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Ocular motility in North Carolina autosomal dominant ataxia . J Neuroophthalmol 1996; 16 : 91 \200\2235 . 114. Kerber KA, Jen JC, Lee H, Nelson SF, Baloh RW. A new episodic ataxia syndrome with lin kage to chromosome 19q13 . Arch Neurol 2007; 64 : 749 \200\22352 . 109. Farmer TW, Mustian VM. Vestibulocerebellar ataxia: a newly defi ned hereditary syndrom e with periodic manifestations . Arch Neurol 1963; 8 : 471 \200\22380 . 115. Julien J, Denier C, Ferrer X, et al. Sporadic late onset paroxysmal cer- ebellar ataxi a in four unrelated patients: a new disease? J Neurol 2001; 248 : 209 \200\22314 . 110. Damji KF, Allingham RR, Pollock SC, et al. Periodic vestibulocerebellar ataxia, an aut osomal dominant ataxia with defective smooth pursuit, is genetically distinct from other au tosomal dominant ataxias . Arch Neurol 1996; 53 : 338 \200\22344 . 116. Cha YH, Lee H, Jen JC, Kattah JC, Nelson SF, Baloh RW. Episodic ver- tical oscillopsia with progressive gait ataxia: clinical description of a new episodic syndrome and evidence of linkage to chromosome 13q . J Neurol Neurosurg Psychiatry 2007; 78 : 1273 \200\2235 . 111. Escayg A, De Waard M, Lee DD, et al. Coding and noncoding variation of the human calci um-channe l beta4-subuni t gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia . Am J Hum Genet 2000; 66 : 1531 \200\2239 . 117. Damak M, Riant F, Boukobza M, Tournier-Lasserve E, Bousser MG, Vahedi K. Late onset he reditary episodic ataxia . J Neurol Neurosurg Psychiatry 2009; 80 : 566 \200\2238 . 112. Jen JC, Wan J, Palos TP, Howard BD, Baloh RW. Mutation in the gluta- mate transporter EAAT1 causes episodic ataxia, hemiplegia, and sei- zures . Neurology 2005; 65 : 529 \200 \22334 . CHAPTER 27 Hereditary and Acquired Cerebellar Ataxias George Koutsis and Nicholas W. Wood Summary \200\230Cerebellar ataxia \200\231 refers to a clinical syndrome caused by dam- ag e to the cerebellum and its connections and characterized by lack of coordination most evid ent in gait, use of the extremities, speech, and ocular movement. Although individual ataxi c disor- ders are relatively rare, the ataxias as a whole represent a common clinical probl em. Acquired ataxias are the most frequent, but her- edoataxias also contribute a substanti al proportion of cases. Over the past two decades, neuroimaging and molecular genetics have revolutionized the fi eld, shedding light on the etiology of these diverse disorders. ataxias eff ective disease-modifying therapies for some of the cur- rently untreatable diso rders will be identifi ed. Introduction \200\230Ataxia \200\231, a Greek word meaning lack of order, refers to a clin ical syndrome characterized by disturbance of coordination most evi- dent in gait, use of the extremities, speech, and ocular movement. \200\230Cerebellar ataxia \200\231 refers to ataxia caused by damage to the cer- ebellum and its connections. Ataxia can also result fr om sensory dysfunction due to lesions of the dorsal columns or proprioceptive peripheral ne urons (sensory ataxia). In the present chapter, heredi- tary and acquired cerebellar ataxia s are discussed in some detail. Clinically \200\230pure \200\231 cerebellar ataxia is a re latively rare phenomenon. Most disorders causing cerebellar ataxia also cause dysfunction o f other neurological systems, and the extent to which other systems are involved varies. An attempt has been made to limit this chapter to disorders in which cerebellar ataxia can be the most prominent clinical feature. Th e diff erential diagnosis of cerebellar ataxia is complex and consists of an extensive l ist of acquired and an ever-expanding list of recognized hereditary causes. Acquired causes include viral cerebellitis, space-occupying lesions, multiple sclerosis, alcoholic cerebel lar