1098 –1125 Table 2 Other metabolic or complex autosomal recessive disorders that have ataxia as an associated feature MDS nomenclature1 or gene Alternate nomenclature2 OMIM Additional clinical clues References name ATX-AHI1 Joubert syndrome Many, Developmental delay, ataxia, hypotonia, neonatal breathing [132, 133] ATX-ARL13B (including COACH see abnormalities, intellectual disability, nephronophthisis, ATX-CEP290 syndrome) 213- congenital onset, agenesis of the cerebellar vermis with molar ATX-CC2D2A 300 tooth sign; in COACH syndrome, associated with ocular ATX-OFD1 colobomas and hepatic fibrosis ATX-TMEM231 ATX-TMEM67 ATX-RPGRIP1L Others ATX-ALDH5A1 Succinic semialdehyde 603147 Developmental delay, intellectual disability, language dysfunction, [134, 135] dehydrogenase hypotonia, hyporeflexia, autistic behavior and hallucinations, deficiency infantile to childhood onset, T2 hypersignal in globi pallidi ATX-ALG6 CDG1c 603147 Developmental delay, hypotonia, seizures, protein-losing [136, 137] enteropathy, psychiatric manifestations, nystagmus, strabismus, failure to thrive, dysmorphic features, neonatal to infantile onset, occasional brain atrophy DYT/ATX-ATP7B Wilson disease 277900 Tremor, dystonia, parkinsonism, choreoathetosis, liver disease, [138] psychiatric involvement, Kayser-Fleischer rings, childhood to adult onset, T2 hypersignal in basal ganglia or brainstem ATP8A2 CAMRQ4 615268 Global development delay, cognitive impairment, microcephaly, [139, 140] ataxia or quadrupedal gait, choreoathetoid movement, congenital onset, cerebellar and cerebral atrophy or delay in myelination HSP/ATX-B4GALNT1 SPG26 609195 Pyramidal signs, amyotrophy, progressive hyporeflexia, cognitive [141] impairment, axonal peripheral neuropathy, occasional cerebellar ataxia and extrapyramidal signs, scoliosis, childhood to teenage onset, cerebral cortical atrophy, T2/F white matter hyperintensity ATX-BTD Biotinidase deficiency 253260 Seizures, hypotonia, developmental delay, optic atrophy, [142, 143] sensorineural hearing loss, skin rash, alopecia, hepatosplenomegaly, optic atrophy, exacerbation during infections, infantile to childhood onset, white matter anomalies including delayed demyelination MYC-CLN5 CLN 256731 Myoclonic epilepsy, psychomotor retardation or regression, ataxia, [144] visual loss, ataxia, infantile to adult onset, cerebellar and cortical atrophy NBIA/DYT/PARK-CP Aceruloplasminemia 604290 Diabetes, dementia, parkinsonism, dystonia, cerebellar ataxia, [145] retinal degeneration, involuntary movements, anemia, low serum and urinary copper, adult onset, decreased signal intensity in thalamus, basal ganglia and dentate nucleus MYC/ATX-CSTB1 Unverricht and Lundborg 254800 Stimulus-sensitive and action-sensitive myoclonus, tonic-clonic [146] disease/EPM1 generalized seizures, mild cerebellar ataxia, cognitive impairment, emotional lability, childhood to adolescent onset, normal brain MRI EIF2B1, EIF2B2, Vanishing white matter 603896 Cerebellar ataxia with spasticity, clinical deterioration following [147, 148] EIF2B3, EIF2B4, disease head trauma, febrile illness or surgery, infantile to adult onset, EIF2B5 symmetric and diffusely abnormal cerebral white matter that appears isointense to CSF MYC/ATX-EPM2A Lafora disease 607566 Myoclonus, generalized tonic-clonic seizures, occipital seizures, [149, 150] MYC/ATX-NHLRC1 headaches, behavioral deterioration, rapidly progressive dementia, cerebellar ataxia, spasticity, adolescent onset, normal initial brain MRI with progressive diffuse atrophy ERCC4 Xeroderma 278760 Photosensitivity, solar lentigine growth retardation, microcephaly, [151, 152] pigmentosum/Cockayne ataxia, chorea, cognitive impairment, adolescent to adult onset, syndrome cerebellar and brainstem atrophy HSP/ATX/NBIA-FA2H SPG35/FAHN 612319 Spastic paraparesis, pyramidal signs, dystonia, ataxia, dysarthria, [153] optic