Machado-Joseph Disease: From first descriptions to new perspectives

Abstract

Machado-Joseph Disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), represents the most common form of SCA worldwide. MJD is an autosomal dominant neurodegenerative disorder of late onset, involving predominantly the cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems; although sharing features with other SCAs, the identification of minor, but more specific signs, facilitates its differential diagnosis. MJD presents strong phenotypic heterogeneity, which has justified the classification of patients into three main clinical types. Main pathological lesions are observed in the spinocerebellar system, as well as in the cerebellar dentate nucleus. MJD's causative mutation consists in an expansion of an unstable CAG tract in exon 10 of the ATXN3 gene, located at 14q32.1. Haplotype-based studies have suggested that two main founder mutations may explain the present global distribution of the disease; the ancestral haplotype is of Asian origin, and has an estimated age of around 5,800 years, while the second mutational event has occurred about 1,400 years ago. The ATXN3 gene encodes for ataxin-3, which is ubiquitously expressed in neuronal and non-neuronal tissues, and, among other functions, is thought to participate in cellular protein quality control pathways. Mutated ATXN3 alleles consensually present about 61 to 87 CAG repeats, resulting in an expanded polyglutamine tract in ataxin-3. This altered protein gains a neurotoxic function, through yet unclear mechanisms. Clinical variability of MJD is only partially explained by the size of the CAG tract, which leaves a residual variance that should be explained by still unknown additional factors. Several genetic tests are available for MJD, and Genetic Counseling Programs have been created to better assist the affected families, namely on what concerns the possibility of pre-symptomatic testing. The main goal of this review was to bring together updated knowledge on MJD, covering several aspects from its initial descriptions and clinical presentation, through the discovery of the causative mutation, its origin and dispersion, as well as molecular genetics aspects considered essential for a better understanding of its neuropathology. Issues related with molecular testing and Genetic Counseling, as well as recent progresses and perspectives on genetic therapy, are also addressed.

Full text

REVIEW Open Access
Machado-Joseph Disease: from first descriptions
to new perspectives
Conceição Bettencourt
1,2,3*
and Manuela Lima
1,2
Abstract
Machado-Joseph Disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), represents the most common
form of SCA worldwide. MJD is an autosomal dominant neurodegenerative disorder of late onset, involving
predominantly the cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems; although sharing
features with other SCAs, the identification of minor, but more specific signs, facilitates its differential diagnosis.
MJD presents strong phenotypic heterogeneity, which has justified the classification of patients into three main
clinical types. Main pathological lesions are observed in the spinocerebellar system, as well as in the cerebellar
dentate nucleus. MJD’s causative mutation consists in an expansion of an unstable CAG tract in exon 10 of the
ATXN3 gene, located at 14q32.1. Haplotype-based studies have suggested that two main founder mutations may
explain the present global distribution of the disease; the ancestral haplotype is of Asian origin, and has an
estimated age of around 5,800 years, while the second mutational event has occurred about 1,400 years ago. The
ATXN3 gene encodes for ataxin-3, which is ubiquitously expressed in neuronal and non-neuronal tissues, and,
among other functions, is thought to participate in cellular protein quality control pathways. Mutated ATXN3 alleles
consensually present about 61 to 87 CAG repeats, resulting in an expanded polyglutamine tract in ataxin-3. This
altered protein gains a neurotoxic function, through yet unclear mechanisms. Clinical variability of MJD is only
partially explained by the size of the CAG tract, which leaves a residual variance that should be explained by still
unknown additional factors. Several genetic tests are available for MJD, and Genetic Counseling Programs have
been created to better assist the affected families, namely on what concerns the possibility of pre-symptomatic
testing. The main goal of this review was to bring together updated knowledge on MJD, covering several aspects
from its initial descriptions and clinical presentation, through the discovery of the causative mutation, its origin and
dispersion, as well as molecular genetics aspects considered essential for a better understanding of its
neuropathology. Issues related with molecular testing and Genetic Counseling, as well as recent progresses and
perspectives on genetic therapy, are also addressed.
Keywords: Ataxin-3, ATXN3 gene, CAG repeats, Polyglutamine disorders, SCA3
Introduction
Spinocerebellar ataxias (SCAs) are autosomal dominant
inherited ataxias, which constitute a heterogeneous
group of typically late-onset, progressive, and often fatal
neurodegenerative disorders, characterized by progressive
cerebellar dysfunction, variably associated with other
symptoms of the central and peripheral nervous systems
[1-3]. Nearly 30 subtypes of SCAs have been described,
and based on the nature of the underlying causative
mutations, these subtypes can be divided into three
major categories: 1) “polyglutamine”ataxias, caused by
CAG repeat expansions that encode a pure repeat of the
amino acid glutamine in the corresponding protein; 2)
non-coding repeat ataxias, caused by repeat expansions
falling outside of the protein-coding region of the respec-
tive disease genes; and 3) ataxias caused by conventional
mutations in specific genes (deletion, missense, nonsense,
and splice site mutations) [1]. The focus of this review,
Machado-Joseph disease (MJD; MIM #109150) [4], also
known as spinocerebellar ataxia type 3 (SCA3) [5],
belongs to the first of the above cited categories [6].
