CAN ALL THE MONOGENIC DYSTONIAS REALLY BE CLASSIFIED AS SUCH?
Carlos Henrique F Camargo, MD, PhD
Movement Disorders Unit, Neurology Service, Hospital de Clínicas, Federal University of Paraná,
Curitiba, Brazil
Neurology Service, Medicine Department, Hospital Universitário, State University of Ponta Grossa,
Ponta Grossa, Brazil
Sarah Teixeira Camargos, MD, PhD
Movement Disorders Unit, Neurology Service, Hospital das Clínicas, Belo Horizonte, Brazil
Francisco Eduardo C Cardoso, MD, PhD
Movement Disorders Unit, Neurology Service, Hospital das Clínicas, Belo Horizonte, Brazil
Hélio Afonso G Teive, MD, PhD
Movement Disorders Unit, Neurology Service, Hospital de Clínicas, Federal University of Paraná
(UFPR), Curitiba, Brazil
Keywords: dystonia, genetics, classification, movement disorders
Word count – 2.648
Abstract count - 149
Tables - 2
Running Title: THE GENETICS OF THE DYSTONIAS
Corresponding author:
Carlos Henrique Ferreira Camargo
Hospital Universitário – Universidade Estadual de Ponta Grossa
Al. Nabuco de Araújo, 601
Uvaranas
84031-510
Ponta Grossa, PR,
Brazil
chcamargo@uol.com.br
Abstract
Many dystonias have been classified as monogenic although the genes responsible
for them and even the chromosomal loci have not been identified. Over the years
various mistakes in classification have come to light and been corrected. Thus,
between dystonias DYT1 and DYT25 there are gaps accounted for by dystonias
that are no longer considered monogenic (DYT9 and DYT14). As our knowledge of
the genetics of movement disorders increases, other dystonias such as DYT2,
DYT4, DYT5b, DYT7, DYT17 and DYT18 may also be reclassified. Perhaps
because of their eagerness to demonstrate an understanding of the genetics of
dystonias, discover new etiologies and create new classifications for dystonias,
researchers rush to create new genetic diseases or modify their previous
understanding of a disease without exercising due care. We therefore suggest that
caution be exercised when reading about changes in the classification of genetic
dystonias or the inclusion of a new “DYT”.
Many dystonias have been classified as monogenic although the genes
responsible for them and even the chromosomal loci have not been identified
(Table 1) [1]. Over the years, various mistakes have come to light and been
corrected. For example, in one study in which the DYT14 locus was linked to the
disease, subsequent analysis identified a heterozygous deletion in the GCH1 gene
in seven patients in the family studied, confirming a diagnosis of DYT5.
The
diagnosis of DYT14 dystonia was therefore incorrect [2]. DYT9 dystonia (PED-1, or
paroxysmal exercise-induced dystonia 1) and DYT18 dystonia (PED-2) are caused
by mutations in the same gene (SLC2A1) and are actually distinct spectra of the
same disease [1]. It is therefore now acceptable to state that there is only one
PED.
Thus, between dystonias DYT1 and DYT25 there are various gaps accounted for by
dystonias that are no longer considered monogenic (DYT9 and DYT14) [1]. DYT22
is only a name reserved by HGNC (the HUGO Gene Nomenclature Committee)
without any description of the gene or locus. As our knowledge of the genetics of
movement disorders increases, other dystonias may also be reclassified. Following
is a brief discussion on what may be the next dystonias to be reclassified: DYT2,
DYT4, DYT5b, DYT7, DYT17 and DYT18.
DYT4 DYSTONIA
The term DYT4 was originally used as an umbrella term to classify families with
dominant autosomal dystonia in which the dystonia was not associated with the
DYT1 gene [3]. However, more recently, DYT4 was used to describe the dystonia
in an Australian family with autosomal dominant inheritance and complete
penetrance presenting with whispering dysphonia, as well as dystonias varying
from the focal to the generalized form [4,5].
