Letters to the Editor Related to Published Articles

Reply: Autopsy-Proven Huntington’s Disease

with 29 Trinucleotide Repeats

Since the development of the genetic test for Huntington dis-ease (HD),1 several large series have found that about 1% ofpatients with the HD phenotype lack the characteristictrinucleotide repeat.2,3 The so called ‘‘phenocopies’’ of HDinclude dentatorubral-pallidoluysian atrophy (DRPLA), Spino-cerebellar Ataxia 17 (SCA17), Huntington’s disease-like type1 (HDL1) and type 2 (HDL2), and a variety of other heredo-degenerative disorders. Our case raises the possibility thatanother explanation for the low number of CAG repeats inan otherwise typical case of HD is that the low limit neededfor the diagnosis of HD may need to be modified. Since theinitial report which characterized the HD genotype, the repeatsize associated with disease has decreased from 42 to 36,about one repeat every 2 years. Although based on a largebody of clinical data, there is relative paucity of informationsupporting the suggested low limit of 36 by clinical-patholog-ical correlations. We are pleased that our case report4 has ini-tiated an active dialogue about this issue and would like totake this opportunity to respond to the thoughtful commentsfrom our colleagues.

With regard to Dr. Reynolds comments, the HD test for theproband was indeed repeated. We have reported the test thatwas done most recently in hopes that its conclusions were moreaccurate. The first time this patient had testing, the CAG repeatsize in the huntingtin gene was equivalent to 28.

Dr. Semaka and colleagues bring up several excellentpoints, but also include a fairly lengthy differential diagnosis,most of which is not relevant in this patient (tardive dyskine-sia, chorea gravidarum, etc). Some of their arguments are cir-cular; they define the genetic criteria and state that there areno existing reports of HD with less than 36 CAG repeats.We know of at least one occasion when a patient with thetypical phenotype and 35 CAG repeats was submitted forpublication, but rejected.

The more important issue is whether this patient could be aHD phenocopy. It cannot be overstated that most of the reportsof HD phenocopies present with overlapping features, butthere is typically some aspect of the case that is unusual forHD: predominant ataxia, autonomic dysfunction, supranuclearpalsy, epilepsy, or atypical MRI findings (pontine atrophy, cer-ebellar atrophy, MRI hot-cross bun sign).5–7 For instance,SCA-17 tends to present with significant cerebellar featuresalong with cerebellar atrophy and MRI findings reminiscent ofmultisystem atrophy.5,6,8 SCA17 is therefore, more typicallyconsidered in the differential diagnosis of multisystem atro-

phy. Our patient presented with classic HD phenomenology asclearly seen in the video from the original publication.4

Since the original publication, additional histochemicalstaining has been completed with the inclusion of a positivecontrol in the laboratory of Dr. Raymund Roos. He foundubiquitin-positive neuronal intranuclear inclusions in the cort-ical and other areas. Although the inclusions did not stainwith antibodies directed against huntingtin, they may not beabsolutely necessary for establishing the neuropathologicaldiagnosis of HD (Jean Paul Vonsattel, MD, personal commu-nication). It is also possible that the antibody designed to rec-ognize huntingtin intranuclear inclusions with an expandedpolyglutamine stretch may not bind properly to an aggregateof huntingtin protein with an intermediate polyglutaminestretch. Although we are grateful to Drs. Reynolds and Sem-aka for their comments, we believe that the preponderance ofevidence still supports the diagnosis of HD in our case and itstrongly suggests that the rather arbitrarily defined low limitof CAG repeat number should be reexamined.

Acknowledgments: The authors wish to express their sin-cere gratitude to Dr. Raymund Roos for completing addi-tional histochemical staining.

Christopher Kenney, MD*Joseph Jankovic, MD

Department of NeurologyBaylor College of Medicine

Houston, Texas*E-mail: christopher.kenney@emdserono.edu

References

1. A novel gene containing a trinucleotide repeat that is expanded andunstable on Huntington’s disease chromosomes. The Huntington’sDisease Collaborative Research Group. Cell 1993;72:971–983.

