0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Observation |

Metabolic Characterization of Spinocerebellar Ataxia Type 6 FREE

Bing-wen Soong, MD, PhD; Ren-shyan Liu, MD; Liang-chih Wu, PhD; Yi-chun Lu, MS; Hsiang-ying Lee, MS
[+] Author Affiliations

From the Department of Neurology, National Yang-Ming University School of Medicine (Dr Soong), and the Neurological Institute (Dr Soong and Mss Lu and Lee) and PET/Cyclotron Center (Drs Liu and Wu), Veterans General Hospital–Taipei, Taipei, Taiwan, Republic of China.


Arch Neurol. 2001;58(2):300-304. doi:10.1001/archneur.58.2.300.
Text Size: A A A
Published online

ABSTRACT

Background  Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disorder characterized by slowly progressive ataxia and dysarthria. The mutational basis is an expanded CAG repeat sequence within the coding regions of the CACNL1A4 gene. Basic clinical, neuroimaging, and pathological, and epidemiological features have been described in the literature. However, the metabolic features of SCA6 have not been elucidated.

Objective  To investigate the metabolic features of SCA6.

Patients and Methods  Seven patients with SCA6 and 7 healthy individuals underwent positron emission tomography using fluorodeoxyglucose F 18.

Results  Cerebral glucose utilization in the 7 patients with SCA6 was characterized by significant hypometabolism in widespread structures, including cortical regions and basal ganglia, as well as the cerebellar hemispheres and brainstem.

Conclusions  The results of the multiple-regional brain hypometabolism suggest that brain dysfunction associated with SCA6 may not be limited to the cerebellum and inferior olive, as previously suggested by the results of other pathologic studies.

Figures in this Article

DOMINANTLY inherited spinocerebellar ataxia (SCA) consists of a clinically, pathologically, and genetically heterogeneous group of neurodegenerative disorders that share clinical characteristics of progressive deterioration in gait and balance (due to degeneration of the cerebellum and its pathways) and various combinations of cerebral, extrapyramidal, bulbar, spinal, and peripheral nervous system involvement.13 Classification of dominant SCAs on the basis of clinical symptoms has been quite controversial because of the overlap in the clinical presentations.4 The genes causing 8 of these diseases, ie, SCA type 1 (SCA1),5 SCA2 (SCA2),68 Machado-Joseph disease and SCA3 (MJD/SCA3),9 SCA6 (SCA6),10 SCA7 (SCA7),11 SCA8 (SCA8),12 SCA12 (SCA12),13 and dentatorubral-pallidoluysian atrophy (DRPLA),14,15 have been identified. The mutational basis for all of the disorders except that of SCA8 is expanded CAG repeat sequences within the coding regions of the involved genes. Detection of these trinucleotide repeat mutations has enabled the classification of dominant SCAs on the basis of molecular analyses.

Spinocerebellar ataxia type 6 (Online Mendelian Inheritance in Man 183086) was originally identified using the expansion of polymorphic CAG repeats at the 3′ end of the human α1A voltage-dependent calcium channel subunit gene (CACNL1A4), which is known to be important for Purkinje cell function and survival.10,16 In the same gene, 4 missense mutations that cause familial hemiplegic migraine and 2 mutations that disrupt the reading frame responsible for episodic ataxia type 2 have also been identified.17

Clinically, SCA6 has been characterized as a "pure" cerebellar syndrome belonging to autosomal dominant cerebellar ataxia type 3.10,1820 Magnetic resonance imaging of the brain in patients with SCA6 has demonstrated cerebellar atrophy with no evidence of brainstem involvement.19,21 Single-photon emission tomography has shown moderately decreased tracer uptake in the cerebellum.22 Neuropathological study results have shown marked cerebellar atrophy and very mild atrophy of the brainstem.23 Microscopic examination results have revealed severe loss of cerebellar Purkinje cells, moderate loss of granule cells and dentate nucleus neurons, and mild to moderate neuronal loss in the inferior olives.10,2325 However, the metabolic characteristics in the brain of individuals with SCA6 remain unclear. Positron emission tomography (PET) has been a useful tool in elucidating the pathophysiological and metabolic characteristics of various movement disorders, including Huntington disease,26 Parkinson disease,27 progressive supranuclear palsy,28 and spinocerebellar degeneration.2932

In the present study, the objective was to clarify the metabolic characteristics associated with SCA6 mutation using PET with fluorodeoxyglucose F-18 (FDG).