atrophy, seizures, cognitive impairment, childhood to adolescent onset, T2 subcortical and periventricular white matter hyperintensity, atrophy of the cerebellum and brainstem ATX/HSP-FOLR1 Neurodegeneration due to 613068 Developmental regression, hypotonia, myoclonic, tonic or astatic [154, 155] cerebral folate transport seizures, cerebellar ataxia, chorea, tremor, autism spectrum deficiency disorder, occasional pyramidal signs, infantile onset, delayed myelination in cerebral white matter, cerebellar atrophy Cerebellum (2019) 18:1098 –1125 1108 Table 2 (continued) MDS nomenclature1 or gene Alternate nomenclature2 OMIM Additional clinical clues References name HSP/ATX-GAN1 Giant axonal neuropathy 1 256850 Peripheral sensorimotor neuropathy, weakness, amyotrophy, [156, 157] areflexia, pes cavus, typical frizzly hair, ataxia, nystagmus, pyramidal signs, seizures, cognitive impairment, childhood onset, cerebellar or cerebral white matter T2 hypersignal DYT/PARK-GLB1 GM1 gangliosidosis type II 230600 Developmental regression in childhood with gait disorder and [158, 159] cognitive impairment, dystonia, hepatosplenomegaly, ataxia, skeletal dysplasia, cardiomyopathy, infantile to childhood onset, progressive diffuse brain atrophy ATX/HSP-HEXA Tay-Sachs disease 272800 Infantile form with weakness, motor regression, startle reaction, [160, 161] myoclonic jerks, decreased attentiveness, cherry red spots, dementia, blindness. Juvenile form with ataxia, dysarthria, incoordination; adult form with ALS-like symptomatology ATX/HSP-HEXB Sandhoff disease 268800 Similar to Tay-Sachs with organomegaly [162] HSD17B4 Perreault syndrome1, 233400 Sensorineural hearing loss, ovarian dysfunction, ataxia, dysarthria, [163, 164] D-bifunctional protein dysmetria, hyperreflexia, cognitive impairment, sensory deficiency neuropathy, childhood onset, cerebellar atrophy HSP-KIAA1840 SPG11 604360 Spasticity, ataxia, cognitive impairment, sensorimotor neuropathy, [165, 166] childhood or teenage onset, thin corpus callosum, signal abnormalities in cervical cord MYC/ATX-KCTD7 EPM3/CLN14 611726 Multifocal myoclonic seizures, status myoclonus, motor and [167, 168] language regression, intellectual disability, cerebellar ataxia, infantile onset, diffuse cerebral and cerebellar atrophy, T2 periventricular white matter hyperintensity ATX-MAN2B1 Alpha-mannosidosis 248500 Dysmorphism, skeletal abnormalities, visceromegaly, sensorineural [169] hearing loss, immunodeficiency, cognitive impairment, psychosis, ataxia, prenatal to adult onset, cerebellar atrophy, partially empty sella turcica, white matter abnormalities HSP/ATX-MLC1 Megalencephalic 604004 Macrocephaly, initial radiological-clinical discrepancy, eventual [170] leukoencephalopathy motor regression, ataxia, spasticity, epilepsy, cognitive decline, with subcortical cysts infantile onset, diffuse supratentorial white matter signal anoma- lies ATX-MSTO1 MMYAT 617619 Myalgia, proximal muscle weakness, psychiatric manifestations, [171, 172] developmental delay, tremor, dysmetria, pigmentary retinopathy, growth retardation, neonatal to childhood onset, cerebellar atrophy MTTP Abetalipoproteinemia 200100 Fat malabsorption symptoms, hypocholesterolemia, [173] hypotriglyceridemia, acanthocytosis, sensory loss, hyporeflexia, ataxia, neonatal onset, absence of cerebellar atrophy MYC/ATX-NEU1 Neuraminidase deficiency 256550 Myoclonic epilepsy, visual impairment, cherry red spots, ataxia, [174, 175] or sialidosis type I and II hyperreflexia, severe phenotype with dysmorphic features, dysostosis multiplex, hepatomegaly, developmental delay, increased urinary bound sialic acid, variable age at onset, diffuse cerebellar and cerebral atrophy NKX6-2 SPAX8 with 617560 Nystagmus, developmental delay, hypotonia followed by rapidly [176, 177] hypomyelinating progressive