2. Kremer B, Goldberg P, Andrew SE, et al. A worldwide study of theHuntington’s disease mutation. The sensitivity and specificity ofmeasuring CAG repeats. N Engl J Med 1994;330:1401–1406.

3. MacMillan JC, Snell RG, Tyler A, et al. Molecular analysis andclinical correlations of the Huntington’s disease mutation. Lancet1993;342:954–958.

4. Kenney C, Powell S, Jankovic J. Autopsy-proven Huntington’s dis-ease with 29 trinucleotide repeats. Mov Disord 2007;22:127–130.

5. Gunther P, Storch A, Schwarz J, et al. Basal ganglia involvement ofa patient with SCA 17—a new form of autosomal dominant spino-cerebellar ataxia. J Neurol 2004;251:896–897.

6. Lin IS, Wu RM, Lee-Chen GJ, Shan DE, Gwinn-Hardy K. TheSCA17 phenotype can include features of MSA-C, PSP and cogni-tive impairment. Parkinsonism Relat Disord 2007;13:246–249.

7. Schneider SA, Walker RH, Bhatia KP. The Huntingdon’s disease-like syndromes: What to consider in patients with a negative Hun-tington’s disease gene test. Nat Clin Pract Neurol 2007;3:517–525.

8. Schneider SA, van de Warrenburg BP, Hughes TD, et al. Phenotypichomogeneity of the Huntington disease-like presentation in aSCA17 family. Neurology 2006;67:1701–1703.

Published online 15 August 2008 in Wiley InterScience (www.

interscience.wiley.com). DOI: 10.1002/mds.21814

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Movement DisordersVol. 23, No. 12, 2008, pp. 1793–1796� 2008 Movement Disorder Society

Re: Autopsy-Proven Huntington’s Disease with

29 Trinucleotide Repeats

We read with great interest the recent case report describingthe diagnosis of Huntington disease (HD) in an individualwith 29 CAG repeats in the HD gene.1 Given the significanceand the potential implications of this finding for the HD com-munity, we wish to comment on the conclusions of the casereport based on the genetic, clinical, and neuropathologicalfindings that were provided.

Since the discovery of an expanded CAG trinucleotide repeatas the mutation underlying HD, confirmation of a clinical diag-nosis of HD has been based on genetic criteria. This clear set ofgenetic criteria,2 specifically a CAG repeat expansion ‡36repeats within the HD gene, will continue to serve as a valuableguideline supporting a clinical diagnosis of HD until additionalevidence is presented that supports a change to the criteria. Theevidence supporting a change to this genetic criteria shouldmeet the same standards and rigor as would be required whenmaking a novel gene-disease association. We disagree with thecurrent case report that sufficient clinical and neuropathologicalfindings are present to support a definitive diagnosis of HD.Rather, the findings are consistent with an HD-phenocopy orHD-like disorder, with a coincidental identification of an inter-mediate allele in the HD gene.

Currently, there are three main categories of CAG alleles inthe HD gene: normal alleles with 7 to 26 CAG repeats, inter-mediate alleles with 27 to 35 CAG repeats, and HD alleleswith ‡36 CAG repeats.2 All HD allele carriers are at risk todevelop HD, but CAG sizes of 36 to 39 frequently showreduced penetrance.3 There have been no definitive casesof HD resulting from less than 36 repeats4; therefore, thisCAG size defines the current threshold for an HD diagnosis.Intermediate alleles have a frequency of �4% in the generalpopulation5 and carriers are not at risk of developing HD.6

However, offspring of intermediate allele carriers are at-risk ofinheriting a new mutation for HD (‡36 CAG repeats) becausethe CAG tract of intermediate alleles is unstable and prone toexpansion upon transmission to the next generation.6