SUBJECTS AND METHODS

SUBJECTS

Seven healthy individuals (4 men and 3 women) and 7 patients (4 men and 3 women) with SCA6 underwent clinical evaluations by a board-certified neurologist (B.W.S.). Age at onset was provided by the patient or close relatives. Informed consent was obtained from all subjects before participation in the study.

MOLECULAR STUDIES

Genomic DNA was isolated from peripheral leukocytes as previously described.33 Polymerase chain reaction analysis was performed using the primers S-5-F1 and S-5-R1 for SCA6.10 The polymerase chain reaction condition was as described in the original report.10 Alleles were separated using electrophoresis on 6% polyacrylamide gels in parallel with an M13 sequencing ladder and were analyzed as previously described.29,33

PET STUDIES

The 7 patients with SCA6 (mean ± SD age, 51.7 ± 6.5 years), identified by the presence of expanded CAG repeats in the SCA6 gene, and the 7 healthy control subjects (mean ± SD age, 46.0 ± 10.3 years) underwent PET using FDG. All subjects were awake, taking no medication known to affect central nervous system function, and blindfolded during the examination. The imaging device was an 8-ring whole-body PET scanner (Scanditronix PC4096-15WB; Scanditronix, Uppsala, Sweden) with an axial resolution of 6 mm and an in-plane resolution of 8 mm at the center of the field of view. Twenty-two frames of dynamic PET images were acquired for 120 minutes after intravenous injection of 370 MBq of FDG. Arterial blood samples were drawn manually for use in obtaining the input function variables for modeling cerebral metabolic rate of glucose (CMRGlc). Thirty-one regions of interest (ROIs) were drawn manually for each patient in the cerebellar hemispheres, brainstem, thalami, basal ganglia, and frontal, parietal, temporal, and occipital cortices, and the corresponding time-activity curves were generated. The mean (± SD) size of the ROIs was 1.6 ± 0.4 cm2 (range, 0.8-3.0 cm2). Extreme caution was exercised in the placement of ROIs to avoid potential signal contamination from adjacent anatomical structures. A modified Sokoloff 3 compartment model3436 was used to describe and evaluate the CMRGlc in milligrams per minute per milliliter using the graphic method of Patlak et al.37,38 The physiological variable CMRGlc was defined as follows:

CMRGlc = Cp/LC × K,

where LC was the lumped constant that summarized the differences between FDG and glucose in transportation and phosphorylation, and was equivalent to 0.404 as previously reported39,40; Cp, the average glucose concentration in plasma from the blood samples during the last 30 minutes; and K, the slope of the Patlak plot.37,38

STATISTICAL ANALYSIS

Statistical analyses were performed using commercially available software (SAS; SAS Institute Inc, Cary, NC). The null hypothesis was rejected for P<.01. Group data were compared using the Wilcoxon rank sum test. The relationships between regional cerebral glucose metabolism and age at onset, age at the time of PET examination, and duration of SCA6 illness were assessed using Pearson correlation analysis.

RESULTS

CLINICAL FEATURES OF SCA6

The main clinical features of the 7 individuals with SCA6 in this study are summarized in Table 1.

Table Graphic Jump LocationTable 1. Clinical Features of 7 Patients With SCA6*
PET STUDIES

Glucose metabolism rate was significantly lower not only in the cerebellar hemispheres, but also in the brainstem, basal ganglia, and frontal, temporal, and occipital cerebral cortices (Table 2 and Figure 1). However, the ages at onset and at the time of PET examination and duration of the illness did not correlate with CMRGlc.

Table Graphic Jump LocationTable 2. Cerebral Glucose Metabolic Rate in Patients With SCA6 and Healthy Controls*
Place holder to copy figure label and caption

Fluorodeoxyglucose F 18 (FDG) positron emission tomography in patient 3 with spinocerebellar ataxia type 6 (SCA6) (A and B) and in a healthy control subject (C and D). Relative to the healthy controls, the FDG uptake in the cerebellar hemispheres, brainstem, basal ganglia, and frontal, temporal, and occipital cortices was lower in all subjects with SCA6.

