Brain, Vol. 125, No. 5, 961-968,
May 2002
© 2002 Guarantors of Brain
The aetiology of sporadic adult-onset ataxia
1 Department of Neurology and 2 Department of Pediatrics, University of Bonn, 3 Department of Neurology and 4 Department of Laboratory Medicine, University of Tübingen, 5 Department of Neurology, St. Josef Hospital, Bochum, 6 Institute of Human Genetics, University of Lübeck and 7 Department of Medical Genetics, University of Rostock, Germany Correspondence: T. Klockgether, Department of Neurology, University of Bonn, Sigmund-Freud-Straße 25, D-53105 Bonn, Germany E-mail: klockgether{at}uni-bonn.de
*These authors contributed equally to this work
Received August 20, 2001. Revised November 22, 2001. Accepted December 12, 2001.
 |
Summary |
|---|
 Top Summary IntroductionMethodsResultsDiscussionReferences |
|---|
The nosology and aetiology of sporadic adult-onset ataxia are poorly understood. The aim of the present study was to answer the following questions: (i) How many sporadic ataxia patients have a genetic cause? (ii) How many sporadic ataxia patients suffer from multiple system atrophy (MSA)? (iii) Is there a specific association between sporadic ataxia and serum anti-glutamic acid decarboxylase (GAD) or antigliadin antibodies? and (iv) What are the clinical features of patients with unexplained sporadic ataxia? The study was performed in 112 patients who met the following inclusion criteria: (i) progressive ataxia; (ii) onset after 20 years; (iii) informative and negative family history (no similar disorders in first- and second-degree relatives; parents older than 50 years); and (iv) no established symptomatic cause. Thirty-two patients (29%) met the clinical criteria of possible (7%) or probable (22%) MSA. The Friedreich’s ataxia mutation was found in five patients (4%), the spinocerebellar ataxia (SCA) 2 mutation in one (1%), the SCA3 mutation in two (2%) and the SCA6 mutation in seven (6%). The disease remained unexplained in 65 patients (58%). We did not detect anti-GAD antibodies in any of our patients. Antigliadin antibodies were present in 14 patients, 10 patients with unexplained ataxia (15%) and 4 patients with an established diagnosis (9%). Patients with unexplained sporadic ataxia had a median disease onset of 56.0 years. Decreased vibration sense (62%), decreased or absent ankle reflexes (40%), increased ankle reflexes (39%), dysphagia (38%) and extensor plantar responses and/or spasticity (34%) were the most frequent extracerebellar symptoms. Compared with MSA, disease progression was significantly slower.
Keywords: antigliadin antibodies; Friedreich’s ataxia; multiple system atrophy; spinocerebellar ataxia
Abbreviations: FRDA= Friedreich’s ataxia; GAD = glutamic acid decarboxylase; IDCA = idiopathic late onset cerebellar ataxia; IgA = immunoglobulin A; IgG = immunoglobulin G; MSA = multiple system atrophy; OPCA = olivopontocerebellar atrophy; SCA = spinocerebellar ataxia
|
Introduction |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
Despite the enormous progress that has been made in the understanding of the genetic basis of hereditary ataxia, the origin of many sporadic ataxias remains obscure. In 1981, Harding proposed labelling the sporadic adult-onset ataxias of unknown aetiology as idiopathic late onset cerebellar ataxias (IDCA) (Harding, 1981
). IDCA is thus distinguished from symptomatic ataxias due to identified exogenous and endogenous causes. The most frequent established causes of sporadic ataxias are chronic alcoholism, remote malignancies (paraneoplastic cerebellar degeneration), vitamin deficiency, various toxic agents and hypothyroidism.
Clinical and radiological studies suggest that IDCA is heterogeneous. In a previous study of 28 IDCA patients (Klockgether et al., 1990), we tentatively divided IDCA into two groups with distinct clinical, radiological and prognostic features. IDCA-plus patients had accompanying extracerebellar features such as parkinsonism, bulbar symptoms, urinary incontinence and pyramidal tract signs. MRI showed cerebellar and brainstem atrophy typical for olivopontocerebellar atrophy (OPCA). Progression was fast with a median survival of only 7.7 years. In contrast, IDCA-cerebellar patients suffered from a lasting purely cerebellar syndrome. They had isolated cerebellar atrophy on MRI and survived for more than 20 years. Subsequent clinical studies showed that many if not all IDCA-plus patients suffered from multiple system atrophy (MSA) (Schulz et al., 1994; Wenning et al., 1994). MSA is a sporadic, adult-onset disease characterized by neurodegeneration in the basal ganglia, brainstem, cerebellum and intermediolateral cell columns of the spinal cord encompassing the former disease categories striatonigral degeneration, sporadic OPCA and Shy–Drager syndrome (Quinn, 1989). The ultrastructural hallmark of MSA is the presence of oligodendroglial cytoplasmic inclusions (Papp and Lantos, 1994). Based on clinicopathological correlation studies, sensitive criteria have been established which allow a highly specific clinical diagnosis of MSA (Gilman et al., 1999).
