Primary dystonia type DYT1 (PD-DYT1) is often referred to as early-onset generalized torsion dystonia and is the most common variant of hereditary dystonia. As can be deduced from the descriptive term, first symptoms manifest in childhood. Lower-limb onset is most common, and the disease tends to spread to the trunk and other limbs. PD-DYT1 is diagnosed by means of the identification of the underlying mutation in the DYT1 gene, and affected individuals are provided symptomatic treatment. There is no cure for PD-DYT1, but modern treatment modalities are generally able to increase the patients' quality of life.
PD-DYT1 is the textbook example for isolated torsion dystonia, a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both . Involuntary movements tend to follow recurring, stereotype-like patterns, may be accompanied by tremor and are often triggered or worsened by voluntary actions. Although patients may claim pain, there are no other neurological abnormalities. Patients have normal cognitive function and are of normal intelligence.
The disease tends to start early in life, in mid- to late childhood, when dystonia of an arm or leg is observed . Twisting and jerking movements, muscle spasms, gait abnormalities and/or difficulties with manual activities are characteristic of this early stage. Symptoms then spread to the trunk and other limbs, sometimes quite rapidly, sometimes in a delayed fashion. On average, children develop generalized dystonia, possibly with fixed postural deformities, within about five years  . The larynx, head, and neck are mostly spared  .
In severe cases, patients may progress to the so-called status dystonicus or dystonic storm. This term describes a medical emergency and very rare complication of generalized dystonia. It may be triggered by infectious diseases, trauma, surgery, or sudden changes in treatment regimens, and consists in increasingly frequent and severe episodes of tonic or phasic dystonia. Status dystonicus may be associated with fever, tachycardia, tachypnea, hypertension, sweating, and autonomic instability and may lead to disabling sequelae or even death  .
It should be noted that focal and segmental dystonia have been described in PD-DYT1 patients and the course of the disease may occasionally be mild. Similarly, symptom onset may be delayed until adolescence or even adulthood. Even within the same family, there is marked phenotypic variability .
Entire Body System
Early-onset, generalized dystonia is an autosomal dominant disorder associated in most cases with a GAG deletion in the coding region of the DYT1 gene (TOR1A) on chromosome 9q34.1,2 Not all individuals with the GAG deletion in the DYT1 gene develop dystonia [n.neurology.org]
1 Novel TOR1A mutation p.Arg288Gln in early-onset dystonia (DYT1). 61 56 6 18477710 2008 2 Frequency and phenotypic variability of the GAG deletion of the DYT1 gene in an unselected group of patients with dystonia. 61 56 6 Grundmann K...Riess O 12975293 [malacards.org]
A GAG deletion at position 946 of the DYT1 gene was the first mutation found, in early-onset dystonia, with an autosomal dominant transmission and reduced penetrance. [jamanetwork.com]
GAG deletion in the DYT1gene, including the two patients whose fathers were of AJ origin. [jmg.bmj.com]
[…] dystonia: a meta-analysis. 61 Holloway KL...Ramakrishnan V 22151759 2006 21 Piriformis muscle syndrome. 61 Kuncewicz E...Samborski W 17385355 2006 22 [Some pathophysiological mechanisms of muscular tone impairment]. 61 Bogdanova LP 15568498 2004 23 Spinal lordosis [malacards.org]
He also added a second Latin descriptor dysbasia lordotica progressiva (progressive gait difficulty with lordosis), as he noted the occurrence of pronounced and progressive lordosis in his patients. [frontiersin.org]
61 Holloway KL...Ramakrishnan V 22151759 2006 21 Piriformis muscle syndrome. 61 Kuncewicz E...Samborski W 17385355 2006 22 [Some pathophysiological mechanisms of muscular tone impairment]. 61 Bogdanova LP 15568498 2004 23 Spinal lordosis with marked opisthotonus [malacards.org]
Dystonic opisthotonus: a “red flag” for neurodegeneration with brain iron accumulation syndromes? Mov Disord. 2013;28:1325–1329. [PMC free article] [PubMed] [Google Scholar] 20. Schneider SA, Aggarwal A, Bhatt MH, et al. [ncbi.nlm.nih.gov]
Pyramidal Tract Signs
tract signs, dystonia of the lower extremities and concentric visual field defects, Clin. [academic.oup.com]
The diagnosis of PD-DYT1 is based on familial and personal history, clinical findings, and genetic studies :
- Most patients do have a positive family history of isolated dystonia. Due to the low penetrance of the disease, this should, however, not be considered an exclusion criterion.