spasticity, weakness, dystonia, dysphagia, ataxia, leukodystrophy visual impairment, infantile to childhood onset, brain hypomyelination, occasional cerebellar atrophy ATX-NPC1 Niemann-Pick type C 257220 Vertical supranuclear ophthalmoplegia, gelastic cataplexy, [178–180] ATX-NPC2 607625 premature cognitive decline, dystonia, hepatosplenomegaly, respiratory failure, seizures, psychiatric features, neonatal to adult onset, variable cerebellar or cerebral atrophy OPA1 Behr syndrome 210000 Optic atrophy, pyramidal signs, sensorimotor peripheral neuropathy, [181, 182] cerebellar ataxia, developmental delay, gastrointestinal symptoms, infantile or childhood onset, cerebellar atrophy; allelic to dominant optic atrophy 1 PEX2 PBD5B/Zellweger 614867 Hypotonia, seizures, inability to feed, ataxia, hyporeflexia, slow [183, 184] spectrum disorder saccades, sensorimotor neuropathy, childhood to adult onset, cerebellar atrophy ATX-PEX7 PBD9B 614879 Retinitis pigmentosa, polyneuropathy, ataxia, anosmia, pes cavus, [185] skeletal abnormalities, ichthyosis, hearing loss, cataracts, 1109 Cerebellum (2019) 18:1098 –1125 Table 2 (continued) MDS nomenclature1 or gene Alternate nomenclature2 OMIM Additional clinical clues References name cardiomyopathy, elevated phytanic acid, childhood or teenage onset, absence of cerebellar atrophy ATX-PHYH Refsum disease 266500 Retinitis pigmentosa, polyneuropathy, increased CSF protein, [186] anosmia, sensorineural hearing loss, ichthyosis, ataxia, teenage onset, elevated serum phytanic acid, absence of cerebellar atrophy NBIA/DYT/PARK-PLA2G6 NBIA 2A 256600 Psychomotor retardation or regression, hypotonia followed by [187, 188] spastic quadriparesis, ataxia, strabismus, nystagmus, infantile to teenage onset, cerebellar atrophy and variable iron accumulation in globi pallidi with associated T2 hypointensity ATX-PMM2 CDG 1a 212065 Intellectual disability, axial hypotonia, visceral involvement with [189, 190] feeding difficulties and cardiac involvement, dysmorphic features, cerebellar ataxia, strabismus, peripheral neuropathy, retinitis pigmentosa, skeletal abnormalities, infantile to adult onset, cerebellar hypoplasia or atrophy PxMD/DYT/ATX-PRRT2 Episodic kinesigenic 614386 Seizures, paroxysmal nonkinesigenic dyskinesia, paroxysmal [191, 192] dyskinesia 1 vertigo, episodic ataxia, hemiplegic migraine, rare progressive ataxia, infantile to childhood onset, occasional cerebellar atrophy ATX-PTRH2 IMNEPD 616263 Developmental delay, intellectual disability, hypotonia, muscular [193, 194] weakness, demyelinating sensorimotor neuropathy, dysmorphism, ataxia, microcephaly, growth retardation, sensorineural deafness, pancreatic insufficiency, infantile onset, variable cerebellar atrophy SEPSECS PCH 2D 613811 Developmental delay, intellectual disability, hypotonia, nystagmus, [195, 196] microcephaly, seizure, ataxia, spasticity, chorea, congenital to infantile onset, cerebellar and cerebral atrophy, thinning of corpus callosum ATX-SLC17A5 Sialic acid storage diseases 604369 Severe neonatal phenotype with ascites, failure to thrive and early [197–199] 269920 death. Milder infantile phenotype with hypotonia, cerebellar ataxia and intellectual disability, infantile to adult onset, hypomyelination, cerebellar atrophy SLC2A1 GLUT1 deficiency 606777 Epileptic encephalopathy, psychomotor retardation, hypotonia, [200, 201] dystonia, microcephaly, ataxia, spasticity, seizures, infantile onset, absence of cerebellar atrophy ATX-SLC52A2 SCAR3/BVVLS2 271250 Sensorimotor neuropathy, optic atrophy, blindness, sensorineural [202–204] 614707 hearing loss, respiratory insufficiency, bulbar involvement, childhood onset, absence of cerebellar atrophy; ataxia is on a spectrum between Brown-Vialetto-Van Laere syndrome type 2 and SCAR3 SLC6A19 Hartnup disorder 234500 Transient manifestations of pellagra, cerebellar ataxia, psychosis, [205] nystagmus