Several alternative designations have been given to this
* Correspondence: mcbettencourt@uac.pt
1
Center of Research in Natural Resources (CIRN) and Department of Biology,
University of the Azores, Ponta Delgada, Portugal
Full list of author information is available at the end of the article
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Commons Attri bution License (http://creativecommons.org /licenses/by/2.0), which permits unrestricte d use, distribution, and
reproductio n in any medium, provided the original work is properly cited.

disorder, namely “Machado disease”[7], “nigro-spino-
dentatal degeneration with nuclear ophthalmoplegia”[8],
“autosomal dominant striatonigral degeneration”[9] and
“Azorean disease of the nervous system”[10]. Presently,
the most widely used designations are MJD and SCA3.
Epidemiology
Globally, SCAs are considered rare disorders, with preva-
lence estimates varying from 0.3 to 2.0 per 100,000 [11].
MJD is presently considered the most common form of
SCA worldwide [12]. The availability of a molecular test
has allowed a thorough identification of cases, changing
the initial geographic distribution pattern of MJD, initi-
ally thought to be related with the Portuguese discoveries
and currently known to be present in many ethnic back-
grounds [12], with strong geographic variation.
Among SCAs, the relative frequency of MJD is higher
in countries such as Brazil (69-92%) [13,14], Portugal
(58-74%) [15,16], Singapore (53%) [17], China (48-49%)
[18,19], the Netherlands (44%) [11], Germany (42%) [20],
and Japan (28-63%) [21,22]. It is relatively less frequent
in Canada (24%) [23], United States (21%) [24], Mexico
(12%) [25], Australia (12%) [26], and India (5-14%)
[27,28], and it is considered as relatively rare in South
Africa (4%) [29] and Italy (1%) [30].
Even within each country the geographic distribution
pattern of MJD is not homogeneous. Although constituting
the most prevalent subtype of SCA, in Portugal, for exam-
ple, MJD is relatively rare in the mainland (1/100,000) [31],
with few exceptions such as a small area of the Tagus River
Valley (1/1,000) [32], but highly prevalent in the Azores
Islands, where the highest worldwide prevalence occurs in
Flores Island (1/239) [33].
Clinical Presentation
MJD is a multisystem neurodegenerative disorder invol-
ving predominantly the cerebellar, pyramidal, extrapyrami-
dal, motor neuron and oculomotor systems. A clinical
diagnosis is suggested in individuals with progressive cere-
bellar ataxia and pyramidal signs, associated with a com-
plex clinical picture extending from extrapyramidal signs
to peripheral amyotrophy [34]. Minor, but more specific,
features such as external progressive ophthalmoplegia
(EPO), dystonia, intention fasciculation-like movements of
facial and lingual muscles, as well as bulging eyes, may
also be of major importance for the clinical diagnosis of
MJD [34]. The mean age at onset is around 40 years, with
extremes of 4 [35] and 70 years [31], and a mean survival
time of 21 years (ranging from 7 to 29 years) [31,36]. Gait
ataxia and diplopia are reported as first symptoms in
92.4% and 7.6% of cases, respectively [31].
MJD is characterized by a high degree of pleomorph-
ism, not only in the variability in the age at onset, but
also in the neurological signs presented by different
patients as well as in the resulting degree of incapacity.
The striking clinical heterogeneity characteristic of this
disease is demonstrated by the history of its initial
description. In fact, the observation of three families of
Azorean ancestry (Machado, Thomas and Joseph), living
in the United States of America, by three distinct groups
of researchers, led to the initial description, during the
1970s, of three apparently independent diseases [7-9].
The subsequent identification of several Portuguese
families living both in the Azores Islands and in the
mainland of Portugal, within some of which were patients
covering the three forms described, led to the unification
of the disease. MJD was afterward considered as a single
genetic entity, with variable phenotypic expression [4].
The marked clinical heterogeneity and the progressive
nature of MJD rendered its clinical classification difficult.
