Focal Dystonia – an Update of Genetic Background and Novel Treatment

1. Introduction

Dystonias are several disorders defined by abnormal repetitive motions or postures caused by excessive contractions of the muscles [1]. The most common forms of dystonia affect a single body region, such as the neck (cervical dystonia), the upper part of the face (blepharospasm), the larynx (spasmodic dystonia), or the top of a limb (focal hand dystonia) (Figure 1.). Although multiple parts of the body may be affected, the pathophysiology of focal dystonias is hypothesized to involve the brain's motor system [2,3].

The most common type of focal dystonia is cervical dystonia (CD). It is characterized by involuntary muscular contractions that result in aberrant head/neck/shoulder motions and postures, as well as tremor and pain [4]. Pain is an important cause of disability and social isolation in patients with cervical dystonia and is frequently the primary reason patients pursue treatment. Pain is regularly identified as a difficult and disabling component of dystonia symptoms in surveys of patients, with a considerable impact on daily activities and work. Mechanisms of pain in CD may be muscle-based and non-muscle-based. Accumulating evidence suggests that non-muscle-based mechanisms (such as dysfunction of descending pain inhibitory pathways as well as structural and network changes in the basal ganglia, cortex, and other areas) may also contribute to pain in CD alongside prolonged muscle contraction [5].

Blepharospasm (BSP) is a main adult-onset focal dystonia that includes involuntary eyelid closing and orbicularis oculi muscle spasms [6]. Henri Meige described ten patients with blepharospasm in 1910: these patients experienced involuntary eyelid closing in combination with jaw muscular contraction. Meige labeled this condition "Convulsions de la Face" in his study [7]. The most noticeable symptom is spasms of ocular closure. Another symptom is frequent blinking, which can be independent or coupled with spasms. A further feature is the inability to open the eyes spontaneously in the absence of orbicularis oculi spasm [8].

Oromandibular dystonia (OMD) represents a very infrequent type of focal idiopathic dystonia. OMD was clinically discovered at the turn of the twentieth century. However, some features of OMD remain unexplained, including the high risk of oral trauma, which is frequently associated with the development of motor symptoms [9]. OMD is a type of focal dystonia characterized by repeated, continuous spasms of the masticatory, lingual, and facial muscles, which results in uncontrolled jaw opening and closing, retractions, protrusion, or a combination of these movements. OMD can occur alone or in conjunction with limb or trunk dystonia caused by toxic, neurodegenerative, metabolic, infectious, postanoxic, post-traumatic, stroke, status epilepticus, primary faciobrachial, or generalized dystonia. The cause could not be determined in some patients [10].

Spasmodic dysphonia (SD) is a type of focal dystonia that involves excessive or incorrect laryngeal muscle contraction during speech. SD is characterized by either inadequate glottic closure (adductor type) or abrupt opening of the vocal folds (abductor type). The predominant symptom of adductor-type SD is a strained or strangled voice, whereas a breathy or absent voice characterizes abductor-type SD. Adductor-type SD accounts for 97% of all SD patients, with 70% exhibiting aberrant extra laryngeal muscle contractions [11].

Focal Hand Dystonia (FHD) is a movement disease that causes involuntary movements, cramps, and spasms. Pathological neuronal microcircuits in the cortical somatosensory system are linked to it. Invasive preclinical techniques allow researchers to explore individual cortical layer and column neuronal microcircuits [12].

A distinct subset of focal dystonia is referred to as occupational dystonia, which includes dystonic illnesses brought on by repeated motor activity and intimately linked to a particular vocation that the affected individual performs for a living. Thus, musicians are a group that is especially susceptible to this illness, which manifests itself when highly skilled motions are performed. It is currently unclear what pathophysiological factors lead to focal dystonia in musicians. Nonetheless, increasing evidence of abnormalities in sensory-motor unity, cortical and subcortical inhibition processes, and the handling of sensory information highlights this disease, thanks to the contributions of neurophysiological research and functional neuroimaging [13].

Focal task-specific dystonia (FTSD) of the hand in musicians is well-studied and is known as musicians' hand dystonia. However, musicians may also experience issues with their laryngeal muscles, lower limbs, and embouchure. When musicians experience dystonia in their perioral and facial muscles while playing embouchure instruments, it is referred to as embouchure dystonia (ED). Diagnosing ED is critical because if the musician keeps playing the instrument, the dystonia could become non-specific and persistent. The only musicians who have been documented to have task-specific dystonia of the lower limbs are drummers. The electromyogram (EMG) of the affected muscles during the task is the basis for the diagnosis. The term "singer's dystonia" (SD) describes a type of laryngeal dystonia that is exclusive to singing tasks [14].

