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.
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:
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].
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
View in own window
| 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:
Burke-Fahn-Marsden dystonia rating scale (BFMDRS) Unified Dystonia Rating Scale (UDRS) Global Dystonia Rating Scale (GDS)
For cervical dystonia: Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) & Comprehensive Cervical Dystonia Rating Scale (CCDRS) |
| 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.
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:
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:
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.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Risk to Family Members – Autosomal Dominant Inheritance
Parents of a proband
About 65% of individuals diagnosed with DYT-GNAL have a parent with dystonia (significant clinical variability is observed within families).
Some individuals diagnosed with DYT-GNAL have the disorder as the result of a
de novo GNAL pathogenic variant [
Dobričić et al 2014]. Because simplex cases (i.e., a single occurrence in a family) have not been evaluated sufficiently to determine if the pathogenic variant occurred
de novo in the proband or was transmitted by a heterozygous, asymptomatic parent, the proportion of DYT-GNAL caused by a
de novo pathogenic variant is unknown.
Molecular genetic testing is recommended for the parents of a proband with an apparent de novo
GNAL pathogenic variant.
If the GNAL pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Though theoretically possible, no instance of a proband inheriting a pathogenic variant from a parent with germline mosaicism has been reported.
The family history of some affected individuals may appear to be negative for DYT-GNAL because of failure to recognize the disorder in family members. Because features of DYT-GNAL may not develop in individuals who are heterozygous for the GNAL pathogenic variant due to reduced penetrance or death before the onset of manifestations, molecular genetic testing is required to clarify the genetic status of parents of a proband.
Sibs of a proband. The risk to the sibs of a proband with heterozygous DYT-GNAL depends on the genetic status of the proband's parents.
If the parents have been tested for the GNAL pathogenic variant identified in the proband and:
A parent of the proband has the
GNAL pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Sibs who inherit the pathogenic variant will likely develop dystonia; however, adults heterozygous for a
GNAL pathogenic variant have been reported to be unaffected [
Fuchs et al 2013,
Vemula et al 2013,
Putzel et al 2016]. There is large phenotypic variability within families (see
Clinical Description,
Intrafamilial phenotypic variability).
The
GNAL pathogenic variant cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
Rahbari et al 2016].
If the parents have not been tested for the GNAL pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for DYT-GNAL because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.
Offspring of a proband
Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has the GNAL pathogenic variant, his or her family members may be at risk.
Prenatal Testing and Preimplantation Genetic Testing
Once the GNAL pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. Note: Because of reduced penetrance and variable expressivity, the results of prenatal testing may not be useful in accurately predicting the onset or severity of DYT-GNAL.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Table A.
DYT-GNAL: Genes and Databases
View in own window
Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
Table B.
View in own window
|
139312 | GUANINE NUCLEOTIDE-BINDING PROTEIN, ALPHA-ACTIVATING ACTIVITY POLYPEPTIDE, OLFACTORY TYPE; GNAL |
|
615073 | DYSTONIA 25; DYT25 |
Gene structure.
GNAL spans more than 80 kb [Vuoristo et al 2000, Vemula et al 2013]. Alternative splicing results in multiple transcript variants encoding different isoforms (1-3). Transcript variant 1 (NM_182978.3) is the longest and encodes the longest protein, isoform 1 (NP_892023.1, 458 amino acids). Isoform 2 (NP_001135811.1, 381 amino acids) is encoded by transcript variant 3 (NM_001142339.2); it is the major transcript, and it differs in the 5'UTR compared to variant 1. Isoforms 1 and 2 differ in exon 1. Transcript variant 5 (NM_001261444.1) lacks a large portion of the 5' coding region and encodes a shorter protein, isoform 3 (NP_001248373.1, 174 amino acids), which is not found in the brain. For a detailed summary of gene, transcript, and protein information, see Table A, Gene.
Benign variants. An intronic splice site variant was found in a Chinese female with cervical dystonia (c.932-7T>G) [Miao et al 2013]; the variant was originally considered likely pathogenic, since in silico analyses showed that this variant may affect the splice efficiency with exon 11 skipping. Although intronic variants that do not affect conserved splice sites are generally considered non-pathogenic, this variant is considered likely benign as Dufke et al [2014] found the variant in 19/137 patients, corresponding to the frequency given in public databases. LeDoux et al [2016] found the variant in 74 patients and classified it as benign (American College of Medical Genetics and Genomics [ACMG] standards published in Richards et al [2008]).
Variants of unknown significance.
Ma et al [2015] reported one missense variant of unknown significance.
Pathogenic variants. Currently, 30 different pathogenic variants causing DYT-GNAL have been described, including three missense variants reported as "likely pathogenic" [Richards et al 2008, LeDoux et al 2016]. Pathogenic variants are missense (n = 15), nonsense (n = 5), and frameshift (n = 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].
In addition, one splice site variant [Fuchs et al 2013, Zech et al 2015], one in-frame deletion [Fuchs et al 2013], and one start codon disruption [Vemula et al 2013] were reported.
Twenty-eight pathogenic variants were found only in a single family. Two pathogenic variants were reported in two independent studies: c.274-5T>C [Fuchs et al 2013, Zech et al 2015] and c.733C>T [Vemula et al 2013, Dufke et al 2014].
Table 4.
GNAL Variants Discussed in This GeneReview
View in own window
| Variant Classification | DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
|---|
|
Likely benign
| c.932-7T>G | |
NM_001142339.2
NP_001135811.1
|
|
Pathogenic
| c.274-5T>C | |
| c.733C>T | p.Arg245Ter |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product. Guanosine triphosphate (GTP) binding proteins (G proteins) are heterotrimers composed of three subunits: the α-, β-, and γ-subunits [McCudden et al 2005]. G proteins are categorized into four subfamilies according to their α-subunits (Gαs, Gαi/o, Gαq, and Gα12). Gα(olf) is regarded as a member of the Gαs family.
GNAL encodes the stimulatory G-alpha subunit Gα(olf) of the G protein. Gα(olf) contains guanine nucleotide binding sites. It couples dopamine type 1 receptors of the direct pathway and adenosine A2A receptors of the indirect pathway to the activation of adenylate cyclase type 5 and to histone H3 phosphorylation. Stimulation of the D1 receptor by dopamine leads to the dissociation of Gα(olf) from the heterotrimer. Gα(olf) is assumed to harbor a Ras-like domain that mediates guanosine triphosphate (GTP) binding. It catalyzes the exchange of guanosine diphosphate to GTP.
Gα(olf) was first identified in the olfactory epithelium as a G protein subunit that mediates odorant signaling. It was later found to be widely expressed in the brain, especially in motor regions that have been linked to dystonia pathogenesis. Gα(olf) is expressed at high levels in the striatum (striatal medium spiny neurons, MSNs), postsynaptically in dopaminoceptive neurons and/or cholinergic interneurons (reviewed by Fuchs et al [2013]). It was also found to be highly expressed in cerebellar Purkinje cells, where it co-localizes with corticotropin-releasing hormone receptors; further brain regions with high Gα(olf) expression include the olfactory bulb, thalamus, and substantia nigra [Vemula et al 2013].
Abnormal gene product. The efficiency of the formation of the G protein heterotrimer and the coupling to D1 dopamine receptors was shown to be impaired in vitro by GNAL pathogenic variants [Fuchs et al 2013]. Thus, a loss-of-function mechanism of the altered Gα(olf) protein is assumed to cause DYT-GNAL. Missense variants that lead to amino acid changes near a GTP binding site may result in the disturbance or disruption of binding GTP [Dobričić et al 2014]. Impaired dopaminergic and cholinergic transmission is assumed to result from GNAL loss-of-function variants. Loss of Gα(olf) function may further disturb the G1-S cell cycle control [Vemula et al 2013].
GNAL
null mice were reported to be anosmic [Belluscio et al 1998].