Graphic Jump Location

COMMENT

The predominant clinical feature of our patients with SCA6 was cerebellar ataxia (loss of balance and dexterity of handwriting) with an onset late in adult life and a very slowly progressive disease course (Table 1). Although brisk deep tendon reflexes were frequently observed, plantar response was normal in all of our patients, indicating that the upper motor neurons were only slightly involved.41 Other noncerebellar features, eg, rigidity, gegenhalten, intellectual impairment, and sphincter disturbances, were rarely found in our patients with SCA6. Patient 1 had a partial right abducens palsy and exhibited a horizontal diplopia on looking toward the right side. Many of our patients also had exacerbation of the sense of imbalance in a visually "busy" environment, as has been previously reported by others with SCA6 (S. H. Subramony, MD, written communication, May 10, 1999). Clinical features associated with other disorders caused by mutations in the CACNL1A4 gene,17 ie, migraine, episodes of hemiplegia, or ataxia were checked for carefully but rarely found in our SCA6 cohort, which is consistent with the findings of Matsumura et al19 and Gomez et al.24 In all patients in this study, the disease had an indolent course, which rarely progressed to severe disability during the first 10 years.

The widespread reduction of glucose metabolism (Table 2 and Figure 1) ranged from 71% to 78% of the healthy controls in all structures except the brainstem, where metabolic rate was 66% of that for controls, and cerebellar hemisphere, where it was 63% of that for controls. These results were unexpected. We exercised extreme caution during the study and ruled out the possibility of a systematic error or a statistical phenomenon that might have caused low values. Positron emission tomography has been shown to be very sensitive in the detection of subtle subclinical abnormalities.2632 The fact that hypometabolism was found in various brain regions does not imply widespread neuronal degeneration but could simply reflect subclinical neuropathological features, or metabolic dysfunction in structurally intact neurons. None of our patients manifested symptoms referable to the basal ganglion or cerebral cortices. Therefore, the clinical relevance of this observation is not clear. The findings of several previous studies might add insight to the mechanisms responsible for these discrepancies. First, a study of SCA1 transgenic mice demonstrated that considerable neuropathological changes occurred without the manifestation of a neurologic phenotype.42 Second, there have been precedents of minor pathologic abnormalities in clinically unexpected areas in other "pure system degenerations" such as hereditary spastic paraparesis. Previous study results have also shown that overt ataxia occurred in mice only after there was loss or dysfunction of a substantial number (50%-75%) of the Purkinje cells.43,44 Thus, it is likely that the absence of cerebral cortical and basal ganglia symptoms in our patients reflects that neuronal cell dysfunction progression in these patients occurred at an insufficiently rapid rate to cause symptoms during the course of our observations. Third, many structures in the cerebellum influence regional cerebral blood flow. Stimulation of the fastigial nucleus has been shown to increase neurogenically the mean carotid blood flow in primates.45,46 The cerebellar vermis projects by way of the fastigial nucleus to the cortical and brainstem regions.47 Hence, cerebellar vermian atrophy theoretically could alter the normal physiologic regulation of regional cerebral blood flow mediated by the fastigial nucleus, resulting in regional hypoperfusion and hypometabolism.48 Further studies are warranted to investigate the contribution of cerebellar structures to cerebral hypometabolism. Last, the calcium receptor subunit affected by the SCA6 mutation has been known to be expressed ubiquitously in neurons of the entire brain, including the hippocampus, cerebral cortex, thalamus, hypothalamus, medulla, inferior olivary nucleus, and the horizontal cells of the retina.49 In patients with familial hemiplegic migraine, which is caused by point mutations in the CACNL1A4 gene,17 altered regional cerebral blood flow and a neuronal dysfunction have been well described.48,5052 This finding might add to the evidence of the involvement of other cerebral structures in calcium channel dysfunction. Altered channel characteristics are expected to profoundly disturb the normal function of cerebral neurons. Further studies in transgenic mice expressing mutant alleles of the CACNL1A4 gene will enable determination of the pathogenic mechanism of SCA6.