While sporadic ataxia patients presenting with autonomic failure can be assigned to MSA, the aetiology in many other patients suffering from sporadic ataxia remains unclear. One hypothesis is that these disorders represent monogenic diseases, either late onset autosomal recessive ataxias or new dominant mutations. In contrast to earlier assumptions, recessive ataxias such as Friedreich’s ataxia (FRDA) may start after the age of 30 years (Klockgether et al., 1993). In a clinical genetic study of 140 FRDA patients, 19 had a disease onset later than 25 years (Dürr et al., 1996). Since recessively inherited disorders are more likely to occur sporadically than clustered in families, sporadic late onset ataxias might represent late onset variants of FRDA or other recessive ataxias. The occurrence of new dominant mutations in spinocerebellar ataxia (SCA) genes is possible, but appears to be rare. However, the parent who transmitted the disease may have died before clinical symptoms became apparent making the family history uninformative. This is particularly probable for SCA6 because average disease onset of SCA6 occurs in late adulthood (Ikeuchi et al., 1997; Schöls et al., 1998). In addition, autosomal dominant disorders may be apparently sporadic due to false fatherhood.
Recently, an association of ataxia with serum anti-glutamic acid decarboxylase (GAD) and antigliadin antibodies has been reported suggesting that some types of sporadic ataxia may have an immunological cause (Hadjivassiliou et al., 1996; Saiz et al., 1997; Hadjivassiliou et al., 1998). However, for antigliadin antibodies, the specificity of the association with sporadic ataxia has been challenged (Bushara et al., 2001).
The aim of the present study was to clarify the nosology of sporadic adult-onset progressive ataxia. To this end, we performed a clinical and laboratory study of 112 ataxia patients. In particular, we aimed to answer the following questions: (i) How many patients with an ataxia of hitherto unknown aetiology have a genetic cause? (ii) How many sporadic ataxia patients suffer from MSA? (iii) Is there a specific association between sporadic ataxia and serum anti-GAD or antigliadin antibodies? and (iv) How many patients have an unexplained ataxia, and what are their clinical features?
|
Methods |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
Inclusion criteria and study population
The medical records of all ataxia patients referred to the Departments of Neurology at the Universities of Bonn and Tübingen (Germany) and the St Josef Hospital in Bochum (Germany) between January 1996 and December 1998 were reviewed and patients with sporadic adult-onset progressive ataxia of unknown aetiology were identified. Inclusion criteria were as follows: (i) progressive ataxia; (ii) disease onset after the age of 20 years; (iii) informative and negative family history (no similar disorders in first- and second-degree relatives; parents older than 50 years, or, if not alive, age at death of >50 years), (iv) no established symptomatic cause [(a) normal CSF studies; (b) no ischaemia, haemorrhage or tumour of the posterior fossa; (c) no alcohol abuse; (d) no chronic intake of anticonvulsant drugs; (e) no other toxic causes; (f) no malignancies; (g) anti-Hu and anti-Yo negative; (h) normal levels of vitamin B12 and E; (i) Venereal Disease Research Laboratories (VDRL) test negative; (j) no evidence of onset of ataxia in association with encephalitis, sepsis, hyperthermia or heat stroke; and (k) normal thyroid function]; and (v) no subacute onset of ataxia [subacute onset of ataxia was defined as progression to stage 2 (see below) within less than 4 months].
One hundred and twelve of the 132 patients who met the inclusion criteria agreed to participate in the study. These patients were seen at our ataxia clinics or visited at home. All subjects gave informed consent. The study was approved by the Ethical Committee of the Medical Faculty at the University of Bonn.
Data collection
In all patients, a detailed history including questions for disease onset and disease progression (see below), urinary symptoms and erectile dysfunction (in males) was taken. All patients were asked whether there was consanguinity of their parents. Bladder dysfunction was assumed when patients complained of urinary urgency, incontinence or retention. Cystometrograms were not performed systematically.
All patients were clinically examined by M.A. (Bonn), K.B. (Tübingen) or L.S. (Bochum) using generally acknowledged definitions of clinical symptoms. Decreased ankle reflexes were defined as barely elicitable or elicitable only with facilitation manoeuvres. Spasticity was defined as an increase of muscle tone related to the velocity of passive stretch. The severity of ataxia was rated as described previously (Klockgether et al., 1990), while the severity of other clinical symptoms was not rated. Examination included repeated measurements of systolic and diastolic blood pressure in recumbent position and within 3 min of standing from the recumbent position. A blood sample was taken in all patients.
