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Neurologic Findings in Machado-Joseph Disease
Relation With Disease Duration, Subtypes, and
(CAG)n
Laura B. Jardim, PhD;
Maria L. Pereira, PhD;
Isabel Silveira, PhD;
Anabela Ferro;
Jorge Sequeiros, PhD;
Roberto Giugliani, PhD
Arch Neurol. 2001;58:899-904.
ABSTRACT
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Context Machado-Joseph disease (MJD), an autosomal dominant spinocerebellar
degeneration caused by an expanded CAG repeat on chromosome 14q32.1, is a
heterogeneous disorder for clinical manifestations. The reasons for the wide
range of neurologic findings in this disease are poorly understood.
Objective To explain part of this heterogeneity through the association of the
neurologic findings with sex, disease duration, age of onset, clinical type,
and size of CAG repeat expansion.
Design A case-control study.
Setting Ambulatory care.
Patients A consecutive sample of 62 patients with MJD.
Main Outcome Measure Neurologic signs.
Results A direct relationship was found between the disease duration and severity
of gait and limb ataxia, dysarthria, dysphagia, fasciculations, pyramidal
syndrome, and ophthalmoplegia (P<.02). The most severe forms
of nuclear ophthalmoplegia were associated with type 1 MJD, whereas those
of supranuclear ophthalmoplegia were associated with type 3 MJD (P<.001).
It was also found that higher mean (CAG)n lengths were associated
with worse degrees of the pyramidal syndrome and dystonia (P<.001).
The presence and severity of nystagmus, eyelid retraction, rigidity and/or
bradykinesia, and optic atrophy were not clearly associated with any of the
predictive variables under study.
Conclusions Disease duration can explain part of the heterogeneity of ataxia, dysarthria,
dysphagia, fasciculations, pyramidal syndrome, and ophthalmoplegia, in MJD.
Type 1 MJD was positively associated with nuclear ophthalmoplegia; type 3
MJD was positively associated with supranuclear ophthalmoplegia. Higher mean
CAG lengths were found to correlate with the pyramidal syndrome and dystonia.
Nystagmus, eyelid retraction, rigidity and/or bradykinesia, and optic atrophy
were hardly attributable to any known reason or variable.
INTRODUCTION
MACHADO-JOSEPH disease (MJD) is a multisystem degeneration of the central
nervous system, inherited as an autosomal dominant disease, and first reported
in North American families of Portuguese-Azorean ancestry.1, 2, 3, 4
It is most often a highly incapacitating disease—typically, patients
will become confined to a wheelchair and will later be beddriden. Disease
manifestations usually start during adulthood, with a mean ± SD age
of onset of 32 ± 12 years among Brazilian patients (L.B.J., I.S., M.L.P.,
A.F., J.S., R.G. and I. Alonso, BSc, M. C. Moreira, MSc, P. Mendonça,
BSc, and F. Ferreirinha, BSc, unpublished data, 2000), or 37 ± 14 years
among the Portuguese and those of Portuguese-Azorean descent.5
The distribution of age of onset is wide, ranging from 5 to 73 years in Portuguese
patients.5 Penetrance is high but incomplete
since there were rare obligate carriers free of symptoms until as late as
the age of 90 years.6 The median survival time
after onset varies from 14 to 25 years.2, 7
The gene associated with MJD is located on chromosome 14q32.18 and contains a CAG repeat motif in the 5' region
of the coding sequence, which is expanded in patients with MJD.5
Normal alleles vary from 12 to 41 repeats, whereas expanded alleles vary between
66 and 84 repeats.9
The wide range of clinical manifestations include cerebellar ataxia,
affecting gait, limb movements, speech articulation and deglutition; a pyramidal
syndrome, with brisk deep tendon reflexes, Babinski sign, and spasticity;
a supranuclear, progressive external ophthalmoplegia, with early limitation
of upward gaze and convergence, and, less frequently, a nuclear ophthalmoplegia;
extrapyramidal signs, including dystonia, rigidity and/or bradykynesia; a
lower motor neuron disease, with fasciculations and amyotrophy; sensation
loss; eyelid retraction; contraction fasciculations; loss of weight; and a
sleep disorder.5
Three classic types were proposed4 and
are widely accepted: patients with type 1 MJD have an earlier onset and a
more severe course, showing severe dystonic and pyramidal signs, progressive
external ophthalmoplegia, and limb and gait ataxia. Patients with type 2 MJD
become sick around the general mean age of onset and have mostly cerebellar
and pyramidal deficits and progressive external ophthalmoplegia. Patients
with type 3 MJD have a less severe, later-onset disease, with peripheral signs
and gait and limb ataxia (with or without progressive external ophthalmoplegia)
with or without pyramidal syndrome. In addition to these well-known phenotypes,
other variants have been proposed.10, 11, 12, 13, 14
The wide variability in age of onset, the complex and heterogeneous neurologic
findings of MJD, as well as the existence of 3 major phenotypes, are evidence
that the disease, caused by a major single gene, is modulated by modifier
factors.
