Autosomal Recessive Cerebellar Ataxias: Paving the Way toward Targeted Molecular Therapies
2019; Cell Press; Volume: 101; Issue: 4 Linguagem: Inglês
10.1016/j.neuron.2019.01.049
ISSN1097-4199
AutoresMatthis Synofzik, Hélène Puccio, Fanny Mochel, Lüdger Schöls,
Tópico(s)Genetics and Neurodevelopmental Disorders
ResumoAutosomal-recessive cerebellar ataxias (ARCAs) comprise a heterogeneous group of rare degenerative and metabolic genetic diseases that share the hallmark of progressive damage of the cerebellum and its associated tracts. This Review focuses on recent translational research in ARCAs and illustrates the steps from genetic characterization to preclinical and clinical trials. The emerging common pathways underlying ARCAs include three main clusters: mitochondrial dysfunction, impaired DNA repair, and complex lipid homeostasis. Novel ARCA treatments might target common hubs in pathogenesis by modulation of gene expression, stem cell transplantation, viral gene transfer, or interventions in faulty pathways. All these translational steps are addressed in current ARCA research, leading to the expectation that novel treatments for ARCAs will be reached in the next decade. Autosomal-recessive cerebellar ataxias (ARCAs) comprise a heterogeneous group of rare degenerative and metabolic genetic diseases that share the hallmark of progressive damage of the cerebellum and its associated tracts. This Review focuses on recent translational research in ARCAs and illustrates the steps from genetic characterization to preclinical and clinical trials. The emerging common pathways underlying ARCAs include three main clusters: mitochondrial dysfunction, impaired DNA repair, and complex lipid homeostasis. Novel ARCA treatments might target common hubs in pathogenesis by modulation of gene expression, stem cell transplantation, viral gene transfer, or interventions in faulty pathways. All these translational steps are addressed in current ARCA research, leading to the expectation that novel treatments for ARCAs will be reached in the next decade. Autosomal-recessive cerebellar ataxias (ARCAs) are a heterogeneous group of rare progressive neurodegenerative genetic diseases. They share the clinical feature of predominant ataxia resulting from progressive damage to the cerebellum and/or its associated afferent tracts (Anheim et al., 2012Anheim M. Tranchant C. Koenig M. The autosomal recessive cerebellar ataxias.N. Engl. J. Med. 2012; 366: 636-646Crossref PubMed Scopus (177) Google Scholar, Synofzik and Németh, 2018Synofzik M. Németh A.H. Recessive ataxias.Handb. Clin. Neurol. 2018; 155: 73-89Crossref PubMed Scopus (0) Google Scholar). In most ARCAs, the neurodegenerative process is not limited to these defining core structures but includes several additional neurologic systems (e.g., retina, cerebral cortex, basal ganglia, corticospinal tracts, and peripheral nerves) as well as non-neurologic tissues (e.g., heart, pancreas, muscle), thus leading to severe, complex multisystemic phenotypes, often starting before the age of 40 (Synofzik and Németh, 2018Synofzik M. Németh A.H. Recessive ataxias.Handb. Clin. Neurol. 2018; 155: 73-89Crossref PubMed Scopus (0) Google Scholar). ARCAs are molecularly defined by the underlying mutated gene. More than 92 autosomal-recessive diseases present with ataxia as a predominant and/or consistent clinical feature, and in an additional 89 autosomal-recessive diseases, ataxia is at least part of the phenotypic spectrum (Figure 1) (Rossi et al., 2018Rossi M. Anheim M. Durr A. Klein C. Koenig M. Synofzik M. Marras C. van de Warrenburg B.P. International Parkinson and Movement Disorder Society Task Force on Classification and Nomenclature of Genetic Movement DisordersThe genetic nomenclature of recessive cerebellar ataxias..Mov. Disord. 