A clinical diagnosis of possible or probable MSA was made following the consensus statement published by Gilman and colleagues (Gilman et al., 1999). In this consensus statement, a distinction is made between features which represent clinical symptoms characteristic of MSA and criteria which are defining features or a composite of several features required for the diagnosis of MSA. Features belong to one of four domains: (i) autonomic/urinary dysfunction; (ii) parkinsonism; (iii) cerebellar dysfunction; and (iv) corticospinal tract dysfunction. All our patients met the criterion of cerebellar dysfunction (gait ataxia and at least one of ataxic dysarthria, limb ataxia and sustained gaze-evoked nystagmus). According to Gilman and colleagues (Gilman et al., 1999), a diagnosis of possible MSA can be made when patients have two additional features from separate domains, such as orthostatic hypotension with drop of systolic blood pressure by at least 20 mm Hg, rigidity or extensor plantar responses. For the diagnosis of probable MSA, patients have to meet the criterion of autonomic failure in addition to that of cerebellar ataxia. Autonomic failure is defined as an orthostatic fall in systolic blood pressure by at least 30 mm Hg or urinary incontinence (persistent, involuntary partial or total bladder emptying, accompanied by erectile dysfunction in men) or both.
Disease progression was studied as described previously (Klockgether et al., 1998). Briefly, we defined the following disease stages: stage 0: no gait difficulties; stage 1: disease onset, as defined by onset of gait difficulties; stage 2: loss of independent gait, as defined by permanent use of a walking aid or reliance on a supporting arm; stage 3: confinement to wheelchair, as defined by permanent use of a wheelchair; and stage 4: death. For each patient, we determined the year of birth, the age at disease onset in years, the current disease stage and the latencies from disease onset in years after which subsequent disease stages were reached. Data were obtained from living patients by a personal structured interview. Patients were allowed to use their own diaries and notes. All information obtained by interview was compared with that from medical records.
Laboratory studies
For determination of anti-GAD antibodies, a photometric immunoassay (Diaplets Anti-GAD, Boehringer Mannheim, Mannheim, Germany) was used. Results were referred to the GAD-specific human monoclonal islet cell antibody clone 3 (MICA3) and calibrated to human immunoglobulin G (IgG) concentration. Samples with an anti-GAD concentration of less than 32 ng/ml were considered negative. The lower detection limit was 20 ng/ml.
Detection of antigliadin IgG and immunoglobulin A (IgA) antibodies in serum samples was performed using a solid phase enzyme immunometric assay (Gluten IgG/IgA EIA, Pharmacia, Erlangen, Germany) following the manufacturer’s instructions. To quantify the absorbance of each serum sample, a human reference serum sample containing a high concentration of antigliadin antibodies was used. Absorbance of the reference sample was set to 100 AU (arbitrary units/100 µl. One AU was equal to 1% absorbance of the reference. Serum samples with values above a threshold of 20 AU were considered positive. The lower detection limit was 6 AU. Endomysial antibodies were measured using indirect immunofluorescence (Viro-Immun Labor Diagnostika, Oberursel, Germany).
Molecular genetic tests were performed using standard laboratory protocols for FRDA (Epplen et al., 1997), SCA1 (Schöls et al., 1995a), SCA2 (Riess et al., 1997a), SCA3 (Schöls et al., 1995b), SCA6 (Riess et al., 1997b), SCA8 (Koob et al., 1999) and TATA-binding protein (Zühlke et al., 2001).
Statistical evaluation
To compare the frequency of clinical symptoms and the prevalence of antigliadin antibodies in different patient groups we used the 
2-test. The Mann–Whitney U-test was used to compare age of onset, age at examination, disease duration and severity of cerebellar ataxia. Disease progression was evaluated using Kaplan–Meier statistics.
|
Results |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
Patients
The study population consisted of 112 patients, 61 males and 51 females. Age at examination ranged from 25 to 84 years with a median of 61 years, age at disease onset from 20 to 82 years with a median of 56.5 years (Table 1). Eighty-one patients had a disease duration of
4 years. Age at examination in this subgroup ranged from 25 to 82 years with a median of 62 years, age at disease onset from 20 to 75 years with a median of 54 years (Table 1). None of the patients was aware of consanguinity of their parents.
|
Prevalence of MSA and genetically defined ataxias
Thirty-two patients (29%) met the clinical criteria of possible (7%) or probable (22%) MSA. The FRDA mutation was found in five patients (4%), the SCA2 mutation in one (1%), the SCA3 mutation in two (2%) and the SCA6 mutation in seven (6%) (Fig. 1A). Thus, a diagnosis could be established in 47 patients (42%), while ataxia remained unexplained in the remaining patients (58%).
|
Since extracerebellar symptoms establishing a clinical diagnosis of MSA may develop up to 4 years after onset of ataxia (Klockgether et al., 1990
), we analysed the subgroup of patients with a disease duration of 4 years separately. The distribution of diagnoses in this subgroup was similar to that in the whole study population: 21 (26%) had MSA (possible: 2%, probable: 23%), five FRDA (6%), one SCA2 (1%), three SCA3 (2%) and six SCA6 (7%) (Fig. 1B).
