Joubert syndrome Joubert syndrome is a rare genetically heterogeneous inherited con- genita l ataxia. It is characterized by hypotonia evolving into ataxia and developmental delay, ne onatal respiratory disturbances, and oculomotor abnormalities. It is defi ned by the presen ce of a char- acteristic MRI fi nding in the posterior fossa known as the \200\230molar to oth \200\231 sign (100). Gillespie syndrome Gillespie syndrome is a rare inherited congenital ataxia character- ized by the triad of ataxia, aniridia, and mental retardation. Th e genetic causes have not bee n fully elucidated. MRI reveals cerebel- lar, and especially vermal, hypoplasia (101). Hypothyroidism Hypothyroidism has long been recognized as a subacute to chronic cause of ce rebellar ataxia. Th yroxine treatment can reverse the symptoms (95). Acute-onset hereditary ataxias with or without intermittent course Episodic ataxias (EAs) T h e EAs are an expanding group of dominantly inherited disorders characterized by intermitt ent episodes of acute cerebellar dysfunc- tion, with more subtle residual neurological dysf unction between episodes. Th ey belong to the large family of hereditary channelopa- thies. Seven EAs have been recognized to date with four genes iden- tifi ed (Table 27.5), but the main forms are EA1 and EA2 (6, 102). Cerebellar ataxia with neuropathy and bilateral vestibular are \202 exia syndrome (CANVAS) CANVAS is a late-onset ataxia characterized by the triad of insidious-onset cerebellar dys function, bilateral vestibulopathy, and sensory neuronopathy. Initially described in the ea rly 1990s, it was recognized as a distinct syndrome in 2004. Patients charac- teristically have an impaired visually enhanced vestibulo-ocular refl ex. Brain MRI shows cerebellar atr ophy in most cases. Th e iden- tifi cation of two aff ected sibling pairs has raised the po ssibility of a late-onset recessive disorder (96). Episodic ataxia 1 EA1 is an autosomal dominant potassium channelopathy caused by mutations in the KCNA1 gene. It is characterized by brief attacks of ataxia (lasting seconds to minut es), oft en triggered by emotional stress, fatigue, postural changes or startle, and interi ctal myokymia. Onset is in childhood. It may respond to antiepileptic medications or acetaz olamide (103). Multiple system atrophy (see also Chapter 13) Multiple system atrophy (MSA) is a late-onset (usually sixth dec- ade) progressive neurodegenerative disease characterized by severe dys autonomia, parkinsonism, and cerebellar ataxia. In around 20% of European patients the cere bellar component is initially predominant (MSA-C), and the other manifestations only become obvious with time (1). MSA represents around 30% of adult-on- set cerebellar ataxias (26). It is associated with severe brainstem and cerebellar atrophy, as well as pontine and midd le cerebellar peduncle hyperintensity (1). Consensus criteria that assist in the diagnosis of MSA have recently been published by an international task force (97). Treatment of the c erebellar component of MSA is disappointing (21). Episodic ataxia 2 EA2, the most common EA, is an autosomal dominant calcium channelopathy c aused by mutations in the CACNA1A gene. It is characterized by more prolonged attacks of at axia (lasting hours to days), oft en triggered by exercise, emotional stress, caff eine, or alcohol, and interictal residual ataxia with nystagmus. Onset, as in EA1, is in childhood. Acute attacks respond well to acetazolamide. EA2 is allelic to familial hemiplegic migrain e (FHM) and SCA6 (104). Idiopathic late-onset ataxia Idiopathic late-onset ataxia (ILOCA) is the most common late-o n- set cerebellar ataxia (5). As with MSA, onset is in the sixth decade. However, although slowly progressive, it is a more benign condi- tion and the lasting absence of dysautonomia diff erentiates it from MSA-C. It is characterized by a relatively pure cerebellar ataxia with mild sensory and pyramidal signs (1). Diagnosis can only be made Inborn errors of metabolism Inborn errors of metabolism can present with acute or intermitt ent ataxia oft en due to metabolic decompensation in response to diet- ary intake or interc urrent illness. Inheritance is usually autosomal recessive. An early-onset ataxia with inte rmittent course, associated Oxford Textbook of Movement Disorders 292 Table 27.5 Th e hereditary episodic ataxias (all autosomal dominant) Duration of Episodic a ttacks ataxia Seconds to minutes EA1 Gene/locus Frequency Other manifestations Interictal manifestations Myokymia Clinical notes KCNA1 /12q13 CACNA1A /19p13 Relatively common None EA2 Most common Hours to days Vertigo, nausea, vomiting, headache Ataxia, nystagmus Progressive ataxia EA3 1q42 Rare Minutes to hours Vertigo, tinnitus, myokymia None EA4 NK Rare Brief Vertigo, diplopia Ataxia, nystagmus Later onset, progressive ataxia EA5 CACNB4beta / 2q22 \200\22323 Rare