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Original Contribution |

Late-Onset Friedreich Ataxia Phenotypic Analysis, Magnetic Resonance Imaging Findings, and Review of the Literature FREE

Roongroj Bhidayasiri, MD, MRCP(UK); Susan L. Perlman, MD; Stefan-M. Pulst, MD, DrMed; Daniel H. Geschwind, MD, PhD
[+] Author Affiliations

Author Affiliations: Department of Neurology, UCLA Medical Center (Drs Bhidayasiri, Perlman, and Geschwind), and Departments of Medicine and Neurobiology (Dr Pulst), The David Geffen School of Medicine at UCLA, Los Angeles, Calif; Division of Neurology, Chulalongkorn University Hospital, Bangkok, Thailand (Dr Bhidayasiri); and Division of Neurology, Cedars-Sinai Medical Center, Los Angeles (Dr Pulst).


Arch Neurol. 2005;62(12):1865-1869. doi:10.1001/archneur.62.12.1865.
Text Size: A A A
Published online

Background  Friedreich ataxia (FA), the most common hereditary ataxia, is caused by pathological expansion of GAA repeats in the first intron of the X25 gene on chromosome 9. Since the discovery of the gene, atypical features are increasingly recognized in individuals with FA, and up to 25% of patients with recessive or sporadic ataxia do not fulfill the Harding or Quebec Cooperative Study on Friedreich’s Ataxia criteria for FA. Late-onset FA (LOFA) is defined as onset after age 25 years.

Objectives  To describe and further delineate the clinical and magnetic resonance imaging findings in patients with LOFA and to review the literature.

Design  Clinical evaluation and comparison of clinical data and investigations.

Setting  Ataxia clinics at UCLA and Cedars-Sinai Medical Center.

Patients  Thirteen patients with LOFA with 13 sex-matched and Inherited Ataxia Progression Scale–matched patients with typical FA.

Results  Gait and limb ataxias were seen in all the participants. Dysarthria, loss of vibration sense, and abnormal eye movements were also common in both groups. Patients with LOFA more often had lower limb spasticity (40% vs 0%; χ2 = 4.0; P = .04) and retained reflexes (46.1% vs 7.7%; χ2 = 3.46; P = .05). They had no complaint of sphincter disturbances, and there was no evidence of cardiomyopathy on echocardiograms (χ2 = 4.0; P = .04). Five of 9 patients with LOFA had cerebellar atrophy on neuroimaging.

Conclusions  Patients with gait and limb ataxias, dysarthria, loss of vibration sense, and fixational instability after age 25 years should be considered for molecular testing for GAA expansion in the FA gene. In contrast to previous studies, cerebellar vermian atrophy is not an uncommon finding.

Figures in this Article

Friedreich ataxia (FA) is the most common hereditary ataxia, with an estimated prevalence of 1 in 50 000 population in central Europe.1 Strict diagnostic criteria have been proposed by the Quebec Cooperative Study on Friedreich’s Ataxia2 and by Harding3 to define a homogeneous group of patients. The Quebec Cooperative Study criteria established that true Friedreich disease must always begin before the end of puberty and at the latest before age 20 years.2 Harding3 considered onset before 25 years of age as an essential diagnostic criterion. However, since the discovery of the FA gene,4 the phenotypic spectrum of FA seems to be wider than defined by both criteria, and up to 25% of patients do not fulfill the Harding or Quebec Cooperative Study criteria for FA.2,3,5,6 These atypical features include late-onset forms,7 forms with retained tendon reflexes,8 and Acadian FA,9 which are all caused by mutations in the X25 gene. Late-onset FA (LOFA) is defined as onset after age 25 years. These patients tend to have an overall milder, slowly evolving disease associated with smaller GAA expansion.10 The time from disease onset to wheelchair confinement was also slower in patients with LOFA.7 Compared with patients with typical FA, those with LOFA also have fewer skeletal abnormalities.11 The frequency of cardiomyopathy in LOFA was found to be similar to that in typical FA in some studies7,12 but significantly lower in others.13 We investigated the genetic, clinical, and laboratory findings in 13 patients with LOFA and in 13 sex-matched and Inherited Ataxia Progression Scale (IAPS)–matched patients with typical FA to identify common clinical features shared between patients with typical FA and LOFA that would suggest the presence of a frataxin mutation in patients with late-onset ataxia.