- Both early onset and generalization are clinical hallmarks of this disease and lay the grounds for a tentative diagnosis of PD-DYT1. The majority of primary dystonias manifest in adulthood or are limited to certain segments of the body, such as the head and neck region. Lower-limb onset as well as cranial and laryngeal sparing are considered further hints on PD-DYT1.
- Nevertheless, the phenotypic heterogeneity of PD-DYT1 should not be underestimated. A consensus has been reached that all dystonia patients presenting symptoms before the age of 26 years should be tested for DYT1 mutations, regardless of the site of onset. Additionally, testing for DYT1 mutations should be carried out in case of a family history of early-onset dystonia, even if the index patient presents later in life.
Causal treatment is not available. Patients are provided symptomatic therapy aiming at a reduction of the frequency and intensity of involuntary muscle contractions :
- In this context, botulinum toxin injections have long since been the mainstay of treatment of focal symptoms. They have been shown to be safe and effective even if administered throughout years. Indeed, PD-DYT1 patients are likely to require repeated injections when the relaxing effect of botulinum toxin subsides after an average of three months.
- Systemic pharmacological therapy is required to manage generalized dystonia. Anticholinergics such as trihexyphenidyl are most commonly applied to this end, but benzodiazepines and baclofen may also be used .
- Finally, severe cases may be treated surgically. Deep brain stimulation of the internal globus pallidus may be considered as well as the intrathecal application of muscle relaxant baclofen.
Patients suspected of developing a status dystonicus should be admitted to an intensive care unit . Here, treatment aims at removing the trigger of this condition and reducing muscle spasms by means of systemic medication. Besides the aforementioned compounds, propofol and non-depolarizing muscle relaxants may be administered to this end. Patients may also undergo emergency deep brain stimulation or surgery for the implantation of an intrathecal baclofen pump.
If symptoms are not evident in a carrier of a pathogenic mutation by the age of 26 years, that individual will usually remain symptom-free for life  . By contrast, young age at the manifestation of first symptoms and lower-limb onset have been identified as unfavorable prognostic factors that augment the risk of loss of ambulation and independence . Accordingly, PD-DYT1 may be the cause of severe physical disability. Fortunately, though, most patients' quality of life can be improved by means of symptomatic treatment, and about 75% of those with generalized dystonia maintain their abilities to walk and cope with everyday life .
PD-DYT1 is caused by mutations in the DYT1 gene. This same gene is also referred to as TOR1A and is to be found on the long arm of chromosome 9. It encodes for torsin 1A, a member of the AAA family of adenosine triphosphatases and an ATPase primarily expressed in the dopaminergic neurons of the pars compacta of the substantia nigra. Pathogenic mutations have a penetrance of only 30%, which may hamper the recognition of the disease' autosomal dominant mode of inheritance . Furthermore, it has been speculated there may be additional genetic and/or environmental factors that contribute to the development of the disease, that trigger the onset of symptoms or favor their generalization, but no such factors have yet been identified  .
The most common mutation of the DYT1 gene is the deletion of three base pairs, namely GAG, in exon 5. This mutation may be inherited from one generation to the next, as is the case in Ashkenazi Jews: Here, a founder mutation presumed to have arisen about 350 years ago in the region of Lithuania and Byelorussia has been passed on to the present . On the other hand, GAG deletions and other DYT1 mutations are occasionally shown to arise de novo.
The prevalence of PD-DYT1 in the general European population has been estimated at 3-5 in 1,000,000 inhabitants. In the United States, the disease may be up to 10 times more common than in Europe . An extraordinarily high prevalence of PD-DYT1 has been reported for Ashkenazi Jews, where the aforedescribed founder mutation can be identified in up to 1 of 2,000 people . Males and females are affected in an equal manner .
Under physiological conditions, torsin 1A co-localizes with endoplasmatic reticulum markers and vesicular markers such as synaptobrevin. An in-frame GAG deletion in exon 5, as observed in the vast majority of PD-DYT1 patients, results in the formation of large inclusion bodies around the nucleus and whorls that appear to derive from the endoplasmatic reticulum . The protein has thus been hypothesized to be involved in the preservation of the integrity of the endoplasmatic reticulum, in membrane trafficking and downstream vesicular release from neurons. Furthermore, and in line with its relation to the Clp protease and heat shock families, torsin1A has been speculated to aid with protein folding and stability as well as the reduction of aggregates of misfolded proteins.
