Review

Continuing Medical EducationNature Clinical Practice Neurology (2007) 3, 517-525
doi:10.1038/ncpneuro0606  
Received 9 May 2007 | Accepted 19 June 2007

The Huntington's disease-like syndromes: what to consider in patients with a negative Huntington's disease gene test

Susanne A Schneider, Ruth H Walker and Kailash P Bhatia*  About the authors

Correspondence *Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK

Email kbhatia@ion.ucl.ac.uk

Summary

Huntington's disease (HD), which is caused by a triplet-repeat expansion in the IT15 gene (also known as huntingtin or HD), accounts for about 90% of cases of chorea of genetic etiology. In recent years, several other distinct genetic disorders have been identified that can present with a clinical picture indistinguishable from that of HD. These disorders are termed Huntington's disease-like (HDL) syndromes. So far, four such conditions have been recognized, namely disorders attributable to mutations in the prion protein gene (HDL1), the junctophilin 3 gene (HDL2), and the gene encoding the TATA box-binding protein (HDL4/SCA17), and a recessively inherited HD phenocopy in a single family (HDL3), the genetic basis of which is currently poorly understood. These disorders, however, account for only a small proportion of cases with the HD phenotype but a negative genetic test for HD, and the list of HDL genes and conditions is set to grow. In this article, we review the most important HD phenocopy disorders identified to date and discuss the clinical clues that guide further investigation. We will concentrate on the four so-called HDL syndromes mentioned above, as well as other genetic disorders such as dentatorubral–pallidoluysian atrophy, neuroferritinopathy, pantothenate-kinase-associated neurodegeneration and chorea–acanthocytosis.

Review criteria

We searched PubMed for articles published up to February 2007 using the following search terms: "Huntington's disease", "Huntington's disease-like syndromes", "HDL", "chorea", "prion protein", "PrP", "junctophilin", "spinocerebellar ataxia 17" or "SCA17", "TATA box-binding protein", "neuroferritinopathy", "Pantothenate-kinase-associated neurodegeneration" or "PKAN", and "neuroacanthocytosis". Relevant articles were retrieved and prioritized for inclusion in this review. Cross-referenced articles from retrieved papers were also considered.

Keywords:

Huntington's disease, Huntington's disease-like syndromes, junctophilin 3, prion disease, spinocerebellar ataxia type 17

Medscape Continuing Medical Education online

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Learning objectives

Upon completion of this activity, participants should be able to:

  1. Describe the prevalence of Huntington's disease (HD) among chorea disorders of genetic origin.
  2. Describe the prevalence of the HD genotype among different populations of the world.
  3. Describe the clinical features of and diagnostic criteria for HD.
  4. Identify the inheritance patterns of the 4 HDL variants of the HD phenotype.
  5. Describe the clinical features of HDL variants of the HD phenotype.

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Introduction

Chorea has numerous causes, including both genetic and acquired etiologies. The most important genetic cause of chorea is Huntington's disease (HD), which is an autosomal dominant neurodegenerative disorder attributable to mutation of the IT15 (also known as huntingtin or HD) gene on chromosome 4.1 The prevalence of HD is high in certain regions of Scotland and Venezuela, but is relatively low in Finland, Norway and Japan.2, 3 In North America and Europe the prevalence is about 4–8 cases per 100,000 individuals. The classic triad of symptoms of HD comprises adult-onset personality changes, generalized chorea, and cognitive decline. Notably, in children or adolescents, HD tends to present as an akinetic–rigid (Westphal) variant rather than with chorea. Other features in both adult-onset and young-onset forms of HD include eye movement abnormalities (impersistence of gaze and difficulty initiating saccades), dysarthria, dysphagia, pyramidal signs, and ataxia resulting in walking difficulties with imbalance and postural instability. Dystonia, myoclonus, tics and tremor can also occur as part of the clinical spectrum of HD. Brain imaging might reveal progressive atrophy of the caudate nuclei that can be present even before the onset of motor symptoms. The diagnosis of HD is established on the basis of genetic testing.

Since the 'HD gene' was identified in 1993,1 it has been recognized that a small proportion of patients with a clinical syndrome resembling HD do not have the HD-causing trinucleotide repeat expansion in the IT15 gene. For example, in a report of 618 patients,4 only 93% of those with the classic clinical phenotype of HD were found to have the HD-associated gene mutation. This evidence indicated the existence of other genetic disorders, which are referred to as 'Huntington's disease-like' (HDL) syndromes. A number of unrelated genes associated with these conditions have been identified.5, 6, 7, 8 Consequently, clinicians have to consider an increasing range of differential diagnoses when confronted with a patient with slowly progressive adult-onset chorea and family history positive for neurological or psychiatric disease, or both. In view of this growing list of recognized disorders, we will review the most common genetic causes of chorea, focusing particularly on the spectrum of HDL syndromes. We will concentrate on the autosomal dominant conditions (Table 1); however, because about 8% of patients with HD present without an apparent family history of the condition, chorea with other modes of inheritance will also be mentioned.