Serological findings
Since anti-GAD and antigliadin antibodies have been reported to occur in association with ataxia, we searched for these antibodies in our study population. We did not detect anti-GAD antibodies in any of our patients. Antigliadin antibodies were found in 14 patients: IgG antibodies in seven patients, IgA antibodies in nine patients and endomysial antibodies in one patient. Two of the patients had both IgG and IgA antibodies and one patient had IgA and endomysial antibodies. Antigliadin antibodies were present both in patients with unexplained ataxia (10 patients; 15%) and in patients with an established diagnosis (four patients; 9%). Of these four patients, three had MSA and 1 FRDA. There was no statistical difference between the frequency of antigliadin antibodies in patients with unexplained ataxia and in patients with an established diagnosis.
Clinical characteristics of patients with unexplained ataxia
Forty of the 65 patients with unexplained sporadic ataxia were male and 25 female. Median age of onset was 56 years (range: 20–82 years) in patients with unexplained ataxia compared with 57 years (range: 24–68 years) in MSA. This difference was not statistically significant.
All patients with unexplained sporadic ataxia presented with a cerebellar syndrome. Severity of ataxia of gait (P < 0.001), ataxia of upper limbs (P < 0.01), dysdiadochokinesis (P < 0.01), ataxia of lower limbs (P < 0.05) and dysarthria (P < 0.001) were less severe than in MSA. Although ataxia was the prominent symptom in patients with unexplained disease, extracerebellar symptoms were observed frequently (Table 2). The most frequent additional symptoms were: decreased vibration sense (62%); decreased or absent ankle reflexes (40%); increased ankle reflexes (39%); dysphagia (38%); bladder dysfunction (34%); and extensor plantar responses and/or spasticity (34%). Decreased or absent ankle reflexes were more frequent in patients with unexplained ataxia than in MSA (40% versus 9%, P < 0.001). In contrast, bladder dysfunction (34% versus 91%, P < 0.001), muscular rigidity (9% versus 53%, P < 0.001), tremor (5 versus 25%, P < 0.01) and dysphagia (38% versus 72%, P < 0.01) were encountered less frequently than in MSA. A comparison of the age of onset and clinical features of antigliadin-positive and antigliadin-negative patients with unexplained ataxia did not reveal any significant differences (data not shown).
|
Disease progression was significantly slower in patients with unexplained ataxia compared with MSA. The median latency to become dependent on walking aids after disease onset was 11.1 years compared with 4.7 years in MSA (P < 0.01) (Fig. 2).
|
Clinical characteristics of SCA and FRDA patients
Ten patients were found to have an SCA mutation even though their family history was informative and negative. The parents of the SCA patients had died at a median age of 77 years (range: 55–96 years). Median age of death of the mothers was 78 years (range: 55–96 years) and of the fathers 75 years (range: 63–83 years). Seven out of 10 SCA patients carried the SCA6 mutation. Median age of onset was 59 years (range: 53–71 years) compared with 56 years (range: 20–82 years) in patients with unexplained ataxia. This difference was not statistically significant. Although SCA6 patients tended to have less severe ataxia of the upper and lower extremities, the clinical presentation was similar to that of patients with unexplained ataxia.
Five patients had the FRDA mutation. Not unexpectedly, they had a younger age of onset than all other groups (median: 27 years, range: 25–36 years). Ankle reflexes were preserved in one patient, while they were absent in the other four. Two had extensor plantar responses, two amyotrophy and four reduced vibration sense. The FRDA group was too small to make meaningful statistical comparisons with other patient groups.
|
Discussion |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
The principal findings of this study can be summarized, as follows: (i) MSA is a frequent cause of sporadic adult-onset ataxia; (ii) mutations of the FRDA or SCA genes account for less than 15% of sporadic adult-onset ataxia patients; (iii) antigliadin antibodies are found in the serum of both patients with unexplained ataxia and patients with MSA or a genetic cause; and (iv) compared with MSA, patients suffering from unexplained sporadic ataxia have a milder phenotype and a better prognosis.
Our finding that 29% of sporadic ataxia patients suffer from MSA corresponds well to data of a recently published study of sporadic OPCA patients who were followed for 3 months to 10 years (Gilman et al., 2000). Within this period, 17 out of 51 patients developed autonomic failure or parkinsonism indicating a diagnosis of MSA. Since these symptoms may develop years after onset of ataxia, a diagnosis of MSA might be missed in patients with a short disease duration. We therefore analysed patients with a disease duration of 4 years separately. A latency of 4 years was chosen because we had found previously (Klockgether et al., 1990) that, if extracerebellar symptoms occur in sporadic ataxia, these symptoms usually develop within the first four years after ataxia onset. The prevalence of MSA in the subgroup of patients with a disease duration of 4 years was not different from that of the whole study population. This finding strongly argues against the possibility that we overlooked a considerable number of MSA cases because patients were examined before typical symptoms of MSA had evolved.
The percentage of sporadic ataxia patients with positive genetic tests was 13%: 4% carried the FRDA mutation, 1% the SCA2 mutation, 2% the SCA3 mutation and 6% the SCA6 mutation. A number of previous studies also looked for gene mutations in sporadic ataxia. In our own earlier study (Klockgether et al., 1994), we failed to identify any SCA1 mutations in 61 IDCA patients. In other studies, the frequency of positive genetic tests in apparently sporadic ataxia patients ranged from 2% to 22% (Matsumura et al., 1997; Moseley et al., 1998; Pujana et al., 1999; Schöls et al., 2000). The discrepancies between the studies are probably due to variable genetic background and to different sub-sets of the study populations. In our study, all patients were examined personally and a careful family history was taken. Patients were included only if their parents were >50 years old or if parents had died when >50 years old. This reduces the likelihood of including patients with dominant ataxia whose parents had died before onset of the disease.
It may be possible that known gene mutations that were not tested, or presently unknown gene mutations may underlie some of the unexplained cases of sporadic ataxia. Both possibilities cannot be ruled out completely. However, there are several reasons that strongly argue against the idea that one or both of these mechanisms account for the disease in a considerable number of our patients. Although we tested only for the FRDA mutation and not for other recessive mutations, we do not believe that patients included in this study suffered from one of the recessive ataxias with known gene mutation or gene locus such as ataxia telangiectasia, ataxia with isolated vitamin E deficiency, abetalipoproteinaemia, autosomal recessive spastic ataxia of Charlevoix–Saguenay or recessive ataxia with ocular apraxia. Ataxia telangiectasia typically begins in early childhood and, although milder variants with later disease onset are possible, a disease onset after the age of 20 years is highly improbable. A recent study failed to find abnormal levels of 
-foetoprotein or mutations of the coding region of the ataxia telangiectasia mutated gene in a group of 34 sporadic ataxia patients aged three to 77 years (Hassin-Baer et al., 1999). Ataxia with isolated vitamin E deficiency and abetalipoproteinaemia can be ruled out because all our patients had been screened for vitamin E deficiency before entry into the study. Autosomal recessive spastic ataxia of Charlevoix–Saguenay patients develop first signs of lower limb spasticity within the first years of life—in most cases observed at gait initiation between 12 and 18 months (Bouchard et al., 1998). It is therefore highly improbable that our series of ataxia patients with a disease onset after 20 years included autosomal recessive spastic ataxia of Charlevoix–Saguenay patients. Recessive ataxia with ocular apraxia has a highly characteristic clinical phenotype which was not encountered among our patients (Barbot et al., 2001). SCA1, SCA2, SCA3 and SCA6 account for 86% of all families suffering from dominant ataxia in Germany (Riess et al., 1997b). In addition, we tested for SCA8 and the TATA-binding protein. If one assumes that the distribution of SCA mutations in German sporadic ataxia patients is similar to that in dominant families, one can estimate that only a negligible number of patients in this study suffered from an SCA mutation other than one of the mutations tested.
The term ‘gluten ataxia’ has been coined to denote sporadic ataxia in patients with cryptic gluten sensitivity as indicated by circulating antigliadin antibodies in the absence of gastrointestinal symptoms (Hadjivassiliou et al., 1998). In one study, 17 out of 25 patients suffering from unexplained sporadic ataxia had raised titres of antigliadin antibodies (Hadjivassiliou et al., 1996). Positive duodenal biopsies were obtained in 35%. Demonstration of inflammatory infiltrates in the cerebellar white matter and posterior column of one gliadin-positive patient further corroborated the idea of a specific association of antigliadin antibodies and sporadic ataxia. In other studies, the prevalence of antigliadin antibodies was lower. Pellecchia and colleagues found antigliadin antibodies in 12.5% (Pellecchia et al., 1999), Bürk and colleagues in 11.5% (Bürk et al., 2001) and Combarros and colleagues in none of their sporadic ataxia patients (Combarros et al., 2000). Quite unexpectedly, a recent study also found a high prevalence of gluten sensitivity (37%) in patients with dominant ataxias including patients with known SCA mutations (Bushara et al., 2001). In our study population, antigliadin antibodies were present not only in patients with unexplained sporadic ataxia (15%), but also in patients with an established diagnosis (9%). The prevalence of antigliadin antibodies in healthy German blood donors is 5% (Bürk et al., 2001). These observations raise the question of whether positive antigliadin antibodies are a consequence rather than the cause of cerebellar degeneration. Further studies are needed to clarify the importance of antigliadin antibodies in sporadic and hereditary ataxis.