CONCLUSIONS

Study of SCA6 by means of PET surprisingly indicated that significantly reduced glucose uptake was present not only in the cerebellum but also in other regions of the brain. Thus, SCA6 may not be a purely cerebellar syndrome. Future comparison of PET findings in different subtypes of SCA may reveal genotype-specific patterns of regional metabolic deficits in the brain, which might sharpen the distinction between these genetically characterized forms of SCA.

Since the submission of the manuscript, the gene causing SCA10 has also been identified recently by Matsuura et al.53

ARTICLE INFORMATION

Accepted for publication September 29, 2000.

We gratefully acknowledge research support from grant NSC 87-2314-14-B075-021 from the National Science Council, Taipei, Taiwan, Republic of China, and grants VGH88-352, VGH89-315, VGH89-389-10 from Veterans General Hospital–Taipei, Taipei.

Presented as a poster at the 51st Annual Meeting of the American Academy of Neurology, Toronto, Ontario, April 20, 1999.

We thank the families of patients with spinocerebellar ataxia whose collaboration was essential to the present study. We would also like to thank Michael Evans, MS, Society of Psychiatry, Taipei, for his critical reading of this manuscript; Wen-yuan Shen, MS, for her statistical analyses; and John Sung for his technical assistance.

Corresponding author and reprints: Bing-wen Soong, MD, PhD, Neurological Institute, Veterans General Hospital–Taipei, Taipei, Taiwan 112, Republic of China (e-mail: bwsoong@vghtpe.gov.tw).