Hours Vertigo Ataxia, nystagmus, seizures Progressive ataxia EA6 SLC1A3 /p13 19q13 Rare Hours Cognitive impairment Ataxia, seizures Progressive ataxia EA7 Rare Hours to days Vertigo, dysarthria None EA, episodic ataxia; NK, not known encephalopathy, seizures, and developmental delay should raise the possibility of inherited metabolic ataxia, especially urea cycle disorders (including ornithine transcarbamylase de fi ciency, which is X-linked), amino acidopathies (including Hartnup and maple syrup urine disease), organic acidopathies (including biotinidase defi ciency), and pyruvate dehydrogen ase defi ciency. Screening for these disorders might include a full blood count, liver func tion tests, arterial blood gasses, blood ammonia, lactate, pyruvate, and ketone, plasma and urinary amino acids, urinary organic acids, and serum biotinidase (Table 27.3) (105). Th e rapeutic management includes dietary restrictions and vitamin administration, such as bioti n in the case of biotinidase defi ciency (106). MRI may show some cord but no cerebellar atrophy. Th e disease is caused by a triplet GAA e xpansion in the FRDA gene coding for frataxin (12). Antioxidants, such as vitamin E, co-enz yme Q10, and idebenone have been used in FRDA with very limited therapeutic success (12). Ataxia with vitamin E de \201 ciency (AVED) Th e clinical phenotype of AVED is very simila r to FRDA. However, cardiomyopathy and diabetes are much more common in FRDA, whereas titub ation and dystonia appear to be specifi c for AVED. Very low levels of vitamin E are charac teristically found in AVED, and this allows the correct diagnosis. Administration of vitami n E supplements can arrest disease progression. Th e disease is caused by a mutation in the ATPP gene coding for alpha-tocopherol trans- fer protein, but genetic diagnosis is usually unnecessary (108). Insidious-onset hereditary ataxias with chronic progression Autosomal recessive cerebellar ataxias Most ARCAs are early-onset disorders, although exceptions to this rule are well doc umented. Th ey are characterized by spinocerebel- lar ataxia, involving both the cerebellum and the dorsal columns, with associated peripheral neuropathy, oft en leading to arefl exi a, and common involvement outside the nervous system (12). Th e prototype and most common A RCA is FRDA. MRI can help dis- tinguish between the ARCAs by revealing the presence or abse nce of cerebellar atrophy. FRDA, AVED, abetalipoproteinaemia (ABL), and RD are characterize d by the absence of cerebellar atrophy. Th e remaining ARCAs show cerebellar atrophy (12). Table 27.6 sum- marizes the most widely recognized ARCAs. Ataxia telangiectasia and ataxia telangiectasia-like disorder AT is the second most common ARCA with a prevalence of 1 \200\2232.5 per 100 000 (99). Onset is usually by the age of 2 years (109). It is characterized by progressive ataxia, oculomotor apraxia, ocu- locutaneou s telangiectasias, immunodefi ciency, and a predilec- tion for malignancy, especially leuke mia and lymphoma. Most patients have elevated AFP levels. MRI reveals cerebellar atrophy (9 9). AT is caused by mutations in the ATM gene which is involved in the DNA damage response pathway (109). AT-like disorder is clinically similar to AT but with later onset, slower pr ogression, no telangiectasias, and normal AFP. It is caused by mutations in the meiotic rec ombination 11 gene ( MRE11 ) (12). Th e progressive myoclonic epilepsies (PMEs), which include Unverricht \200\223Lundborg dis ease and Lafora body disease, are char- acterized by myoclonus, tonic \200\223clonic seizur es, progressive cerebel- lar ataxia, and cognitive decline. Th ey are briefl y mentioned he re because they are mostly autosomal recessive disorders. A more detailed discussion of the PMEs is beyond the scope of this chapter. Ataxia with oculomotor apraxia 1 (AOA1) AOA1 has a clinical phenotype that is similar to AT , although onset is usually a few years later and patients do not develop telangiectasias o r have a predilection for malignancy. Oculomotor apraxia is oft en the fi rst symptom, and chorea may also be common at onset. Most patients have a degree of cognitive impairment (11 0). Laboratory studies reveal normal AFP, hypoalbuminaemia, and hypercholes- terolaemia (11 1). AOA1 is common in Portugal and Japan (18). It is caused by mutations in the APTX gene c oding for aprataxin (112). Friedreich \200\231s ataxia FRDA is the most common hereditary ataxia with a prevalence of around 2 \200\2233 in 100 000 (107). Age at onset is usually between 5 and 25 years. It is characterized neurologically by progressive gait and limb ataxia, dysarthria, loss of posit ion and vibration sense, arefl exia, and extensor plantars. Cardiomyopathy, diabetes, scoli o- sis, and pes cavus are common non-neurological manifestations. Ataxia with oculomotor apraxia 2 (AOA2) AOA2 is the third most common