Clinical data from 13 patients with LOFA (6 men and 7 women) from 13 families were compared with those from 13 patients with typical FA matched for sex and IAPS stage. All the patients were retrospectively identified. Patients with typical FA (age at onset <25 years) were selected from our database of 155 patients with typical FA. Only patients who had undergone neuroimaging were selected for matching. All the patients were homozygous for GAA expansion in the first intron of the X25 gene, and age at onset was known for all. Age at onset was defined as the date that the patient or relatives noticed the first appearance of symptoms such as gait or limb ataxia. Skeletal deformities were not considered in onset of symptoms because it is difficult to establish the exact time of presentation. The smaller and larger in each pair of alleles were identified as GAA1 and GAA2, respectively.

Severity of disease was rated according to the IAPS7: stage 1, asymptomatic affected sibling; stage 2, symptoms present but mild; stage 3, patient needs constant care and cannot work; and stage 4, patient confined to a wheelchair. Patients in the control group were selected from individuals who were homozygous for the expanded GAA sequence, but age at onset was younger than 25 years. In addition, each control subject was matched to a patient with LOFA by sex and IAPS stage in pairs. Magnetic resonance imaging was performed using a 1.5-T system (Magnetom; Siemens, Erlangen, Germany). In addition to detailed clinical evaluations, nerve conduction studies, echocardiography, and fasting blood glucose measurements were performed using standard laboratory procedures. Sural nerve biopsy was performed in 1 patient with LOFA. The shareware program Stata (www.stata.com; StataCorp LP, College Station, Tex) was used to perform statistical tests using the paired t test. The occurrence of features was analyzed using the χ2 test. All P≤.05, adjusted for multiple comparisons, are reported.

The 6 men and 7 women with LOFA (from 13 families) had a mean ± SD age at onset of 28.8 ± 6.4 years (range, 25.5-48.0 years) and a mean ± SD current age of 50.3 ± 10.1 years (range, 32-65 years). One patient developed the disease at age 48 years, consistent with very LOFA. Six patients were in IAPS stage 2, 3 were in IAPS stage 3, and 4 were in IAPS stage 4. Patients with LOFA had significantly smaller GAA1 alleles compared with patients with typical FA (mean ± SD, 176 ± 135 vs 490 ± 52; P = .03). However, the mean ± SD size of the GAA2 allele was not different between patients with LOFA (685 ± 179) and those with typical FA (755 ± 315). Mean ± SD disease durations in patients with LOFA (18.5 ± 9.7 years; range, 2-36 years) and typical FA (16.0 ± 9.1 years; range, 3-30 years) are also similar. Figure 1 shows the frequency of various clinical and laboratory findings in patients with LOFA compared with those with typical FA matched for sex and IAPS stage.

Place holder to copy figure label and caption
Figure 1.

Frequency of various clinical features in patients with typical Friedreich ataxia (FA) vs those with late-onset FA (LOFA). Asterisk indicates P<.05; LL, lower limb; KJ, knee jerk; AJ, ankle jerk; EOM, extraocular movement; UL, upper limb; and VA, visual acuity.

Graphic Jump Location

The most frequent presenting symptoms in both groups were gait and limb ataxias (100% in both groups), followed by dysarthria (85% in the FA group and 92% in the LOFA group). Patients in both groups also had frequent loss of vibration sense (77% and 92%) and abnormal extraocular movements, particularly fixational instability (75% and 92%). Patients with LOFA more often had lower limb spasticity (χ2 = 4.0; P = .04) and retained reflexes (χ2 = 3.46; P = .06) and less often had sphincter disturbances (χ2 = 4.0; P = .04) and abnormal echocardiographic findings.

Peripheral nerve sensory conduction velocities were abnormal in all 8 investigated patients with LOFA and in 4 of 5 tested patients with typical FA. The results indicate axonal sensory neuropathy in 7 of 8 patients with LOFA and in all tested patients with typical FA. One patient with LOFA underwent a sural nerve biopsy showing the absence of large myelinated fibers, prominent Schwann cell nuclear hyperplasia, numerous hypertrophic onion bulb formations, and increased internodal length variability consistent with demyelinating neuropathy. Fiber teasing revealed approximately 70 thinly myelinated fibers. There was no evidence of axonal or wallerian degeneration in this patient. One patient with typical FA had normal nerve conduction study findings 7 years after the onset of symptoms and was in IAPS stage 2.