REFERENCES

Harding  AE The clinical features and classification of the late onset autosomal dominant cerebellar ataxias: a study of 11 families, including descendants of the Drew family of Walworth. Brain.1982;105:1-28.
Trottier  YLutz  YStevanin  G  et al Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias. Nature.1995;378:403-406.
Hurko  O Recent advances in heritable ataxias. Ann Neurol.1997;41:4-6.
Higgins  JJNee  LEVasconcelos  O  et al Mutations in American families with spinocerebellar ataxia (SCA) type 3: SCA3 is allelic to Machado-Joseph disease. Neurology.1996;46:208-213.
Orr  HTChung  MYBanfi  S  et al Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet.1993;4:221-226.
Imbert  GSaudou  FYvert  G  et al Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nat Genet.1996;14:285-291.
Pulst  SMNechiporuk  ANechiporuk  T  et al Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet.1996;14:269-276.
Sanpei  KTakano  HIgarashi  S  et al Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet.1996;14:277-284.
Kawaguchi  YOkamoto  TTaniwaki  M  et al CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet.1994;8:221-228.
Zhuchenko  OBailey  JBonnen  P  et al Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the α1A-voltage-dependent calcium channel. Nat Genet.1997;15:62-69.
David  GAbbas  NStevanin  G  et al Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nat Genet.1997;17:65-70.
Koob  MDMoseley  MLSchut  LJ  et al An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nat Genet.1999;21:379-384.
Holmes  SEO'Hearn  EEMcInnis  MG  et al Expansion of a novel CAG trinucleotide repeat in the 5′ region of PPP2R2B is associated with SCA12. Nat Genet.1999;23:391-392.
Koide  RIkeuchi  TOnodera  O  et al Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nat Genet.1994;6:9-13.
Nagafuchi  SYanagisawa  HSato  K  et al Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Nat Genet.1994;6:14-18.
Diriong  SLory  PWilliams  MEEllis  SBHarpold  MMTaviaux  S Chromosomal localization of the human genes for α1A, α1B and α1E voltage-dependent Ca2+ channel subunits. Genomics.1995;30:605-609.
Ophoff  RATerwindt  GMVergouwe  MNFrants  RRFerrari  MD Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell.1996;87:543-552.
Geschwind  DHPerlman  SFigueroa  KPKarrim  JBaloh  RWPulst  SM Spinocerebellar ataxia type 6: frequency of the mutation and genotype-phenotype correlations. Neurology.1997;49:1247-1251.
Matsumura  RFutamura  NFujimoto  Y  et al Spinocerebellar ataxia type 6: molecular and clinical features of 35 Japanese patients including one homozygous for the CAG repeat expansion. Neurology.1997;49:1238-1243.
Stevanin  GDurr  ADavid  G  et al Clinical and molecular features of spinocerebellar ataxia type 6. Neurology.1997;49:1243-1246.
Murata  YKawakami  HYamaguchi  S  et al Characteristic magnetic resonance imaging findings in spinocerebellar ataxia 6. Arch Neurol.1998;55:1348-1352.
Nagai  YAzuma  TFunauchi  M  et al Clinical and molecular genetic study in seven Japanese families with spinocerebellar ataxia type 6. J Neurol Sci.1998;157:52-59.
Subramony  SHFratkin  JDManyam  BVCurrier  RD Dominantly inherited cerebello-olivary atrophy is not due to a mutation at the spinocerebellar ataxia-I, Machado-Joseph disease, or Dentato-Rubro-Pallido-Luysian atrophy locus. Mov Disord.1996;11:174-180.
Gomez  CMThompson  RMGammack  JT  et al Spinocerebellar ataxia type 6: gaze-evoked and vertical nystagmus, Purkinje cell degeneration, and variable age of onset. Ann Neurol.1997;42:933-950.
Sasaki  HKojima  HYabe  I  et al Neuropathological and molecular studies of spinocerebellar ataxia type 6 (SCA6). Acta Neuropathol (Berl).1998;95:199-204.
Kuhl  DEPhelps  MEMarkham  CHMetter  EJRiege  WHWinter  J Cerebral metabolism and atrophy in Huntington's disease determined by 18FDG and computed tomographic scan. Ann Neurol.1982;12:425-434.
Leenders  KLPalmer  AJQuinn  N  et al Brain dopamine metabolism in patients with Parkinson's disease measured with positron emission tomography. J Neurol Neurosurg Psychiatry.1986;49:853-860.
Otsuka  MIchiya  YKuwabara  Y  et al Cerebral blood flow, oxygen and glucose metabolism with PET in progressive supranuclear palsy. Ann Nucl Med.1989;3:111-118.
