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 . 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Th e introduction of chlo rpromazine in the early 1950s was a great advance in the treatment of psychosis, but it was soon realized that signifi cant neurological side eff ects are associated with this class of drugs. In fact, in the 1950s when it was noted that both chlorpromazine and reserpine in duced extrapyramidal side eff ects (EPS), despite being distinct chemical entities, it was thought that induction of EPS was integral to their clinical antipsychotic effi cacy. Recen t advances in drug development have revealed that this is not true and evidence implicates D2 receptor antagonism and the speed of dissociation of the drug from the receptor in the d evelopment of these EPS (DBAs with less D2 affi nity and more rapid dissociation are less l ikely to produce EPS). Over the last several decades, cumulative experience with the older (typical) and newer (atypical) neuroleptics has high- lighted the wide range of acute to mo re delayed movement disor- ders that may be caused by these agents (Table 28.1) (1). also showed a 2.4-fold higher risk of DBA-induced EPS in AIDS patients compared with age-ma tched psychotic patients without AIDS (7). Cocaine abuse may predispose to acute dystonic r eac- tions (8). Also, in contrast with other antidepressant medications, selective serotoni n-reuptake inhibitors (SSRIs) have been known to induce acute dystonic reactions, mostly ea rly in the course of treatment or aft er a dose increase (2). Th ese reactions have also be en reported with the dopamine depletor tetrabenazine, perhaps because of its partial dopami ne blocking activity. Although the pathophysiology of acute dystonia due to DBAs is unclear, it is well known tha t the propensity of any DBA to cause acute dystonia strongly correlates with its ability to block the D2 receptor in the striatum. It is through this D2-receptor mediated sig- nallin g that the DBA infl uences the intricate neuronal circuitry and modulates the cholinergic, GABAergic, and NO-synthase-positive interneurons in the striatum (2). As far as modulation of cholin- ergic signaling is concerned, one hypothesis is that dopaminergic hypofunction r esults in a relative overactivity of cholinergic mecha- nisms (9). Th is hypothesis is supp orted by a consistent response of acute dystonia to anticholinergic drugs. Another hypothes is pro- poses that DBAs induce paradoxical dopaminergic hyperfunction by blockade of presyn aptic dopamine receptors. As the level of the DBA decreases, postsynaptic receptors are exp osed to the natural release of dopamine from presynaptic terminals (10) which may precipita te the dystonia. Acute dystonia Acute dystonia occurs shortly aft er the introduction of the DBA and occasio nally aft er a dose increase. Estimates of incidence of acute dystonia from DBAs depend on several factors, such as patient population being studied, type and dosage of DBA used, and concurrent medications (2). Studies in patients with a fi rst episode of psychosis treated with DBAs have reported a 34 \200\22360% risk of developing drug-induced acute dystonia (2 \200\2234) and 50% of patients experience the fi rst signs of dystonia within 48 hours of drug intake (5). Clinical features Drug-induced dystonia can aff ect various regions of the body and can be very painful. Based on several prospective studies, Mazurek and Rosebush (2) reported that 42% of acute dystonic reactions involved torticollis or retrocollis as a clinical feature. Involvement of the facial muscles, which may range from grimacing and tight- ness to masse ter spasm, is another common fi nding. Although rare, other facial muscles causing blepharo spasm or lip curling may also be involved. Similarly, the limb muscles may also be involved , although less frequently. Some of the risk factors for developing acute dystonia aft er expo- sure to DBAs are young age, male sex, previous dystonic reaction, higher dose and high potency of DBAs, familial p redisposition, underlying psychiatric illness, mental retardation, and a history of electro convulsive therapy (2, 6). Interestingly, a retrospective study Some of the more severe clinical manifestations involve the throat musculature ( 19%) causi ng swallowing diffi culties or Oxford Textbook of Movement Disorders 304 the objective manifestations of restlessness in the form of move- ments of the limbs, a ten dency to shift body position in the chair while sitting, or marching while standing. Table 28.1 Movement disorders induced by dopamine blocking agents I. Acute \227\206 Acute dystonia Recent studies using large databases clearly indicate that akathisia occurs with the newer DBAs, although the frequency is not as high as with conventional antipsychotics. Th ese sym ptoms have also been associated with the administration of SSRIs. Other drugs that can caus e acute akathisia are listed in Table 28.2. Acute akathisia Drug-induced parkinsonism II. Chronic Tardive dyskinesia/stereotypy