2018; 33: 1056-1076Crossref PubMed Scopus (2) Google Scholar). This genetic pleiotropy is further expanded by the growing number of autosomal-dominant ataxia genes that are now recognized to also cause autosomal-recessive ataxia in case of biallelic inheritance, often giving rise to very severe, early-onset recessive ataxia syndromes (e.g., AFG3L2/SCA 28, SPTBN2/SCA5, ITPR1/SCA29, OPA1) (Synofzik and Németh, 2018Synofzik M. Németh A.H. Recessive ataxias.Handb. Clin. Neurol. 2018; 155: 73-89Crossref PubMed Scopus (0) Google Scholar). The recent progress in next-generation sequencing (NGS) has also allowed us to revise the relative frequencies of ARCA genotypes and to appreciate novel phenotypes. While Friedreich's ataxia (FA) is still by far the most common ARCA, accounting for up to 25% of all ARCAs, it is now increasingly acknowledged that autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS; gene: SACS) and Spectrin repeat-containing nuclear envelope protein (SYNE1) ataxia, which were long thought to be largely restricted to specific French-Canadian populations comprise relatively frequent ARCAs with a worldwide distribution (Coutelier et al., 2018Coutelier M. Hammer M.B. Stevanin G. Monin M.L. Davoine C.S. Mochel F. Labauge P. Ewenczyk C. Ding J. Gibbs J.R. et al.Spastic Paraplegia and Ataxia NetworkEfficacy of exome-targeted capture sequencing to detect mutations in known cerebellar ataxia genes.JAMA Neurol. 2018; 75: 591-599Crossref PubMed Scopus (6) Google Scholar, Fogel et al., 2014Fogel B.L. Lee H. Deignan J.L. Strom S.P. Kantarci S. Wang X. Quintero-Rivera F. Vilain E. Grody W.W. Perlman S. et al.Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia.JAMA Neurol. 2014; 71: 1237-1246Crossref PubMed Scopus (103) Google Scholar, Synofzik et al., 2016Synofzik M. Smets K. Mallaret M. Di Bella D. Gallenmüller C. Baets J. Schulze M. Magri S. Sarto E. Mustafa M. et al.SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study.Brain. 2016; 139: 1378-1393Crossref PubMed Scopus (35) Google Scholar, Synofzik et al., 2013Synofzik M. Soehn A.S. Gburek-Augustat J. Schicks J. Karle K.N. Schüle R. Haack T.B. Schöning M. Biskup S. Rudnik-Schöneborn S. et al.Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS): expanding the genetic, clinical and imaging spectrum.Orphanet J. Rare Dis. 2013; 8: 41Crossref PubMed Scopus (58) Google Scholar). Furthermore, spastic paraplegia type 7 (SPG7), which has been considered for many years only as a major cause of hereditary spastic paraplegia (HSP), is now appreciated as a frequent cause of ARCA (Coutelier et al., 2018Coutelier M. Hammer M.B. Stevanin G. Monin M.L. Davoine C.S. Mochel F. Labauge P. Ewenczyk C. Ding J. Gibbs J.R. et al.Spastic Paraplegia and Ataxia NetworkEfficacy of exome-targeted capture sequencing to detect mutations in known cerebellar ataxia genes.JAMA Neurol. 2018; 75: 591-599Crossref PubMed Scopus (6) Google Scholar, Pfeffer et al., 2015Pfeffer G. Pyle A. Griffin H. Miller J. Wilson V. Turnbull L. Fawcett K. Sims D. Eglon G. Hadjivassiliou M. et al.SPG7 mutations are a common cause of undiagnosed ataxia.Neurology. 2015; 84: 1174-1176Crossref PubMed Scopus (0) Google Scholar). Yet, each of these genes still accounts for only 2%–5% of all ARCAs (Synofzik and Németh, 2018Synofzik M. Németh A.H. Recessive ataxias.Handb. Clin. Neurol. 