Soong  BWCherng  CHLiu  RSShan  D Machado-Joseph disease: clinical, molecular and metabolic characterization in Chinese kindreds. Ann Neurol.1997;41:446-452.
Gilman  SMarkel  DSKoeppe  RA  et al Cerebellar and brainstem hypometabolism in olivopontocerebellar atrophy detected with positron emission tomography. Ann Neurol.1988;23:223-230.
Gilman  SKoeppe  RAJunck  LKluin  KJLohman  MSt Laurent  RT Patterns of cerebral glucose metabolism detected with positron emission tomography differ in multiple system atrophy and olivopontocerebellar atrophy. Ann Neurol.1994;36:166-175.
Soong  BWLiu  RS Positron emission tomography in asymptomatic gene carriers of Machado-Joseph disease. J Neurol Neurosurg Psychiatry.1998;64:499-504.
Sambrook  JFritsch  EFManiatis  T Molecular Cloning: A Laboratory Manual.  Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 1989.
Phelps  MEHuang  SCHoffman  EJSelin  CSokoloff  LKuhl  DE Tomographic measurement of local cerebral glucose metabolic rate in humans with (F-18)2-fluoro-2-deoxy-D-glucose: validation of method. Ann Neurol.1979;6:371-388.
Huang  SCPhelps  MEHoffman  EJSideris  KSelin  CJKuhl  DE Noninvasive determination of local cerebral metabolic rate of glucose in man. Am J Physiol.1980;238:E69-E82.
Huang  SCPhelps  ME Principles of tracer kinetic modeling in positron emission tomography and autoradiography.  In: Phelps  ME, Mazziotta  JC,Schelbert  H, eds. Positron Emission Tomography and Autoradiography: Principles and Applications for the Brain and Heart. New York: Raven Press; 1986:287-346.
Patlak  CSBlasberg  RGFenstermacher  JD Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab.1983;3:1-7.
Patlak  CSBlasberg  RG Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data: generalizations. J Cereb Blood Flow Metab.1985;5:584-590.
Wu  LCFeng  DGWang  JK  et al Quantitative analysis of FDG PET images. Ann Nucl Med Sci.1998;11:29-33.
Feng  DHo  DChen  K  et al An evaluation of the algorithms for determining local cerebral metabolic rates of glucose using positron emission tomography dynamic data. IEEE Trans Med Imaging.1995;14:697-710.
Schols  LKruger  RAmoiridis  GPrzuntek  HEpplen  JTRiess  O Spinocerebellar ataxia type 6: genotype and phenotype in German kindreds. J Neurol Neurosurg Psychiatry.1998;64:67-73.
Burright  ENClark  HBServadio  A  et al SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell.1995;82:937-948.
Feddersen  RMEhlenfeldt  RYunis  WSClark  HBOrr  HT Disrupted cerebellar cortical development and progressive degeneration of Purkinje cells in SV40T antigen transgenic mice. Neuron.1992;9:955-966.
Feddersen  RMClark  HBYunis  WS  et al In vivo viability of postmitotic Purkinje neurons requires pRb family member function. Mol Cell Neurosci.1995;6:153-167.
Mckee  JCDenn  MJStone  HL Neurogenic cerebral vasodilatation from electrical stimulation of the cerebellum in the monkey. Stroke.1976;7:179-186.
Arneric  SPIadecola  CUnderwood  MDReis  DJ Local cholinergic mechanisms participate in the increases in cortical cerebral blood flow elicited by electrical stimulation of the fastigial nucleus in rat. Brain Res.1987;411:212-225.
Korneliussen  HK Histogenesis of the cerebellar cortex and cortical zones.  In: Larsell  O, Jansen  J, eds. The Comparative Anatomy and Histology of the Cerebellum: The Human Cerebellum, Cerebellar Connections, and Cerebellar Cortex. Minneapolis: University of Minnesota Press; 1972:164-174.
Elliott  MAPeroutka  SJWelch  SMay  EF Familial hemiplegic migraine, nystagmus, and cerebellar atrophy. Ann Neurol.1996;39:100-106.
Hillman  DChen  SAung  TTCherksey  BSugimori  MLlinas  RR Localization of P-type calcium channels in the central nervous system. Proc Natl Acad Sci U S A.1991;88:7076-7080.
Gastaut  JLYermenos  EBonnefoy  MCros  D Familial hemiplegic migraine: EEG and CT scan study of two cases. Ann Neurol.1981;10:392-395.
Andersen  ARFriberg  LOlsen  TSOlesen  J Delayed hyperemia following hypoperfusion in classic migraine: single photon emission computed tomographic demonstration. Arch Neurol.1988;45:154-159.
Pierelli  FPauri  FCupini  LMFiermonte  GRizzo  PA Transcranial Doppler sonography in familial hemiplegic migraine. Cephalalgia.1991;11:29-31.
Matsuura  TYamagata  TBurgess  DL  et al Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10. Nat Genet.2000;26:191-194.