degeneration, drug toxicity, paraneoplastic cerebellar degeneration, superfi cial sider osis, multiple system atrophy, and idiopathic late-onset cerebellar ataxia. Hereditary caus es include inborn errors of metabolism, episodic ataxias, autosomal reces- sive cerebellar ataxias, autosomal dominant cerebellar ataxias (also known as spinocerebellar ataxias), X-l inked ataxias, and mitochondrial ataxias. A systematic approach based on relatively straigh tforward clinical rules can be a useful guide to the diagnos- tic process. Determining the age of onset can limit the diff erential to congenital, early-onset (<25 years), and late-o nset (>25 years) causes. Clarifying the mode of onset can further narrow down the list to a cute-onset, subacute-onset, and insidious-onset causes. Th e presence of a non-progressive, intermittent, or progressive course can focus the diagnosis further. Deciding whether an a cquired or hereditary cause should be sought reduces the diff erential to a manageable list . Finally, specifi c information gathered from the history, the examination (including extr acerebellar and extraneural fi ndings), and routine or directed investigations allows the c orrect diagnosis to be made in most cases. Epidemiology Data are lacking on the overall prevalence of ataxia in the general population . Th is is partly due to ataxia \200\231s being a clinical syndrome rather than a disease. Additionally, in the case of acquired ataxias some of the most common conditions, such as v iral cerebellitis or acute drug toxicity, are of short duration and less suited to preva- l ence estimations. Epidemiological data on the hereditary ataxias are generally more compreh ensive. Acquired ataxias are far more frequent than hereditary ataxias, although an overall prevale nce fi gure has not been reported. Quoting the frequency of some of the most common acquire d ataxias should give a feel for their general prevalence in the pop- ulation. Alcoholic ce rebellar degeneration (ACD) is present in 11 \200\22327% of chronic alcohol users (1). Cere bellar infarction rep- resents 3% of all infarcts (2). Acute cerebellitis represents 0.4% o f children with neurological problems (3). Prevalence of multiple system atrophy (MSA) and idiopathic late-onset cerebellar ataxia (ILOCA) has been estimated at 4.4 and 8.4 in 100 00 0, respec- tively (4, 5). Unfortunately, the treatment of cerebellar ataxia, both disease- modifying and symptomatic, remains poor. Among the multitude of disorders which are at present untreatable, it is imp ortant to promptly identify those ataxias which are amenable to treatment. Hopefully, as we gain insights into the molecular pathogenesis of Oxford Textbook of Movement Disorders 282 Th e overall prevalence of heredoataxias is around 1 in 10 000. Th e autosomal recessive ce rebellar ataxias (ARCAs) have a prevalence of 7 in 100 000, with Friedreich \200\231s ataxi a (FRDA) being the most common followed by ataxia telangiectasia (AT) (6). Th e autosomal d ominant cerebellar ataxias (ADCAs), also known as spinocerebel- lar ataxias (SCAs), have a prevalence of 3 in 100 000 (7). SCA3 is the most common, followed by SCA2, SCA6, SCA1, and SCA7 in approximate descending order of frequency (8). X-linked cerebel- lar ataxias are ra re, with fragile X-associated tremor \200\223ataxia syn- drome (FXTAS) representing around 2% of patients in ataxia series (9). Mitochondrial ataxias are also rare, with no fi gure for their overall prevalence repo rted to date. Th e prevalence of congenital ataxias has been estimated at around 1.3 in 10 000 in the 6 \200\22322 age group (10). Th e age of onset of cerebellar ataxias varies widely and covers the entire lifespan. In so me cases, such as the congenital ataxias or AT, symptoms may develop in the fi rst years of life. At the other end of the