2018; 155: 73-89Crossref PubMed Scopus (0) Google Scholar). Despite all progress with NGS, ≈50% of patients with the clinical suspicion of ARCA remain without a molecular diagnosis. This may reflect not only new ARCA genes but also mutations in established genes that escape current diagnostic strategies such as deep intronic mutations, mutations in regulatory regions, epigenetic changes, gene dosage effects, or digenic modes of inheritance (for examples, see Bonifert et al., 2014Bonifert T. Karle K.N. Tonagel F. Batra M. Wilhelm C. Theurer Y. Schoenfeld C. Kluba T. Kamenisch Y. Carelli V. et al.Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.Brain. 2014; 137: 2164-2177Crossref PubMed Google Scholar, Minnerop et al., 2017Minnerop M. Kurzwelly D. Wagner H. Soehn A.S. Reichbauer J. Tao F. Rattay T.W. Peitz M. Rehbach K. Giorgetti A. et al.Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia.Brain. 2017; 140: 1561-1578Crossref PubMed Scopus (8) Google Scholar). Except for FA, which results from a non-coding repeat expansion, almost all other ARCA mutations identified so far constitute conventional mutations. These are identified by current NGS approaches, thus yielding a "NGS-first approach" as the most comprehensive diagnostic strategy for clinical practice. This should become state of the art in the diagnostic workup of ARCA patients if FA is unlikely and no other ARCA candidate is deemed directly obvious (e.g., by changes in plasma biomarkers exemplified in Tables 1, 2, and 3) (Synofzik and Németh, 2018Synofzik M. Németh A.H. Recessive ataxias.Handb. Clin. Neurol. 2018; 155: 73-89Crossref PubMed Scopus (0) Google Scholar).Table 1ARCAs with Impaired Mitochondrial FunctionDisease (abbreviation) [MIM number]GeneMitochondrial functionMain clinical featuresBiomarkerReferenceFriedreich ataxia (FA) [229300]FXNFe-S biogenesisPredominant sensory ataxia, sensory axonal neuropathy. pyramidal weakness, cardiomyopathy, diabetesFrataxin level in leucocytesReetz et al., 2016Reetz K. Dogan I. Hilgers R.D. Giunti P. Mariotti C. Durr A. Boesch S. Klopstock T. de Rivera F.J.R. Schöls L. et al.EFACTS Study GroupProgression characteristics of the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS): a 2 year cohort study.Lancet Neurol. 2016; 15: 1346-1354Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, Schulz et al., 2009Schulz J.B. Boesch S. Bürk K. Dürr A. Giunti P. Mariotti C. Pousset F. Schöls L. Vankan P. Pandolfo M. Diagnosis and treatment of Friedreich ataxia: a European perspective.Nat. Rev. Neurol. 2009; 5: 222-234Crossref PubMed Scopus (160) Google ScholarARSACS [270550]SACSFacilitating mitochondrial fission, correct mitochondrial intracellular localizationCerebellar ataxia, pyramidal tract damage, axonal-demyelinating sensoriomotor neuropathyabnormally fused mitochondrial network in fibroblastsSynofzik et al., 2013Synofzik M. Soehn A.S. Gburek-Augustat J. Schicks J. Karle K.N. Schüle R. Haack T.B. Schöning M. Biskup S. Rudnik-Schöneborn S. et al.Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS): expanding the genetic, clinical and imaging spectrum.Orphanet J. Rare Dis. 2013; 8: 41Crossref PubMed Scopus (58) Google ScholarSPG7 [607259]SPG7Mitochondrial proteaseSpastic paraparesis, cerebellar ataxia, optic neuropathy (often subclinical)–van Gassen et al., 2012van Gassen K.L. van der Heijden C.D. de Bot S.T. den Dunnen W.F. van den Berg L.H. Verschuuren-Bemelmans C.C. Kremer H.P. Veldink J.H. Kamsteeg E.J. Scheffer H. van de Warrenburg B.P. Genotype-phenotype correlations in spastic paraplegia type 7: a study in a large Dutch cohort.Brain. 