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 [email protected]
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) . 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.
diagnosis of DYT14 dystonia was therefore incorrect . 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 . 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) . 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 . 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. , 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,
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 . 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 . 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 . 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 . 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 . 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 . 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) , 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.  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.  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 . Based on the data and reasoning described by Schneider et al. , 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 %) . In such cases, some families may have an inheritance pattern similar to that of recessive inheritance. Khan et al.  and Moretti et al.  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.  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 % . 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 . In the family described by Khan et al. , 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 , the children also presented with generalized dystonia. However, one child had significant cognitive impairment. The patients in Santangelo’s study
impaired visual motor skills, a finding not reported in other DYT2 families. The patients described by Khan et al.  and Moretti et al.  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.  Khan et al. , 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.  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 . 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 . 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 . 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 . In a new study fifteen years after the study by Leube et al.  , 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 . 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 . The discoveries that followed the identification of the DYT1 locus by Ozelius et al.  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*
Inheritanc e pattern
Isolated dystonias Persistent dystonias Childhood- or adolescent-onset
Early-onset primary generalized dystonia
TOR1-A or DYT1
Autosomal recessive idiopathic dystonia
THAP1 or DYT6
Early-onset primary segmental craniocervical dystonia
Idiopathic autosomal recessive primary dystonia
Adult-onset focal dystonia
Late-onset autosomal dominant focal dystonia
Adult-onset primary cervical dystonia
Autosomal dominant craniocervical dystonia
Late-onset autosomal dominant primary focal dystonia
Combined dystonias Persistent dystonias Dystonias with parkinsonism Without any evidence of degeneration
With evidence of degeneration Dystonias with myoclonus
Dystonias with chorea
GCH1, TH and SPR
Dopa-responsive dystonia or Segawa dystonia
Rapid-onset dystonia parkinsonism
Adolescent-onset dystonia parkinsonism
PRKRA or DYT16
X-linked dystonia-parkinsonism or lubag
TAF1 or DYT3
Dystonia with whispering dysphonia
Paroxysmal nonkinesigenic dyskinesia 1
Paroxysmal nonkinesigenic dyskinesia 2
Paroxysmal kinesigenic dyskinesia 1
Paroxysmal kinesigenic dyskinesia 2
Exercise-induced paroxysmal dyskinesia
SLC2A1 or GLUT1
Paroxysmal dystonias Paroxysmal dyskinesias
*Based on and Klein  # AD – Autosomal dominant, AR – Autosomal recessive, XR – X-linked recessive
Table 2. Patients with dystonia with autosomal recessive inheritance. Study
Age of onset
Type of dystonia
Area of onset
(years) Santangelo, 1934
3 siblings born of consanguineous
information not available
Lisker et al., 1984
Mexicans of Iberian
3 siblings born of non-
2 siblings born of non-
M and F
descent Oswald et al., 1986
9 affected individuals in 4 families (3 families with consanguineous marriages)
6 generalized and 3 segmental
feet and cervical
Khan et al., 2003
3 siblings born of consanguineous
2 siblings born of consanguineous
3 siblings born of consanguineous
Moretti et al., 2005
 Chouery et al., 2008