Table 1 Summary of autosomal dominant disorders that cause chorea
Table 1 - Summary of autosomal dominant disorders that cause chorea
Full tableFigures & Tables indexDownload PowerPoint slide (120K)

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Huntington's disease-like syndromes

Huntington's disease-like 1

Huntington's disease-like 1 (HDL1) is an autosomal dominant progressive adult-onset neurodegenerative disorder caused by 192 or 168 base-pair insertions (encoding extra octapeptide repeats) in the region of the prion protein (PRNP) gene on chromosome 20p12.7, 9, 10 The clinical picture of HDL is often similar to that of HD, with abnormal involuntary movements, coordination difficulty, dementia, personality changes and psychiatric symptoms;11 seizures have also been described.7 The mean age at onset is 20–45 years. Atrophy of the basal ganglia, the frontal and temporal lobes and the cerebellum occurs.7 Kuru and multicentric plaques that stain with anti-prion antibodies have also been demonstrated on neuropathological examination.9, 11 Despite the clinical suggestion of spongiform encephalopathy, spongiosis was not prominent.

The normal form of the prion protein (PrPC) is attached to the cellular membranes through a glycophosphatidylinositol anchor, and one of its structural features is a copper-binding site; however, the normal function of the protein is poorly understood.12 The conformational conversion and transformation of the cellular isoform to the pathogenic protein is believed to have an important role in disease pathogenesis. It has been suggested that variations in the site of formation of the pathogenic protein and of its subsequent accumulation might contribute to the existence and broad phenotype of pathologically distinct prion disease entities.13 Overall, PRNP mutations seem to be a rare genetic cause of HD phenocopies.14, 15, 16

Huntington's disease-like 2

HDL2 seems to account for about 2% of HD phenocopies without the IT15 mutation.4, 14 The frequency is, however, higher in the black South African population, in which HDL2 contributes substantially to the overall incidence of the HD phenotype.17, 18, 19 To investigate this phenomenon, Krause et al.19 performed genetic tests on 149 South African patients with the HD phenotype. Whereas 84% (78 out of 93) of white patients had the IT15 expansion, only 36% (18 of 50) of black patients and 50% (3 of 6) of mixed-ancestry patients were found to have this classic HD-causing mutation. The authors found, however, that 24% (12 of 50) of black patients and 50% (3 of 6) of mixed-ancestry patients had HDL2-causing expansions. It has been suggested that the geographical distribution of this disorder can be explained by a founder effect that originated in Africa between 300 and 2,000 years ago.19 North American and Mexican HDL2 families with African origins have been described.20 With the exception of one Brazilian family of Spanish–Portuguese ancestry21 HDL2 has not been reported in white individuals; nor has this syndrome been reported in the Japanese population.15, 16, 18, 20

HDL2 onset occurs in the third or fourth decade of a patient's life, with a clinical picture resembling classic adult-onset HD. A juvenile-onset variant (pedigree W) has also been described, in which seizures are absent and eye movements are often normal.8 Recently, adult-onset cases without chorea that resemble juvenile HD have been reported.22 Pathological examination has shown a picture similar, but not identical, to that of classic HD.17, 22, 23 In about 10% of cases with HDL2, acanthocytes can be detected in the peripheral blood smear.24, 25

HDL2 is caused by a CTGfilled circleCAG triplet-repeat expansion in the junctophilin 3 (JPH3) gene on chromosome 16q24.3.26 The function of junctophilin 3 remains unknown, but a role for the protein in junctional membrane structures and in the regulation of intracellular calcium has been suggested.24 There is an inverse correlation between age at HDL2 onset and CTGfilled circleCAG repeat length. In the normal population, the repeat length ranges from 6 to 28 CTGfilled circleCAG triplets.22, 24 Pathological repeat expansions range in length from 44 to 57 triplets, and there is length instability during maternal transmission.17, 22 To date, the effect of alleles with 29–43 triplet repeats is uncertain. Pathogenicity might be related to the presence of mRNA inclusions.27

Huntington's disease-like 3

Al-Tahan et al.28 and Kambouris et al.6 both reported an autosomal recessive variant of HD from Saudi Arabia that presented with early-onset mental deterioration, dysarthria, dystonia, pyramidal signs, ataxia and gait impairment. Age at onset was 3–4 years. Progressive atrophy of the frontal cortex and the caudate nuclei was demonstrated by brain imaging. This condition was named HDL3, and the disease locus was initially mapped to chromosome 4p15.3;6 however, it has been suggested that the evidence for this linkage is weak.29 Although this condition has been named HDL3, it does not fit into the group of HDL syndromes with respect to the age of onset and the pattern of inheritance.

Huntington's disease-like 4 (spinocerebellar ataxia type 17)

HDL4 has been identified as spinocerebellar ataxia type 17 (SCA17), and is an autosomal dominant triplet-repeat disorder caused by mutation of the TATA box-binding protein (TBP) gene. This gene, which is located on chromosome 6q27, encodes the TATA box-binding protein (TBP), an important general transcription initiation factor.30 Normal CAAfilled circleCAG repeat stretches range from 25 to 42 in white individuals, with larger repeats considered pathological. Reduced penetrance has been reported for alleles with 43–48 CAG repeats compared with those with longer stretches.31 Age at onset of HDL4 is between 19 and 48 years, and childhood onset is rare.32 There is an inverse correlation between age at onset and number of CAAfilled circleCAG repeats, similar to HD. Although cerebellar ataxia is the most common feature of HDL4 (present in 94% of cases), the phenotype is markedly heterogeneous, and extrapyramidal signs (73%), pyramidal signs (37%), epilepsy (22%), dementia (76%) or psychiatric disturbances (27%) might be prominent.33 A clinical picture indistinguishable from that of classic HD has been reported in both heterozygous and homozygous mutation carriers.5, 34 An HDL presentation is observed only sporadically within most families, but a homogeneous HDL phenotype in all members of a family with SCA17 has recently been described.35 The broad spectrum of clinical manifestations in HDL4 correlates with the neuropathological findings, which include cerebellar pathology and involvement of the cerebral neocortex, basal ganglia and hippocampus.36 Intranuclear neuronal inclusion bodies with immunoreactivity to anti-TBP and anti-polyglutamine antibodies have been described to be widely distributed in the gray matter.36

Cerebellar and cortical atrophy have been demonstrated on brain MRI in patients with HDL4.35 Neuroimaging studies using dopamine transporter imaging, single-photon emission computed tomography with 123I-iodobenzamide, and PET have revealed reduced activity of dopamine transporters, reduced glucose metabolism in the striatum, and mildly reduced dopamine D2-receptor-binding capacity.37 In patients with the more common ataxic HDL4 phenotype, voxel-based morphometry has shown degeneration of the gray matter in the cerebellum, the occipitoparietal cortical areas and the basal ganglia, which reflects and is associated with the cerebellar, pyramidal and extrapyramidal signs.38 Patients with HDL4 who have ataxia have also been studied electrophysiologically.39 Electromyography, nerve conduction studies, visual and brainstem auditory evoked potentials, and transcranial magnetic stimulation-induced motor evoked potentials seemed to be normal in all cases; however, abnormalities in somatosensory-evoked potentials—consisting mainly of P14 and P31 wave absence and a prolonged central motor conduction time—were noted.

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Other autosomal dominant disorders

Dentatorubral–pallidoluysian atrophy

Dentatorubral–pallidoluysian atrophy (DRPLA) is in many respects similar to HD. The condition is an autosomal dominant triplet-repeat neurodegenerative disorder,40, 41 and the mutated gene, atrophin 1 (ATN1), has been mapped to chromosome 12p13.31.42 The polyglutamine stretch ranges from 8 to 25 repeat units in healthy individuals, and from 49 to 88 repeats in patients with DRPLA.43, 44 Instability in transmission has been reported, with an average increase in repeat length of four repeats for paternal transmission (a phenomenon known as anticipation) and a decrease of one repeat during maternal transmission.44 Again, repeat size correlates inversely with age at onset and directly with disease severity. Three clinical phenotypes, with an average age at onset between 20 and 30 years, have been described: presentation with prominent chorea similar to HD, with prominent ataxia, and with prominent myoclonus. Severe progressive myoclonus epilepsy and cognitive decline has been described in early-onset cases.41 Late-onset disease can present with mild cerebellar ataxia.45

DRPLA is particularly prevalent in Japan, but has been reported rarely in white, African-American and Chinese populations.46, 47, 48, 49, 50 Le Ber et al.47 recently studied a sample of 809 patients with ataxia and estimated the frequency of DRPLA in Europe as 0.25% in both familial and sporadic cases.

Four Portuguese families with DRPLA were recently found to have two intragenic single nucleotide polymorphisms in introns 1 and 3 of the ATN1 gene, in addition to the CAG repeat expansion.51 Notably, all four Portuguese families shared a particular haplotype, which was also shared by Japanese individuals with DRPLA. This haplotype is the most frequent in Japanese individuals with normal alleles but is rare in Portuguese controls, which might explain the relatively high frequency of DRPLA in Japan compared with Europe.

Neuroferritinopathy

Mutations in the FTL gene—which codes for ferritin light polypeptide—on chromosome 19q13 cause neuroferritinopathy, an autosomal dominant condition that presents with extrapyramidal features that include chorea, dystonia with prominent oromandibular dyskinesias, and parkinsonism (without tremor). Other variably present features include dysarthria, spasticity, cerebellar signs, frontal lobe syndrome and dementia.52, 53 The mean age at onset is 40 years. Neuroferritinopathy is particularly common in the Cumbrian region of the UK owing to a founder effect. A French family with exactly the same gene mutation as the Cumbrian family, and possibly sharing a common ancestor, has also been described.53

Patients with neuroferritinopathy have low serum ferritin levels. MRI imaging reveals abnormal deposition of iron in the brain, cystic changes in the basal ganglia, and bilateral pallidal necrosis.53, 54 The sensitivity of T2* imaging55 was emphasized by Chinnery et al.; particularly in early disease the use of T2* MRI could demonstrate the characteristic pattern of iron deposition even in a presymptomatic carrier.56 Abnormalities of the mitochondrial respiratory chain were demonstrated in skeletal muscle biopsy.56

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Selected autosomal recessive disorders

Numerous autosomal recessive disorders can present with prominent chorea and dementia. Space restrictions limit a detailed discussion of all these conditions, but those in which HDL phenotypes might be seen are listed in Table 2. Of particular importance is Wilson's disease, for which a broad phenotype has been described.57 Although chorea is a rather rare symptom, the diagnosis of Wilson's disease should not be missed as it is a treatable condition.

Table 2 Summary of autosomal recessive and X-linked disorders that cause chorea
Table 2 - Summary of autosomal recessive and X-linked disorders that cause chorea
Full tableFigures & Tables indexDownload PowerPoint slide (111K)

Chorea–acanthocytosis

In a sporadic case of chorea without autosomal dominant family history, the autosomal recessive disorder chorea–acanthocytosis is one of the first conditions to consider in the differential diagnosis. Chorea–acanthocytosis is one of the so-called core 'neuroacanthocytosis syndromes with neurodegeneration of the basal ganglia', and is caused by mutations of the vacuolar protein sorting 13 homolog A (VPS13A) gene—which codes for the protein chorein—on chromosome 9q21.58, 59, 60 Onset is usually in young adulthood, and the clinical features, which include chorea, tics, parkinsonism, eye movement abnormalities, subcortical dementia and psychiatric features, can be similar to those of HD.61, 62 Dystonia with prominent orofacial involvement63 and self-mutilation, as well as the presence of myopathy and neuropathy, might, however, indicate a diagnosis distinct from classic HD.

Blood tests in patients with chorea–acanthocytosis reveal the presence of acanthocytes in the blood smear, and elevated creatine kinase. Liver function tests might be abnormal, indicating hepatomegaly. MRI demonstrates progressive caudate atrophy, with a more prominent predilection for the head of the nucleus than that seen in HD.64 Extensive neuronal loss and gliosis affecting the striatum, pallidum and substantia nigra have been found on postmortem.65

Pantothenate-kinase-associated neurodegeneration

Pantothenate-kinase-associated neurodegeneration (PKAN) was first described in 1922 by Hallervorden and Spatz,66 and is caused by mutations of the pantothenate kinase (PANK2) gene on chromosome 20p13. PKAN is characterized clinically by extrapyramidal symptoms (in 98% of cases)—in particular, generalized dystonia with oromandibular involvement,63 and parkinsonism–spasticity (25%), behavioral changes followed by dementia (29%), and pigmentary retinal degeneration. The mean age at onset is between 3 and 4 years.67, 68 The presentation of PKAN might be atypical if onset is later, and chorea as the main feature has been reported in a late-adult-onset pathologically proven case.69

PKAN is also referred to as neurodegeneration with brain iron accumulation type 1, or NBIA1. This new term reflects the findings on pathological examination—brown discoloration of the globus pallidus and substantia nigra, and iron deposition most abundant in the globus pallidus interna.66 The pallidal abnormalities and the iron deposits can be detected in vivo by MRI. T2-weighted images show a central hyperintensity (probably representing fluid accumulation or edema) of the globus pallidus interna in combination with a rim of signal hypointensity (iron deposition). This 'eye-of-the-tiger' sign is highly correlated with PANK2 mutations,68, 70 and is usually seen early in the disease course.67 By contrast, patients with a clinical picture similar to that of PKAN and evidence of iron deposition on MRI, but without a PANK2 gene mutation, do not show the classic 'eye-of-the-tiger' sign, but show hypointensity in the globus pallidus only.71 Recently, mutations of the PLA2G6 gene—which encodes a calcium-independent phospholipase A2—on chromosome 22q13, were identified as the cause of disease in some of these cases.67, 72

Phenotypic variability has been recognized for PLA2G6 mutations—some cases present as a mainly pyramidal syndrome with infantile neuroaxonal dystrophy, spastic tetraplegia, hyperreflexia and visual impairment,72 as opposed to the extrapyramidal syndrome with dystonia, parkinsonism and choreoathetosis (mentioned above) that can be clinically indistinguishable from the phenotype of patients with PANK2 gene mutations.73 Additional cerebellar atrophy might also be present in patients with PLA2G6 mutations (reported as Karak syndrome).74

Acanthocytes are found in the blood in approximately 10% of PKAN cases, and are possibly related to abnormalities of lipid metabolism.25, 68 Some cases of PKAN with acanthocytes and additional features such as hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa and pallidal degeneration were given the acronym HARP syndrome. HARP is now known to be allelic to PKAN and not a separate entity.75 In addition to the classic neuroacanthocytosis syndrome, the diagnosis of PKAN should also, therefore, be considered if acanthocytes are found in a patient with chorea.

X-linked McLeod syndrome

McLeod syndrome—the other core neuroacanthocytosis syndrome—is clinically similar to chorea–acanthocytosis, with seizures, peripheral neuropathy and myopathy, and can also present with an HDL phenotype.76 The diagnosis is again indicated by elevated liver enzymes and creatine kinase, and can be confirmed by demonstration of the absence of Kx antigens and a reduction in kell antigens on erythrocytes. Cardiomyopathy and arrhythmia are distinguishing features, and might be a cause of sudden death.

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Clinical approach and treatment considerations

To sift through the HDL disorders, it is important to pay attention to certain clinical features. For example, prominent myoclonus might indicate HDL1 or DRPLA. If cerebellar signs are marked, or cerebellar atrophy is demonstrated on neuroimaging, the SCAs and DRPLA should be considered. In the latter condition, high-intensity signals in the cerebral white matter, basal ganglia and brainstem may be present on T2-weighted MRI, in addition to atrophy of the brainstem and cerebellum. These signs are predominantly observed in late-onset adult patients with DRPLA with long disease duration, however, and are only rarely observed in juvenile patients with a short disease history.

PKAN and neuroferritinopathy have characteristic features on MRI imaging. Chorea is rarely an isolated movement disorder in these conditions; dystonia and other features are often dominant. Prominent orolingual involvement with dystonic tongue protrusion is characteristic of PKAN and chorea–acanthocytosis,63 and these disorders also differ from classic HD in their pattern of inheritance.

Treatment for the HDL disorders is symptomatic. Tetrabenazine or dopamine-receptor-blocking agents can alleviate the chorea. More disabling for the patient, however, can be the psychiatric features and mood disturbances associated with the disorders, in which case antidepressants might be indicated. Genetic counseling is recommended on the basis of the molecular diagnosis. The support of social services and ancillary agencies, as well as occupational therapy, speech therapy and physiotherapy, are important components of treatment, and should not be neglected.

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Conclusions

As summarized above, there are a growing number of distinct genetic disorders with an HDL clinical phenotype. Overall, these disorders are rare, and HD remains the leading inherited cause of chorea. It is also clear that the four so-called HDL syndromes account for only a small proportion of cases with the HD phenotype but a negative genetic test for the disorder, and we anticipate that the list of HDL-associated genes will continue to expand. For example, in a study of 252 patients with HDL syndromes, most of whom were white, only two cases of HDL2 and a further two of SCA17 were identified.14 Similarly, Costa et al. screened 107 Portuguese patients with an HDL phenotype and found no mutations in the PRNP, JPH3, TBP or FTL genes, or in two additional candidate genes, CREBBP and POU3F2.15 Absence of mutations in the PRNP and JPH3 genes was also reported by Keckarevic et al.16 for 48 patients from Yugoslavia with an HDL phenotype. Our own experience is that a recognized HDL syndrome will be genetically confirmed in only about 3% of patients with the HD phenotype who are negative for the HD gene mutation. HDL4 (SCA17) seems to be the most common HDL syndrome, followed by HDL2 and then HDL1 (E Wild et al., personal communication). As the prevalence of the various disorders might vary between ethnic groups, however, information about patient background might influence the priority level of requested genetic tests. In Japanese populations, DRPLA occurs relatively frequently, whereas in African Americans it is important to consider a diagnosis of HDL2.

The use of HDL terminology is pragmatic for the discussion of these disorders in the context of the differential diagnosis of progressive adult-onset choreiform conditions, but is grammatically clumsy. The term HDL might obscure the potential phenotypic variation or the critical distinguishing features of some of these disorders. The use of HDL terminology for each of these conditions should probably be ultimately replaced by names that reference genetic etiology, as has occurred for HDL4, which was identified to be SCA17.

Key points

  • Huntington's disease (HD) caused by mutation of the IT15 gene is the most important genetic cause of chorea
  • A diagnosis of HD should be considered in patients presenting with the classic triad of symptoms, comprising adult-onset personality changes, generalized chorea and cognitive decline
  • The syndrome of chorea in combination with other neurological and neuropsychiatric features seen in HD is known to be genetically heterogeneous; phenocopies are termed Huntington's disease-like (HDL) syndromes
  • Mutations underlying HDL syndromes have been identified in the prion gene (HDL1), the junctophilin 3 gene (HDL2) and the gene encoding the TATA box-binding protein (HDL4/SCA17)
  • One family with a recessively inherited HD phenocopy (HDL3) of poorly-understood genetic etiology has also been reported
  • HDL syndromes account for only a small proportion of cases with the HD phenotype, but should be considered in patients who test negative for the classic HD gene mutation

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Acknowledgments

SA Schneider was supported by the Brain Research Trust, UK. Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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References

  1. The Huntington's Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72: 971–983 | Article | PubMed | ISI |
  2. Simpson SA and Johnston AW (1989) The prevalence and patterns of care of Huntington's chorea in Grampian. Br J Psychiatry 155: 799–804 | PubMed | ISI | ChemPort |
  3. Harper PS (1992) The epidemiology of Huntington's disease. Hum Genet 89: 365–376 | Article | PubMed | ISI | ChemPort |
  4. Stevanin G et al. (2002) CAG/CTG repeat expansions at the Huntington's disease-like 2 locus are rare in Huntington's disease patients. Neurology 58: 965–967 | PubMed | ISI | ChemPort |
  5. Bauer P et al. (2004) Trinucleotide repeat expansion in SCA17/TBP in white patients with Huntington's disease-like phenotype. J Med Genet 41: 230–232 | Article | PubMed | ISI | ChemPort |
  6. Kambouris M et al. (2000) Localization of the gene for a novel autosomal recessive neurodegenerative Huntington-like disorder to 4p15.3. Am J Hum Genet 66: 445–452 | Article | PubMed | ISI | ChemPort |
  7. Xiang F et al. (1998) A Huntington disease-like neurodegenerative disorder maps to chromosome 20p. Am J Hum Genet 63: 1431–1438 | Article | PubMed | ISI | ChemPort |
  8. Margolis RL et al. (2001) A disorder similar to Huntington's disease is associated with a novel CAG repeat expansion. Ann Neurol 50: 373–380 | Article | PubMed | ISI | ChemPort |
  9. Lewis V et al. (2003) Novel prion protein insert mutation associated with prolonged neurodegenerative illness. Neurology 60: 1620–1624 | PubMed | ISI | ChemPort |
  10. Moore RC et al. (2001) Huntington disease phenocopy is a familial prion disease. Am J Hum Genet 69: 1385–1388 | Article | PubMed | ISI | ChemPort |
  11. Laplanche JL et al. (1999) Prominent psychiatric features and early onset in an inherited prion disease with a new insertional mutation in the prion protein gene. Brain 122: 2375–2386 | Article | PubMed | ISI |
  12. Caughey B and Baron GS (2006) Prions and their partners in crime. Nature 443: 803–810 | Article | PubMed | ISI | ChemPort |
  13. Gambetti P et al. (2003) Hereditary Creutzfeldt–Jakob disease and fatal familial insomnia. Clin Lab Med 23: 43–64 | Article | PubMed | ISI |
  14. Stevanin G et al. (2003) Huntington's disease-like phenotype due to trinucleotide repeat expansions in the TBP and JPH3 genes. Brain 126: 1599–1603 | Article | PubMed | ISI |
  15. Costa MC et al. (2006) Exclusion of mutations in the PRNP, JPH3, TBP, ATN1, CREBBP, POU3F2 and FTL genes as a cause of disease in Portuguese patients with a Huntington-like phenotype. J Hum Genet 51: 645–651 | Article | PubMed | ChemPort |
  16. Keckarevic M et al. (2005) Yugoslav HD phenocopies analyzed on the presence of mutations in PrP, ferritin, and Jp-3 genes. Int J Neurosci 115: 299–301 | PubMed | ISI | ChemPort |
  17. Margolis RL et al. (2005) Huntington's disease like-2: review and update. Acta Neurol Taiwan 14: 1–8 | PubMed |
  18. Bauer I et al. (2002) Trinucleotide repeat expansions in the junctophilin-3 gene are not found in Caucasian patients with a Huntington's disease-like phenotype. Ann Neurol 51: 662 | Article | PubMed | ISI |
  19. Krause A et al. (2005) HDL2 mutations are an important cause of Huntington's disease in patients with African ancestry [abstract #A17]. J Neurol Neurosurg Psychiatr 76 (Suppl 4): S007
  20. Margolis RL et al. (2004) Huntington's disease-like 2 (HDL2) in North America and Japan. Ann Neurol 56: 670–674 | Article | PubMed | ISI | ChemPort |
  21. Teive HAG et al. (2007) Huntington's disease-like 2: the first case report in Latin America in a patient without African ethnic origin. Mov Disord 22 (Suppl 16): S26 | Article |
  22. Greenstein PE et al. (2007) Huntington's disease like-2 neuropathology. Mov Disord [doi: doi: 10.1002/mds.21417] | Article |
  23. Walker RH et al. (2002) Autosomal dominant chorea–acanthocytosis with polyglutamine-containing neuronal inclusions. Neurology 58: 1031–1037 | PubMed | ISI | ChemPort |
  24. Walker RH et al. (2003) Huntington's disease-like 2 can present as chorea–acanthocytosis. Neurology 61: 1002–1004 | PubMed | ISI | ChemPort |
  25. Walker RH et al. (2007) Neurologic phenotypes associated with acanthocytosis. Neurology 68: 92–98 | Article | PubMed | ISI | ChemPort |
  26. Holmes SE et al. (2001) A repeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease-like 2. Nat Genet 29: 377–378 | Article | PubMed | ISI | ChemPort |
  27. Rudnicki DD et al. (2007) Huntington's disease-like 2 is associated with CUG repeat-containing RNA foci. Ann Neurol 61: 272–282 | Article | PubMed | ISI | ChemPort |
  28. Al-Tahan AY et al. (1999) A novel autosomal recessive 'Huntington's disease-like' neurodegenerative disorder in a Saudi family. Saudi Med J 20: 85–89 | ISI |
  29. Lesperance MM and Burmeister M (2000) Interpretation of linkage data for a Huntington-like disorder mapping to 4p15.3. Am J Hum Genet 67: 262–263 | Article | PubMed | ISI | ChemPort |
  30. Nakamura K et al. (2001) SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. Hum Mol Genet 10: 1441–1448 | Article | PubMed | ISI | ChemPort |
  31. Zuhlke C et al. (2003) Phenotypical variability of expanded alleles in the TATA-binding protein gene: reduced penetrance in SCA17? J Neurol 250: 161–163 | Article | PubMed | ISI | ChemPort |
  32. Maltecca F et al. (2003) Intergenerational instability and marked anticipation in SCA-17. Neurology 61: 1441–1443 | PubMed | ISI | ChemPort |
  33. Craig K et al. (2005) Minimum prevalence of spinocerebellar ataxia 17 in the north east of England. J Neurol Sci 239: 105–109 | Article | PubMed | ISI | ChemPort |
  34. Koide R et al. (1999) A neurological disease caused by an expanded CAG trinucleotide repeat in the TATA-binding protein gene: a new polyglutamine disease? Hum Mol Genet 8: 2047–2053 | Article | PubMed | ISI | ChemPort |
  35. Schneider SA et al. (2006) Phenotypic homogeneity of the Huntington disease-like presentation in a SCA17 family. Neurology 67: 1701–1703 | Article | PubMed | ISI | ChemPort |
  36. Rolfs A et al. (2003) Clinical features and neuropathology of autosomal dominant spinocerebellar ataxia (SCA17). Ann Neurol 54: 367–375 | Article | PubMed | ISI |
  37. Gunther P et al. (2004) Basal ganglia involvement of a patient with SCA 17—a new form of autosomal dominant spinocerebellar ataxia. J Neurol 251: 896–897 | PubMed | ISI | ChemPort |
  38. Lasek K et al. (2006) Morphological basis for the spectrum of clinical deficits in spinocerebellar ataxia 17 (SCA17). Brain 129: 2341–2352 | Article | PubMed | ISI | ChemPort |
  39. Manganelli F et al. (2006) Electrophysiologic characterization in spinocerebellar ataxia 17. Neurology 66: 932–934 | Article | PubMed | ISI | ChemPort |
  40. Naito H and Oyanagi S (1982) Familial myoclonus epilepsy and choreoathetosis: hereditary dentatorubral–pallidoluysian atrophy. Neurology 32: 798–807 | PubMed | ISI | ChemPort |
  41. Kanazawa I (1998) Dentatorubral–pallidoluysian atrophy or Naito–Oyanagi disease. Neurogenetics 2: 1–17 | Article | PubMed | ISI | ChemPort |
  42. Takano T et al. (1996) Assignment of the dentatorubral and pallidoluysian atrophy (DRPLA) gene to 12p13.31 by fluorescence in situ hybridization. Genomics 32: 171–172 | Article | PubMed | ISI | ChemPort |
  43. Nagafuchi S et al. (1994) Structure and expression of the gene responsible for the triplet repeat disorder, dentatorubral and pallidoluysian atrophy (DRPLA). Nat Genet 8: 177–182 | Article | PubMed | ISI | ChemPort |
  44. Koide R et al. (1994) Unstable expansion of CAG repeat in hereditary dentatorubral–pallidoluysian atrophy (DRPLA). Nat Genet 6: 9–13 | Article | PubMed | ISI | ChemPort |
  45. Aoki M et al. (1994) Maternal anticipation of DRPLA. Hum Mol Genet 3: 1197–1198 | Article | PubMed | ISI | ChemPort |
  46. Warner TT et al. (1994) DRPLA in Europe. Nat Genet 6: 225 | Article | PubMed | ISI | ChemPort |
  47. Le Ber I et al. (2003) Prevalence of dentatorubral–pallidoluysian atrophy in a large series of white patients with cerebellar ataxia. Arch Neurol 60: 1097–1099 | Article | PubMed | ISI |
  48. Becher MW et al. (1997) Dentatorubral and pallidoluysian atrophy (DRPLA): clinical and neuropathological findings in genetically confirmed North American and European pedigrees. Mov Disord 12: 519–530 | Article | PubMed | ISI | ChemPort |
  49. Licht DJ and Lynch DR (2002) Juvenile dentatorubral–pallidoluysian atrophy: new clinical features. Pediatr Neurol 26: 51–54 | Article | PubMed | ISI |
  50. Lee IH et al. (2001) Dentatorubropallidoluysian atrophy in Chinese. Arch Neurol 58: 1905–1908 | Article | PubMed | ISI | ChemPort |
  51. Martins S et al. (2003) Portuguese families with dentatorubropallidoluysian atrophy (DRPLA) share a common haplotype of Asian origin. Eur J Hum Genet 11: 808–811 | Article | PubMed | ISI | ChemPort |
  52. Curtis AR et al. (2001) Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat Genet 28: 350–354 | Article | PubMed | ISI | ChemPort |
  53. Chinnery PF et al. (2003) Neuroferritinopathy in a French family with late onset dominant dystonia. J Med Genet 40: e69 | Article | PubMed | ChemPort |
  54. Maciel P et al. (2005) Neuroferritinopathy: missense mutation in FTL causing early-onset bilateral pallidal involvement. Neurology 65: 603–605 | Article | PubMed | ISI | ChemPort |
  55. Anderson LJ et al. (2001) Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J 22: 2171–2179 | Article | PubMed | ISI | ChemPort |
  56. Chinnery PF et al. (2007) Clinical features and natural history of neuroferritinopathy caused by the FTL1 460InsA mutation. Brain 130: 110–119 | PubMed | ISI |
  57. Taly AB et al. (2007) Wilson disease: description of 282 patients evaluated over 3 decades. Medicine (Baltimore) 86: 112–121 | PubMed |
  58. Rubio JP et al. (1997) Chorea–acanthocytosis: genetic linkage to chromosome 9q21. Am J Hum Genet 61: 899–908 | PubMed | ISI | ChemPort |
  59. Rampoldi L et al. (2001) A conserved sorting-associated protein is mutant in chorea-acanthocytosis. Nat Genet 28: 119–120 | Article | PubMed | ISI | ChemPort |
  60. Ueno S et al. (2001) The gene encoding a newly discovered protein, chorein, is mutated in chorea–acanthocytosis. Nat Genet 28: 121–122 | Article | PubMed | ISI | ChemPort |
  61. Hardie RJ (1989) Acanthocytosis and neurological impairment—a review. Q J Med 71: 291–306 | PubMed | ISI | ChemPort |
  62. Gradstein L et al. (2005) Eye movements in chorea–acanthocytosis. Invest Ophthalmol Vis Sci 46: 1979–1987 | Article | PubMed | ISI |
  63. Schneider SA et al. (2006) Severe tongue protrusion dystonia: clinical syndromes and possible treatment. Neurology 67: 940–943 | Article | PubMed | ISI | ChemPort |
  64. Henkel K et al. (2006) Head of the caudate nucleus is most vulnerable in chorea-acanthocytosis: a voxel-based morphometry study. Mov Disord 21: 1728–1731 | Article | PubMed | ISI |
  65. Alonso ME et al. (1989) Chorea–acanthocytosis: report of a family and neuropathological study of two cases. Can J Neurol Sci 16: 426–431 | PubMed | ISI | ChemPort |
  66. Hallervorden J and Spatz H (1922) A peculiar illness of the extrapyramidal system predominantly affecting the globus pallidus and the substantia nigra: a contribution to the relationship between these two nuclei [German]. Z Ges Neurol Psychiatr 79: 254–302 | ISI |
  67. Hayflick SJ (2006) Neurodegeneration with brain iron accumulation: from genes to pathogenesis. Semin Pediatr Neurol 13: 182–185 | Article | PubMed |
  68. Hayflick SJ et al. (2003) Genetic, clinical, and radiographic delineation of Hallervorden–Spatz syndrome. N Engl J Med 348: 33–40 | Article | PubMed | ISI | ChemPort |
  69. Grimes DA et al. (2000) Late adult onset chorea with typical pathology of Hallervorden–Spatz syndrome. J Neurol Neurosurg Psychiatry 69: 392–395 | Article | PubMed | ISI | ChemPort |
  70. Sethi KD et al. (1988) Hallervorden–Spatz syndrome: clinical and magnetic resonance imaging correlations. Ann Neurol 24: 692–694 | Article | PubMed | ISI | ChemPort |
  71. Hayflick SJ et al. (2006) Brain MRI in neurodegeneration with brain iron accumulation with and without PANK2 mutations. AJNR Am J Neuroradiol 27: 1230–1233 | PubMed | ChemPort |
  72. Morgan NV et al. (2006) PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nat Genet 38: 752–754 | Article | PubMed | ISI | ChemPort |
  73. Hortnagel K et al. (2004) Infantile neuroaxonal dystrophy and pantothenate kinase-associated neurodegeneration: locus heterogeneity. Neurology 63: 922–924 | PubMed | ISI | ChemPort |
  74. Mubaidin A et al. (2003) Karak syndrome: a novel degenerative disorder of the basal ganglia and cerebellum. J Med Genet 40: 543–546 | Article | PubMed | ISI | ChemPort |
  75. Ching KH et al. (2002) HARP syndrome is allelic with pantothenate kinase-associated neurodegeneration. Neurology 58: 1673–1674 | PubMed | ISI | ChemPort |
  76. Danek A et al. (2001) McLeod neuroacanthocytosis: genotype and phenotype. Ann Neurol 50: 755–764 | Article | PubMed | ISI | ChemPort |
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Competing interests

The authors declared no competing interests.

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Subject areas under which this article appears: Movement disorders | Neurodegenerative disease