In two studies a new Arg2Gly (c.4C>G) mutation in the TUBB4 (tubulin β-4) gene
was found in all the patients with DYT4 dystonia but not in other members of the
families or in healthy controls [6,7]. At the same time, a mutation in exon 4 of the
TUBB4A (c.745 G>A; p.Asp249Asn) gene was found to be the cause of
leukoencephalopathy with hypomyelination with atrophy of the basal ganglia and
cerebellum (H-ABC). The phenotypic spectrum of H-ABC includes dystonia,
delayed neuro-psychomotor development, spasticity, ataxia, dysarthria, short
stature and microcephaly. MRI in patients with H-ABC reveals cerebellar and
striatal atrophy with diffuse hypomyelinization. Careful analysis of the phenotypes
of DYT4 and H-ABC indicates significant phenotypic overlap. H-ABC has earlier
onset and a more severe phenotype than DYT4. Hence, DYT4 could be a forme
fruste of H-ABC. Although MRI findings have been described as normal in DYT4
patients, technical details of how the images were acquired were not described in
these reports.7 Recently, Miyatake et al. [8], studying a series of patients with HABC with mutations in the TUBB4 gene, described the same Arg2Gly mutation
found in the DYT4 family in a patient in their series. The onset of the disease in this
patient occurred before she was 2 years old, and the patient developed mental
retardation,
dystonia,
chorea,
rigidity
and
spasticity.
MRI
revealed
hypomyelinization with a reduction in volume of the basal nuclei, cerebellum and
corpus callosum.
It is clear therefore that DYT4 should not be classified as an isolated dystonia. The
current tendency is to consider DYT4 a variant of H-ABC and remove it from the
list of monogenic dystonias [7,9].
DYT5B DYSTONIA
Cases of autosomal recessive dopa-responsive dystonia (DDR-b, DYT5-b), a mild
form of tyrosine hydroxylase deficiency, are rare, and some (mainly missense)
mutations have been identified in some of the fourteen exons in the TH gene
[10,11]. The phenotypes in patients who are homozygous for mutations in the TH
gene and in those who are heterozygous may or may not be similar. Homozygous
cases can present with more serious clinical pictures, be less responsive to
levodopa treatment and be more likely to develop dyskinesias [11,12]. Because of
the few series reported in the literature to date, the relationship between genotype
and phenotype in autosomal recessive DRD remains a subject of debate, and
further studies with a greater number of patients are required to draw more reliable
conclusions [13].
As in other diseases, the phenotype and age of onset, which normally occurs in the
first decade of life, may depend on the residual TH activity [12]. However, as the
TH enzyme is found in the adrenal glands and central nervous system, it is not
possible to isolate the mutant enzymes and directly identify how the mutations
affect the enzyme’s activities. Nevertheless, these mutations are known to be able
to affect the stability of TH and decrease its protein or catalytic activity [14]. It has
been postulated that complete TH deficiency is probably incompatible with life. In
animal models a complete absence of TH was lethal for embryos because of
malformation of the heart [15].
The classical clinical features of DYT5B dystonia include progressive motor
retardation with a predominance of early-onset (often in the first three years of life)
movement disorders (primarily dystonia and parkinsonism) and altered muscle
tone without any apparent adverse psychosocial, cognitive or neuropsychological
effects. Not all patients exhibited diurnal fluctuations in their symptoms [11-13].
However, TH deficiency can cause a clinical picture of severe parkinsonism with
onset before the age of six months, retarded motor development, truncal
hypotonia, limb rigidity, oculogyric crises and neuropsychiatric abnormalities,
including attention deficit hyperactivity disorder and impaired speech development
[16-19]. Another phenotype associated with mutations in the TH gene is
progressive infantile encephalopathy, in which there is no remission of the
encephalopathy or motor disability following levodopa treatment [20]. Levodoparesponsive spastic paraparesis may also be a phenotypic presentation of different
mutations of the TH gene [19,21]. The presence of restless leg syndrome in
asymptomatic family members carrying the gene raises the question of the degree
of penetrance of this gene [10].
This broad phenotypic spectrum, which varies from little or no production of TH as
a result of homozygous mutations, with systemic repercussions or malformations
incompatible with life, to minor alterations in TH function caused by heterozygous
missense mutations with levodopa-responsive dystonic symptoms, including
cognitive changes and other movement disorders, could therefore suggest that
there is a more appropriate name for this disease than DDR-b. New cases relating
phenotypic abnormalities to mutations in the TH gene could prove or refute this
hypothesis.