and ophthalmoparesis, cognitive impairment, amino aciduria, early onset SLC25A46 CMT6B 616505 Optic atrophy, blindness, severe sensorimotor neuropathy, [206, 207] hyporeflexia, amyotrophy, pes cavus, sensory loss in lower limbs, sensitive and cerebellar ataxia, nystagmus, divergent strabismus, neonatal to childhood onset, cerebellar and brain atrophy, T2 hyperintensity in cerebellar white matter ATX-SRD5A3 CDG 1q 612379 Hypotonia, intellectual disability, optic nerve atrophy, nystagmus, [208, 209] ocular colobomas, ichthyosis, palmoplantar keratodermia, mild ataxia, congenital to childhood onset, cerebellar vermis hypoplasia ATX-TTC19 MC3DN2 615157 Muscular hypotonia progressing to spasticity, developmental delay, [210–212] neurological regression with loss of language and ambulation, cognitive regression, rapid evolution, axonal motor neuropathy, psychiatric features, infantile to adult onset, cerebral and cerebellar atrophy, T2 hypersignal in basal ganglia, bilateral inferior olive involvement ATX-WDR73 GMS/SCAR5 251300 Intellectual disability, nephrotic syndrome, microcephaly, [213, 214] hypotonia, epilepsy, optic atrophy, skin abnormalities, infantile to childhood onset, cerebellar and cerebral atrophy WFS1 Wolfram syndrome 222300 [215] Cerebellum (2019) 18:1098 –1125 1110 Table 2 (continued) MDS nomenclature1 or gene Alternate nomenclature2 OMIM Additional clinical clues References name Diabetes mellitus, optic atrophy, diabetes insipidus, deafness, renal abnormalities, ataxia, intellectual disability, psychiatric features, childhood to adolescent onset, generalized brain and cerebellar atrophy WWOX SCAR12 614322 Tonic-clonic epilepsy, intellectual disability, spasticity, neonatal to [216, 217] childhood onset, variable cerebellar or cerebral atrophy, phenotypic spectrum with infantile epileptic encephalopathy associated with psychomotor retardation and growth retardation 1 MDS nomenclature: nomenclature proposed by the Movement Disorder Society Task Force on Classification and Nomenclature of Genetic Movement Disorders [4] with a phenotypical prefix followed by the gene name. ATX ataxia, DYT dystonia, HSP hereditary spastic paraplegia, MYC myoclonus, NBIA neurodegeneration with brain iron accumulation, PARK Parkinsonism 2 ALS amyotrophic lateral sclerosis, BVVLS2 Brown-Vialetto-Van Laere syndrome type 2, CAMRQ cerebellar ataxia mental retardation with or without quadrupedal locomotion, CDG congenital disorder of glycosylation, CLN neuronal ceroid lipofuscinosis, CMT Charcot-Marie-Tooth, COACH cerebel- lar vermis hypoplasia, oligophrenia, congenital ataxia, ocular coloboma, and hepatic fibrosis, EPM progressive myoclonic epilepsy, FAHN fatty acid hydroxylase-associated neurodegeneration, GMS Galloway-Mowat syndrome, IMNEPD infantile-onset multisystem neurologic, endocrine, and pan- creatic disease, MC3DN2 mitochondrial complex III deficiency, nuclear type 2, MMYAT mitochondrial myopathy and ataxia, NBIA neurodegeneration with brain iron accumulation, PBD peroxisome biogenesis disorder, PCH pontocerebellar hypoplasia, SCAR spinocerebellar ataxia autosomal recessive, SPAX spastic ataxia, SPG spastic paraplegia immunoglobulins, very long chain fatty acids, and hexos- sequencing, or whole genome sequencing. Several studies aminidase may be relevant according to clinical suspicion. have demonstrated the efficacy and cost efficiency of multigene panels [220], targeted exome sequencing 5. Once the clinical assessment is complete, genetic test- [219, 221], or whole exome sequencing [222, 223], with ing is indicated to confirm the mutated gene or allow a a diagnostic yield varying between 18 and 80%. The more specific diagnosis if the clinical picture is non- highest yield is obtained for patients with early-onset atax- specific. Initial testing should include searching for the ia and positive family