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CHAPTER 21 Huntington \200\231s Disease Look-alikes Edward J. Wild and Sarah J. Tabrizi Summary Around 1% of patients in whom Huntington \200\231s disease (HD) is sus- pected clin ically, lack the genetic mutation that causes HD. Such patients, referred to as having HD l ook-alike syndromes, HD phe- nocopies or HD-like disorders, present a diagnostic challenge. Th is chapter off ers a defi nition of HD look-alikes and reviews the causes and features of HD look-alike syndromes, including HD-like syn- dromes 1, 2, and 3, familial prion disea se, spinocerebellar ataxias 17, 1, 2, and 3, dentatorubral-pallidoluysian atrophy (DRPLA), brain iron accumulation disorders including pantothenate kinase associ- ated neurodegenerat ion (PKAN) and neuroferritinopathy, choreo- acanthocytosis, MacLeod syndrome, Wilson diseas e, Friedreich \200\231s ataxia, mitochondrial disease, and benign hereditary chorea, and co nsiders possible acquired causes. Th e evidence for the rela- tive frequencies of each gene tic cause is reviewed. Th e yield from exhaustive genetic investigation of such patients is only 2%, which is important when it comes to genetic counseling. We propose a rational fra mework for the investigation of HD look-alike patients, based on genetic frequencies and as sociated clinical features. Th e exclusion of treatable causes is a top priority. Expert ge netic coun- selling and multidisciplinary care via a neurogenetics clinic remain the mainst ay of care for such patients. the evidence for their relative frequency, and proposes a rational framework for their inve stigation and management. Prevalence and de \201 nition Overall, Huntington look-alike syndromes are thought to repr e- sent about 1% of patients where HD is suspected clinically (see Fig. 21.1), and they can be extremely challenging in terms of diagnosis, management, and counseling for patients an d family members (1). Specifi c prevalence fi gures for HD look-alike syn- dromes are not a vailable, but the prevalence of manifest HD is estimated at 10 per 100 000 in most Western populations, and so the prevalence of look-alikes ought to be about one per million (2). Ho wever, recent fi gures have suggested that the prevalence of HD is likely to be substantial ly greater than previously estimated (3). Moreover, exactly what constitutes a Huntington l ook-alike syn- drome is poorly defi ned. No formal defi nition exists, but the fi gure of 1 % comes from early studies where patients subsequently rede- fi ned as look-alikes had prev iously had a fi rm clinical diagnosis of Huntington \200\231s disease. However, beyond the classical triad of chorea, subcortical dementia, and psychiatric distur bance, Huntington \200\231s disease is now recognized as producing a wide range of phenotyp es, includ- ing purely psychiatric, akinetic \200\223rigid, dystonic, and ataxic variants. Th erefore we have proposed a more fl exible working defi nition of HD look-alike syndromes as shown in Box 21.1 (4, 5). Introduction Soon aft er the discovery of the genetic mutation responsible for Huntington \200\231s disease (HD) in 1993, enabling the defi nitive genetic testing of all patients wi th a clinical diagnosis of HD, it became apparent that a minority of patients presenting wi th symptoms and signs suggestive of the condition lacked its causative genetic abnormality \200\224an expanded CAG repeat in the HTT gene. Such cases, resembling HD but lacking the H D mutation \200\224are referred to, variously, as HD-like (HDL) syndromes, HD phenocopies, or Huntington \200\231s look-alikes. Th e term \200\230phenocopy \200\231 was coined to me an a phenotype characteristic of a particular genetic syndrome, but produced environmentall y; used more broadly, it can be used to refer to syndromes suggestive with any cause \200 \224genetic or environ- mental \200\224other than the expected genotype. Th is chapter desc ribes the conditions that can produce HD-like presentations, reviews Th e extent to which the combination of the likely increased prev- alence of HD and this br oader defi nition alters the prevalence of HD look-alike syndromes remains to be seen, but our experience suggests that such patients are