ARCA and represents a round 8% of non-FRDA ARCAs (113). It has a neurological phenotype CHAPTER 27 Hereditary and acquired cerebellar ataxias 293 Table 27.6 A clinically oriented classi \201 cation of the autosomal recessive cerebellar ataxias (ARCAs) and X-linked cerebellar ataxias, based on disease frequency data* Inheritan ce Disease Frequency (% of ARCAs) 40% Gene/locus Genetic basis Clinical pointers/notes Autosomal recessive FRDA FRDA /9q13 GAA repeat Cardiomyopathy, diabetes AT 10% ATM /11q22 \200\22323 CM Telangiectasias not always identi \201 able, oculomotor apraxia, immunode \201 ciency AOA2 4 \200\2235% SETX /9q34 APTX /9p13 CM 50% have oculomotor apraxia AOA1 Common in Portugal and Japan CM Chorea, cognitive impairment WD Not rare ATP7B /13q14.3 CM Parkinsonism, dystonia, tremor, Kayser \200\223 Fleischer rings, treatable AVED Rare TTPA /8q13.1 \200\22313.3 MRE11 /11q21 SACS /13q11 SIL1 /5q31 MTP /4q22 \200\22324 PHYH /10 pter-11.2 PEX7 /6q21 \200\22322.2 HEXA /15q23 \200\22324 CYP27 /2q33-ter Variable CM Titubation, cardiomyopathy, treatable AT-like disorder Rare CM Oculomotor apraxia ARSACS Rare CM Common in Quebec province MSS Rare CM Cataracts and mental retardation ABL Rare CM Retinitis pigmentosa, treatable RD Rare CM Anosmia, retinitis pigmentosa, treatable GM2 gangliosidosis Rare CM Amyotrophy, psychiatric symptoms CTX Rare CM Spasticity, tendon xanthomas, treatable Ataxia with co-enzyme Q10 de \201 ciency Rare Seizures, are \202 exia, treatable NPC Rare NPC1 /18p11 NPC2 /14q24 ARSA /22q13.33 EIF2B1 \200\2235 /5 loci FMR1 /Xq27.3 ABCD1 /Xq28 PL P /Xq22 CM Vertical gaze palsy, dystonia, psychiatric symptoms, treatable MLD Rare CM Spasticity, cognitive impairment VWMD Rare CM Rapid deterioration following infection X-linked FXTAS Uncommon CGG repeat Late-onset, pre-mutation ADL Rare CM Spasticity PMD Rare CM Spasticity ARCAs have an overall prevalence of 7 in 100 000. FRDA, Friedreich \200\231s ataxia; AT, ataxia telangiectasia; CM, conventional mutations; A OA, ataxia with oculomotor apraxia; WD, Wilson disease; AVED, ataxia with vitamin E de \201 ciency; ARSACS, autosomal recessive ataxia of Charlevoix-Saguenay; MSS, Marinesco \200 \223Sj gren syndrome; ABL, abetalipoproteinaemia; RD, Refsum \200\231s disease; CTX, cer ebrotendinous xanthomatosis; NPC, Niemann \200\223Pick disease type C; MLD, metachromatic l eucodystrophy; VWMD, vanishing white matter disease; FXTAS, fragile X tremor \200\223ataxia syndrome; ALD, adrenoleucodystrophy; PMD, Pelizaeus \200\223Merzbacher disease. diagnosis in unusual cases and can also allow presymptomatic screening of relatives and ear ly treatment before the onset of com- plications (115). that is very similar to AT and AOA1, although only about 50% of patients have oculomotor ap raxia. Onset is later than in either AT or AOA1 (usually the second decade). Laboratory stu dies reveal elevated AFP and hypercholesterolaemia (113). AOA2 is caused by mutations in th e SETX gene coding for senataxin (114). Marinesco \200\223Sj gren syndrome (MSS) MSS is a rare ARCA characterized by cerebellar ataxia, cataracts, mental retardation, hypogonadotrophic hypogonadism, short stat- ure, and skeletal abnormalities (116). In a recent epidemiological study in France, it was found to be as common as AOA1 (117). MSS is caused by mutations in the SIL gene coding for the BiP- associated protein (116). Wilson disease (see also Chapter 23) WD has a prevalence of 1 \200\2233 in 100 000. It usua lly presents in the second or third decade. It has hepatic, neurological, ophthal- mic, and psychiatric manifestations. Around 40 \200\22350% of patients present with CNS symptoms. I n a minority of these patients, cer- ebellar ataxia can be a prominent symptom, oft en asso ciated with postural tremor. Patients with WD have Kayser \200\223Fleischer rings on slit-l amp examination, reduced serum caeruloplasmin, and high urinary copper. Treatment with copp er chelating agents should be started as soon as possible to prevent neurological deteriora - tion. WD is caused by mutations in the APT7B gene coding for a copper-dependent ATPase. A lthough systematic genetic test- ing for WD remains diffi cult, it can be valuable in confi rming the Autosomal recessive spastic ataxia of Charlevoix-Saguenay Autosomal recessive spastic ataxi a of Charlevoix-Saguenay (ARSACS) is characterized by progressive cerebellar ataxia, pyrami dal signs, and a sensorimotor neuropathy (mixed demyeli- nating \200\223axonal) with amyotr ophy. It was originally described and is commonly found in the province of Quebec in Canada (118). However, more recently it has been found in several other regions. Oxford Textbook of Movement Disorders 294 ARSACS is caused by mutations in the SACS gene coding for sacsin (12). and glycolipids. It is rare, with a frequency of less than 1 in 100 000. Characteristic cli nical features include