Coutinho and Andrade [4] systematized the disease phe-
notypes into three main clinical types. They observed
that almost every patient presents with cerebellar signs
and EPO, associated with pyramidal signs in variable
degrees. Clinical types could, therefore, be distinguished
on the basis of the presence/absence of important extra-
pyramidal signs, and the presence/absence of peripheral
signs. Type 1 ("type Joseph”) is characterized by an early
onset (mean of 24.3 years) and a rapid progression of
symptoms, which together with cerebellar ataxia and
EPO include marked pyramidal and extrapyramidal signs
(such as dystonia). Type 2 ("type Thomas”) corresponds
to presentations with an intermediate onset (mean of
40.5 years), cerebellar ataxia and EPO, with or without
pyramidal sings. When present, the extrapyramidal and
peripheral signs are tenuous. Patients with type 2 features
may maintain these for long periods or evolve (5 to 10
years later) to type 1 or type 3, by the manifestation of
important extrapyramidal or peripheral signs, respec-
tively. Type 3 ("type Machado”) presents a later onset
(mean of 46.8 years) and is characterized by cerebellar
ataxia and EPO, associated with peripheral alterations,
with or without slight pyramidal and extrapyramidal
signs [31]. As previously mentioned, these three clinical
types can occasionally be present in the same family.
Additionally, some authors consider as type 4 a rare pre-
sentation with parkinsonian features, with mild cerebellar
deficits and a distal motor sensory neuropathy or amyo-
trophy [37]. Furthermore, Sakai and Kawakami [38]
observed two siblings that presented spastic paraplegia
without cerebellar ataxia and proposed the existence of a
fifth type for MJD.
Pathological studies reveal, in most cases, that the brain
weight of MJD patients is considerably reduced, in com-
parison to individuals without medical history of neuro-
logical or psychiatric diseases [39-42]. Furthermore,
depigmentation of the substantia nigra, and atrophy of
the cerebellum, pons, and medulla oblongata, as well as
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of the cranial nerves III to XII, has been consistently
observed in MJD brains [40,43-45]. Neuropathological
studies typically reveal neuronal loss in the cerebellar
dentate nucleus, pons, substantia nigra, thalamus, globus
pallidus, anterior horn cells and Clarke’scolumninthe
spinal cord, vestibular nucleus, many cranial motor
nuclei, and other brainstem nuclei [39-41,46-55]. Such
studies indicate that central nervous white matter lesions
are confined to the medial lemniscus, spinocerebellar
tracts and dorsal columns [39,40,45,51-55]. Although the
inferior olive, as well as the cerebellar cortical neurons,
were thought to be typically spared [31,41,56], conflicting
results have been reported [39,40,51-53,55].
Magnetic resonance imaging (MRI) has been consid-
ered a useful tool in the study and in the diagnostic pro-
cess of MJD [42,57-61]. Volumetric analyses performed
on MRI of MJD patients have previously demonstrated
atrophy of the cerebellum, brainstem, caudate nuclei,
and putamen [62]. MR spectroscopy studies have also
shown abnormalities in apparently normal deep white
matter [63]. A recent study [61], using MRI-Texture
analysis, showed significant differences among images
texture of the caudate nucleus, thalamus, and putamen
between patients and a control group, showing that this
could constitute a promising tool for the detection and
quantification of cerebral tissue areas affected in MJD.
Molecular Genetics And Pathogenesis
The disease locus was first mapped to the long arm of
chromosome 14 (14q24.3-q32) by Takiyama et al.in
1993 [64]. In 1994, Kawaguchi et al. [65] showed that an
expansion of a CAG repeat motif at the MJD1 gene,
mapped to 14q32.1, was present in all affected individuals
of a pathologically confirmed MJD family. The genomic
structure of the MJD gene was published seven years
later [66]. The gene was found to span about 48 kb and
was described as containing 11 exons, with the (CAG)
n
tract located at the exon 10 (Figure 1). Two additional
exons, 6a and 9a, were recently described (Figure 1) [67].
Currently, the official name of the gene is ATXN3,but
other aliases, such as MJD and MJD1, are still in use.
Consensually, wild-type alleles range from 12 to 44 CAG
repeats, whereas well established limits of expanded alleles
comprise from 61 to 87 repeat units [32]. Intermediate size
alleles are rare, but there are a few reports of disease asso-
ciated alleles containing 56, 55, 54, 53, 51, and 45 CAG
repeats [68-73]. On the other hand, an allele with 51
repeats was described, in a Portuguese family, apparently
not associated with the disease [32]. Thus, there is the pos-
sibility that low penetrance alleles, of intermediate size,
which are relatively frequent in other polyglutamine disor-
ders, namely in Huntington’s disease (HD) [74], may also
occur in MJD.
