Dyt-Gnal
Summary
Clinical characteristics.
DYT-GNAL caused by a heterozygous GNAL pathogenic variant has been reported in more than 60 individuals to date. It is characterized by adult-onset isolated dystonia (i.e., no neurologic abnormalities other than tremor are evident on neurologic examination). The dystonia is most commonly focal and segmental, and rarely generalized. Dystonia is typically cervical in onset and commonly progresses to the cranial region (oromandibular/jaw, larynx, eyelids) and/or to one arm. Tremor reported in DYT-GNAL may be dystonic (i.e., occurring in a body part that shows at least minimal signs of dystonia) and may precede or follow the onset of dystonia. Intra- and interfamilial variability is considerable.
DYT-GNAL caused by biallelic GNAL pathogenic variants, reported to date in two sibs from a consanguineous family, is characterized by mild intellectual disability and childhood-onset hypertonia that progresses to generalized dystonia.
Diagnosis/testing.
The diagnosis of DYT-GNAL is established in a proband with either isolated dystonia and a heterozygous GNAL pathogenic variant identified by molecular genetic testing or a more complex phenotype (intellectual disability, hypertonia, and generalized dystonia) and biallelic GNAL pathogenic variants.
Management.
Treatment of manifestations: While oral medication is usually the initial treatment of dystonia, experience in DYT-GNAL specifically is limited. Botulinum toxin intramuscular injections have improved cervical dystonia and dystonia affecting other sites in some patients with DYT-GNAL – as well as dystonia in selected muscles in patients with generalized dystonia. Deep-brain stimulation of the globus pallidus internus has been effective in a few patients with DYT-GNAL. Physical therapy may help prevent joint contractures and spine deformities. Treatment of depression and anxiety, commonly associated with cervical dystonia, is per standard practice.
Surveillance: Follow up with a neurologist specializing in movement disorders several times a year is recommended to monitor for worsening of dystonia, development of new manifestations, and treatment effectiveness and side effects.
Agents/circumstances to avoid: Dystonia of limbs can worsen if affected limbs are casted or braced. Similarly, neck collars should be avoided in persons with cervical dystonia.
Genetic counseling.
DYT-GNAL is typically inherited in an autosomal dominant manner (to date, 1 family with autosomal recessive inheritance of DYT-GNAL has been reported).
Most individuals with autosomal dominant DYT-GNAL have an affected parent; the proportion of DYT-GNAL caused by a de novo pathogenic variant is unknown. Each child of an individual with DYT-GNAL has a 50% chance of inheriting the GNAL pathogenic variant; reduced penetrance and large intrafamilial clinical variability have been reported. Once the GNAL pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.
Diagnosis
No formal diagnostic criteria have been established for DYT-GNAL.
Suggestive Findings
DYT-GNAL should be considered in individuals with the following clinical findings, neuroimaging findings, and family history.
Clinical Findings
Dystonia is defined as involuntary contractions of muscles that lead to abnormal movements and abnormal postures. Dystonic movements are typically repetitive, patterned, and often twisting.
DYT-GNAL is characterized by the following:
- Isolated; no neurologic abnormalities other than tremor evident on neurologic examination
- Age at onset typically in adulthood; rarely in childhood [Fuchs et al 2013, LeDoux et al 2016, Masuho et al 2016]
- Most commonly focal and segmental; rarely generalized [Fuchs et al 2013, Miao et al 2013, Vemula et al 2013, Masuho et al 2016]; and rarely laryngeal dystonia only [Putzel et al 2016]
- Onset typically in the cervical region and commonly progressing to the cranial region (oromandibular/jaw, larynx, blepharospasm) and/or to one arm
Neuroimaging Studies
Brain magnetic resonance imaging and computed tomography results are normal, showing no structural intracranial lesions that could be considered a cause of acquired dystonia.
Family History
Consistent with autosomal dominant inheritance (i.e., includes both familial cases and simplex cases [a single occurrence in a family]). The one exception is autosomal recessive inheritance reported in two Turkish sibs [Masuho et al 2016].
Establishing the Diagnosis
The diagnosis of DYT-GNAL is established in a proband with isolated dystonia and a heterozygous GNAL pathogenic variant identified by molecular genetic testing (see Table 1).
A single report found a homozygous GNAL pathogenic variant, associated with a more complex and more severe phenotype (intellectual disability, hypertonia, and generalized dystonia) with age at onset in infancy [Masuho et al 2016].
Molecular Genetic Testing
Because the phenotype of DYT-GNAL is indistinguishable from many other inherited disorders with dystonia, recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing. Note: Single-gene testing (sequence analysis of GNAL, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.
- A dystonia multigene panel that includes GNAL and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
- Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is another good option. Exome sequencing is most commonly used; genome sequencing is also possible.If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in DYT-GNAL
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| GNAL | Sequence analysis 3 | 32/32 4 |
| Gene-targeted deletion/duplication analysis 5 | None reported to date 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Fuchs et al [2013], Miao et al [2013], Vemula et al [2013], Dobričić et al [2014], Dufke et al [2014], Kumar et al [2014], Saunders-Pullman et al [2014], Zech et al [2014], Ziegan et al [2014], Zech et al [2015], Carecchio et al [2016], Dos Santos et al [2016], LeDoux et al [2016], Masuho et al [2016], Putzel et al [2016]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Kumar et al [2014] used quantitative PCR of GNAL exon 9 to test for whole-gene deletions/duplications in 318 patients with dystonia; no deletions or duplications were found. No further data on detection rates of gene-targeted deletion/duplication analyses are available.
Clinical Characteristics
Clinical Description
DYT-GNAL is a mostly adult-onset isolated dystonia (in which no additional neurologic abnormalities other than tremor are evident on neurologic examination). The dystonia is most commonly focal and segmental, and rarely generalized. Dystonia is typically cervical in onset and commonly progresses to the cranial region (oromandibular/jaw, larynx, eyelids) and/or to one arm. DYT-GNAL tremor may be dystonic (i.e., occurring in a body part that shows at least minimal signs of dystonia) and may precede or follow the onset of dystonia).
Since its original description [Fuchs et al 2013, Vemula et al 2013], DYT-GNAL has been reported in:
- 62 individuals with a heterozygous GNAL pathogenic variant [Miao et al 2013, Dobričić et al 2014, Dufke et al 2014, Kumar et al 2014, Saunders-Pullman et al 2014, Zech et al 2014, Ziegan et al 2014, Zech et al 2015, Carecchio et al 2016, Dos Santos et al 2016, LeDoux et al 2016, Putzel et al 2016];
- Two sibs (from a consanguineous union) homozygous for a GNAL pathogenic variant [Masuho et al 2016].
Heterozygous DYT-GNAL
Age of onset. In the 28 individuals first described by Fuchs et al [2013], mean age at disease onset was 31.3 years (± 12.4 years); range: 7-54 years. Mean age at disease onset for an additional 29 individuals was 42.5 years (± 13.2 years); range: 8-68 years.
Initial body region involved. DYT-GNAL most frequently starts as focal dystonia involving the neck (cervical dystonia, torticollis) with or without head tremor. Initial presentation can also occur in the oromandibular region or in the larynx (spasmodic dysphonia).
Data available on 56 individuals revealed the following regarding the first body region affected by dystonia:
- Cervical region: 78%
- Larynx: 9%
- Oromandibular region/jaw/tongue: 7%
- Leg: two individuals
- Face: one individual
Other initial manifestations were dystonic arm tremor (2 individuals) and isolated head tremor (1 individual).
Type of dystonia. Dystonia may remain focal (e.g., cervical dystonia is the only manifestation) or become segmental (e.g., cervical dystonia spreads to the cranial region or an upper limb). The trunk and the legs are rarely affected. Generalized dystonia is far less common.
In a study of 28 individuals, dystonia remained focal in 12 and became segmental in 13 or generalized in three [Fuchs et al 2013]. The phenotypic variability within families was wide.
In 62 individuals the sites involved during the disease course included the following:
- Cervical dystonia: 84%
- Oromandibular dystonia including dystonia of the jaw and tongue: 29%
- Upper facial dystonia including blepharospasm: 22.6%
- Dystonia of the arm or isolated dystonic tremor of the arm: 29%
- Laryngeal dystonia: 21%
- Truncal dystonia: 16%
- Dystonia in a leg: 8%
Tremor was also frequently reported, most commonly as dystonic head and/or arm tremor.
Speech involvement was reported in 44% of 28 patients [Fuchs et al 2013].
Dystonic tremor. In a family with four affected individuals in whom the most disabling manifestation was tremor, age at onset in two family members was 36 and 58 years [Carecchio et al 2016]. EMG performed in two of the four showed the tremor to be dystonic. Other findings included focal speech-induced dystonia (likely due to intermittent oromandibular dystonia), isolated dystonic tremor of the right arm only, and jerky cervical dystonia with laryngeal involvement and arm tremor.
Hyposmia. In one family with five affected individuals who were alive and available for a neurologic examination, two had hand-forearm dystonia and three had anosmia or microsmia [Vemula et al 2013]. It is possible that microsomia is more common than reported to date, since the olfactory dysfunction identified in this family was not self-reported but required specialized testing.
Psychiatric comorbidities. While there are insufficient data on psychiatric manifestations in DYT-GNAL, it is known that psychiatric comorbidities, mainly depression and anxiety, are common in individuals with (cervical) dystonia. Of note, some medications may cause psychiatric side effects (see Management, Treatment of Manifestations).
Intrafamilial phenotypic variability includes age at disease onset, initial body region involved, type of dystonia (focal versus segmental versus generalized), sites involved during the course of the disease, disease severity, and rate of progression [Fuchs et al 2013, Carecchio et al 2016]. In one family the following was observed in five living affected individuals who were examined: age at onset 45 to 63 years; generalized dystonia involving the arms, legs, and neck (1 individual), focal dystonia (torticollis) without progression (1 individual), and segmental dystonia (3 individuals); laryngeal involvement (3 individuals); and blepharospasm (1 individual) [Vemula et al 2013]. Of note, no information was available on the three other deceased individuals who were likely affected.
Biallelic DYT-GNAL
To date the only individuals known to have biallelic DYT-GNAL are two sibs from a consanguineous Turkish family reported by Masuho et al [2016], whose phenotype was more severe than that of heterozygous DYT-GNAL. The initial finding was increased muscle tone at age one year that progressed to generalized dystonia with involvement of the head, neck, trunk, and limbs. Action-induced spasms were observed. Both sibs had mild intellectual disability.
Genotype-Phenotype Correlations
No genotype-phenotype correlations are known for either heterozygous or biallelic GNAL pathogenic variants.
Penetrance
The penetrance for heterozygous DYT-GNAL is currently unknown. The following asymptomatic heterozygotes for a GNAL pathogenic variant have been reported:
- 14 unaffected heterozygotes (mean age: 29 years, age range: 9-51 years) identified in three of four families [Vemula et al 2013]
- One unaffected heterozygote who was a parent of two offspring with DYT-GNAL ages 50 and 59 years [Fuchs et al 2013]
- One unaffected heterozygote who was the mother of a 40-year-old with laryngeal dystonia [Putzel et al 2016]
Nomenclature
Following the new naming system for the genetic dystonias in which the causative gene has been confirmed, the prefix "DYT" is followed by the gene symbol [Marras et al 2016]. Thus, the new designation for DYT25 isolated dystonia is DYT-GNAL.
Prevalence
DYT-GNAL is rare. To date 64 individuals (including two homozygotes) with DYT-GNAL have been reported.
Studies in families of northern European descent with primary torsion dystonia of mixed European origin [Fuchs et al 2013] and in Swiss-German Amish-Mennonite families with primary dystonia [Saunders-Pullman et al 2014] found DYT-GNAL-causing variants in affected family members in 15% and 7.5%, respectively.
In contrast, in studies including mostly simplex cases (i.e., a single occurrence in a family) with mostly isolated dystonia, the prevalence was about 0.5% (0-1.1%) [Miao et al 2013, Vemula et al 2013, Charlesworth et al 2014, Dobričić et al 2014, Dufke et al 2014, Zech et al 2014, Ziegan et al 2014, Ma et al 2015, Zech et al 2015, Dos Santos et al 2016, LeDoux et al 2016].
A study on 57 patients with isolated laryngeal dystonia found a slightly higher prevalence of 1.8% [Putzel et al 2016].
Differential Diagnosis
See Hereditary Dystonia Overview.
Table 2.
Autosomal Dominant Disorders to Consider in the Differential Diagnosis of DYT-GNAL
| Disorder | Gene | Clinical Features of Disorder That Overlap w/DYT-GNAL | Further Details of This Disorder | |||
|---|---|---|---|---|---|---|
| Age at onset of dystonia | Site of dystonia at onset | Dystonia type | Other | |||
| DYT-THAP1 | THAP1 | Craniocervical dystonia &/or laryngeal involvement may be presenting feature(s). |
| Cervical & laryngeal; upper limb | Craniocervical involvement common | Penetrance of ~60% |
| DYT-TOR1A | TOR1A | Isolated blepharospasm or craniocervical dystonia in some |
| Typically in 1 limb |
|
|
| DYT-SGCE (see Myoclonus-Dystonia) | SGCE |
| 1st or 2nd decade | Neck, proximal arm, trunk | Myoclonic jerks of mostly proximal muscles, typically cervical dystonia & writer's cramp |
|
| DYT-ANO3 | ANO3 |
| Early childhood to 6th decade (typically adult onset) | Mostly craniocervical | Segmental/multifocal (craniocervical dystonia, head tremor, upper-limb dystonia, dystonic arm tremor, laryngeal dystonia) | Most have dystonic tremor. |
- 1.
Bressman et al [2009]; patients with familial dystonia
- 2.
Blanchard et al [2011]; review
- 3.
Xiao et al [2010]; cohort consisted mainly of individuals with late-onset focal dystonia (n = 1,210).
- 4.
Bressman et al [2000]
- 5.
See DYT1 Early-Onset Isolated Dystonia.
- 6.
Cervical dystonia may be the only presentation in DYT-SGCE.
- 7.
Carecchio et al [2016]
CIZ1-related dystonia was described in a large family of northern European descent with adult-onset cervical dystonia and an otherwise normal neurologic examination [Xiao et al 2012]. Although Dufke et al [2015] also reported CIZ1 variants in individuals with or without a family history of predominantly cervical dystonia, the significance of these variants remains unknown. Thus, CIZ1 pathogenic variants as a cause for adult-onset cervical dystonia are currently unconfirmed.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with DYT-GNAL, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with DYT-GNAL
| Organ System | Evaluation | Comment |
|---|---|---|
| Neurologic | Complete neurologic exam performed by neurologist specializing in movement disorders | Attention to blepharospasm, oromandibular dystonia, dystonia of jaw/tongue, (jerky) cervical dystonia, dystonia of arms/legs, truncal dystonia, tremor (head or extremities), laryngeal dystonia, hyposmia |
| Eval using a dystonia rating scale | Rating scale such as:
| |
| Eval by physical therapist | Attention to craniocervical dystonia, dystonia of extremities & trunk; geste antagoniste 1 | |
| ENT |
| For those w/laryngeal dystonia |
| Miscellaneous/ Other | Consultation w/clinical geneticist &/or genetic counselor |
- 1.
Voluntary maneuver that temporarily reduces the severity of dystonic postures or movements
Treatment of Manifestations
Dystonia
All treatment options are symptomatic.
Oral medication. A trial with oral medication is usually first. Very few reports on the effect of oral medication specifically in DYT-GNAL are available.
- Oral drugs currently used to treat dystonia:
- Anticholinergics (trihexyphenidyl is most widely used; benztropine). These need to be monitored especially for cognitive side effects.
- Baclofen
- Benzodiazepines (diazepam, clonazepam, lorazepam)
- Additional drugs that may be considered:
- Levodopa. Note: Levodopa/carbidopa was not beneficial in patients with DYT-GNAL [Bressman et al 1994, Carecchio et al 2016].
- Antiepileptics; e.g., gabapentin [Esposito et al 2014, Sarva et al 2019]
- Dopamine-depleting agents, most importantly tetrabenazine, which requires monitoring for psychiatric side effects (depressive episodes). Note: Tetrabenazine provided no benefit in one patient with DYT-GNAL [Carecchio et al 2016].
- Propanolol, cyclobenzaprine, trabenazine, and ethopropazine reported in a recent study [Sarva et al 2019]
Botulinum toxin intramuscular injections, repeated in intervals of about three months, have improved cervical dystonia in some patients with DYT-GNAL [Dobričić et al 2014, Carecchio et al 2016, Dos Santos et al 2016] as well as dystonia affecting other sites (e.g., blepharospasm, oromandibular dystonia, focal dystonia of a limb) including selected muscles in individuals with generalized dystonia.
Deep-brain stimulation of the globus pallidus internus has been effective in treatment of isolated dystonia in the following instances:
- Two patients with DYT-GNAL cervical dystonia accompanied by severe head tremor had a very good response [Carecchio et al 2016].
- One patient with DYT-GNAL cervical and truncal dystonia showed a good response [Ziegan et al 2014].
- In three patients, cervical dystonia improved significantly, while cranial dystonia (including dysarthria) and limb dystonia did not improve or worsened [Sarva et al 2019].
Follow up includes more frequent visits in the first weeks and months after surgery in order to determine the best stimulation parameters.
Physical therapy may help prevent joint contractures and spine deformities.
Psychiatric Comorbidities
Depression and anxiety are treated as per standard practice. Of note, dopamine-depleting agents, anticholinergics, and other drugs may cause or worsen psychiatric and cognitive features.
Surveillance
Follow up with a neurologist specializing in movement disorders several times a year is recommended to monitor for the following:
- Worsening of dystonia
- Development of new manifestations
- Medication side effects
- Issues related to DBS treatment including side effects such as hypokinesia and battery life
Regular monitoring for psychiatric and cognitive features is indicated; medication adjustments and consultation with a psychiatrist may be necessary.
Agents/Circumstances to Avoid
Dystonia of limbs can worsen if affected limbs are casted or braced. Similarly, neck collars should be avoided in persons with cervical dystonia.
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Pregnancy Management
Controlled human studies on the safety of baclofen use during pregnancy have not been completed. Several case reports of baclofen use in the first trimester of pregnancy with normal fetal outcome have been published. Third-trimester exposure may lead to abnormalities in neonatal adaptation.
The use of diazepam during the first trimester of pregnancy may be associated with an increased risk of cleft palate; thus, in situations where use of a benzodiazepine during pregnancy is required, other medications (e.g., lorazepam or clonazepam) may be preferable. Third-trimester use of a benzodiazepine may lead to neonatal complications, such as decreased tone and/or sedation.
Botulinum toxin injections are typically avoided during pregnancy and breastfeeding. However, in several case reports of women who received botulinum toxin A injections in the first trimester of pregnancy, infants were born at full term with no complications.
Data are insufficient to determine if the use of trihexyphenidyl during pregnancy has an effect on the developing fetus.
See MotherToBaby for further information on medication use during pregnancy.
Therapies Under Investigation
The following clinical trials (identified by NCT number) on DBS in "primary dystonia" are listed in ClinicalTrials.gov. (The term "primary dystonia" currently is mainly used for genetic or idiopathic forms of isolated dystonia without a consistent pathologic/structural change.) Note that none is specifically recruiting patients with DYT-GNAL:
- NCT02542839 evaluates repetitive transcranial magnetic stimulation (rTMS) delivered over each cerebellar hemisphere in addition to treatment with botulinum toxin injections in patients with primary cervical dystonia.Other rTMS studies conducted or recruiting:
- NCT02073630 in patients with primary dystonia
- NCT03369613 in patients with cervical dystonia
- NCT03247868 evaluates the influence of motor learning techniques in patients with primary cervical dystonia.
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.