Figures

Place holder to copy figure label and caption

Fluorodeoxyglucose F 18 (FDG) positron emission tomography in patient 3 with spinocerebellar ataxia type 6 (SCA6) (A and B) and in a healthy control subject (C and D). Relative to the healthy controls, the FDG uptake in the cerebellar hemispheres, brainstem, basal ganglia, and frontal, temporal, and occipital cortices was lower in all subjects with SCA6.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Clinical Features of 7 Patients With SCA6*
Table Graphic Jump LocationTable 2. Cerebral Glucose Metabolic Rate in Patients With SCA6 and Healthy Controls*

References

Harding  AE The clinical features and classification of the late onset autosomal dominant cerebellar ataxias: a study of 11 families, including descendants of the Drew family of Walworth. Brain.1982;105:1-28.
Trottier  YLutz  YStevanin  G  et al Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias. Nature.1995;378:403-406.
Hurko  O Recent advances in heritable ataxias. Ann Neurol.1997;41:4-6.
Higgins  JJNee  LEVasconcelos  O  et al Mutations in American families with spinocerebellar ataxia (SCA) type 3: SCA3 is allelic to Machado-Joseph disease. Neurology.1996;46:208-213.
Orr  HTChung  MYBanfi  S  et al Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet.1993;4:221-226.
Imbert  GSaudou  FYvert  G  et al Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nat Genet.1996;14:285-291.
Pulst  SMNechiporuk  ANechiporuk  T  et al Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet.1996;14:269-276.
Sanpei  KTakano  HIgarashi  S  et al Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet.1996;14:277-284.
Kawaguchi  YOkamoto  TTaniwaki  M  et al CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet.1994;8:221-228.
Zhuchenko  OBailey  JBonnen  P  et al Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the α1A-voltage-dependent calcium channel. Nat Genet.1997;15:62-69.
David  GAbbas  NStevanin  G  et al Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nat Genet.1997;17:65-70.
Koob  MDMoseley  MLSchut  LJ  et al An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nat Genet.1999;21:379-384.
Holmes  SEO'Hearn  EEMcInnis  MG  et al Expansion of a novel CAG trinucleotide repeat in the 5′ region of PPP2R2B is associated with SCA12. Nat Genet.1999;23:391-392.
Koide  RIkeuchi  TOnodera  O  et al Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nat Genet.1994;6:9-13.
Nagafuchi  SYanagisawa  HSato  K  et al Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Nat Genet.1994;6:14-18.
Diriong  SLory  PWilliams  MEEllis  SBHarpold  MMTaviaux  S Chromosomal localization of the human genes for α1A, α1B and α1E voltage-dependent Ca2+ channel subunits. Genomics.1995;30:605-609.
Ophoff  RATerwindt  GMVergouwe  MNFrants  RRFerrari  MD Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell.1996;87:543-552.
Geschwind  DHPerlman  SFigueroa  KPKarrim  JBaloh  RWPulst  SM Spinocerebellar ataxia type 6: frequency of the mutation and genotype-phenotype correlations. Neurology.1997;49:1247-1251.
Matsumura  RFutamura  NFujimoto  Y  et al Spinocerebellar ataxia type 6: molecular and clinical features of 35 Japanese patients including one homozygous for the CAG repeat expansion. Neurology.1997;49:1238-1243.
Stevanin  GDurr  ADavid  G  et al Clinical and molecular features of spinocerebellar ataxia type 6. Neurology.1997;49:1243-1246.
Murata  YKawakami  HYamaguchi  S  et al Characteristic magnetic resonance imaging findings in spinocerebellar ataxia 6. Arch Neurol.1998;55:1348-1352.
Nagai  YAzuma  TFunauchi  M  et al Clinical and molecular genetic study in seven Japanese families with spinocerebellar ataxia type 6. J Neurol Sci.1998;157:52-59.
Subramony  SHFratkin  JDManyam  BVCurrier  RD Dominantly inherited cerebello-olivary atrophy is not due to a mutation at the spinocerebellar ataxia-I, Machado-Joseph disease, or Dentato-Rubro-Pallido-Luysian atrophy locus. Mov Disord.1996;11:174-180.
Gomez  CMThompson  RMGammack  JT  et al Spinocerebellar ataxia type 6: gaze-evoked and vertical nystagmus, Purkinje cell degeneration, and variable age of onset. Ann Neurol.1997;42:933-950.
Sasaki  HKojima  HYabe  I  et al Neuropathological and molecular studies of spinocerebellar ataxia type 6 (SCA6). Acta Neuropathol (Berl).1998;95:199-204.
Kuhl  DEPhelps  MEMarkham  CHMetter  EJRiege  WHWinter  J Cerebral metabolism and atrophy in Huntington's disease determined by 18FDG and computed tomographic scan. Ann Neurol.1982;12:425-434.
Leenders  KLPalmer  AJQuinn  N  et al Brain dopamine metabolism in patients with Parkinson's disease measured with positron emission tomography. J Neurol Neurosurg Psychiatry.1986;49:853-860.
