Drug-induced dystonia Drug-induced dystonia may be of acute or delayed (tardive) onset and most commonly occurs with dopamine receptor blocking agents, such as neuroleptics (phenothi azines, butyrophenones, haloperidol, olanzapine, quetiapine) and antiemetics (metoclo- pram ide, prochlorperazine, promethazine). Agents which deplete dopamine, such as tetrabenazine, may also cause dystonia, and there are also reports of dystonia occurring with use of anti depres- sants (SSRIs, MAOIs), calcium antagonists, general anesthetic agents, anticonvulsan ts (carbamazepine, phenytoin), antimalarials, levodopa, ranitidine, ecstasy, and cocaine. Table 19.6 Clinical clues for diagnosing dystonia syndromes Features accompanying dystonia Ataxia peripheral neuropathy Condition Friedreich \200\231s ataxia Ataxia telangiectasia Niemann \200\223Pick type C Spinocerebell ar ataxia (e.g. SCA3) Metachromatic leucodystrophy Wilson disease Neuroacanthocytosis Acute dystonic reactions occur within hours or days of starting or rapidly increasing the d ose of antipsychotic medications (77). (Continued) Oxford Textbook of Movement Disorders 210 7. Ichinose H, Ohye T, Takahiashi E, et al. Hereditary progressive dysto- nia with marked d iurnal fl uctuation caused by mutations in the GTP cyclohydrolase I gene. Nat Genet 1994; 8 : 236 \200\2234 2. Table 19.6 (Continued) Features accompanying dystonia Dementia Condition 8. Furukawa Y, Guttman M, Sparagana SP, et al. Dopa-responsive dystonia due to a large dele tion in the GTP cyclohydrolase I gene. Ann Neurol 2000; 47 : 517 \200\2232 0 . 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Our better understanding of the range of clinical feat ures seen in this complex neuropsychiatric disorder and our ability to detect those earlies t changes is leading to a new era of drugs trials for HD with the prospect of identifying d isease-modifying agents. Th ere is also a new impetus to look at drugs to better treat the symptoms and signs of HD as well as better support the patients and their families in the c ommunity. In this chapter we outline some of these thera- pies as well as providing clinica l tips on how best to assess the HD patient. with full penetrance when the number of CAG repeats is >39 and with incomplete penetrance f or 36 \200\22339 CAG repeats (12, 13). The normal alleles range from 9 to 11 CAG repeats at the low end to 34 \200\22335 at the high end (14), and so every human being carries CAG re peats in the huntingtin gene. HD shows complete dominance, as no difference of phenotype is observed between homozygotes and heterozygotes apart from the fact that the homozygotes ma y progress more quickly (15, 16). There is, however, a strong correlation between the age o f onset in HD and the number of CAG repeats (13, 17). Furthermore, the tri- nucleotide repe at is unstable on replication and shows a pro- pensity to expand, particularly during sperm atogenesis (18, 19). This accounts for the phenomenon of genetic anticipation , in which th e age of onset of HD tends to diminish in successive generations, with juvenile-onset cases (i.e. HD before the age of 21 years) commonly arising from paternal transmission. A cis -a cting haplogroup A comprising 22 single-nucleotide poly- morphisms was identified, which ma y predispose Europeans to CAG instability (20). New-onset cases of HD with a negative famil y history can arise from a parent with an intermediate-size CAG repeat (27 \200\22335), whi ch has expanded into the pathological range in gametes (21). On the other hand, there is al so evidence for contraction of CAG repeats during transmission (21). Essential background Epidemiology HD is a rare genetic disorder which aff ects men and wome n equally (1). Th e prevalence rates are between 4 and 10 per 100 000 in Europe and the USA (2, 3), while HD is less frequent in Finland and Asian countries (around 0.5 per 100 000). In contrast, it is highly preva- lent in some isolated populations, e.g. Lake Maracaibo in Venezuela (>5000 per 100 000) and in secluded parts of Europe (4 \200\2236). Recent data f rom the UK Huntington \200\231s Disease Association suggests that the true prevalence of HD may be >12 per 100 000 (7). HD preva- lence rates are beginning to rise with improved care and life expect- ancy (8), although the numbers are confounded by the low rates of predict ive testing in the HD at-risk population. Moreover, the frequency of HD is likely to have b een underestimated in the black American and African populations, where considerable geneti c heterogeneity exists and the variant Huntington \200\231s disease-like 2 is more frequent (9, 10). Recently, normal and mutant huntingtin were found to