spectrum, certain ataxias can present in late adult life. Ex amples include MSA-C, FXTAS, and SCA6. Table 27.1 broadly divides ataxias based on the age of onset. Table 27.1 Classi \201 cation of cerebellar ataxias based on age of onset, mode of onset, disease course, and inheritance Age of onset Congenital Mode of onset and course Relatively non-progressiv e Non-hereditar y Chiari malformation Dandy \200\223Walker syndrome Ataxic cerebral palsy Hereditary Joubert syndrome Gillespie syndrome Early onset (<25 years) Acute onset with or without intermittent course Acquired Subacute onset with or without progression Acquired Insidious onset with chronic progression Acquired Viral cerebellitis Posterior fossa tumors (primary) Chronic drug toxicity ADEM Vascular malformations Heavy metal poisoning Vascular causes Relapsing MS Hereditary Autosomal recessive Acute drug toxicity SSPE Trauma/hypoxia Cerebellar abscess FRDA Miller Fisher syndrome Opsoclonus \200\223myoclonus syndrome AVED Basilar migraine AT and AT-like disorder Conversion reaction AOA 1 and 2 Hereditary Autosomal dominant Episodic ataxias WD MSS ARSACS Autosomal recessive Ataxia CoQ10 de \201 ciency Inborn errors of metabolism GM2 gangliosidosis Urea cycle disorders ABL Aminoacidopathies RD Organic acidopathies CTX PDH de \201 ciency NPC MLD VWMD PMEs X-linke d Adrenoleucodystrophy PMD Mitochondrial disease Acquired Late onset (>25 years) Acquired Acquired Vascular causes Relapsing MS Alcoholic CD Acute drug toxicity Posterior fossa tumors (metastatic) Primary progressive MS Trauma/hypoxia/heat stroke Vascular malformations Chronic drug toxicity (Continued) CHAPTER 27 Hereditary and acquired cerebellar ataxias 283 Table 27.1 (Continued) Age of onset Mode of onset and course Wernicke \200\231s encephalopathy Paraneoplastic CD Heavy metal poisoning Miller Fisher syndrome In \202 ammatory diseases/vasculitides Vitamin de \201 ciency Cerebellar abscess Super \201 cial siderosis HIV infection Gluten ataxia Whipple \200\231s disease Anti-GAD ataxia Sporadic CJD Hypothyroidism Hashimoto encephalopathy CANVAS MSA ILOCA Hereditary Autosomal dominant Type I ADCAs Type II ADCAs Type III ADCAs GSS X-linke d FXTAS Mitochondrial disease ADEM, acute disseminated encephalomyelitis; PDH, pyruvate dehydrogenase; MS, multiple scler osis; SSPE, subacute sclerosing panencephalitis; FRDA, Friedreich \200\231s ataxia; AVED, a taxia with vitamin E de \201 ciency; AT, ataxia telangiectasia; AOA, ataxia with oculomoto r apraxia; WD, Wilson disease; MSS, Marinesco \200\223Sj gren syndrome; ARSACS, autosoma l recessive ataxia of Charlevoix-Saguenay; ABL, abetalipoproteinaemia; RD, Refsum \200\231s disease; CTX, cerebrotendinous xanthomatosis; NPC, Niemann \200\223Pick disease type C; ML D, metachromatic leucodystrophy; VWMD, vanishing white matter disease; PMEs, progressive my oclonic epilepsies; PMD, Pelizaeus \200\223Merzbacher disease; CD, cerebellar degeneration; CJD, Creutzfeldt \200\223Jakob disease; GAD, glutamic acid decarboxylase; MSA, multiple sy stem atrophy; ILOCA, idiopathic late-onset cerebellar ataxia; ADCAs, autosomal dominant cer ebellar ataxias; GSS, Gerstmann \200\223Str ussler \200\223 Scheinker disease; FXTAS, fr agile X-associated tremor \200\223ataxia syndrome. Etiology and genetics Th e potential causes of cerebellar ataxia comprise an extensive list of diverse entities which are summarized in Table 27.1. Although this table includes the c ommon and most of the rarer causes of ataxia, it is by no means exhaustive. genes, ranging from ion channels to genes involved in transcription regulation, mitochondri al function, or protein phosphorylation. Th ree types of mutations are found: exonic CAG-re peat expansions (SCA1, 2, 3, 6, 7, 17, DRPLA), intronic trinucleotide or pentanucle- otide expansions (SCA8, 10, 12, 31), and