Otsuka  MIchiya  YKuwabara  Y  et al Cerebral blood flow, oxygen and glucose metabolism with PET in progressive supranuclear palsy. Ann Nucl Med.1989;3:111-118.
Soong  BWCherng  CHLiu  RSShan  D Machado-Joseph disease: clinical, molecular and metabolic characterization in Chinese kindreds. Ann Neurol.1997;41:446-452.
Gilman  SMarkel  DSKoeppe  RA  et al Cerebellar and brainstem hypometabolism in olivopontocerebellar atrophy detected with positron emission tomography. Ann Neurol.1988;23:223-230.
Gilman  SKoeppe  RAJunck  LKluin  KJLohman  MSt Laurent  RT Patterns of cerebral glucose metabolism detected with positron emission tomography differ in multiple system atrophy and olivopontocerebellar atrophy. Ann Neurol.1994;36:166-175.
Soong  BWLiu  RS Positron emission tomography in asymptomatic gene carriers of Machado-Joseph disease. J Neurol Neurosurg Psychiatry.1998;64:499-504.
Sambrook  JFritsch  EFManiatis  T Molecular Cloning: A Laboratory Manual.  Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 1989.
Phelps  MEHuang  SCHoffman  EJSelin  CSokoloff  LKuhl  DE Tomographic measurement of local cerebral glucose metabolic rate in humans with (F-18)2-fluoro-2-deoxy-D-glucose: validation of method. Ann Neurol.1979;6:371-388.
Huang  SCPhelps  MEHoffman  EJSideris  KSelin  CJKuhl  DE Noninvasive determination of local cerebral metabolic rate of glucose in man. Am J Physiol.1980;238:E69-E82.
Huang  SCPhelps  ME Principles of tracer kinetic modeling in positron emission tomography and autoradiography.  In: Phelps  ME, Mazziotta  JC,Schelbert  H, eds. Positron Emission Tomography and Autoradiography: Principles and Applications for the Brain and Heart. New York: Raven Press; 1986:287-346.
Patlak  CSBlasberg  RGFenstermacher  JD Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab.1983;3:1-7.
Patlak  CSBlasberg  RG Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data: generalizations. J Cereb Blood Flow Metab.1985;5:584-590.
Wu  LCFeng  DGWang  JK  et al Quantitative analysis of FDG PET images. Ann Nucl Med Sci.1998;11:29-33.
Feng  DHo  DChen  K  et al An evaluation of the algorithms for determining local cerebral metabolic rates of glucose using positron emission tomography dynamic data. IEEE Trans Med Imaging.1995;14:697-710.
Schols  LKruger  RAmoiridis  GPrzuntek  HEpplen  JTRiess  O Spinocerebellar ataxia type 6: genotype and phenotype in German kindreds. J Neurol Neurosurg Psychiatry.1998;64:67-73.
Burright  ENClark  HBServadio  A  et al SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell.1995;82:937-948.
Feddersen  RMEhlenfeldt  RYunis  WSClark  HBOrr  HT Disrupted cerebellar cortical development and progressive degeneration of Purkinje cells in SV40T antigen transgenic mice. Neuron.1992;9:955-966.
Feddersen  RMClark  HBYunis  WS  et al In vivo viability of postmitotic Purkinje neurons requires pRb family member function. Mol Cell Neurosci.1995;6:153-167.
Mckee  JCDenn  MJStone  HL Neurogenic cerebral vasodilatation from electrical stimulation of the cerebellum in the monkey. Stroke.1976;7:179-186.
Arneric  SPIadecola  CUnderwood  MDReis  DJ Local cholinergic mechanisms participate in the increases in cortical cerebral blood flow elicited by electrical stimulation of the fastigial nucleus in rat. Brain Res.1987;411:212-225.
Korneliussen  HK Histogenesis of the cerebellar cortex and cortical zones.  In: Larsell  O, Jansen  J, eds. The Comparative Anatomy and Histology of the Cerebellum: The Human Cerebellum, Cerebellar Connections, and Cerebellar Cortex. Minneapolis: University of Minnesota Press; 1972:164-174.
Elliott  MAPeroutka  SJWelch  SMay  EF Familial hemiplegic migraine, nystagmus, and cerebellar atrophy. Ann Neurol.1996;39:100-106.
Hillman  DChen  SAung  TTCherksey  BSugimori  MLlinas  RR Localization of P-type calcium channels in the central nervous system. Proc Natl Acad Sci U S A.1991;88:7076-7080.
Gastaut  JLYermenos  EBonnefoy  MCros  D Familial hemiplegic migraine: EEG and CT scan study of two cases. Ann Neurol.1981;10:392-395.
Andersen  ARFriberg  LOlsen  TSOlesen  J Delayed hyperemia following hypoperfusion in classic migraine: single photon emission computed tomographic demonstration. Arch Neurol.1988;45:154-159.
Pierelli  FPauri  FCupini  LMFiermonte  GRizzo  PA Transcranial Doppler sonography in familial hemiplegic migraine. Cephalalgia.1991;11:29-31.
Matsuura  TYamagata  TBurgess  DL  et al Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10. Nat Genet.2000;26:191-194.

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 18

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles