Primary dystonia type DYT2 (PD-DYT2) refers to an idiopathic, isolated type of dystonia that is inherited in an autosomal recessive manner and usually manifests during the first two decades of life. The term is based on phenotypic similarities but does not imply genetic homogeneity. Notwithstanding, PD-DYT2 has recently been related to mutations in the HPCA gene. It remains to be clarified whether such mutations are the only cause of what has previously been diagnosed as PD-DYT2.
Dystonic muscle contractions are the clinical hallmark of PD-DYT2. These contractions may be sustained or intermittent, forcing the individual into abnormal postures or repetitive twisting movements. They may be accompanied by pain and tremor . With regards to symptom onset and the involvement of distinct parts of the body, early onset of limb dystonia with slow progression to segmental or generalized dystonia is characteristic of PD-DYT2. In advanced stages of the disease, spasms occurring in the cranio-cervical and possibly brachial regions tend to dominate the clinical picture .
Patients are born healthy and typically reach developmental milestones at the expected ages. First symptoms of PD-DYT2 manifest in childhood or adolescence and may include involuntary movements of feet or hands, gait disturbances, difficulties in realizing manual activities, and limb jerking. Over time, dystonic posturing, cervical dystonia, blepharospasm, grimacing, and teeth grinding may become predominant. Patients may develop dysarthria, dysphonia, dysphagia, and dyspnea  . The spread of dystonic symptoms to the trunk, neck, head, and other extremities in the course of years, with large variations between individual patients. Dystonic muscle contractions may be elicited by voluntary actions  .
As per definition, PD-DYT2 is an isolated type of dystonia, and symptoms besides the actual dystonic movements, tremor, and pain are not to be expected . Notwithstanding, febrile seizures and learning difficulties have been reported in two patients from Turkey .
Until most recently, PD-DYT2 has been an exclusion diagnosis based on clinical findings and anamnestic data. On the one hand, the early onset of symptoms suggests a hereditary condition. On the other hand, PD-DYT2 is inherited in an autosomal recessive mode, unlike other types of the disease, and reduced penetrance has been claimed a universal trait of hereditary dystonias  . Both features diminish the incidence of the disease, so a positive family history is rarely obtained.
Consequently, extensive radiological and biochemical investigations are typically realized to rule out differential diagnoses, with all these tests failing to yield results that would indicate metabolic disorders, infections, abscesses, autoimmune diseases, tumors, infarctions, traumatic or degenerative changes of the nervous system. This once again points at a genetic disease, and molecular biological studies may be realized to confirm this assumption.
DYT loci are most commonly screened in this context. DYT2 is no genetic locus, but mutations in the HPCA gene have recently been detected in some of the affected families  . In this line, the sequencing of HPCA may constitute a direct approach to the diagnosis of PD-DYT2. The respective results should be interpreted in context, though, since too few cases have been reported to estimate the specificity and sensitivity of HPCA screenings in the workup of early-onset dystonia .
Despite PD-DYT2 being the only entity characterized by early-onset isolated dystonia and recessive inheritance, these characteristics can be difficult to confirm in a pediatric patient with an incomplete family history. Thus, screenings may be expanded to other genes known to cause early-onset dystonia, such as DYT1 (mutations in TOR1A, similar phenotype, but autosomal dominant inheritance), DYT6 (mutations in THAP1, prominent cranio-cervical involvement, but typically adult onset) DYT16 (mutations in PPKRA, associated with parkinsonism), and additional loci according to clinical findings and the growing knowledge about the genetics of primary dystonias . In the case of PD-DYT2, these genes are not pathologically altered.
Curative treatment is not available. Patients are provided symptomatic therapy aiming at lowering the frequency and intensity of involuntary muscle contractions, and they should be offered psychological support and possibly additional medication to ameliorate the social consequences of dystonia, if experienced.
With regard to the former, botulinum toxin injections are the mainstay of therapy. The toxin inhibits the release of acetylcholine at the neuromuscular junction and thus forces muscle relaxation. Effects usually last for about three months, when the compound needs to be administered once more. Treatment with botulinum toxin has been demonstrated to be safe and effective, even if employed over years. This is an important point, since most patients require treatment throughout life.
According to the needs of the individual patient and their response to botulinum toxin, different approaches may be taken. In this context, muscarinic receptor antagonists, GABA receptor agonists, benzodiazepines, other antiepileptics, and levodopa have been administered to PD-DYT2 patients, which resulted in variable and incomplete responses  .
Some patients have been followed up for decades and continue to function well in daily life, which resulted in the classification of PD-DYT2 as a relatively mild form of primary dystonia  . Although the severity of PD-DYT2 tends to increase over time, physical disabilities due to limitations of ambulation or fixed deformities have not been described in the respective patients.
A somewhat less optimistic prognosis can be derived from older literature on early-onset dystonia . Here, Spanish adolescents lost their abilities to walk within a few years of symptom onset, and they developed considerable difficulties in eating and speaking during their third decade of life. Permanent disabilities were also observed in Arab siblings diagnosed with PD-DYT2 . These cases may or may not be related to HPCA mutations; a molecular biological workup has never been realized, and the possibility exists that they would now be classified as a separate entity.
Dystonia is a common movement disorder, which may be classified according to its causes, the patients' age at symptom onset, the involvement of distinct parts of the body, and the presence of additional symptoms . In line with this scheme, PD-DYT2 is to be classified as an isolated, early-onset primary dystonia with prominent cranio-cervical involvement . This phenotypic definition is indeed the only definition available.