Four patients with LOFA had lower limb spasticity, whereas no spasticity was observed in patients with typical FA. Of these 4 patients with LOFA and lower limb spasticity, 3 had retained ankle reflexes. No patients with LOFA complained of urinary incontinence, even in the group with IAPS stage 4 (maximum disease duration of 27 years), whereas this symptom was observed in 4 patients with typical FA (maximum disease duration of 30 years). The echocardiographic examination of 11 of 13 patients with typical FA demonstrated abnormal concentric left ventricular hypertrophy in 7 patients. This was in contrast to the 5 tested patients with LOFA, in whom no abnormalities or cardiac symptoms were reported. Four patients with LOFA had scoliosis, in contrast to 10 patients with typical FA. Pes cavus was observed in 5 patients with LOFA and in 7 with typical FA. Magnetic resonance imaging showed atrophy of the cervical cord in all the patients with FA and LOFA. Furthermore, 5 of 9 investigated patients with LOFA demonstrated superior cerebellar vermian atrophy, and this was associated with hemispheric atrophy in 3 patients (Figure 2); conversely, this finding was reported in only 1 patient with FA.

Place holder to copy figure label and caption
Figure 2.

T1-weighted sagittal magnetic resonance image of a patient with late-onset Friedreich ataxia demonstrating atrophy of the cerebellum (arrows) in addition to cervical cord atrophy.

Graphic Jump Location

Age at disease onset has traditionally been regarded as an essential criterion for the diagnosis of FA.2,3,14 For the autosomal recessive–inherited ataxias, an age at onset older than 25 years would conventionally exclude the diagnosis of FA.3 Since the discovery of the FA gene,15 the FA phenotypes have expanded to include patients with late-onset disease (after age 25 years), retained reflexes, and Acadian phenotypes.10,12,1620 Furthermore, the size of the expanded repeat on GAA1 is inversely related to age at onset and disease severity in FA, whereas GAA2 size is a poor predictor of clinical variation.5,12,2123 Earlier age at onset, earlier age when confined to a wheelchair, a more rapid rate of disease progression, and the presence of nonneurologic manifestations, such as scoliosis,5 cardiomyopathy,5 and diabetes mellitus,24 all showed the best correlation with the size of the smaller repeat (GAA1). Sequence variation in GAA repeat expansions may cause different phenotypes in FA, especially in late-onset cases.25

LOWER LIMB SPASTICITY AND RETAINED REFLEXES

A comparison of clinical and laboratory findings between patients with LOFA and typical FA showed an increased occurrence of lower limb spasticity and retained reflexes and a lower occurrence of abnormal echocardiographic findings and sphincter disturbances. Although the present study findings support previous findings13,18 of a lower incidence of cardiomyopathy in patients with LOFA, other studies7,12 reported a similar frequency of cardiomyopathy in both patient groups. In addition, the higher occurrence of spasticity and retained reflexes may suggest an overlap between LOFA and FA with retained reflexes. Coppola et al19 reported a similar finding of 11 patients with FA with retained reflexes with a mean age at onset of 26 years. Indeed, the presence of spasticity and the Babinski sign were observed in the same patients with LOFA, suggesting involvement of the pyramidal tract in these patients. One of our patients with LOFA still had preserved ankle reflexes after 22 years’ disease duration. Advanced pyramidal involvement, supported by a loss of large pyramidal cells in the primary motor areas, is usually a late manifestation in FA, and spastic paraparesis has been reported in 1 patient at the onset age of 24 years and in 2 other patients at the very late onset ages of 49 and 53 years.2628 One of our patients with LOFA, who had a very late age at onset at 48 years, demonstrated preserved ankle jerks but had no spasticity. Spastic ataxia has been reported to be a presenting symptom of late-onset cases.29 In our study, patients with LOFA had fewer skeletal deformities, although the difference did not achieve statistical significance. However, the severity of scoliosis was milder in patients with LOFA compared with those with typical FA with a matched IAPS stage. The neurophysiologic study did not help differentiate patients with LOFA from those with typical FA.

CEREBELLAR ATROPHY

Cerebellar atrophy is not a characteristic finding of FA.30 Pathologically, the cerebellar cortex shows only mild loss of Purkinje cells and occasional axonal torpedoes, in contrast to the deep cerebellar nuclei, where cerebellar efferents originate, which are severely affected.30 Radiologically, the magnetic resonance imaging pattern in patients with LOFA is similar to that in patients with FA showing significant cervical cord atrophy.17,3133 The size of the brainstem and cerebellum was reported to be in the lower reference range, and mild atrophy of the vermis and medulla was observed only in advanced cases in both patient groups.31,34 Junck et al35 reported mild generalized cerebral atrophy in patients with FA who met the diagnostic criteria of Harding that correlated with the clinical severity. In the present study, however, 5 of 9 investigated patients with LOFA had cerebellar atrophy on neuroimaging, in contrast to only 1 patient with typical FA. Of these 5 patients with LOFA, 2 each were in IAPS stages 3 and 4 and 1 was in IAPS stage 2, with a disease duration of more than 10 years in all affected patients. Of the patients with LOFA, the superior vermis rather than the cerebellar hemispheres were particularly affected. De Michele et al32 reported a similar finding in 1 of 5 patients with LOFA demonstrating moderate atrophy in the superior middle vermis and in both cerebellar hemispheres in addition to cervical cord atrophy. In summary, cerebellar atrophy was not an uncommon finding in our series, in contrast to previously described patients with LOFA.

COMMON CLINICAL FEATURES

The clinical presentations of patients with FA and LOFA were similar regarding gait and limb ataxias. In addition, dysarthria, loss of vibration sense, and abnormal extraocular movements (particularly fixational instability) were common in both patient groups. Our typical patients with FA closely matched the characteristics of previously reported series.2,3,12 The frequency of other clinical manifestations, including the presence of knee jerk, extensor plantar response, lower limb weakness, wasting of upper and lower limb muscles, dysphagia, hearing loss, and reduced visual acuity, did not significantly differ. Our patients with LOFA had an overall milder disease, although we cannot compare the severity of disease between patient groups because we selected matched IAPS patients with FA as controls. However, none of our patients with LOFA had abnormal echocardiographic findings. Previous studies12 suggested that the presence of cardiomyopathy correlated with disease severity, judged by earlier age at onset and age when confined to a wheelchair in patients with cardiomyopathy. The incidence of reduced visual acuity and hearing loss was small in both our patient groups and probably reflected disease progression. Similar to all previous observations,1,5,12,24 our patients with LOFA had significantly smaller GAA1 length than patients with typical FA (mean, 176 vs 490). However, the length of the GAA1 repeats in our patients with LOFA ranged from 69 to 410. The smallest symptomatic expansion described in the literature to date involved 66 repeats.1 Normal chromosomes bear fewer than 40 to 42 triplets, whereas FA chromosomes usually contain approximately 70 to more than 1000 triplets, most commonly 600 to 900.36 We observe that the minimal length of GAA1 repeats in our patients with LOFA is much lower than those in previous studies, which were reported to be 120 to 500 repeats.10,16 The Table summarizes the frequency of clinical manifestations in our study compared with previously published studies.

Table Graphic Jump LocationTable. Summary of Reported Studies of Late-Onset and Very Late-Onset Friedreich Ataxia

Identification of the FA gene has expanded the Friedreich disease phenotype and has proved that atypical cases, including LOFA and FA with retained reflexes, are also caused by the same mutation. Although patients with LOFA have more frequent spasticity and retained reflexes, common features, including gait and limb ataxias, dysarthria, loss of vibration sense, and fixational instability, are the same in both patient groups. Furthermore, cerebellar atrophy, particularly of the superior vermian structures, was observed in patients with LOFA more frequently than previously reported. Owing to advances in molecular genetics and expanded phenotypes in FA, we suggest that patients with the common features of gait and limb ataxias, dysarthria, loss of vibration sense, and fixational instability should be considered for FA testing.

Correspondence: Roongroj Bhidayasiri, MD, MRCP(UK), Division of Neurology, Chulalongkorn University Hospital, 1873 Rama 4 Rd, Bangkok 10330, Thailand (rbh@ucla.edu).

Accepted for Publication: June 20, 2005.

Author Contributions:Study concept and design: Bhidayasiri, Pulst, and Geschwind. Acquisition of data: Bhidayasiri, Perlman, Pulst, and Geschwind. Analysis and interpretation of data: Bhidayasiri and Pulst. Drafting of the manuscript: Bhidayasiri. Critical revision of the manuscript for important intellectual content: Bhidayasiri, Perlman, Pulst, and Geschwind. Statistical analysis: Bhidayasiri and Pulst. Obtained funding: Bhidayasiri. Administrative, technical, and material support: Bhidayasiri. Study supervision: Perlman, Pulst, and Geschwind.

Funding/Support: This study was supported by a Lilian Schorr Postdoctoral Fellowship from the Parkinson’s Disease Foundation, New York, NY, and the Parkinson’s Disease Research, Education, and Clinical Center of West Los Angeles Veterans Affairs Medical Center, West Los Angeles, Calif (Dr Bhidayasiri); and by grants from the Carmen and Louis Warschaw Endowment, Los Angeles, Calif, and the National Ataxia Foundation, Minneapolis, Minn, and grant RO1 NS33123 from the National Institutes of Health, Bethesda, Md (Dr Pulst).

Acknowledgment: We thank Giovanni Coppola, MD, for his helpful suggestions and criticism.