hepatosplenomegaly, ver- tical gaze palsy, ataxia, dystonia, seizure s, and neuropsychiatric impairment. Cerebellar ataxia is prominent in late-onset forms (127 ). Diagnosis is by demonstrating impaired intracellular cho- lesterol transportation and ho meostasis in cultured fi broblasts, followed by genetic testing. NPC is caused by mutations in NPC1 and NPC2 , coding for a membrane glycoprotein and a lysosomal protein, respectivel y. Miglustat, an inhibitor of glycosylceramide synthase, has recently been shown to have si gnifi cant disease-modifying eff ects in NPC (127). Ataxia with co-enzyme Q10 de \201 ciency Ataxia with co-enzyme Q10 defi ciency is a rare g enetically hetero- geneous disorder with phenotypic variability. Th e ataxic variant is the most common and is characterized by cerebellar ataxia, nystagmus, pyramidal signs, absent refl exes, and seizures. Diagnosis is based on reduced co-enzyme Q10 levels in muscle (119) . Disease progression may be arrested by treatment with co-enzyme Q10 (120). GM2 gangliosidosis GM2 gangliosidosis in its classic infantile form is characterized by hyp otonia, developmental delay, seizures, blindness, the pres- ence of a \200\230cherry-red s pot \200\231 on fundoscopy, and early death (121). However, late-onset disease oft en prese nts as a cerebellar syndrome with arefl exia, amyotrophy, and psychiatric features (122). T h e disease is caused by mutations in the HEXA gene coding for the enzyme beta-hexosaminida se A. In the late-onset form at least one allele with a less severe mutation results in som e residual enzyme activity (122). Metachromatic leucodystrophy Late-onset metachromatic leucodystrophy (MLD) can present with cerebellar ataxia associated with pyramidal signs, cognitive or psy- chiatric disturbances , and a demyelinating neuropathy (128). It is caused by defi ciency of the enzyme arylsulfa tase A as a result of mutations in the ASA gene. Patients with late-onset MLD are oft en ho mozygous for an allele which allows low enzyme expres- sion (129). Vanishing white matter disease Vanishing white matter disease (VWMD) is a childhood-onset c er- ebellar ataxia, accompanied by spasticity and mild mental decline. Characteristically, the clinical picture can rapidly deteriorate fol- lowing infection or minor trauma. MRI is pathognomonic, reveal- ing progressive rarefaction and cystic degeneration of white matter. VWMD is caused by mutations in the EIF2B 1 \200\223 5 genes coding for the fi ve subunits of a eukaryotic translation initiation factor (130). Abetalipoproteinaemia (ABL) ABL is a rare disorder with a frequency of less than 1 in 100 0 00. Th e fundamental biochemical defect is absence of apolipoprotein-B-containing lipoprote ins. All patients have fat malabsorption, acanthocytosis, hypocholesterolaemia, and absent apoB. Lipid-soluble vitamin malabsorption results in cerebellar ataxia. Th e neurological p icture of ABL can resemble FRDA with additional retinitis pigmentosa. ABL is caused by muta tions in the MTP gene coding for microsomal triglyceride transfer protein. Treatment includ es dietary modifi cation and vitamin supplemen- tation, which may prevent or improve neurol ogical complications (123). Autosomal dominant cerebellar ataxias Th e ADCAs, referred to as SCAs in the genetic nomenc lature, are a rare cause of cerebellar ataxia with an overall prevalence around half that o f ARCAs (7). Onset is usually in the third or fourth dec- ade, although exceptions to this rule with onset in childhood or old age are well documented (8). Th e list of SCAs is ever- expanding, currently standing at 30, including dentatorubral-pallidoluysian atrophy (DRPLA) (8, 13, 131). Refsum \200\231s disease (RD) RD is a rare disorder that usually presents in late childhood with anosmia and visual deterioration caused by retinitis pigmentosa. With progression, ce rebellar ataxia, demyelinating polyneuropa- thy, ichthyosis, and cardiomyopathy are added t o the picture. Th e pathognomonic fi nding is a highly elevated plasma phytanic acid. RD is caused by mutations in the PHYH gene coding for the peroxi- somal enzyme phytanoyl-CoA hyd roxylase, and less commonly in the PEX7 gene coding for peroxin 7 receptor protein. Treatme nt is by dietary restriction of phytanic acid, which can gradually improve neurological com plications (124). Several SCAs are caused by coding CAG repeat expansions and are known as \200\230polygluta mine expansion SCAs \200\231 (SCA1, 2, 3, 6, 7, 17 and DRPLA). With the notable exception o f SCA6, these SCAs are prone to the phenomenon of genetic anticipation, with successive gen erations having larger CAG expansions, younger disease onset, and more severe disease cours e. Th is is particularly true for DRPLA and SCA7 (8). Before the era of molecular diagnostics, Harding (132) sug- gested a way of classifying the se disorders, which is still clinically useful. Type I ADCAs are \200\230complicated ataxi as \200\231 characterized by cerebellar ataxia plus optic atrophy, ophthalmoplegia, dementi a, pyramidal signs, extrapyramidal features, and amyotrophy. Type II ADCAs include only SCA 7, which is a complicated ataxia like type I ADCAs, but in addition features visual loss du e to pigmentary retinal degeneration. Type III ADCAs are relatively \200\230pure ataxias \200\231, possibly with mild pyramidal signs. Cerebrotendinous xanthomatosis (CTX) CTX is a rare disorder of bile acid metabolism which r esults in abnormal deposition of cholestanol and cholesterol in multiple tissues. It is cha racterized by premature cataracts, tendon xantho- mas, cerebellar ataxia, pyramidal signs, peripheral neuropathy, and dementia. It is diagnosed by fi nding elevated serum cholestanol (125). CTX is caused by mutations in the CYP27 gene coding for the mitochondrial enzyme st erol 27-hydroxylase. Treatment is by administration of chenodeoxycholic acid, which can pre vent or improve the neurological symptoms (126). Th e ADCAs are characterized by brainstem and cerebellar atro- phy. In general, MRI reveals predominant brainstem atrophy with lesser cerebellar atrophy in ADCA I and II and cerebell ar atrophy without brainstem atrophy in ADCA III (8). However, overlap exists and it remain s unclear how useful this distinction is clinically (7). Niemann \200\223Pick disease type C (NPC) NPC is a neurovisceral lysosomal lipid storage di sorder character- ized by intracellular accumulation of cholesterol, sphingomyelin, CHAPTER 27 Hereditary and acquired cerebellar ataxias 295 Only the most common SCAs are discussed briefl y in this chap- ter. Th e rest are included for reference in Table 27.7. To aid the clin- ician, SCAs have been classifi ed in order of descending frequency in the table. into ophthalmoplegia, pyramidal signs, extrapyramidal signs, amyotrophy, peripheral neuropa thy, and cognitive impairment (133, 134). Onset is usually in the fourth decade. SCA1 is ca used by an exonic CAG repeat expansion in the ATXN1 gene coding for ataxin-1 (8). Gerstmann \200\223Str ussler \200\223Scheinker disease is discussed briefl y in this sec tion as it is an autosomal dominant trait, although it is not part of the SCAs. SCA2 SCA2 represents around 15% of SCAs (6). It is similar clinically to SCA1 but might be diff erentiated by the prominence of saccadic slowing, hyporefl exia, tremor, and titubatio n (135). SCA2 is caused by an exonic CAG repeat expansion in the ATXN2 gene coding for atax in-2 (8). Type I autosomal dominant cerebellar ataxias SCA1 SCA1 represents around 10% of SCAs (7). I t is characterized by cerebellar ataxia, dysarthria, oculomotor abnormalities evolving Table 27.7 A clinically oriented classi \201 cation of the autosomal dominant cerebellar a taxias (ADCAs) based on Harding \200\231s scheme and disease frequency data* Harding classi \201 cation SCA class Frequency (% of ADCAs) 20 \200\22350% Gene/locus Genetic basis Clinical pointers/notes ADCA I (ataxia optic atrophy, ophthalmoplegia, dementia, extrapyramidal features, amyotr ophy) SCA3 ATXN3 /14q24.3 \200\22331 CAG repeat Prominent extrapyramidal features SCA2 15% ATXN2 /12q24 CAG repeat Slow saccades, reduced re \202 exes SCA1 10% ATXN1 /6p23 TBP /6q27 PPP2R2B /5q31 \200\22333 ATN1 /12p13.31 AFG3L2 /18p11.22q11.2 ATXN8 a nd ATXN8OS /13q21 NK CAG repeat SCA17 3% CAG repeat HD-like features, seizures SCA12 7% in India CAG repeat Arm tremor DRPLA Common in Japan CAG repeat HD-like features, myoclonus SCA28 <1% CM SCA8 Probably rare CTG repeat Uncertain pathogenicity SCA9 Probably rare NK SCA10 Probably rare ATXN10 /22q13 KCNC3 /19q13.3-q13.4 7q31 ATTCT repeat Seizures SCA13 Probably rare CM Cognitive impairment SCA18 Probably rare NK SCA19 Probably rare 1p21-q21 NK SCA20 Probably rare 11q12 NK Dysphonia SCA21 Probably rare 7p21 NK Extrapyramidal features SCA25 Probably rare 2p11-p21 NK Severe sensory neuropathy SCA27 Probably rare FGF14 /13q34 TGM6 /20p13 ATXN7 /3p21.1-p12 CM SCA35 Probably rare CM ADCA II (as ADCA I + pigmentary retinal degeneration) SCA7 3 \200\2235% CAG repeat Visual loss ADCA III (pure cerebellar ataxia mild pyramidal signs) SCA6 15% CACNA1A /19p13 BEAN-TK 2 / 16q22 16q22 CAG repeat Late onset, allelic to EA2 SCA31 Common in Japan TGGAA repeat SCA4 Probably rare NK SCA5 Probably rare SPTBN2 /11q13 TTBK2 /15q14-q21.3 PRKCG /19q13.4-qter ITPR1 /3p26-p25 1p21-q23 CM SCA11 Probably rare CM SCA14 Probably rare CM Myoclonus SCA15/16 Probably rare CM SCA22 Probably rare NK Allelic to SCA 19 SCA23 Probably rare PDYN /20p13 19p13 CM SCA26 Probably rare NK SCA30 Probably rare 4q34 NK ADCAs have an overall prevalence of around 3 in 100,000 but this, along with the frequency of individual SCAs, can vary considerably according to country of origin. ADCA, autosomal dominant cerebellar ataxia; SCA, spinocerebellar