far more common than the one per million sug gested by traditional approaches. Note that autosomal dominant inheritance, or indeed a family history, is not an absolute re quirement for a patient to be con- sidered an HD look-alike. As many as 25% of new HD patie nts presenting to specialist clinics have no such family history (6) \200\224a fi gure brou ght about by HD \200\231s historically entrenched stigma, the emergence of new cases throug h intergenerational CAG repeat expansion, and complications such as non-paternity and adopt ion. Of course, there are no treatments that have been proved to slow down the progression of Huntington \200\231s disease in humans, and Oxford Textbook of Movement Disorders 224 (a) Suspected HD cases (b) HD look-alike cases (c) Genetically diagonsed look-alikes Prion 10% FA 15% 1% 3% HDL2 30% SCA17 44% Undiagnosed 97% HD 99% Fig. 21.1 Relative frequencies of (a) Huntington \200\231s disease and look-alike cases, (b ) undiagnosed and genetically diagnosed look-alikes, and (c) individual look-alike syndrome s. FA, Friedreich \200\231s ataxia; HD, Huntington \200\231s disease; Prion, familial prion disease. (Modi \201 ed from Wild E, Tabrizi S. Huntington \200\231s disease phenocopy syn dromes. Curr Opin Neurol 2007; 20: 681 \200\2237, by permission of Wolters Kluwer Health/Li ppincott \200\223Williams & Wilkins) inheritance with early-adult onset and causes chorea, ataxia, cog- nitive decline, personal ity change, and basal ganglia atrophy. Th e name HDL1 refers specifi cally to this genotype \200\223phenotype combi- nation, which is restricted to just a handful of reported pedigre es (7). However, it is now known that an HD-like syndrome with prominent rigidity and ataxi a can be caused by other PRNP muta- tions, such as the more common six-octapeptide repeat i nsertion. Such mutations are known to produce a variety of phenotypes, even within a single pedigree, including behavioral change, demen- tia, myoclonus, seizures, chorea, and pyrami dal, cerebellar, and extrapyramidal signs, so it is perhaps unsurprising that Huntington lo ok-alikes are within their gamut (8). Th erefore screening of the entire PRNP gene (15 kb), rather than focused testing for the spe- cifi c mutation causing HDL1, is recommended in t he evaluation of Huntington look-alike patients. Box 21.1 Working de \201 nition of Huntington \200\231s disease look-alike syndromes 1. A movement disorder consistent with HD as determined by an experienced neurologist AND 2. A negative test for the pathogenic CAG repeat expansion in the HTT gene AND 3. At least one of the following: family history suggestive of autosomal dominant inheritance; cognitive impairment; behavioral or psychiatric symptoms. unfortunately the same is true of many of its described look-alike syndromes. Th is is not universally the case, and disease-modifying treatments are available for some conditions, s uch as Wilson dis- ease, provided that a diagnosis is made in a timely manner. HDL2 HDL2 is one of the more common genetic causes of a Huntington look-alike syndrome. It is caused by GTC/CAG triplet expansions in the JPH3 gene encoding junctophilin-3, a compone nt of junc- tional complexes that mediates crosstalk between cell surface and intracellular ion channels. Its inheritance is autosomal dominant; JPH3 alleles with over 41 repeats are pathogenic, while normal alle- les have 6 \200\22328 repeats. However, even in the absence of a specifi c treatment, there is still benefi t in seeking a diagnosis for these rare conditions. It is useful for patients and relatives to have a spe cifi c name for their condi- tion, both psychologically and in order to obtain access to ap pro- priate symptomatic, supportive, and social assistance. Obtaining a genetic diagnosis e nables family members to be counseled with accuracy on their genetic risk, off ered predict ive or diagnostic genetic testing, and given access to assisted fertility techniques that m ay prevent them passing on an incurable genetic condi- tion to their children. Finally, an accurate diagnosis gives patients and those at risk the option of taking part in specifi c clinical and genetic research programs that may benefi t them or future generations. HDL2 was fi rst