DYT18 DYSTONIA
DYT18 dystonia, or paroxysmal exercise-induced dyskinesia (PED), is a rare
disease first described in a family that presented with dystonic attacks brought on
by prolonged exercise [22,23]. Two missense mutations and a 4 bp deletion were
identified in the SLC2A1 gene in members of three families affected by this
condition. The SLC2A1 gene consists of 10 exons and encodes the glucose
transporter protein-1 (GLUT1) [24], which facilitates passive diffusion of glucose
across the cellular membrane.
GLUT1 is the main molecule responsible for
mediating the transport of glucose into red blood cells, across the endothelium of
the blood-brain barrier and into and out of astrocytes. The last two of these
transport sites probably contributed to the neurologic symptoms observed in this
family as both are involved in the cell nutrition process in the central nervous
system. It is possible that the energy demand increases under conditions of
prolonged exercise and exceeds the energy supply, which is reduced in patients
with mutations in the SLC2A1 gene. This hypothesis is supported by the
therapeutic success of intravenous administration of glucose during physical
exercise and a permanent ketogenic diet, in which the brain’s main energy source
is no longer glucose but ketones. As basal nuclei are particularly sensitive to
hypoxia and energy deficits, it is possible that PED dyskinesias are caused by a
transient energy deficit in the basal nuclei [24,25].
The classic GLUT1-deficiency syndrome was described by De Vivo et al. [26] and
was the result of primarily heterozygous de novo mutations in the SLC2A1 gene,
which codes for the GLUT1 protein. The disease is probably caused by a
haploinsufficiency mechanism. The phenotype of this disease consists of slow
brain and skull growth, severe mental and motor retardation, epilepsy that is
difficult to control and progression to complex neurologic symptoms with spasticity,
dystonia and ataxia. The most significant abnormality observed in laboratory tests
is hypoglycorrachia. Other phenotypes with mild mental retardation and episodic
ataxia, a predominance of dystonia, paresis or paralysis (paraparesis with
equinovarus foot, quadriparesis and hemiparesis) and without epilepsy have been
reported [27-29].
Schneider et al. [30] described two new mutations of the SLC2A1 gene in two
sporadic cases of PED, both with ataxia and one with hemiplegic migraine. The
authors suggested that GLUT1-related disorders could present with a broad
spectrum of severity, varying from a severe clinical picture (known as classic
GLUT1-deficiency syndrome) to mild, episodic symptoms (PED, epilepsy or
migraine). The authors speculate that this variable phenotype depends on the type
of mutation. Mutations that lead to destruction of the protein and complete loss of
function would result in a severe phenotype, whereas partial protein function would
result in a better course of disease. Furthermore, the differences in phenotype may
also be explained by intra- and inter-familiar heterogeneity. Environmental factors
may be one of the reasons for the same mutation causing more cases with varying
degrees of severity in different families [28].
Based on the data and reasoning described by Schneider et al. [30], PED would be
a clinical variant of GLUT1-deficiency syndrome rather than DYT18.
RECESSIVE DYT2 and DYT17 DYSTONIAS
The majority of cases described as DYT2 are found in the offspring of
consanguineous parents, have an autosomal dominant inheritance and present
mainly with generalized dystonia, with some cases of segmental dystonia (Table 2).
Some families described as having DYT2 dystonia had a phenotype very similar to
that of DYT1 [31-33]. In families with DYT1 mutations there were also asymptomatic
patients, who either did not have the mutation or had the mutation but without
clinical manifestations because of the reduced phenotypic penetrance (between 30
% and 40 %) [34]. In such cases, some families may have an inheritance pattern
similar to that of recessive inheritance. Khan et al. [32] and Moretti et al. [33]
discarded the possibility of this type of dystonia in patients who tested negative for a
mutation in the TOR1-A gene and had an autosomal recessive inheritance pattern.
DYT2 cases can be confused not only with DYT1 but also with DYT6. Camargo et
al. [35] described a DYT6 family with two affected cousins, both daughters of
asymptomatic parents, illustrating how the presentation of an autosomal dominant
dystonia can mimic that of a recessive dystonia. Penetrance of the THAP1 gene is
estimated to be around 60 % [36]. Reports of DYT2 families predate identification of
the THAP1 gene, and to our knowledge there are no reports in the literature
published since this gene was identified of attempts to exclude this diagnostic
hypothesis in these families [37].