DYT2 does not refer to a specific gene but rather a hypothetic locus that may be involved in a certain variant of primary dystonia: Similar phenotypes and a recessive mode of inheritance have been observed in a few families, and in the absence of a molecular explanation, affected members were diagnosed with PD-DYT2 . In recent years, PD-DYT2 has repeatedly been linked to mutations in the HPCA gene  . Affected individuals may be homozygous or compound heterozygous for pathogenic mutations of this gene, but it remains to be clarified whether anomalies in the respective calcium-binding protein are the only genetic cause of PD-DYT2 .
The majority of genetic dystonias is inherited in an autosomal dominant fashion, and the existence of autosomal recessive forms has long since been questioned  . These doubts were not only due to knowledge gaps regarding the etiology of the disease but also the rarity of this type of dystonia. To date, less than a handful of families affected by PD-DYT2 have been described. While initial reports referred to an Italian family and Spanish gypsies, more recent diagnoses were made in Turkish families, Arabs, Iranian Jews and an individual Sri Lankan woman      . Consanguinity of the patients' parents was reported in all cases.
The pathogenesis of PD-DYT2 is incompletely understood. In general, primary dystonias are assumed to be caused by a malfunction of the basal ganglia. No structural or degenerative abnormalities have been detected in the brains of affected individuals, so functional disturbances are hypothesized to provoke the diseases .
More specific observations can be made with regard to HPCA-related cases of PD-DYT2. The HPCA gene encodes for a calcium-binding protein and is primarily expressed in the striatum, other areas of the brain, and the retina. The gene product is hippocalcin and has been proposed to play a role in regulating voltage-dependent calcium channels . Calcium sensitivity is conferred to hippocalcin by four EF-hand domains that act as Ca2+ binding sites. In PD-DYT2 patients, these binding sites may be altered: Mutations related to this type of dystonia may lead to the incorporation of a positively charged lysine into a highly conserved sequence of negatively charged or neutral amino acids, resulting in the repulsion of positively charged calcium ions from the binding site. PD-DYT2-related mutations of HPCA may similarly affect other regions of the protein and interfere with their function, thereby disturbing calcium signaling signal transduction in the striatum, an area of the brain intimately connected with movement disorders like dystonia  .
Affected families may benefit from genetic counseling. In general, consanguinity increases the risk of PD-DYT2 and many other hereditary diseases, and the general public should be informed and educated accordingly. The linkage between mutations in the HPCA gene and PD-DYT2 requires further confirmation but may pave the way towards the identification of carriers and the pre- and postnatal diagnosis of the disease. In a similar way, this applies to other mutations that may be related to PD-DYT2 in the future.
Dystonia is a common movement disorder associated with involuntary muscle contractions provoking abnormal postures or repetitive movements. Primary dystonia has initially been deemed an idiopathic condition, but several variants of the disease could be linked to specific gene defects in recent years. Prior to the advent of the molecular biological classification, phenotypic features have been the mainstay of typification. In this context, the extent of involvement of distinct body regions gives rise to the distinction between focal dystonia, segmental dystonia, hemidystonia, and generalized dystonia. Symptom onset may occur in pediatric patients or be delayed until adulthood. As a general rule, the earlier symptom onset occurs, the more likely the patient develops generalized dystonia. PD-DYT2 is in line with this rule. Affected children or adolescents present with focal or segmental dystonia of the limbs and subsequently develop generalized dystonia with cranio-cervical predominance. As for the genetic causes of PD-DYT2, several questions remain unanswered. However, significant progress has been made by Charlesworth and colleagues, who related the disease to mutations in the HPCA gene . Such mutations have been confirmed in families diagnosed more than a decade earlier and have later been detected in new cases of PD-DYT2 . It remains to be seen whether all future cases of PD-DYT2 can be linked to HPCA mutations, or whether other gene defects are revealed.
Dystonia refers to involuntary muscle contractions. They may be sustained or intermittent and force the individual into abnormal postures or repetitive twisting movements. Dystonias may present as part of an underlying metabolic or neurological disorder, infection, autoimmune disease, or other pathological process. These types of dystonia are referred to as secondary dystonia. In some cases, though, there is no neurological injury or disease processes, and the patient is diagnosed with primary dystonia. Primary dystonia is indeed a hereditary condition, and it may manifest in different ways at different ages.
With regard to primary dystonia type DYT2 or DYT2-like primary dystonia (PD-DYT2), symptom onset occurs in childhood or adolescence. The pediatric patients generally present with muscle spasms affecting single muscle groups in their limbs, e.g., one of their feet or hands. This may lead to involuntary movements of these parts of the body, gait disturbances, difficulties in realizing manual activities, and limb jerking. Over the course of the following years, the disease tends to spread to the trunk, neck, and head. Then, the clinical picture is dominated by dystonic posturing, cervical dystonia, involuntary eyelid closure, grimacing, and teeth grinding. Patients may have difficulties with speaking, swallowing, and breathing.
To date, PD-DYT2 has only been diagnosed in a handful of cases. It is therefore difficult to determine a patient's prognosis. Curative therapy is not available, but muscle contractions may be inhibited by means of botulinum toxin injections. Botulinum toxin is administered in intervals of several months, with most patients requiring therapy throughout life.
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