conventional mutations (SCA5, 11, 13, 14, 15/16, 27, 28, 35) (8, 13). Mitochondrial ataxias (Table 27.8) can be caused by conventional mutations in mitochon- drial genes coding for transfer RNAs, ribosomal RNAs, and respira- tory chain su bunits, or in nuclear genes coding for respiratory chain subunits and assembly factors, pro teins involved in inter genomic signaling, and mitochondrial transportation machinery (14). Congenital ataxias can result from sporadic developmental anomalies, such as Chiari malform ation and Dandy \200\223Walker com- plex, or hereditary conditions which are oft en genetic ally heteroge- neous, such as Joubert syndrome and Gillespie syndrome. Acquired ataxias can have a wide range of causes including chronic alcohol use, drug toxici ty, immune-mediated infl amma- tion ranging from post-infectious cerebellitis to paraneopla stic syndromes, stroke, tumors, vitamin defi ciency, endocrine abnor- malities, CNS infecti on, and leptomeningeal iron deposition lead- ing to superfi cial siderosis. MSA is a sporad ic degenerative disease classifi ed pathologically as an alpha-synucleinopathy, whose cause at present remains unknown. ILOCA, as the name suggests, is essentially a diagnosis of exc lusion (1). Topography and pathophysiology All cerebellar ataxias are ultimately caused by dysfunction of the cer- ebellum itself or its connections. From a clinical viewpoint, lesions aff ectin g midline cerebellar structures (vermis) primarily aff ect stance and gait, whereas lesions aff ecting the lateral hemispheres cause limb ataxia. As a general rule, appendicular moto r impair- ment is ipsilateral to the side of the cerebellar lesion. Dysarthria is oft en ca used by lesions in the paravermal regions, whereas oculo- motor abnormalities can result fr om lesions in the so-called oculo- motor vermis, which includes the inferiorly placed fl oc culonodular lobe (15). Th e specifi c genetic mutations underlying diff erent heredoataxias are discussed in more detail in the relevant sections and summarized in Tables 27.5, 27.6, 27.7, and 27.8. In the case of episodic ataxias (Table 27.5), conventional mutations in ion channels are responsi - ble for the disease manifestations (11). Th e ARCAs (Table 27.6) are a heterogeneous grou p of disorders caused by mutations in genes involved in mitochondrial function, metabolic p athways and DNA repair. With the exception of FRDA, which is caused by an intronic GAA expa nsion, ARCAs are caused by conventional mutations (6, 12). Th e ADCAs (Table 27.7) can be c aused by mutations in diverse Th e topography of cerebellar defi cits becomes relevant in under- standing the pathogenesi s of specifi c cerebellar symptoms in ataxias resulting from focal damage. Th e pathophysio logical mechanisms involved refl ect the underlying causes, which include stroke, infl am- mation, tumors, and abscesses. However, most cerebellar ataxias Oxford Textbook of Movement Disorders 284 result from diff use damage to the cerebellum and lesion topogra- phy is less relevant. point (Table 27.1) (25). Determining the age of onset, although not always straightforward, can narrow the diff erential diagnosis down by pointing to congenital early-onset (defi ne d as <25 years for ataxias) or late-onset causes (25). Th e mode of onset, whether acute, s ubacute, or insidious, can also signifi cantly limit the spec- trum of potential causes. Th e presence of a non-progressive, inter- mittent, or progressive course can further focus t he diagnostic process. Ataxia caused by diff use cerebellar dysfunction can be divided from a pathophysiological p erspective into conditions which aff ect the function of cerebellar neurons without causing neurodegen- eration and conditions which aff ect structure and function con- comitantly, r esulting in cerebellar degeneration and