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Reply: Late onset Huntington's disease with 29 CAG repeat expansion
Reply: Late onset Huntington’s disease with 29 CAG repeat expansion Mayke Oosterloo, Martine J. Van Belzen, Emilia K. Bijlsma, Raymund A.C. Roos PII: DOI: Reference:
S0022-510X(16)30434-8 doi: 10.1016/j.jns.2016.07.021 JNS 14685
To appear in:
Journal of the Neurological Sciences
Received date: Accepted date:
2 May 2016 11 July 2016
Please cite this article as: Mayke Oosterloo, Martine J. Van Belzen, Emilia K. Bijlsma, Raymund A.C. Roos, Reply: Late onset Huntington’s disease with 29 CAG repeat expansion, Journal of the Neurological Sciences (2016), doi: 10.1016/j.jns.2016.07.021
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Reply: Late onset Huntington's disease with 29 CAG repeat expansion Mayke Oosterloo, Martine J. Van Belzen, Emilia K. Bijlsma and Raymund A.C. Roos
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We read with interest the case report describing a patient diagnosed as manifest Huntington’s disease (HD) caused by a 29 CAG repeat expansion in the Huntingtin (HTT) gene[1]. We do regret however, that the authors have not referred to our recent paper, regarding a review of all published cases of symptomatic carriers of intermediate alleles (IAs) (n=10), combined with a database search of 60 patients with IAs in the Netherlands[2] . As argued in our paper, we strongly question the evidence that intermediate repeats in the HTT gene can cause HD.
MA
NU
As in most of the cases we reviewed, the patient described by Garcia-Ruiz et al. does not show a convincing HD phenotype. They describe a patient with late mild generalized chorea at the age of 82 years especially in the lower limbs and an increased latency of saccade. The latter is explained by poor visual acuity due to macular degeneration the patient is known with. There are no other motor abnormalities like hypo- or bradykinesia or motor impersistency. An isolated chorea without any other motor abnormalities, no cognitive decline over time, no psychiatric symptoms and signs and no family history of HD is very unlikely Huntington’s disease.
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The authors quote that there are several reports of similar patients with late onset chorea and intermediate CAG repeats[3, 4]. In our paper we reviewed all published patients and found only four individuals with an intermediate repeat size and symptoms and signs comparable with those seen in HD (motor, psychiatric, and cognitive signs). Still, we are reluctant to conclude to a causal relationship, as there are several factors that have to be taken into account before a definite conclusion can be reached. As limits for expanded CAG repeats are determined but not definite, it is hard to assume that IAs can never cause HD symptoms and signs. However the frequency of IAs in the general population is high and therefore it is likely that the combination of an IA and symptoms resembling HD do occur and are based on coincidence[5, 6]. With evolving genetic insight and the finding of new genetic causes for HD like syndromes, it may be more likely that the symptoms are caused by a yet unknown or recently discovered HD mimic like the C9orf72 expansion [7].Taken together, we find it premature to conclude that IAs can cause HD in general, and we are not convinced that the patient described by Garcia-Ruiz et al. has manifest HD. Publishing cases like this one creates a publication bias. Given the tremendous consequences in diagnosing and premanifest counseling HD, this is an undesirable situation. Foremost, concluding that an intermediate allele can cause HD must be well considered. We therefore suggest the authors to exclude now known HD phenocopies like C9orf72 and TBP (SCA17). As there is no cognitive decline or psychiatric symptoms and signs, little progression of the chorea over time and no positive family history, we find that this patient should not be diagnosed as manifest HD. We would rather consider senile chorea, as most other causes of chorea are ruled out and this is still regarded a clinical entity[8]. As in all IAs cases with signs of chorea, we recommend careful follow-up and eventually post mortem brain pathology. Also family studies, both clinical and genetical, may give a better insight in the potential pathology of IAs.
References
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Garcia-Ruiz, P.J., et al., Late onset Huntington's disease with 29 CAG repeat expansion. J Neurol Sci, 2016. 363: p. 114-5. Oosterloo, M., et al., Is There Convincing Evidence that Intermediate Repeats in the HTT Gene Cause Huntington's Disease? J Huntingtons Dis, 2015. 4(2): p. 141-8. Kenney, C., S. Powell, and J. Jankovic, Autopsy-proven Huntington's disease with 29 trinucleotide repeats. Mov Disord, 2007. 22(1): p. 127-30. Ha, A.D. and J. Jankovic, Exploring the correlates of intermediate CAG repeats in Huntington disease. Postgrad Med, 2011. 123(5): p. 116-21. Semaka, A., et al., High frequency of intermediate alleles on huntington disease-associated haplotypes in British Columbia's general population. Am J Med Genet B Neuropsychiatr Genet, 2013. Sequeiros, J., et al., Large normal and reduced penetrance alleles in Huntington disease: instability in families and frequency at the laboratory, at the clinic and in the population. Clin Genet, 2010. 78(4): p. 381-7. Hensman Moss, D.J., et al., C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies. Neurology, 2014. 82(4): p. 292-9. Shinotoh, H., et al., Normal CAG repeat length in the Huntington's disease gene in senile chorea. Neurology, 1994. 44(11): p. 2183-4.