history and consanguinity among Friedreich ataxia-associated trinucleotide repeat ex- parents. NGS panels allow for better coverage of included pansion in the FXN gene considering the high preva- genes and reduce the volume of genetic variants that are lence of this mutation, its incomplete coverage through unrelated to the clinical phenotype, while exome sequenc- the next-generation sequencing methods [1], and the ing may reveal mutations in genes that were not previous- heterogeneous clinical phenotype. Searching for a ly known to be associated with ataxia [1]. Whole genome FXN repeat expansion can be done with frataxin pro- sequencing may be considered in selected cases with ap- tein analysis or gene analysis with Southern blot or propriate genetic counseling, but its diagnostic yield is PCR. Moreover, clinicians may consider testing for uncertain [224]. Once genetic testing is completed and a another specific gene through Sanger sequencing or pathogenic mutation has been identified, it is of primary multiplex ligation-dependent probe amplification importance to provide specialized genetic counseling for (MLPA) if the clinical and paraclinical data are highly the patient and his or her relatives along with symptom evocative of a particular disorder, if there is a con- management and disease treatment when available. firmed mutation in a relative or in isolated populations Figure 2 presents a graphical summary of the proposed where selected disorders are highly prevalent. Finally, clinical approach. a panel for the dominantly inherited CAG-repeat ex- pansion spinocerebellar ataxias may also be considered as part of the initial assessment if family history is Pathophysiological Mechanisms Underlying inconclusive regarding the mode of inheritance and Autosomal Recessive Cerebellar Ataxias considering the high prevalence of these mutations and their incomplete coverage through the next- The importance of a proper recessive ataxia classification goes generation sequencing methods [1]. beyond the clinical diagnosis perspective. Autosomal reces- sive ataxias can be regrouped according to the deficient cellu- 6. If single gene testing does not provide a molecular diag- lar and metabolic pathways involved, which provide a better nosis, one should consider the high-throughput NGS understanding of cerebellar physiology and of its selective methods either with a multigene panel, whole exome vulnerability to certain metabolic defects. This is also essential 1111 Cerebellum (2019) 18:1098 –1125 Fig. 1 Clinical classification of autosomal recessive ataxias. The gene some disorders have more complex or variable phenotypes and are placed associated with each primary recessive ataxia is classified according to in the overlapping areas between two categories. Genes presented in the most frequent clinical syndrome described for this disorder. Note that larger font represent the most prevalent ataxias from a therapeutic perspective, as disorders that belong to the (Table 3). Interestingly, many of the disorders caused by mi- same metabolic pathway may respond to the same treatment tochondrial dysfunction also present with a mitochondrial options, indicating potential for drug repurposing. Figure 3 clinical syndrome as shown in Fig. 1. Disorders of DNA repair presents a pathophysiological classification of autosomal re- mechanisms are also common, with double-strand break re- cessive ataxias. Certain genes are presented more than once pair pathway or single-strand break repair complexes predom- since some proteins are involved in several metabolic path- inantly involved. Pathogenic mutations in these genes are also ways or may interfere with other cellular processes as they associated with a susceptibility to ionizing radiations and pre- accumulate in neurons or glial cells. Table 3 presents a more disposition for cancers, but