atrophy. In the case of acquired ataxias, examples of conditions causing purely transitory functional eff ects include acute drug toxicity and basi- lar migraine. Acute ethanol-induced cerebellar ataxia may result from temporary inhi bition of granule cell sensory responses (16). In basilar migraine the possibility of sprea ding depression aff ecting the cerebellar cortex has been raised (17). Paraneoplastic cereb el- lar disease may also cause functional loss without degeneration in the early stages. In cerebellar ataxia associated with Lambert \200\223Eaton myasthenic syndrome, antibodies ag ainst voltage-gated calcium channels are thought to reduce transmission at the parallel fi bre \200\223 Purkinje cell synapse (11). In the case of hereditary ataxias, tran- sitory fu nctional eff ects without neuronal loss are seen in some episodic ataxias (EAs). Th e ion c hannel mutations observed in EAs cause dominant-negative eff ects by aff ecting multimeric channel assembly, which impairs channel function (11). Dividing cerebellar disorders into non-hereditary and hereditary can be the next step in th e diagnostic algorithm. A three-generation pedigree will allow adequate assessment of the f amily history, assisting in the identifi cation of any hereditary ataxias. Autosomal domina nt inheritance is suggested by aff ected members in con- secutive generations, and it is al ways worth looking for evidence of male \200\223male transmission which excludes X-linked a nd mito- chondrial DNA inheritance. Autosomal recessive inheritance may be suggested by the presence of multiple aff ected members in a single generation or by evidence of consanguin ity. X-linked trans- mission is characterized by aff ected males in the maternal line. Mito chondrial disease can be caused by mitochondrial or nuclear gene mutations. Mitochondrial m utations follow maternal inherit- ance. Nuclear mutations can be dominant or recessive. How ever it should be noted that up to 15% of apparently sporadic cases can have a hereditary c ause (26). Conditions which aff ect function through diff use cerebellar neurodegeneration represent t he majority of cerebellar ataxias. Cerebellar neurons are particularly vulnerable to oxidat ive stress, NMDA-mediated excitotoxicity, DNA repair/transcriptional dysreg- ulation, or to xic protein accumulation (18). In the case of acquired ataxias, examples of conditions caus ing diff use cell loss include ACD and MSA. In ACD a combination of ethanol with vitamin B 1 defi - ciency leads to diff use cerebellar neuronal cell loss through mech- anisms includ ing excitotoxicity, oxidative stress, and apoptosis (1, 19, 20). In MSA, glial cytoplasmic and neuronal nuclear inclu- sions containing alpha-synuclein are thought to underlie the ne urodegeneration observed primarily in the olives, pons, and cer- ebellum in cases of MSA-C (21). In the case of hereditary ataxias, diff erent mechanisms underlie the neuronal loss s een in ARCAs and ADCAs. In ARCAs, loss-of-function mutations in genes involved in mitochond rial function, metabolic pathways, and DNA repair lead to neuronal cell death (6, 12). For example, in FRDA an intronic GAA repeat expansion in the gene coding for frataxin disturbs iron homeostasis and mitochondrial function (22). In ADCAs, three pathophysiological mechan isms are observed. Exonic CAG-repeat expansions lead to polyglutamine-containing inclusion bodies which cause toxic gain of function through aberrant protein aggre- gation. Intronic repeat expansions also cause toxic gain of function, but via RNA mechanisms. In the case of conventional mutation SCAs, haploinsuffi ciency (SCA5, 11, 15), or dominant-negative eff e cts (SCA 13, 27) can underlie the pathogenesis of neuronal cell loss (8, 11, 23, 24). Once the ataxic disorder has been broadly classifi ed, the