In the family described by Khan et al. [32], although onset was in the legs, the
patients developed primarily craniocervical symptoms and one had bulbar
abnormalities. In the family with consanguineous parents described by Santangelo
[38], the children also presented with generalized dystonia. However, one child had
significant cognitive impairment. The patients in Santangelo’s study
[38] had
impaired visual motor skills, a finding not reported in other DYT2 families. The
patients described by Khan et al. [32] and Moretti et al. [33] did not exhibit cognitive
impairment. Other movement disorders are not part of the DYT2 phenotype, with
the exception of mycoclonias, which were described in one of the three families
studied by Gimenez-Rolden et al. [31] Khan et al. [32], although they did not find the
corresponding clinical symptoms, tested their family for the SGCE (dystoniamyoclonia, DYT11) gene, but failed to detect any mutation.
Despite these small differences, i.e., cognitive impairment, abnormal eye
movements and myoclonias, all of which occurred infrequently, it is still possible to
propose a clinical presentation for DYT2 that combines all the common clinical
characteristics reported for this dystonia to date. DYT2 could be described as a
childhood-onset autosomal recessive dystonia that initially manifests in the limbs or
craniocervical region and tends to become generalized with spread primarily to the
craniocervical muscle [31-33,38-40]. However, there is still the possibility that some
families with DYT2 may have mutations in the THAP1 or TOR1-A genes or even in
some as yet undiscovered gene with similar reduced penetrance.
Chouery et al. [41] described a family in which three sisters born of consanguineous
parents had the clinical features of dystonia inherited in an autosomal recessive
manner. Genetic evaluation of this family resulted in the mapping of the DYT17
locus. The only thing that differentiates this family from DYT2 families is onset
during adolescence rather than childhood. Clinically, DYT17 is quite similar to DYT2
dystonia.
However, until a causative gene is identified, doubts will remain about the existence
of DYT2 dystonia. Although similar, the patients described by various authors
(Table 2) may correspond to different dystonias and possibly even to clinical
pictures of autosomal dominant presentation with reduced penetrance. The
possibility that some patients described as having DYT2 may have DYT17, or that
DYT17 and DYT2 may in fact be the same disease, should also be considered. We
suggest, therefore, that for patients with the phenotype described here for DYT2 the
possibility of DYT1 or DYT6 dystonia be eliminated.
DYT7 DYSTONIA
DYT7 dystonia was originally linked to chromosome 18p in seven members of a
family in northwest Germany with autosomal dominant inheritance and incomplete
penetrance, six members of which had late-onset cervical dystonia (between 28
and 70 years; mean 43 years). Minor facial involvement, upper-limb involvement
and spasmodic dysphonia were observed in the same family. The dystonic
symptoms remained focal in all cases after an average of nine years follow-up (two
to thirty years) in the seven patients with defined focal dystonia [42-43].
The gene locus was mapped to a 30 cM region of chromosome 18p [43]. The same
researchers subsequently reported allelic associations for various markers in
chromosome 18 in sporadic cases of cervical dystonia and in other families. These
findings suggest that adult-onset cervical dystonia can be caused by a mutation
inherited from a common ancestor although this has yet to be confirmed [44].
Another family in which three brothers presented with writer’s cramp and postural
arm tremor, in whom onset of symptoms occurred between 50 and 68 years of age,
had changes in the DYT7 locus [45].
Nevertheless, genetic testing in families with a phenotype similar to that of DYT7 in
which there were various cases of cervical dystonia that tended to remain focal or
segmental failed to reveal a link with the DYT7 locus. This was also true for twins
with cervical dystonia and a family history of the condition [46]. In a new study
fifteen years after the study by Leube et al. [43] , analysis of candidate genes on the
short arm of chromosome 18 in affected patients in the same German family failed
to reveal any changes. No potential mutation in this chromosome that could have
caused the disease was detected by exome sequencing [47].
These results suggest that there may be a new DYT7 locus.
FINAL CONSIDERATIONS
The systematic approach to the study of movement disorders and the correct
definition of the concept of dystonia, particularly since the work of Charles D
Marsden, has led to an exponential growth in knowledge about dystonias [48]. The
discoveries that followed the identification of the DYT1 locus by Ozelius et al. [49]
paved the way for countless important studies on the genetics of dystonias.
However, as often happens in the scientific world, the correct importance was not
always attached to each new discovery, and important findings very probably
remain overlooked, waiting to be rediscovered, while other findings have been
overvalued. Thus, in their eagerness to demonstrate their ability to understand the
genetics of dystonias, discover new etiologies and create new classifications for
dystonias, researchers may rush to create new genetic diseases or modify their
previous understanding of a disease without exercising due care. We therefore
suggest that caution be exercised when reading about changes in the classification
of genetic dystonias or the inclusion of a new “DYT”.