The clinical and neuropathological findings in this casereport are consistent with HD; however, these findings arealso consistent with many other neuropathological disorders.Prior to making a diagnosis of HD with less than 36 CAGrepeats in the HD gene, a thorough exclusion of all other HDphenocopy and HD-like disorders with known etiologies isrequired. For example, the HD-phenocopy disorders, HDL-1(HD Like-1) and HDL-2 (HD Like-2), are clinically and neu-ropathologically indistinguishable from HD, but have clearetiologies other than CAG repeat expansion in the HDgene.7,8 Given the high prevalence of intermediate alleles inthe HD gene in the general population, it would not besurprising to find a patient with either an HD phenocopy orHD-like disorder who coincidentally carries an intermediateallele for HD. While the authors excluded disorders such asDRPLA and Neuroacanthocytosis when evaluating thispatient, the exclusion of the following disorders where rele-

vant would strengthen a definitive HD diagnosis: Cerebrallupus, Chorea gravidarum, Tardive dyskinesia, Thyrotoxico-sis, Sydenham chorea, Ataxia-telangiectasia, autosomal domi-nant Spinocerebellar ataxia, particularly SCA17, Choreoacan-thocytosis (ChAc), Dentatorubral-pallidoluysian atrophy(DRPLA), FAHR disease, Huntington disease-like 2 (HDL2),Huntington disease-like 1 (HDL1), Lesch-Nyham syndrome,Neuroacanthocytosis, Pantothenate kinase-associated neuro-degeneration, and Wilson disease.

In an effort to provide clinicians guidance on what evi-dence would be sufficient for a definitive HD diagnosis inthe absence of ‡36 CAG repeats, we propose the followingguidelines (Table 1). These recommendations include clinicaland neuropathological findings consistent with HD, as dem-onstrated in the current case report. Further, findings specificto HD, such as Huntingtin inclusions in the brain, would addcredibility to the diagnosis. Most importantly, and lacking inthe current case report, is the requirement to exclude disor-ders with clinical overlap to HD. Additionally, these guide-lines require the clear demonstration of cosegregation of thegenetic change (i.e., CAG size) with the disease. Notably,CAG repeat size instability is not a criterion that supports aHD diagnosis, particularly since intermediate allele carriersare known to have instability in their CAG tract.

The conclusion that a repeat length of 29 CAG repeatscan cause HD would significantly change genetic counselingof HD families, HD therapeutic trials, and the current under-standing of the molecular pathogenesis of the disease. Theimpact of an incorrect diagnosis of this nature would be det-rimental to the HD community. Given the evolving nature ofmolecular understanding of disease, in the future, it is possi-ble a case will be presented that would substantiate a changeto the genetic criteria that supports a clinical diagnosis ofHD. However, it is our view this case report is consistentwith a HD intermediate allele carrier who is affected with anHD-phenocopy or HD-like disorder.

Alicia Semaka1,2

Simon Warby1,2

Bliar R. Leavitt1,2

Michael R. Hayden1,2*1Centre for Molecular Medicine and Therapeutics

Vancouver, Canada2Department of Medical Genetics

University of British ColumbiaVancouver, Canada

*E-mail: mrh@cmmt.ubc.ca

TABLE 1. Guidelines for diagnosing HD with <36 CAGrepeats in the HD gene

1. Clinical Criteria:A phenotype consistent with HD including a progressiveextrapryamidal movement disorder, including cognitive decline,and/or psychiatric disturbancesExclusion of disorders with clinical overlap to HD

2. Neuropathological criteria:Predominant neuronal cell loss in striatum by autopsyPresence of huntingtin inclusions

3. Genetic criteria (evidence of heritability):Demonstration of autosomal dominant inheritance patternDemonstration of cosegregation of genetic change with disease

Published online 11 June 2008 in Wiley InterScience (www.

interscience.wiley.com). DOI: 10.1002/mds.21820

Movement Disorders, Vol. 23, No. 12, 2008

1794 LETTERS TO THE EDITOR

References

1. Kenney C, Powell S, Jankovic J. Autopsy-proven Huntington’s dis-ease with 29 trinucleotide repeats. Mov Disord 2007;22:127–130.

2. Potter NT, Spector EB, Prior TW. Technical standards and guide-lines for Huntington disease testing. Genet Med 2004;6:61–65.

3. McNeil SM, Novelletto A, Srinidhi J, Barnes G, Kornbluth I, AltherrMR, Wasmuth JJ, Gusella JF, MacDonald ME, Myers RH. Reducedpenetrance of the Huntington’s disease mutation. Hum Mol Genet1997;6:775–779.

4. Langbehn DR, Brinkman RR, Falush D, Paulsen JS, Hayden MR. Anew model for prediction of the age of onset and penetrance for Hun-tington’s disease based on CAG length. Clin Genet 2004;65:267–277.

5. Maat-Kievit A, Losekoot M, Van Den Boer-Van Den Berg H, et al.New problems in testing for Huntington’s disease: the issue of inter-mediate and reduced penetrance alleles. J Med Genet 2001;38:E12.

6. Semaka A, Creighton S, Warby S, Hayden MR. Predictive testingfor Huntington disease: interpretation and significance of intermedi-ate alleles. Clin Genet 2006;70:283–294.

7. Holmes SE, O’Hearn E, Rosenblatt A, et al. A repeat expansion inthe gene encoding junctophilin-3 is associated with Huntingtondisease-like 2. Nat Genet 2001;29:377–378.

8. Moore RC, Xiang F, Monaghan J, Han D, Zhang Z, Edstrom L, Anv-ret M, Prusiner SB. Huntington disease phenocopy is a familial priondisease. Am J Hum Genet 2001;69:1385–1388.

Spectrum of Anxiety Symptoms in

Hyperkinesias

We read with interest the recent article by Ozel-Kizil et al.1

In the study, the authors examined 20 patients each withhemifacial spasm (HFS), essential tremor, and cervical dysto-nia using various anxiety and depression scales. They founda high frequency of patients with secondary social anxietysymptoms and a younger age and depressive symptoms wereassociated with the severity of the anxiety disorder.

We like to draw the authors’ attention to two previousstudies that have highlighted anxiety and depressive symp-toms in HFS.2,3 The first involved 238 subjects (90 HFSpatients, 96 healthy controls, and 52 outpatient controls)using the SCL-90R, which screened for nine major symptomdimensions (somatization, obsessive compulsive, interperso-nal sensitivity, depression, anxiety, hostility, phobic anxiety,paranoia, and psychoticism). General anxiety, phobic anxiety,and depressive symptoms were significantly higher in HFScompared to controls in at least one of the case–control sets.HFS patients had a higher mean HAM-A (Hamilton AnxietyRating Scale) score compared to controls (10.0 vs. 5.0). Mostof these patients also satisfied the DSM-IV diagnostic criteriaof generalized anxiety disorder. It is interesting to note thatin the Ozel-Kizil et al.’s study, the mean HAM-A score inpatients with social anxiety was 9.9 compared to the 5.9score in those without, and mean HAM-A in HFS was about7. This seems to suggest that social anxiety symptoms occuras part of the wider spectrum of the symptoms of generalizedanxiety disorder in these patients. However, it is puzzlingthat the authors found no correlation between the LiebowitzSocial Anxiety score and HAM-A score. Could this be

explained by the fact that some of these patients exhibitedsocial anxiety symptoms only, whereas others have in addi-tion, generalized anxiety symptoms? If so, have the authorsbeen able to differentiate these two groups of patients?

In a separate study involving 90 HFS patients using theBeck Depression Inventory (BDI) and DSM-IV criteria, theprevalence of depressive disorder was found to be around16%, with younger women at greater risk.3 Thus the studyby Ozel-Kizil et al. reaffirms previous observations that at ayounger age, depressive and anxiety symptoms are interre-lated in patients with hyperkinesias. Early recognition ofthese at-risk patients can prevent unnecessary morbidity.

Ozel-Kizil et al. also concluded from their study that therewas no difference in the occurrence of social anxiety symp-toms between HFS, essential tremor, and cervical dystonia.1

We would advise caution in drawing such a conclusion as asample of 20 subjects in each group was small, and the se-verity of each of these movement disorders based on assess-ment with validated or nonvalidated scales cannot be equi-tably compared. Furthermore, the study did not take intoaccount treatment effects of the underlying hyperkinesias,and the impact of associated comorbidities was not exam-ined. Previous studies have shown that there was a correla-tion of an improvement of the anxiety score with treatmentof the anxiety symptoms.2 Thus, it would be interesting toknow if such clinically relevant information is available inthis study.

Eng-King Tan, MD, FRCP*Ling-Ling Chan, MD

Department of NeurologySingapore General Hospital

National Neuroscience InstituteSingapore

*E-mail: gnrtek@sgh.com.sg

References

1. Ozel-Kizil ET, Akbostanci MC, Ozguven HD, Atbasoglu EC. Sec-ondary social anxiety in hyperkinesias. Mov Disord 2008;23:641–645.

2. Tan EK, Fook-Chong S, Lum SY. Case-control study of anxietysymptoms in hemifacial spasm. Mov Disord 2006;21:2145–2149.

3. Tan EK, Lum SY, Fook-Chong S, Chan LL, Gabriel C, Lim L.Behind the facial twitch: depressive symptoms in hemifacialspasm. Parkinsonism Relat Disord 2005;11:241–245.

Re: Autopsy-Proven Huntington’s Disease

with 29 Trinucleotide Repeats

As clinicians who perform genetic tests for the diagnosis ofHuntington’s disease (HD), we agree with Drs. Kenny,Powell, and Jankovic that we should use caution in rulingout HD when less than 36 CAG repeats are identified in the

Published online 15 August 2008 in Wiley InterScience (www.

interscience.wiley.com). DOI: 10.1002/mds.22105

Published online 11 June 2008 in Wiley InterScience (www.

interscience.wiley.com). DOI: 10.1002/mds.21821

1795LETTERS TO THE EDITOR

Movement Disorders, Vol. 23, No. 12, 2008

huntingtin gene.1 Allelic comparisons with the parent whoseHD gene has been inherited is especially important in thisregard. If the HD allele does not correspond with the parentalgene, then repeating the genetic test is wise. Normal shifts inexpansions or contractions of CAG repeat size from 1 to 5repeats is not a cause for concern.2 Inheritance of largerCAG repeat expansions is thought to occur from meioticinstability during gametogenesis,3 occurring more commonlyin paternal than in maternal transmission.4 This may lead toan earlier onset of phenotypic conversion (‘‘anticipation’’).

Although Drs. Kenny, Powell, and Jankovic carefullyreview a differential diagnosis for their case of autopsy veri-fied HD, they fail to report any attempt to clarify the validityof the CAG repeat value of 29 attributed to their patient. Fur-thermore, to attribute paternal anticipation to the patient’sson with CAG repeat sizes of 32 and 19 is quantitativelyuntenable. Without reassurance of repeat studies to validatethe original HD gene as having an allelic pair of 29/20 CAGrepeats, the case report only serves to offer an unsubstanti-ated devastating fear to at risk HD patients including the sonof the patient being reported. It is unlikely that a blood sam-ple of the patient’s father (who displayed involuntary move-

ments) is available unless blood banked, but redoing thepatient’s HD genetic test with a second sample could cer-tainly have been done to clarify the CAG repeat size.

Norman Reynolds, MD*VAMC – Neurology

Milwaukee, Wisconsin*E-mail: nreynjr@pol.net

References

1. Kenny C, Powell S, Jankovic J. Autopsy-proven Huntington’s dis-ease with 29 CAG repeats. Mov Disord 2007;22:127–130.

2. Nance MA, Mathias-Hagen V, Breningstall G, et al. Analysis of avery large trinucleoltide repeat in a patient with juvenile Hunting-ton’s disease. Neurology 1999;52:392–394.

3. Leeflang EP, Zhang L, Tavare S, et al. Single sperm analysis ofthe trinucleotide repeats in the Huntington’s disease gene: quantifi-cation of the mutation frequency spectrum. Hum Mol Genet1995;4:1519–1526.

4. Merritt AD, Conneally PM, Rahman NF, et al. Juvenile Huntington’schorea. In: Barbeau A, Brunette TR, editors. Progress in neurogenetics.Amsterdam: Excerpta Medica Foundation; 1969. p 645–650.

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