presence of characteristic const ellations of extracerebellar and extraneural fi ndings may allow the clinician to reach a s pecifi c diagnosis. Clinical features Th e patient with cerebellar ataxia may complain of gait unsteadi- ness, frequent falls, \200\230dizziness \200\231, clumsiness, slurring of speech, or blurring of vision. Features of the past medical history that may prove useful in the diff erential di agnosis include alcohol abuse, past episodes of optic neuritis, recent febrile illness, kno wn malignancy, headache or vomiting, recent trauma, diarrhea, diabetes, seizures, dysautono mic symptoms, symptoms of connective tissue disease, cardiac involvement, or deafness (Tabl e 27.2). On examination, the ataxic patient may have wide-based gait, dif- fi culty in tandem gait, truncal ataxia, titubation, intention tremor, dysmetria, dysdiadochokinesis, hypotonia or s lurring, and scan- ning dysarthria. Oculomotor assessment may reveal square-wave jerks, sac cadic pursuit, dysmetric saccades, skew deviation, or gaze-evoked nystagmus. Oculomotor apr axia may be seen in dis- orders such as AT and ataxia with oculomotor apraxia (AOA). A cogn itive cerebellar syndrome has been reported, but signs are very subtle and from a clinical viewpoint less relevant. Defi cits may be more detectable in cases of acute cerebellar dysf unction, such as stroke (15). Careful examination of other neurological sys- tems should be carried out to determine the presence of pigmen- tary retinopathy, ophthalmoplegia, hearin g loss, pyramidal signs, extrapyramidal signs, myoclonus, sensory neuropathy, amyotro- phy, arefl exia, postural hypotension, or cognitive impairment. A careful general examination s hould also be carried out in order to reveal signs including Kayser \200\223Fleischer rings , cataracts, oculo- cutaneous telangiectasias, skin rashes, dysmorphic features, short stat ure, scoliosis, pes cavus, tendon xanthomas, or hepatomegaly (Table 27.2). Classi \201 cation Arriving at the correct diagnosis in a patient with cerebellar ataxia c an be a daunting task, given the multitude of acquired causes and the ever-expanding list o f recognized hereditary causes. A clinically useful classifi cation is oft en the fi rst st ep to a correct diagnosis. Classifying cerebellar ataxias according to the age of onset, mo de of onset of symptoms, and course of the disease is a good starting CHAPTER 27 Hereditary and acquired cerebellar ataxias 285 Table 27.2 Clinical features that can aid in the di \200 erential diagnosis of cerebellar ataxia Clinical feature Possible diagnosis From the history Alcohol abuse Alcoholic CD, Wernicke \200\231s encephalopathy Drug use and abuse Drug toxicity, solvent toxicity, HIV Recent or current infection Viral/postviral cerebellitis, ADEM, Miller Fisher syndrome Past optic neuritis MS Fever Cerebellar abscess, viral cerebellitis, Whipple \200\231s disease Hypertension Vascular causes, cerebellar haemangioblastomas and phaeochromocytoma in VHL Diabetes Vascular causes, FRDA, anti-GAD ataxia, mitochondrial disease Seizures Tumors, inborn errors of metabolism, mitochondrial disease, PMEs, ADCAs (DRPLA, SCA17, SCA1 0, SCA14), GM2 gangliosidosis, NPC Intermittent ataxia Basilar migraine, inborn errors of metabolism, EAs Hearing loss Super \201 cial siderosis, mitochondrial disease, RD, NPC Dysautonomic symptoms MSA, FXTAS Headache and vomiting Hemorrhage, abscess, tumor, basilar migraine, EA2 Diarrhea Gluten ataxia, Whipple \200\231s disease, de \201 ciency states due to malabsorption Hair loss Hypothyroidism Dry eyes-mouth, venous thrombosis, photosensitivity Sj gren \200\231s syndrome, APS, SLE Known malignancy Paraneoplastic CD, metastatic disease, AT Heavy metal exposure Lead, mercury, or thallium ataxia Precipitant infection or high protein load Inherited metabolic