inter- act to aff ect disease severity in HD, which weakens the associa- tion between mutant CAG repeat length and age of onset. Normal alleles at the high end are associated with an earlier age of onset when mutant CAG repeat length is low (36 \200\22344) and with a later age of onset when mutant CAG repeat l ength is >44 (17). In gen- eral, the CAG repeat number only explains 60 \200\22370% of the variance in age of onset, with the remainder being infl uenced by modifi er genes and the e nvironment (22). Th erefore we strongly recom- mend against making prognostic statements ba sed on the number of CAG repeats in the huntingtin gene. Indeed, to reinforce this point, i t has been reported that there is a remarkable phenotypic discordance for HD in monozygotic twins (23, 24), and CAG repeat length mosaicism may account for some of this (24). In term s of genetic modifi ers, polymorphisms in the glutamate receptor GluR6, the N -methyl- d -a spartate (NMDA) receptor subunits 2A/B (GRIN2A/B), and the huntingtin-associated protein 1 (HAP-1) genes have all been described (25, 26). Etiology and genetics HD is caused by a CAG (cytosine \200\223adenine \200\223guanine) trin ucle- otide repeat expansion in the first exon of the huntingtin gene on chromosome 4p (11) . Inheritance is autosomal dominant Oxford Textbook of Movement Disorders 214 Pathophysiology It was hoped that the identifi cation of the gene causing HD in 1993 would quickly lead to an understanding of the pathophysiology of the condition and with this a cu re. However, nearly 20 years later it is still unclear exactly how the mutant huntingtin ca uses disease, and indeed what the function of normal huntingtin is (see Fig. 20.1). defi cient in the huntingtin gene show early embryonic death prior to the formation of the nervous system (28). Reductions of hunting- tin levels below 50% result in structural abnor malities of the cortex and striatum (29), suggesting that huntingtin is implicated in nor- mal brain development and that loss of normal huntingtin func- tion may be at least in part involved in HD pathogenesis. In fact, huntingtin is an anti-apoptotic protein, which prote cts neurons from excitotoxic cell death (30). Normal huntingtin also stimulates the transcr iption of brain-derived neurotrophic factor (BDNF) and secures the vital delivery of BDNF t o striatal neurons via cortico- striatal aff erents, which may explain the particular vulne rability of these brain regions in HD (31). Importantly, normal huntingtin is Huntingtin is a ubiquitously expressed protein of high molecular weight (348 kDa). Th e CAG repeat in the huntingtin gene trans- lates into a polyglutamine (polyQ) strand in the N-te rminal part of this protein, which may have emerged more recently in evolution compared wit h the ancient rest of the molecule, along with more complex brain development (27). Hunting tin is a vital protein; mice Cortical pyramidal neuron BDNF mRNA \206\223 ROS Activated microglia/ macrophages Reduced microtubule transportation Astrocyte 3-HK \206\221 BDNF Dynactin KMO HAP-1 Reduced glutamate uptake GLT-1 \206\223 GLU \206\221 Proin \202ammatory cytokines/ROS BDNF \206\223 NMDAR TrkB Excitotoxicity P S D 9 5 Ca2+ \206\221 UPS, autophagy, chaperones \206\223 Mitochondrial dysfunction/ apoptosis intranuclear mHtt inclusions mHtt aggregates SREBP CREB SP-1 HAT/HDAC dysbalance REST RE1 Toxic mHtt fragments Caspase-6 cleavage Striatal medium spiny neuron Fig. 20.1 Potential pathogenetic mechanisms in HD. Mutant huntingtin (mHtt) is cleaved in t he cell by proteases resulting in toxic fragments, which aggregate and interfere with chape rone, proteasome (UPS), and macro-autophagy activities. In the nucleus, the polyglutamine ( polyQ) stretch in mHtt interacts with transcription factors/epigenetic modi \201 ers and i mpairs the expression of target genes, such as neurotransmitter receptors and brain-derived neurotrophic factor (BDNF). Medium spiny neurons in the striatum are particularly vulnerab le in HD. Th ey depend on BDNF which is delivered by cortical neurons, but less so in HD si nce vesicular transportation along microtubules is disturbed by mHtt. Medium spiny neurons also depend on glutamate release from cortical a \200 erents. In HD, excitotoxic damage re sults from enhanced NMDA glutamate receptor sensitivity on striatal neurons, reduced cleara nce of extracellular glutamate by the astroglial glutamate transporter (GLT)-1, and mHtt-me diated impairment of mitochondrial calcium bu \200 ering capacity, which promotes apoptosi s. Microglia and macrophages are activated in HD and secrete proin \202 ammatory cytokines . Kynurenine 3-monooxygenase (KMO) also produces 