2012; 135: 2994-3004Crossref PubMed Scopus (50) Google ScholarAFG3L2/SPAX5 [614487]AFG3L2Mitochondrial proteaseCerebellar ataxia, dystonia myoclonus, epilepsy–Pierson et al., 2011Pierson T.M. Adams D. Bonn F. Martinelli P. Cherukuri P.F. Teer J.K. Hansen N.F. Cruz P. Mullikin For The Nisc Comparative Sequencing Program J.C. Blakesley R.W. et al.Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases.PLoS Genet. 2011; 7: e1002325Crossref PubMed Scopus (0) Google ScholarCOQ8A/ADCK3 [612016]COQ8ACoQ10 biogenesisCerebellar ataxia, exercise intolerance, mild-severe intellectual disability, seizuresCoQ10 ↓ in muscle biopsiesLagier-Tourenne et al., 2008Lagier-Tourenne C. Tazir M. López L.C. Quinzii C.M. Assoum M. Drouot N. Busso C. Makri S. Ali-Pacha L. Benhassine T. et al.ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency.Am. J. Hum. Genet. 2008; 82: 661-672Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar, Mignot et al., 2013Mignot C. Apartis E. Durr A. Marques Lourenço C. Charles P. Devos D. Moreau C. de Lonlay P. Drouot N. Burglen L. et al.Phenotypic variability in ARCA2 and identification of a core ataxic phenotype with slow progression.Orphanet J. Rare Dis. 2013; 8: 173Crossref PubMed Scopus (30) Google ScholarPOLG/SANDO/SCAE [607459]POLGReplication of mtDNACombined afferent and cerebellar ataxia, external ophthalmoparesis, sensory axonal neuropathy, epilepsy–Synofzik et al., 2012Synofzik M. Srulijes K. Godau J. Berg D. Schöls L. Characterizing POLG ataxia: clinics, electrophysiology and imaging.Cerebellum. 2012; 11: 1002-1011Crossref PubMed Scopus (27) Google ScholarTwinkle/Mitochondrial DNA depletion syndrome 7 [271245]TWNKMitochondrial helicase associated with mitochondrial nucleoidsCombined afferent and cerebellar ataxia, external ophthalmoparesis, sensory axonal neuropathy, hypogonadism–Nikali et al., 2005Nikali K. Suomalainen A. Saharinen J. Kuokkanen M. Spelbrink J.N. Lönnqvist T. Peltonen L. Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky.Hum. Mol. Genet. 2005; 14: 2981-2990Crossref PubMed Scopus (138) Google ScholarATAD3A; Harel-Yoon syndrome [617183]ATAD3AMitochondrial inner membrane ATPase, controlling christae structure and mitochondrial DNA and cholesterol metabolismMissense mutations: Ataxia, congenital cataracts, intellectual disability, dysmorphic featuresDeletions/nonsense mutations: congenital pontocerebellar hypoplasia–Desai et al., 2017Desai R. Frazier A.E. Durigon R. Patel H. Jones A.W. Dalla Rosa I. Lake N.J. Compton A.G. Mountford H.S. Tucker E.J. et al.ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism.Brain. 2017; 140: 1595-1610Crossref PubMed Scopus (10) Google ScholarSCAR2PMPCAAlpha subunit of mitochondrial processing peptidase, cleavage of nuclear-encoded mitochondrial precursor proteinsEarly-onset ataxia, variable intellectual disability, spasticity, seizures, developmental delay–Jobling et al., 2015Jobling R.K. Assoum M. Gakh O. Blaser S. Raiman J.A. Mignot C. Roze E. Dürr A. Brice A. Lévy N. et al.PMPCA mutations cause abnormal mitochondrial protein processing in patients with non-progressive cerebellar ataxia.Brain. 2015; 138: 1505-1517Crossref PubMed Scopus (18) Google ScholarMultiple mitochondrial dysfunctions syndrome 6 [617954]PMPCBBeta subunit of the mitochondrial processing peptidaseDevelopmental delay, seizures, variable microcephaly, optic atrophy, ataxia, dystonia, spastic quadriplegia–Vögtle et al., 2018Vögtle F.N. Brändl B. Larson A. Pendziwiat M. Friederich M.W. White S.M. Basinger A. Kücükköse C. Muhle H. Jähn J.A. et al.Mutations in PMPCB encoding the catalytic subunit of the mitochondrial presequence protease cause neurodegeneration in early childhood.Am. J. Hum. Genet. 