the neurological syndrome is char- detailed listing of the pathogenic pathways involved along acterized by cerebellar involvement and extrapyramidal with relevant references. movement disorders. It remains debated whether defective Certain pathways are predominantly involved, notably mi- DNA repair is the main pathogenic mechanism causing the tochondrial dysfunction, which may result from abnormal mi- neurological phenotype [230], but the fact that several tochondrial DNA maintenance with progressive mutagenesis, interacting genes in this pathway are involved in degenerative defective mitochondrial protein synthesis and quality control, cerebellar ataxias suggests that the cerebellum has a peculiar increased levels of reactive oxygen species and oxidative susceptibility to DNA damage for which the underlying mech- stress, deficient coenzyme Q10 metabolism, altered mitochon- anism is not understood. Finally, altered synaptic morphology drial dynamics, defective mitochondrial chain assembly, or or synaptic dysfunction of Purkinje cells (PC) is frequently abnormal mitochondrial RNA maturation and processing involved in recessive ataxias and is associated with aberrant Cerebellum (2019) 18:1098 –1125 1112 classification goes beyond the listing of disorders and must organize diseases in a way that allows better understanding and clinical mastery of this group of disorders. Hence, we proposed a clinical classification along with a pathophysiolog- ical classification, which enabled us to observe that there is significant overlap between these two classifications, highlighting how clinical presentation is in some cases a good projection of the underlying biochemical defect. This has po- tential applications from bench to bedside since treatments that address a specific pathogenic pathway may have thera- peutic potential in all disorders in which this pathway is af- fected. The clinical classification is presented along with a structured clinical approach to a patient presenting with ataxia, which is intended as a clinical tool for expert and nonexpert clinicians. Despite the increasing accessibility of the NGS techniques, there remains a critical place for clinical judgment in the prescription of genetic tests and interpretation of results, taking into account the technical limitations and risk of finding variants of unknown significance. Recently, Renaud and col- leagues published the results of a diagnostic algorithm for recessive ataxias that integrates 124 clinical features to pro- pose three potential diagnoses among a list of 67 recessive disorders that may present with ataxia [285]. This is a very promising tool, but its pragmatic impact on molecular testing Fig. 2 Graphical summary of the clinical approach to a patient presenting strategy, final diagnostic rate, patient management, or time with ataxia efficiency remains to be validated. In the meantime, it is es- sential for clinicians to be at ease with a general approach to recessive ataxias with the NGS techniques often permitting morphology at the PC/parallel fiber synapse, impaired den- molecular diagnosis when the clinical picture is nonspecific. dritic architecture, or dysregulation of glutamate transmission. One of the major strengths of this classification proposal is Other disorders have been implicated in synaptic dysfunction that it is based on a consensus from a panel of international through indirect evidence, for example, SLC9A1, which lo- ataxia experts, thereby ensuring a proper representation of calizes in presynaptic terminals and is involved in the modu- regional differences in the prevalence and clinical approach lation of synaptic activity [254, 275]. Of interest, many of to ataxias. Moreover, the literature search was based on a these disorders are characterized by significant cognitive im- systematic scoping review of the literature