ataxia; DRPLA, dentatorubr al-pallidoluysian atrophy; CM, conventional mutations; HD, Huntington \200\231s disease; NK , not known. Oxford Textbook of Movement Disorders 296 Gerstmann \200\223Str ussler \200\223Scheinker disease Gerstmann \200\223Str ussler \200\223Scheinker disease (GSS) is an autosomal dominant hereditary prion disease which cla ssically presents as a chronic cerebellar ataxia with associated pyramidal signs. Dementia develops later in the course of the disease. Th e EEG in these patients lacks the typical p eriodic discharges seen in sCJD. GSS is caused by mutations in the PRNP gene, usually a Pro 102Leu amino acid substitution (76). SCA3 SCA3, also known as Machado \200\223Joseph disease, is the most com- mon SCA with a fr equency of 20 \200\22350% among SCAs (6). Its pheno- type is amongst the most variable of S CA phenotypes, but typical type I ADCA signs are found in most patients (7). Dystonic \200 \223rigid extrapyramidal features can be prominent. SCA3 is caused by an exonic CAG repeat expansion in the ATXN3 gene coding for ataxin-3 (8). SCA17 SCA17 is a rare SCA, with a frequency of around 3% in some ADCA populations (136). It has a highly variable disease phenotype. A proportion of patients have a predominantly ata xic phenotype, but others may present with a Huntington \200\231s disease-like phenotype (1 37). SCA17 is caused by an exonic CAG repeat expansion in the TBP gene coding for a TATA-bi nding protein (8). X-linked cerebellar ataxias X-linked cerebellar ataxias were traditionally thought to be ve ry rare. However, with the delineation of FXTAS, they now form a small but signifi cant par t of neurodegenerative cerebellar disease (Table 27.6) (9, 141). Fragile X-associated tremor \200\223ataxia syndrome FXTAS is characterized by limb and gait ataxia associated with parkinsonian features, cognitive impairment, neuropathy, and dys au tonomia (141). It is seen in males carrying a pre-mutation (55 \200\223200 CGG repeats) in the FMR1 gene. Full mutation in the FMR1 gene (>200 repeats) causes fragile-X-associated me ntal retardation (142). Penetrance of FXTAS increases with age, and about 50% of males carr ying the pre-mutation will develop symptoms by age 60. Th e frequency of males carrying the pre-mutation in the general population (1 in 800) should make FXTAS a relatively common ca use of late-onset cerebellar ataxia. However, in ataxia series the percentage of FXTAS case s has been only around 2% and in MSA series only around 1% (9, 143). FXTAS has a very chara cteristic MRI appearance of hyperintense signal changes lateral to the den- tate nuclei and into the middle cerebellar peduncle (141). SCA12 SCA12 is rare in the West, but is relatively common in India, rep- resenting 7% of SC As (138). In addition to the more typical clinical features of type I ADCAs, it is characte rized by a postural tremor of the upper limbs (6). SCA12 is caused by a non-coding CAG repe at expansion in the PPP2R2B gene coding for protein phosphatase 2 (8). Dentatorubral-pallidoluysian atrophy DRPLA is rare worldwide, but is particularly prevalent in Japan (7). Myoclonic epilepsy is a typical feature of these patients, as is a neurologi cal presentation resembling Huntington \200\231s disease (139). DRPLA is caused by an exoni c CAG repeat expansion in the ATN1 gene coding for atrophin-1 (8). Type II autosomal dominant cerebellar ataxias SCA7 SCA7 represents around 3% of SCAs (7). I t is the only type II ADCA and is characterized by the presence of visual loss secondary to pigmentary macular degeneration (132). Th e fi rst signs of retinal involvement are reduce d central visual acuity and dyschromatop- sia in the blue \200\223yellow axis. SCA7 display s pronounced expanded repeat instability with prominent anticipation, and children some- ti mes develop symptoms before their parents (7). SCA7 is caused by an exonic CAG repeat expan sion in the ATXN7 gene coding for ataxin-7 (8). Adrenoleucodystrophy Adrenoleucodystrophy (ALD) can rarely present as a spinocerebel- lar v ariant with predominant ataxic features, usually associated with pyramidal signs (144). ALD is diagnosed by the presence of very-long-chain fatty acids in peripheral blood. MRI abnor mali- ties in some of these patients may be restricted to the brainstem and cerebellum and resemble patients with ADCAs (145). ALD is caused by mutations in the ABCD1 gene, which cod es for a peroxi- somal ATP-binding cassette transporter (144). Pelizaeus \200\223Merzbacher disease Pelizaeus \200\223Merzbacher disease is another rare X -linked leucodys- trophy with cerebellar ataxia and nystagmus as prominent features, in add ition to spastic paraparesis. It is caused by mutations, usu- ally duplications, in the PLP gene and is allelic to type 2 X-linked hereditary spastic paraplegia (146). Type III autosomal dominant cerebellar ataxias SCA6 SCA6 represents around 15% of