Although the molecular background remains to be clarified, abnormalities of torsin 1A can be safely assumed to interfere with the function of neurons that rely on this protein, namely those to be found in the substantia nigra. The substantia nigra is closely connected to the striatum and affects the direct and indirect pathways of the cortico-striato-thalamo circuit, which, in turn, transmit an increase or reduction of motor activity .
The identification of carriers is based on genetic studies and may be carried out prenatally, if so wished. The preimplantation genetic diagnosis of PD-DYT1 has also been described . In order to avoid needless anxiety as a result of a familial workup, asymptomatic relatives of PD-DYT1 patients should be informed that the onset of symptoms beyond the age of 26 is highly unlikely and, if it actually occurs, symptoms are usually mild and unlikely to progress .
Dystonia is a common movement disorder, and subtypes have long since been classified according to phenotypic features. Among those features, the patients' age at symptom onset, the extent of involvement of distinct body regions, and the presence of additional symptoms are among the most important ones . "Early-onset generalized torsion dystonia" describes the former two parameters, refers to dystonia manifesting in pediatric patients, affecting several segments located on both sides of the body. The term does not relate to the presence of additional symptoms, which would reflect in the distinction between isolated, combined, and complex forms of the disease :
- In isolated dystonia, dystonia is the only motor feature, although tremor may be present. The prime example for isolated generalized dystonia manifesting in childhood is PD-DYT1.
- In combined dystonia, dystonia is accompanied by another movement disorder. The clinical hallmarks of primary dystonia type DYT16, for instance, are dystonia and parkinsonism.
- In complex dystonia, neurological disorders unrelated to movement and/or systemic manifestations are observed. Wilson disease falls into this category. Affected individuals typically present with signs of liver failure but may also show dystonia and other neurological deficits.
On the other hand, subtypes of dystonia may be defined in line with their cause . While secondary dystonia is related to neurological injuries or disease processes, primary dystonia is due to hereditary conditions. Knowledge gaps persist regarding the specific causes of distinct types of primary dystonia, which is why the phenotypic classification is still used by clinicians.
In sum, isolated, combined, and complex types of primary or secondary dystonia may present as early-onset generalized torsion dystonia. This is a broad spectrum of diseases, and it is beyond the scope of this article to discuss them in detail. To obtain an overview of differential diagnoses, the interested reader is referred to excellent reviews available in the literature. In 2015, an extensive discussion on the genetic backgrounds and phenotypes of isolated and combined dystonias has been published by Balint and Bhatia , and Klein et al. published a review on the causes, presentation, and workup of dystonia, which is regularly updated . The latter includes a list of hereditary neurodegenerative or metabolic disorders that may trigger complex dystonia and expands on brain lesions, drugs, and psychological conditions that may induce the disease.
In clinical practice, "early-onset generalized torsion dystonia" is most commonly diagnosed in patients suffering from primary dystonia due to mutations in the DYT1 gene. This article will thus focus on PD-DYT1.
Torsion dystonia refers to a rather common type of movement disorder. It is characterized by sustained or intermittent, involuntary muscle contractions. Torsion dystonia may be caused by gene defects, or develop as a consequence of neurological injuries, metabolic disorders, and other pathologies. With regards to possible gene defects, mutations in the DYT1 gene are among the most common triggers of torsion dystonia. Patients carrying such mutations typically present first symptoms in childhood, which reflects in the designation as early-onset disease. Children initially show twisting or jerking movements, painful muscle spasms and/or tremor, often in one leg or arm. Gait abnormalities or difficulties with manual activities are a common consequence of this, still focal, dystonia. Over the course of the disease, symptoms spread to the trunk and other limbs, giving rise to generalized dystonia. Accordingly, primary dystonia type DYT1 is generally referred to as early-onset generalized torsion dystonia. Affected individuals may eventually develop disabling, fixed postural deformities, but the disease may also follow a milder course. Causal therapy is not available, but the majority of patients maintains their ability to independently cope with everyday life when provided with adequate symptomatic treatment.
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