The first and better studied modifying factor was the (CAG)n
length itself. It was shown that the repeat length has a strong negative correlation
with the disease onset and some relationship to clinical subtype.15, 16
However, the variable neurologic picture could be, in some extent, related
to disease duration. It is plausible that some findings are present in one
patient and not in another, depending only on time of evolution.
The main purpose of this study was to help recognize which neurologic
findings are attributable to disease duration, sex, subphenotype, age of onset,
and CAG repeat length, and which are not attributable to any of the former,
keeping in mind that the latter could be seen as independent neurologic markers
of some, yet unknown, modifier factor.
SUBJECTS AND METHODS
SUBJECTS
Sixty-two patients with MJD were recruited among a large case-series
of patients with spinocerebellar ataxia, originating from Rio Grande do Sul,
the southernmost state of Brazil. All were confirmed by molecular analysis.
These patients belonged to 34 families: 31 of Portuguese ancestry, 2 of African
Brazilian ancestry, and 1 of German ancestry. Data, such as age at onset,
sex distribution, and disease duration, are summarized in Table 1 and have been extensively commented on elsewhere (L.B.J.,
I.S., M.L.P., A.F., J.S., R.G. and I. Alonso, BSc, M. C. Moreira, MSc, P.
Mendonça, BSc, and F. Ferreirinha, BSc, unpublished data, 2000).
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Table 1. Clinical Characteristics of 62 Subjects With Machado-Joseph
Disease (MJD)
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METHODS
All patients were interviewed and examined by the same physician (L.B.J.).
A standardized procedure included a thorough neurologic examination and determining
the age at onset, disease duration, first sign at onset. Onset was considered
as the time when the patient or a close relative was able to date the appearance
of the first symptoms.
Patients were classified among the 3 clinical subtypes, according to
neurologic findings, as previously described. The age of onset, however, was
not used as a criterion for their classification. Expansion of the MJD1 gene was analyzed according to conditions previously described.17
Study variables were analyzed according to the presence and degree of
several neurologic findings. To evaluate which neurologic findings would be
attributable to time of evolution, differences in disease duration were assessed
by analysis of variance (ANOVA) with test for linear trend. Since disease
duration could be debated for its subjective character, patients were also
divided according to their degree of incapacitation, using the degree of gait
ataxia: (1) subtle gait ataxia, observed only when walking on toes, heels,
or in tandem; (2) moderate ataxia, on spontaneous gait, with gait autonomy
still preserved; (3) walking with help, of another person or using a cane;
and (4) wheelchair bound, the total inability to walk. Differences between
the level of incapacitation and the degree of several neurologic findings
were assessed by linear-by-linear association. To evaluate which neurologic
findings (other than those used for their definition) could be attributable
to one of the classic phenotypes, differences among the 3 clinical subtypes
were assessed using the Fisher exact test. The association between the degree
of each clinical variable and age at onset was tested by ANOVA; the association
between the presence of a neurologic sign and sex was tested using the Fisher
exact test. Finally, the association between the degree of neurologic findings
and the CAG repeat length was measured by Mann-Whitney test (when comparing
2 groups) or by Kruskal-Wallis test (for multiple comparisons) since CAG length
distribution was not normal.
RESULTS
Gait ataxia was the initial sign in all patients. Table 2 gives further details about the neurologic signs found in
the entire sample. We have found 8 patients (13%) with type 1 MJD, 26 (42%)
with type 2 MJD, and 21 (34%) with type 3 MJD. Their ages at onset (Table 1) were compatible with data from
the literature.4, 5, 15, 16
We were unable to classify 7 patients (11%) because they presented concurrently
with severe extrapyramidal and peripheral findings, and for this reason they
were labeled "unclassified." Since these patients had the longest disease
duration, the difficulty in classifying them may simply reflect their advanced
stage in the disease (Table 1).
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Table 2. Neurologic Findings Among 62 Subjects With Machado-Joseph
Disease
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Neurologic signs were classified according to their degree of severity
or just according to their presence or absence (Table 3). Amyotrophy, in particular, was rarely seen (2 of 62 patients).
Indeed, well-delineated muscles were seen in 15 of the 62 patients, even though
several of them were already very incapacitated.
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Table 3. Degree of Severity of Each Neurologic Sign
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WHICH NEUROLOGIC FINDINGS PROGRESS WITH TIME?