whose methodolo- pairment that goes beyond what is expected in the cerebellar gy has been published before and which permitted an unbi- cognitive-affective syndrome and cause intellectual disability, ased appraisal of all potentially relevant articles. Nevertheless, developmental delay, or dementia, highlighting the impor- there are some limitations to this classification proposal that tance of synaptogenesis in cognitive development. are inherent to classifying a group of diseases that evolves very rapidly and that is highly heterogeneous. First, as new evidence emerges regarding the identification of novel ataxia- Discussion associated genes and as new phenotypes are described for previously described disorders, this classification will need We present a new clinical classification of autosomal recessive to be updated. This was highlighted by the significant addi- ataxias in parallel with a pathophysiological classification. tions to the list of primary recessive ataxias since the original The objective of this classification is to provide a tool for systematic review was conducted in 2016. Indeed, many new clinicians and researchers that facilitates the understanding genes and new phenotypes of previously described genes have of this complex group of disorders and defines this field of been reported in only 2 years, which suggests that there is a research. This work is based on the results of our systematic need for periodic updates to the present classification or an scoping review of the literature [3]. We updated this literature online resource. Moreover, several decisions were made in the review and regrouped a panel of 12 international ataxia ex- elaboration of this classification regarding general orientation, perts to build a consensus on the definition and classification purpose of a classification, inclusion of specific disorders, and of cerebellar ataxias. The task force vision is that a classification categories. The lists presented here offer in our 1113 Cerebellum (2019) 18:1098 –1125 Fig. 3 Pathophysiological classification of autosomal recessive ataxias. gene is classified at one or more subcellular localizations according to A Purkinje cell is depicted along with a granule cell and parallel fibers. the different metabolic pathways involved Subcellular organelles and structures are represented graphically. Each opinion the best compromise between synthesis and exhaus- exclude disorders in which cerebellar involvement is a minor tiveness for the expert and nonexpert clinician. or late finding in a complex multisystem phenotype or disor- Compared with a previously published report by the ders that are already classified on their own, such as genes Movement Disorders Society Task Force [4], we decided to associated with Joubert syndrome. The objective was to Cerebellum (2019) 18:1098 –1125 1114 Table 3 Detailed pathogenic mechanisms involved in autosomal recessive cerebellar ataxias Pathophysiological mechanism Genes involved References Mitochondrial defect Mitochondrial DNA maintenance PNKP, POLG, TWNK [225–227] Mitochondrial protein synthesis or AFG3L2, PMPCA, SPG7 [94, 228, 229] quality control Increased reactive oxygen species and ATM, FXN, TTPA [230–233] oxidative stress Coenzyme Q10 metabolism APTX, COQ8A [234, 235] Altered mitochondrial dynamics SACS, VPS13D [127, 236–238] Mitochondrial respiratory chain COA7, COX20 [54, 55] assembly Mitochondrial RNA maturation and DARS2, MTPAP [91, 239, 240] processing Others DNAJC19, L2HGDH, STUB1 [241–243] DNA break repair Double-strand break repair ATM, MRE11A, SETX, TDP2 [118, 230, 244, 245] dysfunction Single-strand break repair APTX, PNKP, XRCC1 [130, 225] RNA transcription or processing defect CWF19L1, POLR3A, POLR3B, SETX [57, 104, 246] Synaptic dysfunction Aberrant morphology at the PC/parallel CA8, CAPN1, GRID2, ITPR1 [50, 247–249] fibers