The ATXN3 gene encodes for a protein named ataxin-3,
which was originally reported to be composed of 339
amino acid residues plus a variable number of glutamine
repeats, with an estimated molecular weight of 40-43 kDa
for normal individuals [65]. Northern blot analysis showed
that the ATXN3 mRNA is ubiquitously transcribed in neu-
ronal and non-neuronal human tissues [66]. Moreover,
such ubiquitous expression was also demonstrated, by
immunohistochemical studies, at the protein level, which
is expressed not only in the brain but also throughout the
body, existing both in the cytoplasm and the nucleus of
various cell types. However, in neurons, ataxin-3 is predo-
minantly a cytoplasmic protein [50]. Given its ubiquitous
pattern, cellular expression of the disease gene is not itself
sufficient to explain selective neuronal degeneration, sug-
gesting that other cell-specific factors are involved in the
restricted neuropathology observed in MJD [50].
At least four different species of ATXN3 transcripts
with different sizes, estimated in approximately 1.4, 1.8,
4.5, and 7.5 kb, were reported by Northern blot analysis
[66]. These different mRNA species are thought to
result from differential splicing of, at least, exons 10 and
11 of ATXN3 gene, and alternative polyadenylation of
exon 11. From sequence analysis of cDNA clones, Ichi-
kawa et al. [66] reported the existence of a minimum of
five MJD gene products (MJD1a; pMJD1-1; pMJD2-1;
pMJD5-1; H2). The MJD1a was first described by Kawa-
guchi et al. [65]. Three additional transcripts (pMJD1-1;
pMJD2-1; pMJD5-1) that differ from the MJD1a, mainly
at the C-terminal, were then reported by Goto et al.
[75]. Finally, Ichikawa et al. [66] described the variant
H2 as having an amino acid sequence identical to the
one of pMJD1-1, except for a gap of 55 amino acids,
which results from the skipping of exon 2 by alternative
splicing. Additional ATXN3 splicing variants have been
deposited in databases, such as ASPicDB [76]. Recently,
a large number of alternative splicing variants (n = 56)
generated by four types of splicing events (exon skip-
ping, new exons, usage of alternative 5’or 3’splice
sites),occurringinasimpleorcombinedway,were
described for the ATXN3 gene [67]. Fifty of those had
not been previously described (either in the literature or
in databases), and are thought to constitute new alterna-
tive splicing variants for this gene. This suggests that
alternative splicing may be an important mechanism
regulating ataxin-3 diversity, and clearly indicates that
there are mechanisms generating variability, beyond
genomic DNA.
Ataxin-3 belongs to the family of cysteine proteases.
Structurally, it is composed of a globular N-terminal Jose-
phin domain (amino acid residues 1-182 in the human
protein) [77] with a papain-like fold, combined with a
more flexible C-terminal tail that contains 2 or 3 ubiquitin
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interaction motifs (UIMs) and the polymorphic polygluta-
mine tract (polyQ tract) [78]. The Josephin domain (JD)
contains highly conserved amino acids, reminiscent of the
catalytic residues of a deubiquitinating cysteine protease.
The catalytic pocket consists of a glutamine (Q9) and a
cysteine (C14) residue located in the N-terminal part of
JD, and of a histidine (H119) and an asparagine (N134) in
the JD C-terminal part. The cysteine, the histidine, and the
asparagine constitute the catalytic triad characteristic of
cysteine proteases [79]. Although the physiologic role of
ataxin-3 is still unclear, it has been proposed that the wild-
type form acts as a deubiquitinating enzyme (DUB) in the
ubiquitin-proteasome pathway [80,81]. Moreover, it has
been established that ataxin-3 can be directly activated by
ubiquitination [82]. Additionally, ataxin-3 has been
described having a deneddylase activity [83]. Its involve-
ment in transcriptional regulation has also been proposed
[80,84]. Furthermore, the participation of ataxin-3 in the
regulation of aggresome formation, as well as in the degra-
dation of proteins sent from the endoplasmic reticulum
has been described [85]. Taken together with its enzymatic
properties, these facts suggest that ataxin-3 normally parti-
cipates in protein quality control pathways in the cell
[46,82]. Recently, it has been suggested that this protein
may also be important for a correct cytoskeletal organiza-
tion [86], as well as for muscle differentiation through the
regulation of the integrin signaling transduction pathway
[87]. In its mutated form, when the polyQ tract reaches
the pathological threshold (about 50 glutamine residues),
the protein is thought to gain a neurotoxic function that,
as a consequence, leads to selective neuronal cell death
through a not fully understood process [50,88].
From the recently described ATXN3 alternative splicing
variants, 20 are thought to encode distinct ataxin-3 iso-
forms. Although by the analysis of their domain composi-
tion, it can be predicted that some may play a protective
role while others may lead to increased toxicity [67],
their effective role is still unknown. It also remains unex-
plored if differential expression of the distinct ataxin-3
isoforms could be involved in the specificity of neuronal
vulnerability. Nevertheless, it has been observed that the
subcellular distribution of ataxin-3 (independently of its
isoform) differs in diseased brain versus normal brain.
While normally it is a predominantly cytoplasmic protein
in neurons (as mentioned earlier), ataxin-3 becomes con-
centrated in the nucleus of neurons during disease.