A number of studies reported an association of cerebellar ataxia with anti-GAD antibodies (Saiz et al., 1997; Abele et al., 1999; Trivedi et al., 2000; Honnorat et al., 2001). Most of the GAD-positive patients had also insulin-dependent diabetes mellitus or other autoimmune endocrine manifestations. Our present search for anti-GAD antibodies was completely negative, showing that the association of sporadic ataxia with anti-GAD antibodies is rare.
In the largest subgroup of our study population, ataxia remained unexplained. As in MSA, age of onset is between 50 and 60 years. Compared with MSA, however, these patients have a milder phenotype and slower disease progression. Although cerebellar ataxia is the prominent symptom in these patients, many have clinical features suggesting additional involvement of pyramidal tracts, posterior columns and peripheral nervous system. The clinical phenotype of the present patients with unexplained ataxia broadly resembles that of the patients labelled as IDCA by Harding (1981). Harding subdivided her patients into a group with severe ataxia of gait, another group with prominent resting and postural tremor, and a larger group comprising patients who did not fit into either of these groups. However, statistical analysis comparing the frequency of clinical symptoms in her three groups did not show any relevant differences. In most of our patients, ataxia of gait and stance was the prominent symptom, whereas tremor was an infrequent finding. Although it is not possible to prove clinical homogeneity of our patients with unexplained ataxia, our data give no rational basis for further subdivision into subgroups.
|
References |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
Abele M, Weller M, Mescheriakov S, Bürk K, Dichgans J, Klockgether T. Cerebellar ataxia with glutamic acid decarboxylase autoantibodies. Neurology 1999; 52: 857–9.
Barbot C, Coutinho P, Chorao R, Ferreira C, Barros J, Fineza I, et al. Recessive ataxia with ocular apraxia: review of 22 Portuguese patients. Arch Neurol 2001; 58: 201–5.
Bouchard JP, Richter A, Mathieu J, Brunet D, Hudson TJ, Morgan K, et al. Autosomal recessive spastic ataxia of Charlevoix-Saguenay. Neuromuscul Disord 1998; 8: 474–9.[Web of Science][Medline]
Bürk K, Bösch S, Müller CA, Melms A, Zühlke C, Stern M, et al. Sporadic cerebellar ataxia associated with gluten sensitivity. [Review]. Brain 2001; 124: 1013–9.
Bushara KO, Goebel SU, Shill H, Goldfarb LG, Hallett M. Gluten sensitivity in sporadic and hereditary cerebellar ataxia. Ann Neurol 2001; 49: 540–3.[Web of Science][Medline]
Combarros O, Infante J, Lopez-Hoyos M, Bartolome MJ, Berciano J, Corral J, et al. Celial disease and idiopathic cerebellar ataxia. Neurology 2000; 54: 2346.
Dürr A, Cossee M, Agid Y, Campuzano V, Mignard C, Penet C, et al. Clinical and genetic abnormalities in patients with Friedreich’s ataxia. New Engl J Med 1996; 335: 1169–75.
Epplen C, Epplen JT, Frank G, Miterski B, Santos EJ, Schöls L. Differential stability of the (GAA)n tract in the Friedreich ataxia (STM7) gene. Hum Genet 1997; 99: 834–6.[Web of Science][Medline]
Gilman S, Low PA, Quinn N, Albanese A, Ben Shlomo Y, Fowler CJ et al. Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci 1999; 163: 94–8.[Web of Science][Medline]
Gilman S, Little R, Johanns J, Heumann M, Kluin KJ, Junck L, et al. Evolution of sporadic olivopontocerebellar atrophy into multiple system atrophy. Neurology 2000; 55: 527–32.
Hadjivassiliou M, Gibson A, Davies Jones GA, Lobo AJ, Stephenson TJ, Milford-Ward A. Does cryptic gluten sensitivity play a part in neurological illness? Lancet 1996; 347: 369–71.[Web of Science][Medline]
Hadjivassiliou M, Grunewald RA, Chattopadhyay AK, Davies-Jones G, Gibson A, Jarratt JA, et al. Clinical, radiological, neurophysiological, and neuropathological characteristics of gluten ataxia. Lancet 1998; 352: 1582–5.[Web of Science][Medline]
Harding AE. "Idiopathic" late onset cerebellar ataxia. A clinical and genetic study of 36 cases. J Neurol Sci 1981; 51: 259–71.[Web of Science][Medline]
Hassin-Baer S, Bar-Shira A, Gilad S, Galanty Y, Khosravi R, Lossos A, et al. Absence of mutations in ATM, the gene responsible for ataxia telangiectasia in patients with cerebellar ataxia. J Neurol 1999; 246: 716–9.[Web of Science][Medline]
Honnorat J, Saiz A, Giometto B, Vincent A, Brieva L, de Andres C, et al. Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients. Arch Neurol 2001; 58: 225–30.