described in the USA in 2001 in an African American family and subsequent p edigrees have revealed it to be almost exclusively confi ned to populations of African desc ent. It is now known to be more common than HD itself in some black African populations (9) . However, more recent cases have been reported in Middle Eastern and European patients (4, 10). Clinically, HDL2 is a very close phenocopy of HD, especially the Westphal rigid variant of HD typically seen in juvenile patients and adults with younger onset. Onset of HDL2 is typi cally in the fourth decade. Most patients experience cognitive and psychiatric dysfunction, dystonia, extrapyramidal rigidity, and weight loss; many also display chorea. Th ere is sa id to be a lower frequency of eye-movement abnormalities of the kind seen in HD, and seizur es are less frequent than in juvenile HD (11). Individual Huntington look-alikes In addition to the three conditions named HDL1 \200\2233, various other genetic disorders can produce phenotypes resembling HD. Th ese are summarize d in Table 21.1 and discussed individually below. Neuroimaging in HDL2 is somewhat similar to HD, show- ing atrophy of the caudate, putamen, and cerebral hemispheres. Microscopically there are also similarities with ubiquitin-positi ve neuronal intranuclear inclusions and a loss of medium-sized neu- rons in the striatum in a dorsal \200\223ventral gradient. Some patients with HDL2 develop acanthocytosis in perip heral blood. HDL1 and familial prion disease HDL1 was the fi rst HD look-alike syndrome for which a gene tic cause was identifi ed. It is a form of familial prion disease, caused by a mutation in the PRNP gene resulting in an eight-octapeptide insertion in the prion protein. Th e diseas e has autosomal dominant CHAPTER 21 Huntington \200\231s Disease Look-Alikes 225 Table 21.1 Principal causes of Huntington \200\231s disease look-alike syndromes Gene Condi tion PRNP Familial prion disease JPH3 Unknown Protein Prion Inheritance AD Notes Includes HDL1 HDL2 Junctophilin 3 AD African ancestry HDL3 Unknown AR Two pedigrees only SCA17 TBP ATXN1 ATXN2 ATXN3 ATN1 PANK2 TATA-binding protein AD Cerebellar atrophy and ataxia SCA1 Ataxin 1 AD SCA2 Ataxin 2 AD SCA3 Ataxin 3 AD DRPLA Atrophin 1 AD Myoclonic epilepsy PKAN (NBIA1) Pantothenate kinase AR MRI \200\230eye of the tiger sign \200\231, pigmentary retinopathy Neuroferritinopathy FTL Ferritin light chain AD Early dysarthria and persistent asymmetry Choreoacanthocytosis CHAC XK ATP7B FRDA mtDNA or nuclear mitochondrial genes Chorein AR Mutilating orofacial dystonia MacLeod syndrome Kell antigen XR Systemic features Wilson disease Copper-transporting ATPase AR Kayser \200\223Fleischer rings etc. Friedreich \200\231s ataxia Frataxin AR Rarely resembles HD Mitochondrial disease Benign hereditary chorea TITF1 e.g. Sydenham \200\231s chorea, antibasal ganglia antibodies, neuro-SLE, thyrotoxicos is, vascular disease, medications Th yroid transcription factor 1 AD Non-choreic features, rare Acquired causes AD, autosomal dominant; AR, autosomal recessive; XR, X-linked recessive. For other abbrevia tions, see text. However, the pathogenesis of HDL2 is curious. As in myot- onic dystrophy type 1 (DM1), and quite unlike in HD, there is no evidence that the mutant protein is harmful; rather, foci c ontain- ing JPH3 RNA are seen neuronal nuclei, and it appears that the triplet-expanded RNA itself may be the toxic species in HDL2 (12). A recently developed mouse model of HDL2, ex pressing a bacte- rial artifi cial chromosome (BAC), promises to shed light on the pathogen esis of the condition and may reveal shared mechanisms for HD-like disorders including HD i tself (13). SCA17 causes a wide variety of phenotypes. Th e most com- mon features are intellectual dec line (in 100% of patients), ataxia (90%), and epilepsy (50%), so the majority of cases of S CA17 are not particularly HD-like and calls for the disease to be renamed HDL4 may not, ove rall, be well-founded (15). However, in the 20% of SCA17 patients who develop chorea, it ca n be an extremely close HD look-alike. Moreover, SCA17 tends to be phenotypi- cally homogen eous within individual families, so aff ected off - spring of an HD-like SCA17 patient are likely to