synapse Impaired dendritic architecture SPTBN2, SYNE1 (MF/CGN synapse) [250, 251] Dysregulation of glutamate transmission ATCAY, GRM1 [252, 253] Others GOSR2, RNF216, SLC9A1, UCHL1 [254–257] Abnormal cytoskeleton architecture SACS, SYNE1 [251, 258] Abnormal protein folding or quality control SACS, SIL1, STUB1 [259–261] Golgi apparatus dysfunction COQ8A, GOSR2, SCYL1 [235, 255, 262] Calcium homeostasis dysregulation AFG3L2, ANO10, CA8, ITPR1, SPG7 [79, 247, 263–266] Lysosomal dysfunction GRN, TPP1 [267, 268] Disrupted autophagy SNX14, VPS13D [238, 269] Defective ubiquitin-proteasome pathway RNF216, STUB1, UCHL1 [256, 257, 261] Altered intracellular trafficking GOSR2, SCYL1, SPTBN2, SYNE1, TTPA [250, 251, 255, 262, 270] Altered lipid metabolism ABHD12, CYP27A1, CYP7B1, DNAJC19, GBA2, [60, 233, 241, 269, PNPLA6, SNX14, TTPA 271–274] Axonal dysfunction DARS2, GJC2, KCNJ10, PNPLA6, SLC9A1 [239, 274–277] Abnormal myelin structure or composition ABHD12, CLCN2, GJC2, KCNJ10, KIF1C, L2HGDH, [242, 276–281] POLR3A, POLR3B Disrupted intrinsic Purkinje cell firing SACS, SPTBN2 [250, 282] Abnormal cellular stress response GDAP2 [68] Peroxisome dysfunction PEX10 [92] Impaired mitosis WDR81 [283] Abnormal neuronal migration VLDLR [284] CGN cerebellar granule neuron, MF mossy fiber, PC Purkinje cell identify the core disorders that are involved in autosomal re- as primary ataxias per se. From this perspective, our classifi- cessive ataxias in order to define this field of research and cation complements the proposal by the Movement Disorders build a classification that would be accessible for all clini- Society Task Force. cians. Indeed, with the progressive advent of affordable There remain some important challenges to be addressed in NGS diagnostic testing, we believe that it is most important the field of autosomal recessive ataxias. First, the issue of a for clinicians to be at ease with one classification and familiar proper nomenclature system has been much debated. with the most frequent disorders in their unique ethnical and Recently, the Movement Disorders Society Task Force pro- clinical context. Disorders in which ataxia has been reported posed a revised naming system based on an ataxia prefix as- as a rare or late finding should be included in large NGS sociated with the gene name [4]; this was part of a larger effort testing strategies, but in our opinion should not be categorized to revise the nomenclature of all genetic movement disorders. 1115 Cerebellum (2019) 18:1098 –1125 This system overcomes the limitations of the numbered no- expansions with short-read next-generation sequencing. F1000Res. 2018;7. https://doi.org/10.12688/f1000research. menclature, notably unconfirmed genes, and erroneously at- 13980.1. tributed phenotypes, but its ease of use by nonexperts and 3. Beaudin M, Klein CJ, Rouleau GA, Dupre N. Systematic review patients remains uncertain. 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Conflict of Interest The authors declare that they have no conflict of https://doi.org/10.1038/ng1303. interest. 14. Le Ber I, Bouslam N, Rivaud-Pechoux S, Guimaraes J, Benomar Open Access This article is distributed under the terms of the Creative A, Chamayou C, et al. Frequency and phenotypic spectrum of Commons Attribution 4.0 International License (http:// ataxia with oculomotor apraxia 2: a clinical and genetic study in creativecommons.org/licenses/by/4.0/), which permits unrestricted use, 18 patients. Brain. 2004;127(Pt 4):759–67. https://doi.org/10. distribution, and reproduction in any medium, provided you give appro- 1093/brain/awh080. priate credit to the original author(s) and the source, provide a link to the 15. Anheim M, Fleury M, Monga B, Laugel V, Chaigne D, Rodier G, Creative Commons license, and indicate if changes were made. et al. 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