Task-specific dystonia can be noticeable when performing fine motor control tasks like not only writing, and playing an instrument, but also other chores. It can also happen when playing specific sports and could even be harmful to the careers of professional athletes. Consequently, movement disorder neurologists and sports physicians must be knowledgeable about the phenomenology and presentation of sports-related dystonia (SRD) [15].

3. Classification and comorbidities in dystonia

The etiology of dystonia is incredibly varied. The deep grey matter structures called basal ganglia, which oversee initiating and regulating voluntary movement, are implicated in the final common pathway; nevertheless, the reasons for this failure span practically the whole area of neurology. According to Albanese et al., there are two subaxes along which to classify etiology: inherited vs acquired disease, and either the existence or absence of degenerative or structural lesions. The term "primary dystonia," which lacks a specific and widely accepted description, has been less and less common since the release of the more modern Albanese classification. Therefore, in the first instance, a different classification might only differentiate between acquired and hereditary causes of dystonia [16,17].

Dystonia can be acquired from any process that damages the basal ganglia. These processes include vascular (dystonic cerebral palsy is primarily caused by perinatal hypoxic-ischaemic encephalopathy, but stroke is also a significant cause of dystonia in all age groups), toxic (heavy metal poisoning, for example), iatrogenic (such as antipsychotic drugs), traumatic brain injury, or the existence of a space-occupying lesion [18].

Genetic dystonias encompass both situations where the primary symptom is dystonia (e.g., TOR1A variations, due to ANO3 mutations, etc.) and conditions where dystonia is a co-occurring feature of a more complex condition. There is some overlap in the neurological, neuropsychiatric, and systemic characteristics associated with almost all hereditary dystonias, making this distinction imprecise. Dystonia is one of many features of a wide range of genetic problems, such as neurotransmitter abnormalities, neurometabolic disorders, and neurodegenerative diseases. While many diseases have early onset, other significant ones, like Huntington's disease (HD), may not exhibit symptoms until late adulthood [19].

Parkinson's disease and dystonia are inextricably related. Flexion postures of the limbs and trunk are a main sign of Parkinson's disease that was notably prevalent prior to the use of levodopa. These occasionally resulted in severe abnormalities that were misdiagnosed as joint disorders such as rheumatoid arthritis [20]. Dystonia can be present in 30% or more of Parkinson's disease patients, and it is more common when the disease begins under the age of 40 [21]. Parkinsonism and dystonia co-occur in several disorders, and indeed parkinsonism is often associated with mutations in genes like TAF1, ATP1A3, PRKRA, including those involved in the dopamine synthesis pathway, e.g. GCH1, TH [22].

Both dystonia and LID (levodopa-induced dyskinesia) are hyperkinetic movement disorders. Dystonia usually develops on its own, but it can sometimes occur because of a stroke, an injury, or genetic factors. LID relates to Parkinson's disease (PD), arising due to chronic levodopa medication, and can be dystonic or choreiform. LID and dystonia share several phenomenological characteristics and processes. LID and dystonia are both caused by an integrated circuit that includes the cortex, basal ganglia, thalamus, and cerebellum. They also have problems in striatal synaptic plasticity and dysregulation of striatal cholinergic signaling. The extended duration of both LID and dystonia suggests that underlying epigenetic dysregulation could be a proximate cause [23].

4. Diagnostic of dystonia

Finding an underlying etiology for focal dystonia, including acquired, inherited, and idiopathic origins, requires accurate phenotyping of the condition. The last several years have seen a rise in interest in both motor symptoms and the related nonmotor symptoms, as well as their negative effects on quality of life. The growing number of recently identified genes linked to dystonia complicates the diagnosis process. The goal of recent initiatives has been to advance the development of algorithms and recommendations to help with diagnosis and with utilizing diagnostic instruments [24].

The term dystonia refers to a collection of illnesses in which dystonia is the primary clinical symptom, as well as a clinical description of an aberrant posture, sometimes with a twisting quality. There are various causes of dystonias, including idiopathic, hereditary, acquired, and others. While imaging and laboratory tests are usually normal in patients with dystonia, there is no good diagnostic test for idiopathic dystonia. In cases of genetic dystonia, however, genetic testing may provide a conclusive diagnosis. Effect by voluntary action, overflow/mirror dystonia, and a "null point" are among the clinical characteristics of dystonia. It is important to ask precise questions and evaluate sensory tricks through investigation. Clinical factors (onset age, body distribution, temporal pattern, and related clinical aspects) and origin (such as nervous system pathology or whether the disorder is inherited, acquired, or idiopathic) are used to categorize dystonia. Dystonia diagnosis is a difficult task. Patients with functional dystonia (also known as "psychogenic"), scoliosis, myoclonus, tics, Parkinson's disease, and headaches are frequently misdiagnosed [25,26].