Ikeuchi T, Takano H, Koide R, Horikawa Y, Honma Y, Onishi Y et al. Spinocerebellar ataxia type 6: CAG repeat expansion in 1A voltage-dependent calcium channel gene and clinical variations in Japanese population. Ann Neurol 1997; 42: 879–84.[Web of Science][Medline]
Klockgether T, Schroth G, Diener HC, Dichgans J. Idiopathic cerebellar ataxia of late onset: natural history and MRI morphology. J Neurol Neurosurg Psychiatry 1990; 53: 297–305.
Klockgether T, Chamberlain S, Wüllner U, Fetter M, Dittmann H, Petersen D, et al. Late-onset Friedreich’s ataxia. Molecular genetics, clinical neurophysiology, and magnetic resonance imaging. Arch Neurol 1993; 50: 803–6.
Klockgether T, Bürk K, Schulz JB, Dichgans J, Wessel K, Auburger G. Absence of SCA1 mutation in idiopathic cerebellar ataxia [letter]. J Neurol Neurosurg Psychiatry 1994; 57: 1439–40.
Klockgether T, Lüdtke R, Kramer B, Abele M, Bürk K, Schöls L et al. The natural history of degenerative ataxia: a retrospective study in 466 patients. Brain 1998; 121: 589–600.
Koob MD, Moseley ML, Schut LJ, Benzow KA, Bird TD, Day JW, et al. An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nature Genet 1999; 21: 379–84.[Web of Science][Medline]
Matsumura R, Futamura N, Fujimoto Y, Yanagimoto S, Horikawa H, Suzumura A, 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: 1238–43.
Moseley ML, Benzow KA, Schut LJ, Bird TD, Gomez CM, Barkhaus PE et al. Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families. Neurology 1998; 51: 1666–71.
Papp MI, Lantos PL. The distribution of oligodendroglial inclusions in multiple system atrophy and its relevance to clinical symptomatology. Brain 1994; 117: 235–43.
Pellecchia MT, Scala R, Filla A, De Michele G, Ciacci C, Barone P. Idiopathic cerebellar ataxia associated with celiac disease: lack of distinctive neurological features. J Neurol Neurosurg Psychiatry 1999; 66: 32–5.
Pujana MA, Corral J, Gratacos M, Combarros O, Berciano J, Genis D, et al. Spinocerebellar ataxias in Spanish patients: genetic analysis of familial and sporadic cases. The Ataxia Study Group. Hum Genet 1999; 104: 516–22.[Web of Science][Medline]
Quinn N. Multiple system atrophy—the nature of the beast. [Review]. J Neurol Neurosurg Psychiatry 1989; Suppl: 78–89.
Riess O, Laccone FA, Gispert S, Schöls L, Zühlke C, Vieira-Saecker AM, et al. SCA2 trinucleotide expansion in German SCA patients. Neurogenetics 1997a; 1: 59–64.[Web of Science][Medline]
Riess O, Schöls L, Bottger H, Nolte D, Vieira-Saecker AM, Schimming C, et al. SCA6 is caused by moderate CAG expansion in the alpha1A-voltage-dependent calcium channel gene. Hum Mol Genet 1997b; 6: 1289–93.
Saiz A, Arpa J, Sagasta A, Casamitjana R, Zarranz JJ, Tolosa E, et al. Autoantibodies to glutamic acid decarboxylase in three patients with cerebellar ataxia, late-onset insulin-dependent diabetes mellitus, and polyendocrine autoimmunity. Neurology 1997; 49: 1026–30.
Schöls L, Riess O, Schöls S, Zeck S, Amoiridis G, Langkafel M, et al. Spinocerebellar ataxia type 1: clinical and neurophysiological characteristics in German kindreds. Acta Neurol Scand 1995a; 92: 478–85.[Web of Science][Medline]
Schöls L, Vieira-Saecker AM, Schols S, Przuntek H, Epplen JT, Riess O. Trinucleotide expansion within the MJD1 gene presents clinically as spinocerebellar ataxia and occurs most frequently in German SCA patients. Hum Mol Genet 1995b; 4: 1001–5.
Schöls L, Szymanski S, Peters S, Przuntek H, Epplen JT, Hardt C, et al. Genetic background of apparently idiopathic sporadic cerebellar ataxia. Hum Genet 2000; 107: 132–7.[Web of Science][Medline]
Schöls L, Krüger R, Amoiridis G, Przuntek H, Epplen JT, Riess O. Spinocerebellar ataxia type 6: genotype and phenotype in German kindreds. J Neurol Neurosurg Psychiatry 1998; 64: 67–73.
Schulz JB, Klockgether T, Petersen D, Jauch M, Müller-Schauenburg W, Spieker S et al. Multiple system atrophy: natural history, MRI morphology, and dopamine receptor imaging with 123IBZM-SPECT. J Neurol Neurosurg Psychiatry 1994; 57: 1047–56.
Trivedi R, Mundanthanam G, Amyes E, Lang B, Vincent A. Autoantibody screening in subacute cerebellar ataxia. Lancet 2000; 356: 565–6.[Web of Science][Medline]
Wenning GK, Ben Shlomo Y, Magalhaes M, Daniel SE, Quinn NP. Clinical features and natural history of multiple system atrophy. An analysis of 100 cases. Brain 1994; 117: 835–45.
Zühlke C, Hellenbroich Y, Dalski A, Kononowa N, Hagenah J, Vieregge P, et al. Different types of repeat expansion in the TATA-binding protein gene are associated with a new form of inherited ataxia. Eur J Hum Genet 2001; 9: 160–4.[Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J N Wagner, M Glaser, T Brandt, and M Strupp Downbeat nystagmus: aetiology and comorbidity in 117 patients J. Neurol. Neurosurg. Psychiatry, June 1, 2008; 79(6): 672 - 677. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A Rasmussen, M Gomez, E Alonso, and S I Bidichandani Clinical heterogeneity of recessive ataxia in the Mexican population. J. Neurol. Neurosurg. Psychiatry, December 1, 2006; 77(12): 1370 - 1372. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. F. Abdo, B.P.C. van de Warrenburg, M. Munneke, W. J.A. van Geel, B. R. Bloem, H. P.H. Kremer, and M. M. Verbeek CSF analysis differentiates multiple-system atrophy from idiopathic late-onset cerebellar ataxia Neurology, August 8, 2006; 67(3): 474 - 479. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R J Lock, D S N A Pengiran Tengah, D J Unsworth, J J Ward, and A J Wills Ataxia, peripheral neuropathy, and anti-gliadin antibody. Guilt by association? J. Neurol. Neurosurg. Psychiatry, November 1, 2005; 76(11): 1601 - 1603. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Wullner, M. Reimold, M. Abele, K. Burk, M. Minnerop, B.-M. Dohmen, H.-J. Machulla, R. Bares, and T. Klockgether Dopamine Transporter Positron Emission Tomography in Spinocerebellar Ataxias Type 1, 2, 3, and 6 Arch Neurol, August 1, 2005; 62(8): 1280 - 1285. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M B Muzaimi, J Thomas, S Palmer-Smith, L Rosser, P S Harper, C M Wiles, D Ravine, and N P Robertson Population based study of late onset cerebellar ataxia in south east Wales J. Neurol. Neurosurg. Psychiatry, August 1, 2004; 75(8): 1129 - 1134. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. D.S.N.A. Pengiran Tengah, R. J. Lock, D. J. Unsworth, and A. J. Wills Multiple sclerosis and occult gluten sensitivity Neurology, June 22, 2004; 62(12): 2326 - 2327. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Samuel, N. Torun, P. J. Tuite, J. A. Sharpe, and A. E. Lang Progressive ataxia and palatal tremor (PAPT): Clinical and MRI assessment with review of palatal tremors Brain, June 1, 2004; 127(6): 1252 - 1268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Migliaccio, G. M. Halmagyi, L. A. McGarvie, and P. D. Cremer Cerebellar ataxia with bilateral vestibulopathy: description of a syndrome and its characteristic clinical sign Brain, February 1, 2004; 127(2): 280 - 293. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Y. Bang, K. Huh, P. H. Lee, and H. J. Kim Clinical and Neuroradiological Features of Patients With Spinocerebellar Ataxias From Korean Kindreds Arch Neurol, November 1, 2003; 60(11): 1566 - 1574. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Jasinska, G. Michlewski, M. de Mezer, K. Sobczak, P. Kozlowski, M. Napierala, and W. J. Krzyzosiak Structures of trinucleotide repeats in human transcripts and their functional implications Nucleic Acids Res., October 1, 2003; 31(19): 5463 - 5468. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Abele, L. Schols, S. Schwartz, and T. Klockgether Prevalence of antigliadin antibodies in ataxia patients Neurology, May 27, 2003; 60(10): 1674 - 1675. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hadjivassiliou, R. Grunewald, B. Sharrack, D. Sanders, A. Lobo, C. Williamson, N. Woodroofe, N. Wood, and A. Davies-Jones Gluten ataxia in perspective: epidemiology, genetic susceptibility and clinical characteristics Brain, March 1, 2003; 126(3): 685 - 691. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||