2018; 102: 557-573Abstract Full Text Full Text PDF PubMed Scopus (7) Google ScholarPITRM1PITRM1Post-cleavage mitochondrial transit peptides ATP-dependent metalloproteaseDevelopmental delay, ataxia, intellectual disability–Langer et al., 2018Langer Y. Aran A. Gulsuner S. Abu Libdeh B. Renbaum P. Brunetti D. Teixeira P.F. Walsh T. Zeligson S. Ruotolo R. et al.Mitochondrial PITRM1 peptidase loss-of-function in childhood cerebellar atrophy.J. Med. Genet. 2018; 55: 599-606Crossref PubMed Scopus (2) Google Scholar Open table in a new tab Table 2ARCAs Caused by Impaired DNA RepairDisease (abbreviation) [MIM number]GeneFunction in DNA repairMain clinical featuresBiomarkerReferenceDouble-strand break repairAtaxia telangiectasia (AT) [208900]ATMDouble-strand break repairChildhood-onset ataxia (often age < 5 years), oculomotor apraxia, choreo-athetosis, dystonia, cognitive impairment, sensorimotor neuropathy, telangiectasias, immunodeficiency, cancer susceptibilityAFP ↑↑ (>65 μg/L)Rothblum-Oviatt et al., 2016Rothblum-Oviatt C. Wright J. Lefton-Greif M.A. McGrath-Morrow S.A. Crawford T.O. Lederman H.M. Ataxia telangiectasia: a review.Orphanet J. Rare Dis. 2016; 11: 159Crossref PubMed Scopus (67) Google ScholarAT-like disorder 1 (ATLD) [604391]MRE11ADouble-strand break repair, nonhomologous end joining and meiotic homologous recombinationChildhood-onset ataxia, oculomotor apraxia, myoclonusAFP normalTaylor et al., 2004Taylor A.M. Groom A. Byrd P.J. Ataxia-telangiectasia-like disorder (ATLD)-its clinical presentation and molecular basis.DNA Repair (Amst.). 2004; 3: 1219-1225Crossref PubMed Scopus (0) Google ScholarAtaxia with ocular apraxia type 2 (AOA2) [606002]SETXResolving RNA:DNA hybrids forming at DNA double-strand breaksChildhood-onset ataxia (often ages 7–25 years), oculomotor apraxia, chorea, dystonia, cognitive impairment, axonal sensorimotor neuropathyAFP ↑ (15–65 μg/L)Moreira and Koenig, 1993Moreira M.C. Koenig M. Ataxia with oculomotor apraxia type 2.in: Adam M.P. Ardinger H.H. Pagon R.A. Wallace S.E. Bean L.J.H. Stephens K. Amemiya A. GeneReviews. University of Washington, Seattle1993Google ScholarRIDDLE syndrome [611943]RNF168E3 ubiquitin ligase to catalyze ubiquitin conjugates promoting DSB repairChildhood-onset ataxia, radiosensitivity, immunodeficiency, dysmorphic features, telangiectasiasAFP ↑↑ (>50 μg/L)Stewart et al., 2007Stewart G.S. Stankovic T. Byrd P.J. Wechsler T. Miller E.S. 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University of Washington, Seattle1993Google ScholarAtaxia with ocular apraxia type 4 (AOA4) [616267]PNKPSingle-strand break repair: facilitating DNA repair by restoring termini suitable for DNA polymeraseMicrocephaly, seizures, and developmental delay, ataxia, sensorimotor neuropathyAFP (↑)Bras et al., 2015Bras J. Alonso I. Barbot C. Costa M.M. Darwent L. Orme T. Sequeiros J. Hardy J. Coutinho P. Guerreiro R. Mutations in PNKP cause recessive ataxia with oculomotor apraxia type 4.Am. J. Hum. Genet. 2015; 96: 474-479Abstract Full Text Full Text PDF PubMed Google ScholarSpinocerebellar ataxia with axonal neuropathy (SCAN1) [607250]TDP1Single-strand break repairCerebellar ataxia, axonal sensorimotor neuropathy, seizures,mild hypercholesterolemia; borderline hypoalbuminemiaAFP normal/levels not reportedTakashima et al., 2002Takashima H. Boerkoel C.F. John J. Saifi G.M. Salih M.A. Armstrong D. Mao Y. Quiocho F.A. Roa B.B. Nakagawa M. et al.Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy.Nat. Genet. 2002; 32: 267-272Crossref PubMed Scopus (325) Google ScholarXRCC1-associated ataxia with oculomotor apraxia (SCAR26) [194360]XRCC1Single-strand break repairAdult-onset cerebellar ataxia, oculomotor apraxia, axonal sensorimotor neuropathyAFP levels not reportedHoch et al., 2017Hoch N.C. Hanzlikova H. Rulten S.L. Tétreault M. Komulainen E. Ju L. Hornyak P. Zeng Z. Gittens W. 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Lehmann A.R. et al.Neurological symptoms and natural course of xeroderma pigmentosum.Brain. 2008; 131: 1979-1989Crossref PubMed Scopus (64) Google ScholarCockayne syndrome (CS) [216400][133540]ERCC8, ERCC6Nucleotide excision repairGrowth failure, microcephalus, mental retardation, cutaneous photosensitivity, pigmentary retinopathy, sensorineural hearing loss, ataxia, sensori-motor neuropathyAFP normalLaugel, 2013Laugel V. Cockayne syndrome: the expanding clinical and mutational spectrum.Mech. 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Dawson C. et al.International Niemann-Pick Disease Registry (INPDR)Consensus clinical management guidelines for Niemann-Pick disease type C.Orphanet J. Rare Dis. 2018; 13: 50Crossref PubMed Scopus (0) Google ScholarCerebrotendinous xanthomatosis (CTX) [213700]CYP27A1Defective sterol 27-hydroxylaseChronic diarrhea, cataract, cognitive deficits, psychiatric features, cerebellar ataxia, spasticity, peripheral neuropathyPlasma cholestanol ↑27-hydroxycholesterol ↓Nie et al., 2014Nie S. Chen G. Cao X. Zhang Y. Cerebrotendinous xanthomatosis: a comprehensive review of pathogenesis, clinical manifestations, diagnosis, and management.Orphanet J. Rare Dis. 2014; 9: 179Crossref PubMed Google ScholarGlycerophospholipidsPNPLA6/neuropathy target esterase (NTE) [612020]PNPLA6Impaired de-esterification of phosphatidylcholine into its constituent fatty acids and glycerophosphocholineVariable phenotypic clusters on a phenotypic continuum: cerebellar ataxia, spasticity, chorioretinal dystrophy, hypogonadismNone yetSynofzik et al., 2014Synofzik M. Gonzalez M.A. Lourenco C.M. Coutelier M. Haack T.B. Rebelo A. Hannequin D. Strom T.M. Prokisch H. Kernstock C. et al.PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum.Brain. 2014; 137: 69-77Crossref PubMed Scopus (0) Google ScholarPLA2G6 [256600]PLA2G6Impaired deacylation of phosphatidylcholine with release of unsaturated fatty acid chains such as arachidonic acidVariable phenotypic clusters on a phenotypic continuum: cerebellar ataxia, dystonia, parkinsonism, optic atrophy, psychiatric features, cognitive deficitsNone yetKurian and Hayflick, 2013Kurian M.A. Hayflick S.J. Pantothenate kinase-associated neurodegeneration (PKAN) and PLA2G6-associated neurodegeneration (PLAN): review of two major neurodegeneration with brain iron accumulation (NBIA) phenotypes.Int. Rev. Neurobiol. 2013; 110: 49-71Crossref PubMed Scopus (34) Google ScholarSphingolipidsMetachromatic Leukodystrophy (MLD) [250100]ARSASulfatide accumulation and decreased galactosylceramideVariable depending on age at onset (late-infantile, juvenile, adult), affects both the central and peripheral nervous systems. Ataxia mostly in juvenile and adult forms.ARSA activity ↓, sulfatide urine ↑Rauschka et al., 2006Rauschka H. Colsch B. Baumann N. Wevers R. Schmidbauer M. Krammer M. Turpin J.C. Lefevre M. Olivier C. Tardieu S. et al.Late-onset metachromatic leukodystrophy: genotype strongly influences phenotype.Neurology. 