3-hydroxykynurenine (3-HK), a free radical generator (ROS) that mediates neuronal cell death. CHAPTER 20 Huntington \200\231s Disease 215 involved in intraneuronal vesicular transportation and axonal traffi cking (32), as well as synaptic transmission. to the acetyltransferase domain of the CREB-binding protein (CBP) and blocks its activity, resulting in reduced gene transcrip- tion (47). Th is can be overcome by the administration of histone deacetylase (HDAC) inhibitors. Besides transcriptional dysregu- lation, loss of BDNF in corticostriatal aff erents also results from impaired vesicular transportation of BDNF in HD, possibly as a result of reduced association of the huntingtin \200\223HAP-1 \200\223p150 dynactin complex with microtubules (48). An overwhelming body of evidence suggests that HD results from a toxic gain of function of the mutant huntingtin protein. Huntingtin has numerous sites for post-translational modifi ca- tions (e.g. phosphorylation, palmitoylation, acetylation, ubiq- uitination, and sumoyla tion) which control protein stability, localization, and function. Th ese processes can be impaired by mutant huntingtin, resulting in enhanced neurotoxicity due to reduced clearance by the proteasome, the lysosome, or autophagy (33, 34). Post-translational modifi cations also play a role in the proteolytic cleavage of huntingtin by caspases, calpain, and other proteases. Cleavage of huntingtin by caspase-6 appears to be a critical event in HD pathoge nesis (35). Proteolysis of huntingtin liberates toxic fragments with expanded polyQ, which are prone to aggregate. In fact, ubiquitinated mutant huntingtin aggre- gates are a neuropa thological hallmark of HD, and are present as nuclear and cytoplasmic inclusions in cortica l neurons and in the medium-sized spiny neurons in the striatum, which are par- ticularly v ulnerable to degeneration (36). Nuclear aggregates are mainly composed of N-terminal huntin gtin fragments compris- ing the polyQ strand, whereas cytoplasmic inclusions contain full-l ength and truncated mutant huntingtin (37). Aggregate formation occurs via soluble and non- soluble intermediates, including oligomers, globular intermediates, protofi brils, and amyl oid-like fi bres. Th e propensity of mutant huntingtin frag- ments to form amyloid-like agg regates depends on the polyQ repeat length, the protein concentration, and time (38), which may help to explain why disease manifestation requires a certain CAG repeat length. Failur e of the ubiquitin \200\223proteasome system (UPS) to degrade mutant huntingtin is implicat ed in aggregate formation and may explain the preferential vulnerability of neu- rons in HD , which have lower UPS activity compared with glia (39). However, controversy still exists over whether mutant hunt- ingtin aggregates are neurotoxic or neuroprotective. Toxicity cou ld arise from the sequestration of transcription factors in the nucleus or from interferenc e with the axonal transportation machin- ery. On the other hand, aggregation of mutant hunt ingtin could also represent an attempt by neurons to sequester toxic soluble oligomers and globular and protofi bril intermediates. Along these lines, pharmacological promotion of in clusion formation was found to reduce the toxicity of mutant huntingtin (40). Aggregate for mation could also be protective by stimulating the clearance of mutant huntingtin via autop hagy, i.e. the process of sequestra- tion of intracellular proteins and organelles by autop hagosomes and their subsequent degradation upon fusion with lysosomes (41). Th ere is ample evidence to suggest that mutant hunting- tin directly interferes with the cellular transcr iption machinery. Expanded polyQ repeat huntingtin can bind to DNA to repress transcription (42), or it can inhibit the activity of transcription factors and co-activators on gene pr omoters \200\224for example, SP1 and TFIID/TFIIF (43), CBP and CREB (44), and SREBP and SRE (45). Th e latter also implicate impaired brain cholesterol bio- synthesis in the pathogen esis of HD (46). Target genes of REST/ NRSF, including BDNF (promoter II), are downregulate d in HD as a result of loss of normal huntingtin function, increased REST/ NRSF release, an d activation of the nuclear RE1/NRSE silencer (46). Epigenetic modifi cations, such as acet ylation and deacetyla- tion of histones, also play a role in HD. Th e expanded polyQ binds Mutant huntingtin may promote problems within the local neu- ronal microenvironment and the dialog between neurons and glia, causing excitotoxicity in glutamate-rich areas, such as t he striatum. In fact, astrocytes, which express mutant huntingtin, fail to remove extracell ular