Four different forms of dystonia can be distinguished based on their temporal pattern. The occurrence and intensity of dystonia follow a consistent pattern that is similar throughout the day. Dystonia that is specific to an action or task, such as typing, singing, performing an instrument, or writing, only manifests itself during that specific activity. Paroxysmal dystonia is characterized by abrupt, distinct dystonia episodes that end with a return to the neurologic baseline. In dopa-responsive dystonia, diurnal variation—mild symptoms upon arising that get worse as the day goes on—is typically observed. One can treat dystonia alone or in conjunction with another movement problem. Apart from tremor, which is typically phenomenologically dystonic in origin, dystonia is the sole clinical motor symptom associated with solitary dystonia. However, various movement disorders such as myoclonus, parkinsonism, ataxia, or chorea/dyskinesias are linked to combination dystonia. While neuropsychiatric symptoms are often linked to dystonia, cognitive impairment is often limited to degenerative/progressive dystonias. Differentiating dystonia can be based on how quickly symptoms manifest. At least initially, focal dystonias usually occur after a gradual or subacute deterioration of symptoms, which is then followed by a plateau. Although it usually plateaus, further expansion to segmental/multifocal dispersion is possible [27].

Not only can Parkinson's disease manifest with concurrent dystonia, but in some circumstances, parkinsonian characteristics might be mistaken for dystonia. Dystonia is a common presenting feature in patients with Parkinson's disease, which can complicate diagnosis. Of these, 30% generate off-state dystonia, and 10% to 15% may develop (usually lower) limb dystonia. Other possible complications include blepharospasm, apraxia of eyelid opening (primarily in atypical parkinsonism), as well as truncal/axial dystonia, which includes camptocormia and Pisa syndrome. Furthermore, dystonia can also imitate PD. For example, a dystonic limb's delayed movement might be mistaken for parkinsonian bradykinesia, dystonia's elevated tone can be mistaken for stiffness, and a dystonic tremor at rest can be mistaken for a parkinsonian tremor [28].

Misdiagnosis of Parkinson's disease can occur even in people with genetically dystonia syndromes, such as DYT-TOR1A and dopa-responsive dystonia.4 But aside from tremor, isolated dystonia lacks the development of diagnostic features of parkinsonism without true rigidity (the presence of "lead pipe" rigidity, with or without cogwheeling at the wrist), or bradykinesia (a necessary criterion of parkinsonism, which includes slowness with particular features of decrement/fatiguing accompanied by several iterations, or hesitations/interruptions). In mixed types of dystonia, especially in dystonia-parkinsonism, where actual parkinsonism does exist, it is more difficult to distinguish between dystonia and Parkinson's disease. Genetic dystonia parkinsonism causes typically manifest at a much younger age than conventional Parkinson's disease; nonetheless, there may be cases where there is no discernible clinical difference, in which case the medical professional may rely on pertinent symptoms, imaging, and family history to make a diagnosis [29].

6. Conclusions and future perspectives

The mechanism behind dystonia is becoming clearer as genetically based types of the illness are discovered. The action of the protein products of numerous genes may explain the underlying mechanism of dystonias and provide a path to permanently alleviate patient symptoms. However, we still do not know all the mutations and genes involved in the development of focal dystonias, which forces the further development of the genomic background. There are symptomatic treatments available, including pharmaceutical therapy (anticholinergics), intramuscular botulinum toxin injection, and deep brain stimulation; nevertheless, future studies will hopefully lead to reliable biomarkers and better treatments. There is a significant therapeutic gap in current dystonia therapy options, as well as an obvious need for a reliable new treatment. Because most individuals with focal dystonia receive therapy by BoNT, testing any new medication is difficult. There are two key challenges to finding a unique therapeutic solution for dystonia sufferers. The first step is to recognize the current treatment gap. Second, moving some of our dystonia research goals to clinical trial preparation is critical if we are to test innovative treatment medicines. There are currently no reports of gene therapies regarding the introduction of correct genes, but the development of such a treatment modality may be considered in patients with primary dystonia.