Schols  LAmoiridis  GPrzuntek  HFrank  GEpplen  JTEpplen  C Friedreich's ataxia: revision of the phenotype according to molecular genetics. Brain 1997;1202131- 2140
PubMed Link to Article
Geoffroy  GBarbeau  ABreton  G  et al.  Clinical description and roentgenologic evaluation of patients with Friedreich ataxia. Can J Neurol Sci 1976;3279- 286
PubMed
Harding  AE Friedreich's ataxia: a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features. Brain 1981;104589- 620
PubMed Link to Article
Campuzano  VMontermini  LMolto  MD  et al.  Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 1996;2711423- 1427
PubMed Link to Article
Durr  ACossee  MAgid  Y  et al.  Clinical and genetic abnormalities in patients with Friedreich's ataxia. N Engl J Med 1996;3351169- 1175
PubMed Link to Article
Filla  ADe Michele  GCoppola  G  et al.  Accuracy of clinical diagnostic criteria for Friedreich's ataxia. Mov Disord 2000;151255- 1258
PubMed Link to Article
De Michele  GFilla  ACavalcanti  F  et al.  Late onset Friedreich's disease: clinical features and mapping of mutation to the FRDA locus. J Neurol Neurosurg Psychiatry 1994;57977- 979
PubMed Link to Article
Palau  FDemichele  GVilchez  JJ  et al.  Early-onset ataxia with cardiomyopathy and retained tendon reflexes maps to the Friedreichs ataxia locus on chromosome 9Q. Ann Neurol 1995;37359- 362
PubMed Link to Article
Barbeau  ARoy  MSadebelouiz  MWilensky  MA Recessive ataxia in Acadians and “Cajuns”. Can J Neurol Sci 1984;11526- 533
PubMed
Ragno  MDe Michele  GCavalcanti  F  et al.  Broadened Friedreich ataxia phenotype after gene cloning: minimal GAA expansion causes late-onset spastic ataxia. Neurology 1997;491617- 1620
PubMed Link to Article
De Michele  GFilla  ABarbieri  F  et al.  Late onset recessive ataxia with Friedreich's disease phenotype. J Neurol Neurosurg Psychiatry 1989;521398- 1401
PubMed Link to Article
Montermini  LRichter  AMorgan  K  et al.  Phenotypic variability in Friedreich ataxia: role of the associated GAA triplet repeat expansion. Ann Neurol 1997;41675- 682
PubMed Link to Article
Maione  SGiunta  AFilla  A  et al.  May age onset be relevant in the occurrence of left ventricular hypertrophy in Friedreich's ataxia? Clin Cardiol 1997;20141- 145
PubMed Link to Article
Filla  ADe Michele  GCaruso  GMarconi  RCampanella  G Genetic data and natural history of Friedreich’s disease: a study of 80 Italian patients. J Neurol 1990;237345- 351
PubMed Link to Article
Chamberlain  SShaw  JRowland  A  et al.  Mapping of mutation causing Friedreich’s ataxia to human chromosome 9. Nature 1988;334248- 250
PubMed Link to Article
Geschwind  DHPerlman  SGrody  WW  et al.  Friedreich's ataxia GAA repeat expansion in patients with recessive or sporadic ataxia. Neurology 1997;491004- 1009
PubMed Link to Article
Klockgether  TChamberlain  SWullner  U  et al.  Late-onset Friedreich ataxia: molecular genetics, clinical neurophysiology, and magnetic resonance imaging. Arch Neurol 1993;50803- 806
PubMed Link to Article
Gellera  CPareyson  DCastellotti  B  et al.  Very late onset Friedreich's ataxia without cardiomyopathy is associated with limited GAA expansion in the X25 gene. Neurology 1997;491153- 1155
PubMed Link to Article
Coppola  GDe Michele  GCavalcanti  F  et al.  Why do some Friedreich's ataxia patients retain tendon reflexes? a clinical, neurophysiological and molecular study. J Neurol 1999;246353- 357
PubMed Link to Article
Richter  APoirier  JMercier  J  et al.  Friedreich ataxia in Acadian families from Eastern Canada: clinical diversity with conserved haplotypes. Am J Med Genet 1996;64594- 601
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De Michele  GFilla  ACriscuolo  C  et al.  Determinants of onset age in Friedreich's ataxia. J Neurol 1998;245166- 168
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Filla  ADeMichele  GCavalcanti  F  et al.  The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia. Am J Hum Genet 1996;59554- 560
PubMed
McDaniel  DOKeats  BVedanarayanan  VVSubramony  SH Sequence variation in GAA repeat expansions may cause different phenotype display in Friedreich's ataxia. Mov Disord 2001;161153- 1158
PubMed Link to Article
Gates  PCParis  DForrest  SMWilliamson  RMcKinlay Gardner  RJ Friedreich's ataxia presenting as adult-onset spastic paraparesis. Neurogenetics 1998;1297- 299
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Lhatoo  SDRao  DGKane  NMOrmerod  IE Very late onset Friedreich's presenting as spastic tetraparesis without ataxia and neuropathy. Neurology 2001;561776- 1777
PubMed Link to Article
Sorbi  SForleo  PCellini  E  et al.  Atypical Friedreich ataxia with a very late onset and an unusual limited GAA repeat. Arch Neurol 2000;571380- 1381
PubMed Link to Article
Berciano  JMateo  IDe Pablos  CPolo  JMCombarros  O Friedreich ataxia with minimal GAA expansion presenting as adult-onset spastic ataxia. J Neurol Sci 2002;19475- 82
PubMed Link to Article
Koeppen  AH The Purkinje cell and its afferents in human hereditary ataxia. J Neuropathol Exp Neurol 1991;50505- 514
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Wullner  UKlockgether  TPetersen  DNaegele  TDichgans  J Magnetic resonance imaging in hereditary and idiopathic ataxia. Neurology 1993;43318- 325
PubMed Link to Article
De Michele  GDisalle  FFilla  A  et al.  Magnetic resonance imaging in typical and late-onset Friedreich’s disease and early onset cerebellar ataxia with retained tendon reflexes. Ital J Neurol Sci 1995;16303- 308
PubMed Link to Article
Mascalchi  MSalvi  FPiacentini  SSorbi  SBartolozzi  C MRI of the cervical spinal cord in patients with Friedreich’s ataxia. Neurology 1994;44A143- A144
Ormerod  IECHarding  AEMiller  DH  et al.  Magnetic resonance imaging in degenerative ataxic disorders. J Neurol Neurosurg Psychiatry 1994;5751- 57
PubMed Link to Article
Junck  LGilman  SGebarski  SSKoeppe  RAKluin  KJMarkel  DS Structural and functional brain imaging in Friedreich’s ataxia. Arch Neurol 1994;51349- 355
PubMed Link to Article
Pandolfo  M Molecular basis of Friedreich ataxia. Mov Disord 2001;16815- 821
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Frequency of various clinical features in patients with typical Friedreich ataxia (FA) vs those with late-onset FA (LOFA). Asterisk indicates P<.05; LL, lower limb; KJ, knee jerk; AJ, ankle jerk; EOM, extraocular movement; UL, upper limb; and VA, visual acuity.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