resemble HD themselves (16). HDL3 HDL3 is an autosomal recessive HD-like disorder linked to chro- mosome 4p15.3. Th e ca usative gene is unknown and the disorder has been reported in only two pedigrees (14). Unlike HD, SCA17 almost invariably causes cerebellar atrophy which can be visualized on MR scanning. Selective enhancement of the putamen has also been reported, which is not seen in HD or the other SCAs (17). Pathologically, SCA17 causes neuronal loss in the cortex, stria- tum, and cerebellum. Prote in aggregates containing polyglutamine and TBP accumulate widely in neuronal nuclei (18). T h e fact that SCA17 is caused by a mutated transcription factor makes it an exciting target for providing insights into the role of gene tran- scription dysregulation in neurodegener ative disease as a whole, and HD in particular. Recent work in a mouse model expressing pol yglutamine-expanded TBP has shown that SCA17 is associated with downregulation of the high- affi nity nerve growth factor recep- tor TrkA (19), which has been implicated in the pathog enesis of both Alzheimer \200\231s and Huntington \200\231s diseases (20, 21). SCA17 and other spinocerebellar ataxias Th e spinocerebellar ataxias are a heterogeneous gr oup of hereditary degenerative disorders causing cerebellar ataxia and a spectrum of associ ated features. Although cerebellar ataxia is seldom the sole feature of Huntington \200\231 s disease, it is commonly seen as a component of the compound movement disorder. SCA17 is c aused by CAG or CAA repeat expansions in the TBP gene, resulting in lengthened polyglutamin e tracts in the TATA binding protein, a key transcrip- tion factor (15). Overall, SCA17 is rare, with a prevalence of around 0.2 per 100 000. Because of the clinical heterogeneity of both Huntington \200\231s disease and the spinocer ebellar ataxias, many of the other SCAs can mimic HD to diff erent extents. In particular, SCAs 1, 2, and 3 (caused by abnormal CAG repeat expansions in the genes encoding ataxin 1, 2, and 3) can cause a combination of hypokinetic and hyperkinetic movement disorders, inclu ding chorea, that may resemble HD (22). Unaff ected individuals have 42 or fewer repeats, with most aff ected patients having over 50; milder symptoms have been reported with as few as 43 repeats. Th e interrupted confi gu ration of the triplet-repeat alleles appears to be responsible for a relatively low inciden ce of genetic anticipation, which is common in HD with its contiguous CAG repeats. Oxford Textbook of Movement Disorders 226 Dentatorubral-pallidoluysian atrophy Although DRPLA was probably fi rst described in 1958 b y Smith and colleagues (23), it bears the eponym Naito \200\223Oyanagi disease and is most commonly seen in families of Japanese descent. It has autosomal dominant inheritance. In 19 94, shortly aft er the HD gene was cloned, the genetic cause of DRPLA was found \200\224ano ther CAG triplet repeat expansion, in the atrophin 1 gene (ATN1) on chromosome 12 (24). Lik e HD, the length of the CAG repeat expansion correlates inversely with age at onset; in fac t, among the CAG triplet repeat disorders, DRPLA most prominently exhibits genetic anticipa tion because of the tendency of its CAG repeat tract to lengthen when inherited paternally (25). is most useful aft er MRI to elucidate the specifi c cause of the iron accumulation (28). Th e majority of NBIA cases are accounted for by NBIA1, an auto- somal recessive disorder c aused by mutations in the PANK2 gene encoding pantothenate kinase. Th e condition is now ca lled PKAN (pantothenate kinase-associated neurodegeneration) rather than its previous epony m, Hallervorden \200\223Spatz disease, which is now considered ethically inappropriate. Rather confusingly, PANK2 mutations also cause HARP syn- drome, which constitutes hypoprebe talipoproteinaemia, acanthocy- tosis, retinitis pigmentosa, and pallidal degeneration. Incr easingly it is recognized that HARP syndrome, which resembles PKAN but also produces lipopr otein abnormalities, is part of the PKAN dis- ease spectrum (29). In common with many of the diseases mentioned in this chapter, DRPLA may present with a div ersity of phenotypes. Th e core fea- tures are myoclonic epilepsy, dementia, ataxia, and ch oreoathetosis. Onset is typically earlier than in Huntington \200\231s disease (in the twen - ties), although the course of the disease is usually about the same (15 \200\22320 years) . Th e frequent presence of myoclonic epilepsy is a dis- tinguishing feature of DRPLA; epil epsy is only rarely a prominent feature of HD, although seizures are quite common in juveni le HD patients. Intractable myoclonic epilepsy should prompt suspicion of a diagnosis other than HD. Most cases of PKAN do not closely resemble HD. Classically, PKAN presents in early childhoo d with gait diffi culty and progresses rapidly to a picture of prominent dystonia and corti co- spinal tract involvement producing upper motor neuron signs. In contrast, corticospinal signs are not a feature of juvenile HD (jHD) and, conversely, PANK2 does not cause the eye -movement disorder and propensity to seizures of jHD. Moreover, jHD seldom presents de novo within a family with no prior history (except in cases of non-paternity) because it is mos t unusual for an HTT triplet repeat expansion to increase, in a single transmission, from a range con- sistent with a symptom-free parent to an expansion large enough to cause jHD in their child. As the name suggests, DRPLA produces degenerative brain atrophy, predominantly aff ecting t he dentatorubral system, which connects the cerebellar dentate to the midbrain red nucleus, and the pallidoluysian system, which unites the globus pallidus and the subthalamic nucleu s (nucleus of Luys). However, the spectrum of PKAN presentations certainly over- laps with that of HD. Atypical PKAN can present in early adult life, progress slowly, and produce dysarthria, psychiatric symptoms including depression, emotional lability, and impulsivity, in addi- tion to extrap yramidal dysfunction (28). Clues to a diagnosis of PKAN over HD include a paucity of chorea and the presence of pigmentary retinopathy. Like HD, DRPLA is a disease of protein accumulation. Polyglutamine-expanded atrophin 1 aggr egates in DRPLA brain as inclusions (25). Atrophin-1 interacts with many other proteins, bu t appears to function as a transcriptional repressor, an activity which becomes attenuated in the presence of an expanded CAG repeat tract (26). intracytoplasmic ubiquitinated neuronal MRI of such patients generally reveals iron deposition in a typi- cal pattern: symmetric re gions of hypointensity in the medial glo- bus pallidus containing central areas of hyperint ensity. Th is \200\230eye of the tiger \200\231 sign (Fig. 21.2) is said to be pathognomon ic of PKAN (30). Dedicated MR sequences can confi rm the presence of abnor- mal iron deposi ts with more specifi city, and may also be more sen- sitive than basic T 2 imaging. Th ese are T 2 *, also known as gradient echo (GRE), and susceptibility-weighted imaging (SWI) seq uences (Fig. 21.2). As well as atrophy of the aff ected brain regions, especially the brainstem and cerebellum, MRI scanning in DRPLA may show hyperintense cerebral white matter T 2 lesions (25). Interestingly, the same CAG repeat expansion in the ATN1 gene can also cause a pathological ly distinct illness called \200\230Haw River syndrome \200\231 aft er the North Carolina t own where its large inaugural pedigree was described. Patients display clinical features si milar to \200\230classical \200\231 DRPLA but without myoclonic seizures. Pathologically, there is calcifi cation of the basal ganglia, subcortical demyelina- tion, and neuroaxonal dystrophy \200\224features not typically seen in DRPLA (27). Neuroferritinopathy , caused by mutations in the ferritin light chain gene FTL , is a relat ively recent addition to the canon of HD look-alikes. Aside from being the only autosomal d ominant brain iron accumulation disorder, it is a close clinical mimic, oft en pro- ducing an adult-onset syndrome with chorea, dystonia, cognitive decline, and behavioral features. Limb chorea in neuroferritino- pathy may be strikingly asymmetric and, unlike in HD, such a symmetry persists throughout the disease course. Another dis- tinguishing feature is the ea rly development of dysarthria due to action-specifi c orofacial dystonia triggered by speec h. In males, neuroferritinopathy may be disclosed by low serum ferritin, but this may be ob scured by menstrual-related changes in females. Abnormalities on MRI are invariable, howeve r, and can also dis- tinguish neuroferritinopathy cases from other causes of NBIA. Iron acc umulation is seen on T 2 * or SWI sequences even in asympto- matic mutation-positive indivi duals (Fig. 21.2), and later progresses to cause cystic change in the caudate and putamen ( 31). Iron accumulation disorders Neurodegeneration with brain iron accumulation (NBIA) is the te rm for a family of conditions in which a progressive neurological syndrome with neurodegene ration is accompanied by the abnor- mal deposition of iron in brain tissues, especially the basal ganglia. NBIA disorders are clinically and genetically heterogeneous and can arise i n early childhood or adult life, but share a tendency to produce extrapyramidal syndromes w ith cognitive and behavioral features (see also Chapter 12). Th e iron accumulation disorders are generally, though not invar- iably, distinguishable fr om HD and the other look-alike syndromes through the ability of MRI to detect deposited iro n in brain tissue. In the absence of a known family history, targeted genetic testing CHAPTER 21 Huntington \200\231s Disease Look-Alikes 227 (a) PKAN (b) Neuroferritinopathy Fig. 21.2 MRI in brain iron accumulation disorders: (a) axial T 2 -weighted brain MRI in PK AN demonstrating the \200\230eye of the tiger \200\231 sign due to globus pallidus hypoint ensity (arrow head) containing a high intensity focus (arrow). (Image reproduced from Harti g MB et al. Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodege neration with brain iron accumulation. Ann Neurol 2007; 59: 248 \200\22356, by permission o f Wiley Interscience) (b) T 2 * MRI scan in neuroferritinopathy, showing reduced signal in the basal ganglia (arrow) and thalamus (arrow head). (Image reproduced from Chinnery PF et al. Clinical features and natural history of neuroferritinopathy caused by the FTL1 460InsA mutation, Brain 2007; 130: 110 \200\22319, by permission of Oxford University Press) Th e other brain iron accumulation diseases, although heteroge- neous, are suffi ciently di ff erent from Huntington \200\231s disease that they need not be considered look-alikes. Ac eruloplasminaemia, caused by CP mutations resulting in systemic absence of ceruloplasmin, h as adult onset and can produce chorea, but is dominated by retinal degeneration and diabete s mellitus in addition to blepharospasm, facial and neck dystonia, tremor, and ataxia. PLA2 G6 -associated neurodegeneration (PLAN), of which the most common presenta- tion is infanti le neuroaxonal dystrophy (INAD), generally causes rapidly progressive psychomotor, corticos pinal, cerebellar, and dystonic features in the presence of high brain iron. Likewise, fatt y acid hydroxylase-associated neurodegeneration (FAHN), Woodhouse \200\223Sakati syndrome, and Kufor \200\223Rakeb syndrome are dominated by dystonia and neurological and systemic fe atures not seen in HD (28). Choreocanthocytosi s is an autosomal recessive condition caused by mutations in the CHAC ge ne, encoding the chorein protein, which may resemble HD clinically. It causes a range of mo ve- ment disorders including chorea, tics, and dystonia. Later, patients develop dementia a nd psychiatric features similar to those seen in HD. Age at onset is younger than HD, on av erage, but there is substantial overlap. Th e defi ning characteristic of choreoacan- thocy tosis is dominant orofacial dystonia, commonly with tongue protrusion, with biting of the t ongue and lips, resulting in per- manent damage in some cases. In addition, seizures are se en in around half of cases, and other features such as neuropathy, distal amyotrophy, and e levation of serum creatine kinase are not shared with HD (32). MacLeod syndrome is another neuroacanthocytosis that may mimic HD. Caused by mutations in t he XK gene encoding the Kell erythrocyte antigen, its inheritance is X-linked recessive; sy mp- toms are restricted to hemizygous males, while females with a single mutant allele are asymptomatic carriers. However, in small pedigrees, the inheritance may be ambiguous. MacLe od syndrome patients experience limb chorea, facial tics, subcortical