glutamate because of the downregulation of the glial glutamate transporter GLT-1 (49). Moreover, striatal neurons show increased sensitivity of NMDA receptors as a result of red uced gene expression and increased calpain cleavage of the NR2B subunit (50). Th e polyQ in mutant huntingtin also impairs the ability of normal huntingtin to bind to the postsynapti c den- sity (PSD) 95 molecule, resulting in the sensitization of NMDA receptors (51). Loss of striatal cannabinoid CB1 receptors (52) and downregulation of dopamine D1 and D2 recepto rs (53) also render striatal neurons more sensitive to excitotoxicity. Th e over- activatio n of glutamate receptors results in increased intracellu- lar calcium concentrations in neu rons, worsened by the fact that mutant huntingtin also enhances calcium release via intrace llular inositol (1,4,5)-triphosphate receptors (54). In addition, mitochon- dria from patie nts with HD exhibit defects in calcium homeostasis, and they depolarize at lower calcium lo ads (55). Th e alterations in mitochondrial function may be due to direct deleterious eff e cts of mutant huntingtin on mitochondria, changes in energy metabolism and/or interaction o f mutant huntingtin with transcription factors that regulate the expression of genes respon sible for mitochondrial function, e.g. PGC-1 alpha (56). Mutant huntingtin also increases p 53 levels and promotes apoptosis (57). In addition, there is now great interest in the role of infl amma- tion in neurodegenerativ e processes within the brain. PET stud- ies revealed that microglia are activated in HD, an d the degree of microglial activation correlates with disease severity and striatal atrophy (58). Involvement of the innate immune system in HD is also emphasized by fi ndings of ele vated cytokine levels, such as interleukin 6, in the peripheral blood of pre-manifest HD ge ne carriers (59). Recently, a link between the kynurenine pathway generated by tryptophan d egradation and neurodegeneration was established (60). Kynurenine 3-mono-oxygenase (KMO) is expressed at high levels in macrophages and functions as a branch- ing point of the kynure nine pathway. KMO metabolizes kynurenine to 3-hydroxykynurenine (3-HK), a free-radical gene rator (ROS) that mediates neuronal cell death. Peripheral inhibition of KMO confers neuropr otection through the accumulation of kynurenic acid (60). Whatever the exact pathophysiological mechanisms in HD, the net result is neuronal dysfunct ion, shrinkage, and ultimately loss in a wide range of structures, which have traditionally been classifi ed using striatal atrophy and Vonsattel staging (61). Th is approach, whilst being a useful way to stage tissue for analysis, can be mis- leading as it relegates the a trophy and cell loss at other sites to being of secondary importance, when this might well not be the case given much of the recent imaging and clinical work in pre-manifest and esta blished disease (62, 63). Whatever the exact sequence of Oxford Textbook of Movement Disorders 216 pathological events and cell loss, the advanced HD brain is char- acterized by extensive ne uronal loss, atrophy, and the formation of intracellular inclusions with a marked astroglio sis (64). resting. With time, these movements become more prominent and involve all body parts symmet rically; it is very unusual to see any major asymmetry. Th e resultant picture is of patien ts with invol- untary facial grimaces and smiles, a tongue that they cannot keep protruded (see Video 20.3), and slightly slurred speech. Th eir gait becomes abnormal in a way that i s hard to characterize, as it has elements of chorea, dystonia, and some ataxia (see Video 20.4). As the patients advance, they oft en move into a phase of the illness where the chor ea becomes less prominent and is replaced by a more bradykinetic dystonic movement disorder (see Fig. 20.2), with signs of spasticity in the legs and, in some instances, a degree of hemibal- lismus which is very hard to treat (see below). In younger-onset cases, especially the juvenile Westphal variant of HD, the patient typically develops a parkinsonian syndrom e with relatively little if any chorea (66). Clinical features (see videos and Table 20.1) Th e clinical features of HD are well describ ed and classically con- sist of a triad of problems involving disorders of movement, cog- n ition, and mood (65). However, which of these is predominant varies from patient to patient , and indeed there are a host of other features that are now increasingly recognized as bei ng a part of HD, and which may even occur before the overt motor features of the illness. Th e earliest features of HD vary depending on the extent