Moreover, in many brain regions, ataxin-3 forms intra-
nuclear inclusions [89]. These neuronal inclusions, which
are also found in other polyglutamine disorders, are
heavily ubiquitinated and contain certain heat shock
molecular chaperones and proteasomal subunits, suggest-
ing that they are repositories for aberrantly folded, aggre-
gated proteins [90]. The presence of ubiquitinated
neuronal intranuclear inclusions (NIIs) has thus been
recognized as a neuropathologic hallmark of these dis-
eases, although the significance of NIIs in the pathogen-
esis remains a matter of controversy [45]. Relatively
recent neuropathologic studies [91,92] suggest that inclu-
sions are not directly pathogenic structures and may
rather be the byproduct of neuronal efforts to wall off
abnormal proteins in a nontoxic manner.
Origins And Mechanisms Of Mutation
Two large studies focus the worldwide origin of the MJD
mutation [93,94]. Gaspar et al. [93], by haplotype ana-
lyses of three intragenic SNPs (A
669
TG/G
669
TG,
C
987
GG/G
987
GG, and TAA
1118
/TAC
1118
), found that two
(ACA and GGC), out of the four observed MJD haplo-
types, were present in 94% of the MJD families. For the
families of Azorean extraction, these two main haplo-
types were found, presenting a distribution specific to the
island of origin: ACA was observed in the families from
Figure 1 Schematic representation of the ATXN3 gene structure. Exons are numbered from 1 to 11 and are presented as boxes. Filled blue
boxes indicate the coding regions, hatched horizontal boxes represent the 5’-untranslated region (UTR), and hatched diagonal boxes correspond
to the 3’-UTR. The location of the polymorphic (CAG)
n
tract is indicated. Polyadenylation consensus sequences are marked from A1 to A8.
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Flores Island, while GGC was found in the families from
São Miguel Island. These results indicated that two dis-
tinct mutational events accounted for the presence of
MJD in the Azorean Islands and in families of Azorean
extraction, a fact previously evidenced by studies based
on the genealogical reconstruction of affected families
[95,96]. In Portugal mainland, both haplotypes were also
found. Worldwide, 72% of the families share the ACA,
further supporting the idea of few mutational events.
Based on haplotype analyses, it has been suggested that
two main founder mutations may explain the present
global geographic distribution of MJD [93,94]. In opposi-
tion to the Portuguese/Azorean origin that was proposed
at the time of the initial descriptions of the disease, an
Asian origin was recently suggested by Martins et al.
[94]. Their work, which aimed to determine the origins,
age, and spread of the two main mutational events,
through more extensive haplotype analyses, revealed that
the worldwide spread lineage TTACAC reaches its high-
est diversity in Asia (Japanese population). An ancestral
STR-based haplotype was identifiedinthatpopulation,
and a postneolithic mutation with about 5,774 ± 1,116
years old was suggested. More recent introductions of
this lineage are reported for North America, Germany,
France, Portugal, and Brazil. A second mutational event,
in the GTGGCA lineage, is thought to be more recent
(about 1,416 ± 434 years old). The matter of its origin is
more controversial, but its dispersion may be mainly
explained by recent Portuguese emigration [94].
The existence of repeat instability has been reported for
mutated MJD alleles, similarly to what has been described
for the group of “polyglutamine”disorders or for the even
larger group of triplet repeat disorders, in which MJD is
included [97]. However, the underlying mutational process
that allows for alleles in the normal range to, ultimately,
expand to pathological size is not clearly understood. Lima
et al. [98], on a study of nearly 2,000 chromosomes of the
Portuguese population, found an allelic distribution biased
towards the smaller alleles, not supporting, therefore, the
idea that the larger alleles could constitute a reservoir
from where expanded alleles could be continuously gener-
ated. Analysis of the distribution of the CAG repeat length
frequency within the four most frequent wild-type lineages
(defined by intragenic polymorphisms) supports the exis-
tence of a multistep mutation mechanism on the basis of
the evolution of ATXN3 alleles, either by gene conversion
or DNA slippage [99].
Inheritance And Genotype-Phenotype
Correlations
MJD displays an autosomal dominant pattern. Therefore,
each sibling of an affected individual, or an asymptomatic
carrier, has an a priori risk of 50% of being itself a carrier,
with both genders having equal probabilities of receiving/
transmitting the mutated allele and expressing the dis-
ease. Very few cases (2%) of non-penetrance are known
[100], and therefore, in the context of genetic counseling
(GC), MJD is considered fully penetrant. However, given
the fact that MJD penetrance displays an age-dependent
pattern (table 1), the probability of being a mutation car-
rier, and consequently the a posteriori risk, diminishes
with age in asymptomatic individuals, reaching approxi-
mately zero at the age of 70 years [33].