SCAs (7). It is the prototype type III ADCA, characterized by relatively \200\230pure \200\231 cere bellar ataxia, although mild pyramidal signs and peripheral neuropathy may develop. Another characteristic feature of SCA6 is its late onset, with 60% of patients developing symptoms aft er age 50 (7). It is thus commonly found in patients with apparently sporadic cerebel- lar ataxia. SCA6 is caused by an exonic CAG repeat expansion in the CACNA1A gene coding fo r a calcium channel subunit (8). It is therefore a channelopathy allelic to FHM and EA2 (10 4). Mitochondrial cerebellar ataxias Mitochondrial disorders (MIDs) encompass an ever-expanding spectrum of disease. Th ey can be caused by defects of mitochon- drial or nuclear DNA and hence can follow autosomal, X-linked, or maternal patterns of inheritance or be sporadic. M IDs are mul- tisystem disorders. Th ey can include involvement of the peripheral and centra l nervous systems, endocrine glands, heart, eyes, inner ears, gastrointestinal tract, kidne y, bone marrow, and skin. One of the most prevalent CNS manifestations of MIDs is cerebella r ataxia (14). SCA31 SCA31 has only recently been identifi ed and is thought to rank as the third most com mon SCA in Japan, aft er SCA3 and SCA6 (140). It is a type III ADCA, presenting as \200 \230pure \200\231 cerebellar ataxia. SCA31 is caused by a non-coding TGGAA repeat expansion in the BEAN and TK2 genes (140). Ataxia can be a prominent manifestation of both syndromic and non-syndromic MIDs (14). Mito chondrial syndromes associated CHAPTER 27 Hereditary and acquired cerebellar ataxias 297 Table 27.8 Mitochondrial syndromes associated with cerebellar ataxia Mitochondrial syndrome Other extracerebella r manifestations Gene Mutations in mitochondrial DNA MELAS Stroke -like episodes, lactic acidosis, dementia, deafness, seizures, myopathy Myoclonus, s eizures, deafness, myopathy tRNALeu, tRNASer tRNALys RC subunits MERRF LHON Optic neuropathy, peripheral neuropathy NARP Neuropathy, retinitis pigmentosa, dementia, seizures ATP6 ND1 \200\2236, ATP6, COXIII, tRNALys MILS Developmental delay, pyramidal signs, extrapyramidal signs, lactic acidosis, neuropathy PS Pancytopenia, developmental delay, hepatic involvement, kidney failure Deletions in mitochondrial DNA KSS Ophthalmoplegia, retinitis pigmentosa, arrhythmias, elevated CSF protein Deletions in mitochondrial DNA MIDD Diabetes, sensorineural deafness tRNALeu, tRNALys tRNALys MSL Multiple lipomas, PEO, myopathy, neuropathy Mutations in nuclear DNA LS Developmental delay, pyramidal signs, extrapyramidal signs, respiratory failure, seizures, lactic acidosis SURF1, NDUFS1 \200\2238, NDUFV1 \200\2232 PEO Ophthalmoplegia, myopathy, deafness, neuropathy POLG1, C10orf2 (Twinkle), ANT1 POLG1, C10orf2 POLG1, C10orf2, ANT1 POLG1 TYMP OPA1 C10orf2 SANDO Neuropathy, ophthalmoplegia, myopathy SCAE Seizures AS Developmental delay, seizures, stroke-like episodes, hepatic failure MNGIE Nausea, vomiting, diarrhea, ophthalmoplegia, neuropathy, myopathy ADOAD Optic atrophy, deafness, neuropathy, ophthalmoplegia, myopathy IOSCA Seizures, extrapyramidal signs, deafness, ophthalmoplegia, hypogonadism, neuropathy MIRAS Mild cognitive impairment, involuntary movements, psychiatric symptoms, seizures POLG1 MEMSA Seizures, myopathy, neuropathy POLG1 ABC7 XLSA/A Sideroblastic anemia MELAS, mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes; MERRF, myocl onic epilepsy with ragged red \201 bres; LHON, Leber \200\231s hereditary optic neuropath y; NARP, neurogenic muscle weakness, ataxia, retinitis pigmentosa; MILS, maternally inherit ed Leigh syndrome; PS, Pearson syndrome; KSS, Kearns \200\223Sayre syndrome; MIDD, mitochon drial diabetes and deafness; MSL, multiple systemic lipomatosis; LS, Leigh syndrome; PEO, p rogressive external ophthalmoplegia; SANDO, sensory ataxic neuropathy, dysarthria, ophthalm oplegia; SCAE, juvenile-onset spinocerebellar ataxia and epilepsy; AS, Alpers syndrome; MNG IE, mitochondrial neuro-gastrointestinal encephalomyopathy; ADOAD, autosomal dominant optic atrophy and deafness; IOSCA, infantile onset spinocerebellar ataxia; MIRAS, mitochondrial recessive ataxia syndrome; MEMSA, myoclonus epilepsy myopathy and sensory ataxia; XLSA/A, X -linked sideroblastic anemia with ataxia. with ataxia are shown in Table 27.8 (14, 18). An ataxic syndrome caused by mutations in the POLG1 gene is increasingly recognized as a common form of autosomal recessive ataxia in Eu ropean popu- lations (147). recessive, X-linked, and mitochondrial ataxic syndromes have been characterized at the mole cular level. In the case of SCAs, the causative genes for SCA5, 10, 11, 13, 14, 15/16, 27, 28, 31, and 35 have recently been identifi ed (8, 13). It is primarily the group of convent ional-mutation SCAs that has been rapidly growing in recent years. In fact, the causative g ene for SCA35 was the fi