Disease Duration
Gait ataxia, dysarthria, dysphagia, and fasciculations progressed with
time (P .02) (Table 4), whereas nystagmus, pyramidal signs, limb ataxia, ophthalmoplegia,
dystonia, rigidity and/or bradykinesia, eyelid retraction, and optic atrophy
did not (Table 4). Because fasciculations
are markers of type 3 MJD and because this subgroup of patients showed long
disease duration (Table 1), we
tested the association of disease duration with fasciculations within patients
with type 3 MJD only and found a positive result, confirming former findings
(P<.046, Table
4).
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Table 4. Associations Between Neurologic Signs and Disease Duration,
Disease Incapacitation (Gait Ataxia), Clinical Types, and CAG Length
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Degree of Incapacitation
We chose one neurologic variable, gait ataxia, as a marker of incapacitation
because disease duration being subjective information and biological time,
as aging, is not the same to everyone. Gait ataxia was the initial sign in
all patients, the main report in most, and showed a strong linear association
with duration of disease.
Limb ataxia, pyramidal syndrome, dysarthria, dysphagia, ophthalmoplegia,
and fasciculations all worsened at the same time as gait ataxia (or incapacitation)
progressed (Table 4). No linear
association was found between the degree of gait ataxia and nystagmus, eyelid
retraction, sensation loss, dystonia, rigidity and/or bradykinesia, or optic
atrophy (Table 4).
WHAT NEUROLOGIC FINDINGS ARE RELATED TO SEX?
Thirty patients were male and 32 were female. Nystagmus was present
in all of the women, while 5 of 30 men did not show it, a difference that
was statistically significant (P<.02, Fisher exact
test) (Table 4).
WHAT NEUROLOGIC FINDINGS ARE LINKED TO THE CLASSIC TYPES OF MJD?
When the severity of each neurologic finding (other than those used
for the definition of the clinical types) was analyzed among the 3 classic
types, no association was found in most cases (Table 4). The severity of ophthalmoplegia, however, showed some
association with phenotype (P<.001) (Table 4). Supranuclear ophthalmoplegia
(manifesting as a medial longitudinal fasciculus syndrome, or a limitation
in upward gaze and convergence [Table 3]) was more frequent among patients with type 3 MJD, while nuclear
ophthalmoplegia—mainly of the sixth nerve—was more common in patients
with type 1 MJD and in patients who were unclassified.
WHAT NEUROLOGIC FINDINGS DEPEND ON AGE AT ONSET?
If neurons would be prone to disease process in specific intervals along
a time line, then their signs of dysfunction would be linked to the age of
onset. In this possible cause-effect relationship, disease duration is a likely
confounder because, as the disease lasts longer, the more likely is the appearance
of certain signs. Only patients with disease duration up to 5 years (n = 18)
were used to test this hypothesis. Their mean age of onset was 27.3 years
(age range, 12-47 years); earlier than that found in the global sample. In
this subgroup, pyramidal signs, dysarthria, dystonic postures, and rigidity
and/or bradykinesia were associated with an early onset of the disease (P = .04, P = .01, P = .003, and P = .04, respectively).For example,
the 14 patients without rigidity and/or bradykinesia had a mean age of onset
of 30 years, whereas the 4 patients with these symptoms had a mean age of
onset of 17 years. These results are statistically significant, but should
be viewed with caution, owing to the small size of the sample.
WHAT NEUROLOGIC FINDINGS ARE ASSOCIATED WITH THE CAG REPEAT LENGTH?
The severity of neurologic signs was also tested for a possible association
with the CAG repeat length (Table 4).
A higher mean CAG length was then associated with a worse degree of the pyramidal
syndrome and dystonia (Table 5).
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Table 5. CAG Repeat Lengths in Pyramidal and Dystonic Findings
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COMMENT
Clinical heterogeneity is one of the most puzzling characteristics within
the spinocerebellar ataxias in general and in MJD in particular. The variable
expressivity in age at onset, the complex and heterogeneous neurologic findings,
as well as the existence of 3 subphenotypes, suggest the existence of some
modifier factors.
It is not very clear to what extent the heterogeneity of neurologic
signs is due to the natural history of the disease, or is due to other genetic
and environmental influences. Following the chronology of symptoms in a cohort
study would be the best way to find the answer. This kind of study has been
partially conducted18; however, owing to the
recent advances in the molecular knowledge of MJD, a more comprehensive study
is still missing. We tried to circumvent this difficulty by looking for association
between the severity of several findings and time of evolution of the disease,
using disease duration (chronological time) and degree of incapacitation (biological
time).