An inverse correlation is found between the size of the
CAG repeat tract at the expanded alleles (and conse-
quently the size of the polyQ tract) and the age at onset
of the disease. Depending on the series of patients in
study, it accounts from 50% to nearly 75% of variation in
the age of appearance of the first symptoms [101,102]. A
similar inverse correlation has also been described at the
mRNA level [103]. Furthermore, the size of the expanded
alleles has also been associated with the frequency of
other clinical features, such as pseudoexophthalmos and
pyramidal signs, which are more frequent in subjects
with larger repeats [104]. Moreover, a gene dosage effect
seems to be present in MJD, since homozygosity aggra-
vates the clinical phenotype, with a more severe progres-
sion and an early age at onset in subjects carrying the
expanded allele in both chromosomes [35,105,106].
Anticipation has been reported for MJD and other triplet
repeat (TR) diseases [97,107]. Such phenomenon impli-
cates more severe phenotypes and/or earlier ages at onset
in successive generations. This can be explained by the
dynamic process of mutation underlying TR diseases,
which involves intergenerational instability. Normal
alleles are usually transmitted to the offspring without
modifications [108], while most expanded alleles are
unstable upon transmission due to germinal instability,
especially in male meiosis [109]. The observed tendency
of expanded alleles to further increase the size of its
repeat tract, in successive generations, is thought to be
the genetic cause of anticipation [97].
Besides the (CAG)
n
tract size, familial factors that may
increase the explanation of the onset variance have been
described [31,110,111]. Although the influence of environ-
mental factors cannot be excluded, the fact that variability
within families is lower than the one observed between
families supports the contribution of other genetic factors,
namely modifier genes, to the remaining phenotypic var-
iance. Modifier genes of the MJD phenotype have been, so
far, searched using a candidate-gene approach. Jardim
et al. [112] analyzed the polymorphic CAG repeats in
other repeat loci (SCA2, SCA6 and DRPLA), and con-
cluded that the CAG repeat length of the larger SCA2
allele (22-23 CAG repeats) is associated with the severity
of fasciculations. No associations were found with the
remaining phenotypic features, namely age of onset, antici-
pation, and clinical types. An exhaustive search for MJD
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modifier genes remains difficult to perform, among other
aspects, because of constrains in sample size.
Genetic Testing And Counseling
In the early stages of the disease, when minor but specific
signs are missing, when the disease seems sporadic, when
it is present in patients belonging to small family units, or
when the ethnic or geographic background of the patient
is thought to be unusual for this disease, a clinical diagno-
sis of MJD may not be simple to establish. The identifica-
tion of MJD’s causative gene allowed the direct detection
of the mutation, thus enabling the molecular diagnosis of
the disease [101]. Furthermore, it allowed worldwide
molecular studies about MJD, leading, as previously
referred, to a distribution of cases that was clearly different
from the initial scenario, obtained exclusively by clinical
criteria [113]. Predictive Testing (PT) also became possible
for at-risk family members, providing an accurate confir-
mation of the carrier/non-carrier status in asymptomatic
individuals. Targeted mutation analysis of the ATXN3
gene is also used for the Prenatal Diagnosis (PND) of this
disease [114]. However, since a positive result for the MJD
mutation raises issues concerning the termination of the
pregnancy, several psychological and ethic questions
emerge. An alternative for PND, the Preimplantation
Genetic Diagnosis (PGD) is also presently available [115].
Levels of adherence to these genetic tests remain to be
determined at a large scale. In the Azores Islands, partici-
pation in PT was estimated as being around 21%. If, how-
ever, only the small Azorean island of Flores is considered,
the adherence levels reach nearly 36% [116]. In another
small community, the rural region of the Tagus Valley
(Portugal mainland), adherence levels to PT program were
also high (over 80%) [117]. These high adherence levels in
small, isolated communities raise interesting issues, since
in such populations genetic diseases can represent a
source of stigmatization to the affected families [116].
Therefore, a careful intervention regarding genetic tests,
adapted to each specific context, is mandatory.
There is a current lack of effective therapeutics for
MJD (see “Patients Management”). Therefore, it is crucial
to provide adequate GC to patients and their families,
providing information concerning the nature of the dis-
ease, the current lack of disease treatment, the risk for
other family members as well as the availability of mole-
cular tests, previously mentioned. PT, PND and PGD are
offered within the frame of a GC Program. As an exam-
ple, the Portuguese GC Program, which was based mainly
on the experience with HD, aims to provide to at-risk
adults the access to the genetic information that can
reduce the uncertainty about their genetic status.