rst to be identifi ed through exome sequencing (13). Among the ARC As, genes for MSS, AOA1, and AOA2 have also been identifi ed in the past decade (14). Th e clinical delineation of FXTAS was also one of the major recent breakthroughs in the ataxia fi eld (141). Finally, mitochondrial ataxias caused by nuclear genes such as POLG1 , Twinkl e, and ANT1 have only recently been adequately recognized and diagnosed (14). Mitochondrial recessive ataxia syndrome (MIRAS) due to POLG mutations MIRAS is a common for m of autosomal recessive ataxia. It is char- acterized by cerebellar ataxia, dysarthria, mi ld cognitive impair- ment, involuntary movements, psychiatric symptoms, and seizures (147). It is caused by homozygous or compound heterozygous mutations in the POLG1 gene coding for the mitochondrial DNA polymerase gamma catalytic subunit (14). It should be noted that mut ations in POLG1 can cause, beyond MIRAS, extensively hetero- geneous phenotypes (148). Advances in immunology have also added new knowledge to the fi eld through the identifi cat ion of novel antineuronal antibod- ies associated with paraneoplastic CD, such as mGluR1, Z ic4, and PKCgamma (62). Key advances Advances in the genetic etiology of heredoataxias have domi- nated the ataxia fi eld over the past 10 years. New knowledge has been accumulating at an impressive rate an d numerous dominant, In the case of polyglutamine expansion disorders, knowledge of the genetic etiology has all owed the development of cell and animal models. Th ese have been used in the past decade fo r the development Oxford Textbook of Movement Disorders 298 of potential disease-modifying therapies. Strategies explored include the use of RNA interf erence to silence gene expression, the adminis- tration of histone deacetylase inhibitors t o counteract the inhibitory action of mutant polyglutamine proteins on histone acetyltrans- ferases, and the overexpression of chaperone proteins such as HSP70 that prevent protein m isfolding and aggregation (6, 149). Classifying ataxias according to the age of onset, the mode of onset, the disease course, a nd the presence of family history can assist in making a correct diagnosis. \227\206 MRI and molecular genetics have revolutionized the diagnosis of congenital, acquired and he reditary ataxias. \227\206 Regarding genetic testing: \227\206 Future developments Over the next few years the genetic characterization of heredo- ataxias is likely to expand further. More genes will be identifi ed and novel disease mechanisms w ill be uncovered. Th e proportion of genetically uncharacterized SCAs and ARCAs will gradua lly diminish. Th e use of new-generation sequencing techniques, such as exome sequencing, w ill allow the discovery of new genes that are diffi cult to identify using more traditional genetic methodology. \227\206 In early-onset ARCAs, testing for FRDA is recommended. Positive biochemical fi nd ings should guide testing for AT, AOA1, and AOA2. AVED should be excluded. \227\206 In ADCAs, testing for SCA1, 2, 3, 6, and 7 should be off ered. In the case of EAs testing for EA1 and 2 should be off ered if available. \227\206 If X-linked inheritance is suspected, testing for FXTAS is recommended. Advances are also likely to be made in the development of poten- tial disease-modifying the rapies through the continuing use of cell and animal models of polyglutamine disease. It is not inconceivable that the fi rst phase I trials in human subjects may commence. Th e abil ity to identify pathogenic mutations early, in presymptomatic individuals, provides an inva luable window of opportunity for the administration of agents that may prevent disease deve lopment. Th ere is every reason to be optimistic that in the more distant future such debil itating diseases may be preventable. \227\206 Th e possibility of a mitochondrial ataxia should always be borne in mind, especi ally disorders caused by nuclear genes such as POLG1 . Prompt identifi cation of ataxic disorders which are amenable to disease-modifying treatmen t is very important. \227\206 Th e symptomatic and disease-modifying treatment of ataxias remains poor. \227\206 References 1. Klockgether T. Sporadic ataxia with adult onset: classifi cation and diag- Conclusions Th e cerebellar ataxias represent one of the most complex areas of clinical neu rology. Th e diversity of potential causes can seem daunting to any physician. Over the pas t two decades, neuroim- aging and molecular genetics have revolutionized the fi eld, delin- eating numerous distinct well-characterized syndromes. Although individual ataxic disorder s are relatively rare, the ataxias as a whole represent a common clinical problem. nostic criteria. Lancet Neurol 2010; 9 : 94 \200\22310 4 . 2. Edlow JA, Newman-Toker DE, Savitz SI. Diagnosis and initial manage- ment of cerebellar infarction. Lancet Neurol 2008; 7 : 951 \200\2236 4 .