dementia, and neurops ychiatric problems, with less dystonia than is seen in choreoacanthocytosis. However, it al so produces non-HD-like fea- tures including axonal neuropathy, hepatosplenomegaly, cardiom y- opathy, and haemolytic anemia (32). Neuroacanthocytosis Conditions in which neurological symptoms are seen in the pres- ence of acanthocytes (erythrocytes with thorn-like protrusions) in peripheral blood are collective ly referred to as neuroacanthocyto- sis syndromes. Th is classifi cation is awkward, as sev eral conditions meeting these criteria belong primarily to other disease families because a canthocytosis was not part of the initial description, or because acanthocytes are seen onl y rarely. Hyperkinetic movement disorders appear to be a feature of the \200\230core \200 \231 neuroacanthocytosis syndromes; in addition to choreoacanthocytosis and MacLeod syndrom e, acanthocytes may be seen in both NBIA and HDL2, described above. Demonstrating the presence of acanthocytes in peripheral blood may be instructive in the cl inical assessment of an HD-like patient, but is not necessarily straightforward. Acanthocyt es are seen in many common systemic conditions, including hypothyroidism Oxford Textbook of Movement Disorders 228 and chronic renal failure, and therefore may be an incidental find- ing, statistically spea king, as often they are of no neurological significance. In addition, even in cases of neur oacanthocyto- sis, several blood films may be required and sample handling has a bearing on yield. \200\230True \200\231 acanthocytosis may be missed in a significant proportion of cases because of the use of dry blood smears or EDTA blood tubes. Instead, it is recommende d that whole blood is mixed in a one-to-one ratio with a solution containing 10 units of he parin per milliliter of normal saline; after 30 minutes of agitation, phase-contrast micros copy of a wet preparation should be used to examine for spiculated cells (the normal value is less than 6.3%) (33). This approach offers diagnostic sensitivity approaching 100% but i s not universally available; thus biochemical techniques such as Western blot- ting for cho rein protein, and of course genetic testing, may be needed in suspected neuroacanthocytosis cases whether or not acanthocytes have been found. whom negative genetic testing for Huntington \200\231s disease preceded a positive test for Friedreich \200\231s ataxia (4). Th e situation is not common but should be borne in mind. Other causes We recently reinvestigated our cohort in the light of the discovery of an expa nded hexapeptide repeat in the fi rst intron of the C9orf72 gene in familial frontotemporal dementia and motor neuron dis- ease (39, 40). Of 514 subjects, ten (2%) had the expansion. In our cohort, this is therefore the commonest genetic cause of HD-like clinical presentat ions (unpublished data). We therefore tentatively propose screening for this expansion in t he diagnostic workup of HD-like patients. Mutations in mitochondrial DNA, and in nuclear genes encod- ing mitochondrial proteins, can produce a notoriously broad spec- trum of symptoms, which is ever increasing as more mutat ions are described. Myoclonus and dystonia are the most common move- ment disorders seen in mitochondrial disease , but chorea can occur and may be accompanied by cognitive decline o r psychiatric fea- tures (37). Wilson disease Wilson disease (hepatolenticular degeneration), which is described in detail in Chapter 23, is a genetic disorder of cop- per metabolism with autosomal recessive inher itance caused by mutations in ATP7B encoding a copper-transporting ATPase protein. It produ ces a wide range of clinical phenotypes con- sisting of hepatic dysfunction, neurological s ymptoms, and psychiatric disorder. The presence of all three is rare, and pure neurological or neuropsychiatric presentations are common. The neurological spectrum of Wilson disease includes chorea, choreoathetosis, and dystonia, while the psychiatric features include depr ession, anxiety, and psychosis; frontal and subcor- tical cognitive decline is also seen. T hus, with the right com- bination of features, Wilson \200\231s disease may mimic Huntingto n \200\231s disease, closely or otherwise.