to which one searches for defi ci ts (63), but in clinic they are oft en the choreiform movements (see Videos 20.1 and 20.2) which typi- cally are brought out by walking or other motor actions, such as repetitive han d-tapping. Th ese movements oft en consist of slight fl icks of chorea around the head, sho ulder, or fi ngers, and are oft en not noticed by the patient themselves. Indeed it is wort h asking the patient \200\231s partner whether they have noticed abnormal fi dgety movement s at night in bed or in the evening when the patient is Whilst these are the typical movement disorders seen in HD, some patients, especially young er-onset cases, can develop myo- clonus, but tremor is very rare and any focal motor defi c its should Table 20.1 Clinical features of HD Motor Chorea; ballismus; dystonia; parkinsonism Cognitive Frontal executive dysfunction with problems of set-shifting and attention; dementia in adva nced cases Psychiatric Depression; mood swings; impulsiveness and irritability; suicidality; paranoia and psychoti c episodes; obsessive behavior; apathy Non classical features: \200 epilepsy \200 circadian rhythm abnormalities with insomnia and daytime somnolence \200 weight loss \200 vomiting \200 constipation z Video 20.2 Common choreiform movements of the extremities and trunk. z Video 20.1 Intermittent choreiform movements of the extremities and trunk. z Video 20.3 Impersistence of tongue protrusion. CHAPTER 20 Huntington \200\231s Disease 217 Cognitively, the earliest defi cits in HD are an inability to make decisions about issues t hat are oft en not that important, such as choosing outfi ts to wear or food items to buy. Some patients can articulate these types of defi cit, but more typically patients and their families complain that the patient has lost the ability to make deci- sions over complex i ssues or that they are fi ne as long as they fol- low routines. Th us a change in circumsta nce (job change etc.) can sometimes precipitate and expose the cognitive problems which bec ome more apparent as the disease progresses, with all patients developing dementia in the a dvanced stages of the disease. Th ese cognitive abnormalities can be seen by using formal n europsycho- logical tests such as the STROOP or trail-making tasks and high- light that the early cognitive defi cits have a mainly frontostriatal basis (67, 68). It is very rare for patients with HD to present with major memory or language defi cits, and it is worth remem bering that a patient who has become almost mute could be depressed. Th is may also be impo rtant in some patients who, for some reason, seem to have suddenly become much more cogniti vely impaired. z Video 20.4 Choreiform and dystonic gait. Psychiatric features can be very varied (69, 70). Some patients remain well throughout thei r illness, with no fl orid psychiatric fea- tures. However, some patients can develop depre ssion, which may be exacerbated by some of the medications used to treat the motor features of HD (e.g. tetrabenazine). In other cases the depression seems to run independently of th e disease (i.e. precedes the devel- opment of overt motor features of the illness by years) . Th e most common problems in the early stages of HD are much more likely to be irritabili ty and impulsiveness as well as major mood swings, with patients getting very worked up ove r oft en trivial issues. Th is can lead to violent outbursts and problems with the law. Mor eover, one in four HD patients attempts suicide (71, 72). With time these problems resolve and are oft en replaced by a more abulic apathetic stage of disease which can be very frust rating for the carers and family, as it can be perceived as the patient being lazy. Independence score 100 LATE EARLY P R E M A N I F E S T Chorea Agitated/mood swings Distractable Dystonic/bradykinetic Abulic Demented 20 Years ? Levodopa ? Hypnotic ?PEG Respite care Advanced directives Psychotic problems can be seen in HD but are less common than perseverations. When present, these can cause profound problems, as can the more frontal presentation of HD when patient s have no insight into their problems so that they do not seek help or take the required me dication for their condition (73). Finally, in juve- nile HD, behavioral problems can be th e dominant problem with development of obsessive behaviors associated with violent out- bur sts when confronted about them. Atypical antipsychotics Antidepressants Antiepileptics Fig. 20.2 Schematic diagram of the progress of HD over time. Other features which can also be seen in HD include the following. Circadian rhythm disturbances may begin early in the course of the illness and become more