disorders, VWMD From the examination Extracerebellar \201 ndings Sensory neuropathy Alcoholic CD, paraneoplastic CD, connective tissue disease, Miller Fisher syndrome, vitamin de \201 ciency, heavy metal poisoning, CANVAS, ARCAs (including FRDA, AOA, AT, AVED, ABL) , FXTAS, ADCAs Amyotrophy ARCAs, ADCAs, GM2 gangliosidosis Reduced re \202 exes Miller Fisher syndrome, paraneoplastic CD, ARCAs, SCA2 Ophthalmoplegia MS, Wernicke \200\231s encephalopathy, Miller Fisher syndrome, mitochondrial disease, Whipp le \200\231s disease, AOA1, ADCAs, NPC Oculomotor apraxia AT, ATLD, AOA1, AOA2 Lateralized brainstem signs Vascular causes, posterior fossa tumors, MS Pyramidal features MS, ADEM, super \201 cial siderosis, FRDA, AVED, GM2 gangliosidosis, CTX, ARSACS, mitochon drial disease, AT, AOA2, ADCAs, ALD, MLD, PMD Myoclonus CJD, gluten ataxia, Hashimoto encephalopathy, hypoxia, paraneoplastic CD, SSPE, MSA, PMEs, inborn errors of metabolism, GM2 gangliosidosis, CTX, mitochondrial disease, AT, AOA2, SCA1 4 Extrapyramidal features MSA, ADCAs, FXTAS, GM2 gangliosidosis, CTX, AT, ATLD, AOA1, AOA2, WD, NPC Cognitive impairment/mental retardation Alcoholic CD, CJD, Hashimoto encephalopathy, MS, SSPE, hypothyroidism, ADCAs (DRPLA, SCA17, SCA13), GSS, FXTAS, GM2 gangliosidosis, CTX, mitochondrial disease, AOA1, AOA2, ARSACS, MS S, Gillespie syndrome, inborn errors of metabolism, NPC Psychiatric disturbances Alcoholic CD, paraneoplastic CD, CJD, Hashimoto encephalopathy, ADCAs (DRPLA, SCA17), GM2 g angliosidosis, CTX, mitochondrial disease, hypothyroidism, NPC, MLD Retinitis pigmentosa AVED, ABL, RD, mitochondrial disease Degenerative maculopathy ADCAII (SCA7) Extraneural \201 ndings Short stature Mitochondrial disease, MSS Scoliosis FRDA, AOA1, AOA2, MSS Dysmorphic features PDH de \201 ciency, RD, MSS Pes cavus FRDA, other ARCAs Cataracts MSS, CTX Aniridia Gillespie syndrome Kayser \200\223Fleischer rings WD (Continued) Oxford Textbook of Movement Disorders 286 Table 27.2 (Continued) Clinical feature Telangiectasias Possible diagnosis AT, ACD Skin rash SLE, Lyme disease, Hartnup disease Tendon xanthomas CTX Cervical lipomas Mitochondrial disease Arthritis SLE, Whipple \200\231s disease Cardiomyopathy Alcoholic CD, vascular causes, FRDA, AVED, ABL, RD Hepatomegaly Urea cycle disorders, NPC CD, cerebellar degeneration; ADEM, acute disseminated encephalomyelitis; MS, multiple scler osis; VHL, von Hippel \200\223Lindau disease; FRDA, Friedreich \200\231s ataxia; GAD, gluta mic acid decarboxylase; PMEs, progressive myoclonic epilepsies; ADCA, autosomal dominant ce rebellar ataxia; SCA, spinocerebellar ataxia; DRPLA, dentatorubral \200\223pallidoluysian a trophy; NPC, Niemann \200\223Pick disease type C; EA, episodic ataxia; RD, Refsum \200\231s disease; MSA, multiple system atrophy; FXTAS, fragile X tremor \200\223ataxia syndrome; AP S, antiphospholipid syndrome; SLE, systemic lupus erythematosus; AT, ataxia telangiectasia; VWMD, vanishing white matter disease; CANVAS, cerebellar ataxia with neuropathy and bilate ral vestibular are \202 exia syndrome; ARCAs, autosomal recessive cerebellar ataxias; AOA, ataxia with oculomotor apraxia; AVED, ataxia with vitamin E de \201 ciency; ABL, abetalip oproteinaemia; ATLD, ataxia telangiectasia-like disorder; CTX, cerebrotendinous xanthomatos is; ARSACS, autosomal recessive spastic ataxia of Charlevoix-Saguenay; ALD, adrenoleucodyst rophy; MLD, metachromatic leucodystrophy; PMD, Pelizaeus \200\223Merzbacher disease; CJD, C reutzfeldt \200\223Jakob disease; SSPE, subacute sclerosing panencephalitis; GSS, Gerstmann \200\223Str ussler \200\223Scheinker disease; WD, Wilson disease; MSS: Marinesco \200 \223Sj gren syndrome; PDH, pyruvate dehydrogenase. Investigations Magnetic resonance imaging Th e advent of MRI has revolutionized the diagnos is of cerebel- lar