The disease progression, measured either by duration or by incapacitation,
seemed to be responsible for the worsening that occurred in gait and limb
ataxia, dysarthria, dysphagia, fasciculations, and pyramidal signs (Table 4). No association was found between
the duration of the disease process and nystagmus, eyelid retraction, dystonic
postures, rigidity and/or bradykinesia, and optic atrophy. Other reasons should
explain their presence. To look for these reasons, the severity of neurologic
signs was assessed according to MJD type, age of onset, sex, and CAG repeat
length.
The few patients with a short disease duration prevented our attempt
to relate the different neurologic signs to age of onset. Also, the small
numbers that link nystagmus with female sex demand some caution.
The CAG repeat length of the expanded allele also did not explain the
presence of nystagmus, eyelid retraction, rigidity and/or bradykinesia, and
optic atrophy. Therefore, the heterogeneity in these neurologic signs remained
unexplained.
The only association found between sign and clinical type was those
related to ophthalmoplegia. The supranuclear ophthalmoplegia was more severe
among patients with type 3 MJD, whereas nuclear ophthalmoplegia was more common
in patients with type 1 MJD and in those who were unclassified. Because type
1 MJD is the most severe form and patients who were unclassified were those
who have a longer duration of illness, nuclear ophthalmoplegia could be linked
with the severity of the general clinical picture. Nuclear ophthalmoplegia
was also associated with large CAG tracts. Since large CAG tracts are the
main determinants of type 1 MJD,15 this result
seems to confirm the former. Severity of gait and limb ataxia and dysarthria
seemed to be exclusively attributed to disease progression.
The pyramidal syndrome did not differ statistically among the 3 subtypes,
whereas we expected to find the more severe forms among patients with type
1 MJD.4, 5, 16 Because
we observed that its severity was associated with the CAG repeat length (Table 5), we can speculate that the former
lack of statistical significance could be due to a small sample of type 1
MJD cases.
The present findings related to disease duration almost reproduce those
described by Barbeau et al19 and by Coutinho,18 but the same cannot be said about the other results,
mostly because of differences in the way the neurologic examination was plotted
in the 3 studies. Barbeau et al found that "nystagmus, when present, does
not appear to be progressive."19(p522) Unfortunately,
they did not mention eyelid retraction, optic atrophy, and rigidity and/or
bradykinesia.19 Coutinho followed up 67 patients
for 3.5 years, on average, and found associations with disease duration that
were similar to our data, the exception being the pyramidal syndrome. She
also noted that eyelid retraction did not worsen with disease duration.18 Both previous studies were performed before the molecular
discoveries, so that these data were lacking.18, 19
A third study described the relationship of some variables of the natural
history of MJD.7 They found that the CAG repeat
length increased the rate of disease progression, whereas the age of onset
did not. Our results agreed with the latter findings, but not with the former
findings. Finally, although it had a design that was similar to ours, the
study of Klockgether et al20 evaluated only
the risk factors for peripheral neuropathy in MJD.
CONCLUSIONS
Heterogeneity of several neurologic findings seem to be partly explained
by duration of the disease, clinical type, and CAG repeat length. Nystagmus,
eyelid retraction, rigidity and/or bradykinesia, and optic atrophy, however,
were hardly attributable to any factor. We speculate that they could be seen
as independent neurologic markers of some unknown modifier factor.
AUTHOR INFORMATION
Accepted for publication November 28, 2000.
This work was partly supported by Fundação de Amparo à
Pesquisa do Rio Grande do Sul (FAPERGS), Porto Alegre, Brazil, Comissão
de Aperfeiçoamento de Pessoal do Ensino Superior (CAPES), Brasília,
Brazil, and Instituto de Cooperaçã Científica e Tecnológica
Internacional (ICCTI) Lisboa, Portugal.
We gratefully acknowledge the statistical review of Bernardo Lessa Horta,
MD, PhD, Escola de Medicina e de Psicologia, Universidade Católica
de Pelotas, Pelotas, Brazil.
From the Medical Genetics Service, Hospital de Clínicas de Porto
Alegre, Porto Alegre, Brazil (Drs Jardim, Pereira, and Giugliani); Departments
of Internal Medicine (Dr Jardim), Biochemistry (Dr Pereira), and Genetics
(Dr Giugliani), Universidade Federal do Rio Grande do Sul, Porto Alegre; and
UniGENe, Instituto de Biologia Molecular e Celular, ICBAS, Universidade do
Porto, Porto, Portugal (Drs Silveira, and Sequeiros and Ms Ferro).
Corresponding author: Laura B. Jardim, MD, Medical Genetics Service,
Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, 90035-003
Porto Alegre, Brazil (e-mail: laurajardim{at}terra.com.br).
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