Dystonias
Dystonias constitute a heterogeneous group of movement disorders characterized by involuntary and prolonged muscle contractions, leading to abnormal movements, distorted or fixed postures, and, in some cases, tremors. These movements can involve different regions of the body, including the face, neck, limbs, and trunk, and present either continuously or intermittently, with varying degrees of severity. In some forms, dystonic tremor represents the primary manifestation.
Dystonias can have a genetic, acquired, or idiopathic origin. Genetic forms are often caused by mutations in genes involved in the regulation of muscle tone and neuronal transmission in the basal ganglia, a set of brain structures fundamental for movement control. Some of these forms present in childhood or adolescence, while others onset in adulthood. Acquired dystonias, on the other hand, can result from brain damage related to perinatal events, trauma, infections, exposure to toxins (such as manganese or lead), or the prolonged use of certain medications, particularly neuroleptics and antiemetics. In many cases, however, the cause remains unknown, and these are referred to as idiopathic dystonias.
Dystonias are classified based on the distribution of the body parts involved. Focal forms affect only one body district and include, for example, cervical dystonia (also known as spasmodic torticollis), writer’s cramp, and blepharospasm. Segmental dystonias involve two contiguous body areas, while generalized forms, which are rarer, manifest with extensive body involvement and usually onset at an early age. Symptoms can worsen with movement or stress and temporarily improve with specific “sensory tricks” (gestes antagonistes), such as touching the chin or face in the case of cervicofacial dystonias
The diagnosis of dystonia is essentially clinical, but it may require further investigation to identify its cause and define its type. An expert neurological evaluation is fundamental to distinguish dystonia from other movement disorders, such as parkinsonism or chorea. When a hereditary form is suspected, genetic analysis can be used to search for pathogenic variants. Our group specifically focuses on this: we employ advanced technologies such as whole-exome sequencing (WES) or whole-genome sequencing (WGS) to identify new genetic causes of dystonia, even in cases where traditional genetic testing has not yielded a positive result. This research activity has already led to the discovery of new genes responsible for rare forms of dystonia, contributing to a better understanding of the disease.
Available therapies
The treatment of dystonia must be personalized based on the type, extent, and severity of the disorder, as well as the specific needs of each patient. Therapeutic options include pharmacological, physical, and, in selected cases, neurosurgical approaches. Commonly used medications include anticholinergics and, in certain selected forms, levodopa, which is particularly effective in dopa-responsive dystonias. A widely used treatment for focal forms consists of botulinum toxin injections, which allow for a targeted and temporary reduction of abnormal muscle activity, providing significant symptomatic relief.
In severe generalized or segmental forms that do not respond adequately to conservative therapies, Deep Brain Stimulation (DBS) may be indicated. This neurosurgical procedure involves the implantation of electrodes in specific brain areas, such as the globus pallidus internus, and can lead to a substantial improvement in motor control.
Finally, the treatment of dystonia also utilizes rehabilitative support through physiotherapy, speech therapy, and occupational therapy programs, which are fundamental for improving daily functionality and counteracting the musculoskeletal complications associated with the pathology.
.
Research in progress
Research on dystonias focuses primarily on two complementary areas: on one hand, the identification of the genetic and biological causes underlying different forms of dystonia; on the other, the study of specific pathogenetic mechanisms for each subgroup, with the aim of developing more targeted and effective therapies.
In our center, we use next-generation sequencing (NGS) technologies, both short-read and long-read, to discover new mutations involved in hereditary forms of dystonia, particularly in cases unexplained by currently known genes. At the same time, we are working on the identification of molecular biomarkers, both cellular and humoral, useful for facilitating early diagnosis and more accurately distinguishing between different clinical variants.
An additional research front is represented by the development of innovative preclinical models, such as striatal organoids generated from patient-derived induced pluripotent stem cells (iPSCs). These in vitro models allow for an in-depth study of the cellular and molecular mechanisms underlying dystonia and represent a promising platform for testing new therapeutic strategies.
Reference laboratory
Contacts and informations
Dott. Alessio Di Fonzo
Mail: alessio.difonzo@policlinico.mi.it
Administrative Office: elena.oriani@policlinico.mi.it