ataxias. A large number of acquired causes can be diagnosed with its ass istance. Th ese include tumors, abscesses, demyelinat- ing lesions, other infl ammatory les ions, infarcts, hemorrhages, or superfi cial siderosis. Gradient-echo T 2 * sequences are p articularly sensitive for picking up superfi cial siderosis. MRI can also assist in the dia gnosis of sporadic degenerative ataxias, such as Creutzfeldt \200\223 Jakob disease (CJD), MSA, and ILOCA, as well as many of the hereditary degenerative ataxias. However, it should be noted that in such cases MRI fi ndings are oft en non-specifi c, consisting of cer- ebel lar and/or brainstem atrophy (25). available, is recommended. Testing for other rarer hereditary ataxias is currently only per formed within research settings. Management Th e treatment of cerebellar ataxia, both disease-modifying and symptomatic, rem ains poor. Signifi cant advances made on patho- genesis have not yet been translated into s uccessful disease-modifying therapy. However, among numerous cerebellar disorders which are at present untreatable, it is important to identify those ataxias which are amenable to di sease modifi cation. Within the acquired ataxias, these include disorders due to toxic eff ects, vitamin defi - ciencies, vascular pathology, immune-mediated infl ammation and neurod egeneration, tumors or endocrine abnormalities. Among the hereditary ataxias, conditions am enable to modifi cation include some autosomal recessive metabolic disorders, such as ataxi a with vitamin E defi ciency (AVED), Wilson disease (WD), Refsum \200\231s dis- ease (RD), cerebrotendinous xanthomatosis (CTX), ataxia with co- enzyme Q10 defi ciency and Niemann \200\223Pick disease type C (NPC). In the EAs carbonic anhydrase inhibitors can reduce the frequency of attacks and may have an eff ect on disease progression (25). More details on s pecifi c disease-modifying treatments are given in the corresponding paragraphs on diff ere nt ataxias. Th e absence of fi ndings on MRI can also be helpful in the diagno- sis of cerebellar ataxi a, with paraneoplastic CD (in its early stages) and FRDA being characteristic examples. Congenital ataxias, including Chiari malformation, Dandy \200\223 Walker syndrome and Joube rt syndrome, also have characteristic MRI appearances. Other tests including genetic testing A multitude of other diagnostic tests can shed light on the patient with cerebellar ataxia. Th ese include electrophysiological tests (nerve con duction studies, EMG, EEG, visual evoked potentials, somatosensory evoked potentials, and c entral motor conduction time), CSF analysis, and numerous routine and more specialized bloo d tests. Such tests may steer the diagnosis towards more spe- cifi c disorders (Table 27.3) . In the case of FRDA, data implicating oxidative stress in its pathogenesis have led to ther apeutic trials involving antioxidant agents such as vitamin E, co-enzyme Q10, and idebenone . No defi nitive improvement in ataxia was clearly demonstrated in these trials. A potentia lly signifi cant cardioprotective eff ect of idebenone reported initially has not been born e out by more recent larger trials (28, 29). Regarding specifi c genetic testing, guidelines have been recently published by a European task force (27). In the case of ADCAs, testing should include SCA1, 2, 3, 6, and 7. Th ese tests are widely avail able. For episodic ataxias (EAs), testing for EA1 and EA2, available in specialist and research laboratories, is recommended. Concerning ARCAs, testing for FRD A (widely available) should be initially requested. Testing for AT, AOA1 and AOA2 should be done in patients with positive biochemical fi ndings, such as hypoalbu- minaemia, hypercho lesterolaemia or elevated alpha-fetoprotein (AFP). For the X-linked ataxias, testing for FX TAS, which is widely