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Table 1. The hereditary dystonias*
Clinical category
Designation
Clinical characteristics
Locus
Gene
Inheritanc
e pattern
Isolated dystonias
Persistent dystonias
Childhood- or adolescent-onset
DYT1
Early-onset primary generalized dystonia
9q
TOR1-A or DYT1
AD
DYT2
Autosomal recessive idiopathic dystonia
-
-
AR
DYT6
Mixed dystonia
8p
THAP1 or DYT6
AD
DYT13
Early-onset primary segmental craniocervical dystonia
1p
-
AD
DYT17
Idiopathic autosomal recessive primary dystonia
20pq
-
AR
DYT7
Adult-onset focal dystonia
18p
-
AD
DYT21
Late-onset autosomal dominant focal dystonia
2q
-
AD
DYT23
Adult-onset primary cervical dystonia
9q
CIZ1
AD
DYT24
Autosomal dominant craniocervical dystonia
11p
ANO3
AD
DYT25
Late-onset autosomal dominant primary focal dystonia
18p
GNAL
AD
dystonias
Adult-onset dystonias
Combined dystonias
Persistent dystonias
Dystonias with parkinsonism
Without any evidence of
degeneration
With evidence of degeneration
Dystonias with myoclonus
Dystonias with chorea
14q/1p
GCH1, TH and
SPR
/2p
AD and
DYT5
Dopa-responsive dystonia or Segawa dystonia
AR
DYT12
Rapid-onset dystonia parkinsonism
19q
ATP1A3
AD
DYT16
Adolescent-onset dystonia parkinsonism
2p
PRKRA or DYT16
AR
DYT3
X-linked dystonia-parkinsonism or lubag
Xq
TAF1 or DYT3
XR
DYT11
Myoclonus-dystonia
7q
-
AD
DYT15
Myoclonus-dystonia
18p
SGCE
AD
DYT4
Dystonia with whispering dysphonia
19p
TUBB4
AD
DYT8
Paroxysmal nonkinesigenic dyskinesia 1
2q
MR-1
AD
DYT20
Paroxysmal nonkinesigenic dyskinesia 2
2q
-
AD
DYT10
Paroxysmal kinesigenic dyskinesia 1
16pq
PRRT2
AD
DYT19
Paroxysmal kinesigenic dyskinesia 2
16q
-
AD
DYT18
Exercise-induced paroxysmal dyskinesia
1p
SLC2A1 or GLUT1
AD
Paroxysmal dystonias
Paroxysmal dyskinesias
*Based on and Klein [1]
# AD – Autosomal dominant, AR – Autosomal recessive, XR – X-linked recessive
Table 2. Patients with dystonia with autosomal recessive inheritance.
Study
Ethnic origin
Patient
Gender
Age of onset
Type of dystonia
Area of onset
(years)
Santangelo, 1934
Italians
[38]
3 siblings born of consanguineous
F
9
generalized
parents
F
9
generalized
F
9
generalized
information not
available
Lisker et al., 1984
Mexicans of Iberian
3 siblings born of non-
M
7
generalized
craniocervical
[39]
and indigenous
consanguineous parents
F
7
generalized
craniocervical
F
7
generalized
craniocervical
2 siblings born of non-
M
10
generalized
probably
consanguineous parents
F
4
generalized
craniocervical
M and F
15±6,6
descent
Oswald et al., 1986
Africans
[40]
Giménez-Rodán,
Iberian gypsies
1988 [31]
9 affected individuals in 4 families (3
families with consanguineous
marriages)
6 generalized
and 3 segmental
feet and cervical
Khan et al., 2003
Iranian Sephardic
3 siblings born of consanguineous
F
7
segmental
cervical
[32]
Jews
parents
M
8
generalized
left foot
F
5
segmental
face
2 siblings born of consanguineous
F
6
generalized
right foot
parents
M
4
generalized
right foot
3 siblings born of consanguineous
F
14
segmental
cervical
parents
F
17
generalized
cervical
F
19
generalized
cervical
Moretti et al., 2005
Arabs
[33]
Chouery et al., 2008
[41]
Lebanese Arabs
18