Another of its goals is to provide the necessary psycholo-
gical support to allow the proper adaptation to the test
results [118]. Candidates for the MJD PT Program have
beendefinedasthose:a)at50%riskandwishingto
receive genetic information; b) over 18 years old and cap-
able of providing informed consent; c) with a molecularly
confirmed familial history of MJD; and d) asymptomatic
for the disease [118].
Teams offering GC to MJD families must provide ade-
quate and comprehensible information concerning the
genetics of MJD to the affected families. A study with
Azorean MJD families, conducted prior to the application
of the PT in this population [119] showed that a large
percentage of individuals were unable to comprehend the
notion of “pre-symptomatic carrier”and, therefore, could
not quantify the objective risk of inheriting/transmitting
the disease.
Analysis of the motives for undertaking the PT and of the
impact of the test on the psychological well-being of those
tested is of major importance for the design of effective GC
programs. Leite et al. [120] developed a Psychological Gen-
eral Well-Being Schedule, to evaluate psychological well-
being in persons coming for MJD pre-symptomatic testing
in comparison with normal population. These authors
observed that, contrarily to what was expected, individuals
at-risk presented higher psychological well-being indicators
than the control group. Two possible explanations were
suggested by Leite et al.[120] to justify such results: a) the
group of individuals at-risk has a defensive and denial atti-
tude, and/or b) the group of individuals at-risk is psycholo-
gically more resilient, which may have motivated their
Table 1 Age-dependent risk for asymptomatic individuals with an MJD a priori risk of 50% (data from Bettencourt
et al. [33])
Age in years Probability of detectable gene expression Probability of heterozygous if unaffected
10 0.02 0.50
20 0.03 0.49
30 0.22 0.44
40 0.53 0.32
50 0.80 0.17
60 0.96 0.04
70 1.00 ~0
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adhesion to pre-symptomatic testing, through their own
self-selection. Gonzalez et al. [116], in a short-term study of
the impact of PT in the Azores, found no differences in the
mean scores of depression or anxiety before and one year
after the PT. These authors concluded that the disclosure
of the genetic status did not decrease the psychological
well-being of the individuals that undertook testing.
Accordingly, the study by Rolin et al.[121],whichcom-
pared data obtained before and 3 to 6 months after the dis-
closure of genetic testing results, showed no significant
changes in well-being and specific distress of PT applicants,
both in the individuals identified as carriers and non-car-
riers. A similar result to what was observed in another
study in Japan [122]. Furthermore, it has been shown that
the anxiety levels are reduced in those who received a non-
carrier result [122,123].
With the advent of pre-symptomatic testing, several
laboratory difficulties emerged, and improvements in the
diagnosis of MJD had to be made. The first problem
was the occurrence of intermediate size alleles, for
whichitisstillnotpossibletodeterminewhetherthey
are associated with a phenotype or not [32]. To mini-
mize this constrain, clinical and molecular analysis,
including the determination of CAG repeat length and
the establishment of intragenic haplotypes, of large pedi-
grees of the affected families, is essential. Furthermore,
the study of the healthy population, from the same
region, to assess the distribution of the normal (CAG)
n
length in that specific population, may also be important
[98]. The second problem relied on the presence of
homoallelism, i.e., homozygosity for two normal alleles
with exactly the same (CAG)
n
length (about 10% of all
test results). This was solved by studying intragenic
polymorphisms, which allowed the distinction of the
two normal chromosomes. Furthermore, using a new
Southern blot based method, the possibility of existence
of an expanded allele in the presumed homoallelic indi-
viduals can also be excluded [32]. There are limitations
in sizing precision of the CAG repeats due to the exis-
tence of somatic mosaicism [124], which originates dif-
ferences in (CAG)
n
length among subpopulations of
lymphocytes as well as between lymphocytes (where
length is usually measured) and central nervous system
cells. However, for molecular diagnosis purposes, an
error of ±1 CAG repeat is considered as acceptable [32].
Patients Management And New Perspectives In
Treatment
On what concerns disease treatment, effective pharmaco-
logic approaches for the MJD treatment as well as for
other SCAs are still lacking or inadequate. Symptomatic
pharmacologic therapeutics are used to alleviate some of
the clinical signs, namely spasticity [125,126], parkinson-
ism [127,128], dystonia [129,130], and muscle cramps
[131]. Several clinical trials have also been carried out.
The initial double-blind, placebo-controlled, clinical trials
were performed with sulfamethoxazole and trimetho-
prim, in a small number of MJD patients [126,132-134].
From those studies, encouraging results were obtained in
terms of lessened spasticity, improvements in walker-
assisted gait [132], improvements in contrast sensitivity
[133], mild improvements of hyperreflexia of knee jerks
and of rigospasticity of the legs [134], beneficial effects
on gait and coordination [126]. However, in a larger
study, also double-blind and placebo-controlled, tri-
methoprim-sulfamethoxazole therapy showed no signifi-
cant effects [135]. The treatment of MJD patients with
fluoxetine, failed to improve motor abilities [136]. On the
other hand, the use of taltirelin hydrate, was shown to be
effective on the ataxic speech of patients with MJD [137].