T1-weighted sagittal magnetic resonance image of a patient with late-onset Friedreich ataxia demonstrating atrophy of the cerebellum (arrows) in addition to cervical cord atrophy.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Summary of Reported Studies of Late-Onset and Very Late-Onset Friedreich Ataxia

References

Schols  LAmoiridis  GPrzuntek  HFrank  GEpplen  JTEpplen  C Friedreich's ataxia: revision of the phenotype according to molecular genetics. Brain 1997;1202131- 2140
PubMed Link to Article
Geoffroy  GBarbeau  ABreton  G  et al.  Clinical description and roentgenologic evaluation of patients with Friedreich ataxia. Can J Neurol Sci 1976;3279- 286
PubMed
Harding  AE Friedreich's ataxia: a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features. Brain 1981;104589- 620
PubMed Link to Article
Campuzano  VMontermini  LMolto  MD  et al.  Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 1996;2711423- 1427
PubMed Link to Article
Durr  ACossee  MAgid  Y  et al.  Clinical and genetic abnormalities in patients with Friedreich's ataxia. N Engl J Med 1996;3351169- 1175
PubMed Link to Article
Filla  ADe Michele  GCoppola  G  et al.  Accuracy of clinical diagnostic criteria for Friedreich's ataxia. Mov Disord 2000;151255- 1258
PubMed Link to Article
De Michele  GFilla  ACavalcanti  F  et al.  Late onset Friedreich's disease: clinical features and mapping of mutation to the FRDA locus. J Neurol Neurosurg Psychiatry 1994;57977- 979
PubMed Link to Article
Palau  FDemichele  GVilchez  JJ  et al.  Early-onset ataxia with cardiomyopathy and retained tendon reflexes maps to the Friedreichs ataxia locus on chromosome 9Q. Ann Neurol 1995;37359- 362
PubMed Link to Article
Barbeau  ARoy  MSadebelouiz  MWilensky  MA Recessive ataxia in Acadians and “Cajuns”. Can J Neurol Sci 1984;11526- 533
PubMed
Ragno  MDe Michele  GCavalcanti  F  et al.  Broadened Friedreich ataxia phenotype after gene cloning: minimal GAA expansion causes late-onset spastic ataxia. Neurology 1997;491617- 1620
PubMed Link to Article
De Michele  GFilla  ABarbieri  F  et al.  Late onset recessive ataxia with Friedreich's disease phenotype. J Neurol Neurosurg Psychiatry 1989;521398- 1401
PubMed Link to Article
Montermini  LRichter  AMorgan  K  et al.  Phenotypic variability in Friedreich ataxia: role of the associated GAA triplet repeat expansion. Ann Neurol 1997;41675- 682
PubMed Link to Article
Maione  SGiunta  AFilla  A  et al.  May age onset be relevant in the occurrence of left ventricular hypertrophy in Friedreich's ataxia? Clin Cardiol 1997;20141- 145
PubMed Link to Article
Filla  ADe Michele  GCaruso  GMarconi  RCampanella  G Genetic data and natural history of Friedreich’s disease: a study of 80 Italian patients. J Neurol 1990;237345- 351
PubMed Link to Article
Chamberlain  SShaw  JRowland  A  et al.  Mapping of mutation causing Friedreich’s ataxia to human chromosome 9. Nature 1988;334248- 250
PubMed Link to Article
Geschwind  DHPerlman  SGrody  WW  et al.  Friedreich's ataxia GAA repeat expansion in patients with recessive or sporadic ataxia. Neurology 1997;491004- 1009
PubMed Link to Article
Klockgether  TChamberlain  SWullner  U  et al.  Late-onset Friedreich ataxia: molecular genetics, clinical neurophysiology, and magnetic resonance imaging. Arch Neurol 1993;50803- 806
PubMed Link to Article
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