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1.
S0022-510X(16)30434-8 doi: 10.1016/j.jns.2016.07.021 JNS 14685
To appear in:
Journal of the Neurological Sciences
Received date: Accepted date:
2 May 2016 11 July 2016
Please cite this article as: Mayke Oosterloo, Martine J. Van Belzen, Emilia K. Bijlsma, Raymund A.C. Roos, Reply: Late onset Huntington’s disease with 29 CAG repeat expansion, Journal of the Neurological Sciences (2016), doi: 10.1016/j.jns.2016.07.021
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Reply: Late onset Huntington's disease with 29 CAG repeat expansion Mayke Oosterloo, Martine J. Van Belzen, Emilia K. Bijlsma and Raymund A.C. Roos
SC R
IP
T
We read with interest the case report describing a patient diagnosed as manifest Huntington’s disease (HD) caused by a 29 CAG repeat expansion in the Huntingtin (HTT) gene[1]. We do regret however, that the authors have not referred to our recent paper, regarding a review of all published cases of symptomatic carriers of intermediate alleles (IAs) (n=10), combined with a database search of 60 patients with IAs in the Netherlands[2] . As argued in our paper, we strongly question the evidence that intermediate repeats in the HTT gene can cause HD.
MA
NU
As in most of the cases we reviewed, the patient described by Garcia-Ruiz et al. does not show a convincing HD phenotype. They describe a patient with late mild generalized chorea at the age of 82 years especially in the lower limbs and an increased latency of saccade. The latter is explained by poor visual acuity due to macular degeneration the patient is known with. There are no other motor abnormalities like hypo- or bradykinesia or motor impersistency. An isolated chorea without any other motor abnormalities, no cognitive decline over time, no psychiatric symptoms and signs and no family history of HD is very unlikely Huntington’s disease.
AC
CE P
TE
D
The authors quote that there are several reports of similar patients with late onset chorea and intermediate CAG repeats[3, 4]. In our paper we reviewed all published patients and found only four individuals with an intermediate repeat size and symptoms and signs comparable with those seen in HD (motor, psychiatric, and cognitive signs). Still, we are reluctant to conclude to a causal relationship, as there are several factors that have to be taken into account before a definite conclusion can be reached. As limits for expanded CAG repeats are determined but not definite, it is hard to assume that IAs can never cause HD symptoms and signs. However the frequency of IAs in the general population is high and therefore it is likely that the combination of an IA and symptoms resembling HD do occur and are based on coincidence[5, 6]. With evolving genetic insight and the finding of new genetic causes for HD like syndromes, it may be more likely that the symptoms are caused by a yet unknown or recently discovered HD mimic like the C9orf72 expansion [7].Taken together, we find it premature to conclude that IAs can cause HD in general, and we are not convinced that the patient described by Garcia-Ruiz et al. has manifest HD. Publishing cases like this one creates a publication bias. Given the tremendous consequences in diagnosing and premanifest counseling HD, this is an undesirable situation. Foremost, concluding that an intermediate allele can cause HD must be well considered. We therefore suggest the authors to exclude now known HD phenocopies like C9orf72 and TBP (SCA17). As there is no cognitive decline or psychiatric symptoms and signs, little progression of the chorea over time and no positive family history, we find that this patient should not be diagnosed as manifest HD. We would rather consider senile chorea, as most other causes of chorea are ruled out and this is still regarded a clinical entity[8]. As in all IAs cases with signs of chorea, we recommend careful follow-up and eventually post mortem brain pathology. Also family studies, both clinical and genetical, may give a better insight in the potential pathology of IAs.
References
ACCEPTED MANUSCRIPT
8.
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SC R
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CE P
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Garcia-Ruiz, P.J., et al., Late onset Huntington's disease with 29 CAG repeat expansion. J Neurol Sci, 2016. 363: p. 114-5. Oosterloo, M., et al., Is There Convincing Evidence that Intermediate Repeats in the HTT Gene Cause Huntington's Disease? J Huntingtons Dis, 2015. 4(2): p. 141-8. Kenney, C., S. Powell, and J. Jankovic, Autopsy-proven Huntington's disease with 29 trinucleotide repeats. Mov Disord, 2007. 22(1): p. 127-30. Ha, A.D. and J. Jankovic, Exploring the correlates of intermediate CAG repeats in Huntington disease. Postgrad Med, 2011. 123(5): p. 116-21. Semaka, A., et al., High frequency of intermediate alleles on huntington disease-associated haplotypes in British Columbia's general population. Am J Med Genet B Neuropsychiatr Genet, 2013. Sequeiros, J., et al., Large normal and reduced penetrance alleles in Huntington disease: instability in families and frequency at the laboratory, at the clinic and in the population. Clin Genet, 2010. 78(4): p. 381-7. Hensman Moss, D.J., et al., C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies. Neurology, 2014. 82(4): p. 292-9. Shinotoh, H., et al., Normal CAG repeat length in the Huntington's disease gene in senile chorea. Neurology, 1994. 44(11): p. 2183-4.
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