The treatment with tandospirone pointed for a reduction
of ataxia and of depression levels, alleviation of insomnia
and leg pain, suggesting that this is a useful drug for
these symptoms in patients with MJD [138]. Another
trial [139] involved the clinical response of lamotrigine
(LTG) on MJD patients with early truncal ataxia and the
effect of LTG on the alteration of ataxin-3 expression in
the transformed MJD lymphoblastoid cells. Results from
this trial indicated that LTG may have significant benefits
in relief of gait disturbance in MJD patients with early
ataxia, which may be related to the decreased expression
of mutant ataxin-3. Notwithstanding some promising
results, all these trials were carried out in a small number
of patients (1 to 22 patients) and over short periods of
time. Studies with a length, design and sample size to
provide adequate power to detect meaningful effects
should be carefully planned on the basis of underlying
basic science before undergoing trials [140].
In addition to pharmacological approaches, phy-
siotherapy may help the patients to cope with the dis-
ability associated with gait problems [141]. Physical aids,
such as walkers and wheelchairs, can assist the patients
in their everyday activities. Moreover, regular speech
therapy evaluation for dysarthria and dysphagia as well
as occupational therapy may also help patients [141].
Recent advances have been made in the field of genetic
therapy. The use of small interfering RNA (siRNA) has
been taken as a promising approach for treating autoso-
mal dominant disorders. Although the mouse [142] and
Caenorhabditis elegans [143] knockout models for
ataxin-3 were viable and displayed no overt phenotype,
suggesting that ataxin-3 is a non-essential protein, in
both cases its importance as a DUB enzyme was con-
firmed. Nevertheless, there is no correspondent model in
humans at our days that could support the hypothesis of
ataxin-3 as a non-essential protein. Therefore, discrimi-
nation between wild-type and mutant transcripts should
be an important point to be addressed in therapeutics
Bettencourt and Lima Orphanet Journal of Rare Diseases 2011, 6:35
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development, in order to preserve wild-type ataxin-3
expression and function. Strategies based on the presence
of a single nucleotide polymorphism (SNP) have been
proposed to ensure discrimination between wild-type
and mutant transcripts [144]. After the understanding of
the worldwide distribution of the MJD haplotypes
[93,94], the intragenic SNP G
987
GG/C
987
GG at the 3’end
of the CAG tract, which variant C is present in more
than 70% of the expanded alleles, seemed to bring good
perspectives to the possibility of discriminating between
wild-type and mutant ATXN3 alleles. Promising results
were obtained by Alves et al. [145], who, using siRNA
assays targeting that SNP, reached therapeutic efficacy
and selectivity in a rat model of MJD. However, transpos-
ing this to MJD patients would result inefficient in the
case of homozygosis for the C variant, or in the absence
of this variant in the expanded allele. Thus, the search for
ATXN3 transcript variation is still imperative for the
application of such siRNA approaches. Recently, another
strategy for allele-specific silencing of the mutant ATXN3
mRNA was applied [146], via antisense oligomers, that
discriminate between the wild-type and the expanded
alleles on the basis of the (CAG)
n
repeat length in
cell lines. Much is still needed to transpose those allele-
specific silencing strategies to effective treatment of
patients, but good perspectives are foreseen in the future.
Acknowledgements
This work was supported by the project “Transcriptional variation of the
ATXN3 gene as modulator of the clinical heterogeneity in Machado-Joseph
disease (MJD)”(PIC/IC/83074/2007, funded by “Fundação para a Ciência e a
Tecnologia”- FCT). C.B. is a postdoctoral fellow of FCT [SFRH/BPD/63121/
2009].
Author details
1
Center of Research in Natural Resources (CIRN) and Department of Biology,
University of the Azores, Ponta Delgada, Portugal.
2
Institute for Molecular
and Cellular Biology (IBMC), University of Porto, Porto, Portugal.
3
Laboratorio
de Biología Molecular, Instituto de Enfermedades Neurológicas de
Guadalajara, Fundación Socio-Sanitaria de Castilla-La Mancha, Guadalajara,
Spain.
Authors’contributions
CB drafted the manuscript. ML revised critically the content of the
manuscript. Both authors have read and gave their final approval of the
version to be published.
Competing interests
The authors declare that they have no competing interests.
Received: 7 September 2010 Accepted: 2 June 2011
Published: 2 June 2011
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doi:10.1186/1750-1172-6-35
Cite this article as: Bettencourt and Lima: Machado-Joseph Disease:
from first descriptions to new perspectives. Orphanet Journal of Rare
Diseases 2011 6:35.
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