2006; 67: 859-863Crossref PubMed Scopus (0) Google ScholarKrabbe disease [245200]GALCIncreased galactosylceramideVariable depending on age at onset (late-infantile, juvenile, adult), affects both the central and peripheral nervous systems. Ataxia is most common in adult onset forms.galactocerebrosidase activity ↓Shao et al., 2016Shao Y.H. Choquet K. La Piana R. Tétreault M. Dicaire M.J. Boycott K.M. Majewski J. Brais B. Care4Rare Canada ConsortiumMutations in GALC cause late-onset Krabbe disease with predominant cerebellar ataxia.Neurogenetics. 2016; 17: 137-141Crossref PubMed Google ScholarGaucher disease type 3 [231000]GBA1Reduced activity of lysosomal glucocerebrosidase →reduced hydrolysis of glucosylceramide into ceramideProgressive myoclonic epilepsy, seizures, oculomotor apraxia, ataxiaGBA1 activity ↓ lysoglucosylceramide ↑Winkelman et al., 1983Winkelman M.D. Banker B.Q. Victor M. Moser H.W. Non-infantile neuronopathic Gaucher's disease: a clinicopathologic study.Neurology. 1983; 33: 994-1008Crossref PubMed Google ScholarGBA2; spastic ataxia [614409]GBA2Reduced activity of ER glucocerebrosidaseEarly-onset spastic ataxiaGBA2 activity ↓Martin et al., 2013Martin E. Schüle R. Smets K. Rastetter A. Boukhris A. Loureiro J.L. Gonzalez M.A. Mundwiller E. Deconinck T. 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Peroxisomal Disorders: A Review on Cerebellar Pathologies.Brain Pathol. 2015; 25: 663-678Crossref PubMed Scopus (0) Google Scholar Open table in a new tab AFP, Alphafetoprotein; (↑), elevated only in a subset of patients ARCAs often present with multisystemic phenotypes showing a wide inter- and intra-familial variability (e.g., POLG ataxia; Synofzik et al., 2012Synofzik M. Srulijes K. Godau J. Berg D. Schöls L. Characterizing POLG ataxia: clinics, electrophysiology and imaging.Cerebellum. 2012; 11: 1002-1011Crossref PubMed Scopus (27) Google Scholar), with phenotypic spectra dramatically expanding for many ARCAs over the last 6 years (for examples, see SYNE1 [Synofzik et al., 2016Synofzik M. Smets K. Mallaret M. Di Bella D. Gallenmüller C. Baets J. Schulze M. Magri S. Sarto E. Mustafa M. et al.SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study.Brain. 2016; 139: 1378-1393Crossref PubMed Scopus (35) Google Scholar] and PNPLA6 [Synofzik et al., 2014Synofzik M. Gonzalez M.A. Lourenco C.M. Coutelier M. Haack T.B. Rebelo A. Hannequin D. Strom T.M. Prokisch H. Kernstock C. et al.PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum.Brain. 2014; 137: 69-77Crossref PubMed Scopus (0) Google Scholar]). Current phenotypically driven classifications of ARCAs are based on ataxia or non-ataxia features (Anheim et al., 2012Anheim M. Tranchant C. Koenig M. The autosomal recessive cerebellar ataxias.N. Engl. J. Med. 2012; 366: 636-646Crossref PubMed Scopus (177) Google Scholar, Renaud et al., 2017Renaud M. Tranchant C. Martin J.V.T. Mochel F. Synofzik M. van de Warrenburg B. Pandolfo M. Koenig M. Kolb S.A. Anheim M. RADIAL Working GroupA recessive ataxia diagnosis algorithm for the next generation sequencing era.Ann. Neurol. 2017; 82: 892-899Crossref PubMed Scopus (4) Google Scholar) but are of only limited help for the diagnostic strategy and a systematic understanding of ARCAs. The next step is to move toward a mechanistically inspired approach based on the underlying gene and the underlying molecular mechanism and pathways, which might even be shared across several ARCAs. This approach can be used both for grouping ARCAs (as done in this review) and to try t
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