Which dystonic gene is associated with blepharospasm with retrocollis?

Blepharospasm with Retrocollis: Associated Dystonic Genes

The specific dystonic gene associated with blepharospasm combined with retrocollis (or anterocollis) remains unidentified, as this represents a distinct subphenotype of segmental craniocervical dystonia that does not map to known dystonia loci including DYT1, DYT6, DYT7, DYT13, or THAP1. 1, 2

Clinical Characterization

This combination represents a unique subphenotype of segmental craniocervical dystonia with specific features:

• Blepharospasm typically appears first (in approximately 85% of cases), followed by spread to cervical muscles 1
• The cervical dystonia component predominantly manifests as anterocollis rather than retrocollis, though both can occur 1
• Disease remains confined to the craniocervical region without spread to limbs or trunk, even when laryngeal or lower facial muscles become involved 1
• Family history of dystonia is present in approximately 57% of cases, suggesting genetic contribution 1

Genetic Investigation Results

Genes Excluded in This Subphenotype

Comprehensive genetic testing has systematically excluded the major known dystonia genes:

• DYT1 (TorsinA gene): No mutations identified in patients with this specific subphenotype 1, 2
• THAP1: Negative for mutations 1
• DYT6, DYT7, and DYT13 loci: Linkage analysis excluded segregation with these known primary torsion dystonia loci 2

Genetic Studies in Isolated Blepharospasm

Research examining isolated blepharospasm (without the specific retrocollis/anterocollis component) has shown:

• DYT1 polymorphisms: Inconsistent associations across populations, with some evidence in Italian cohorts but not in North American series 3
• DRD5 (D5 dopamine receptor): No consistent association identified 3
• Inheritance pattern: When familial, blepharospasm follows autosomal dominant inheritance with reduced penetrance 2

Clinical Implications

Diagnostic Approach

When evaluating a patient presenting with blepharospasm and cervical dystonia:

• Document the temporal sequence: Determine which symptom appeared first and the interval to spread 1
• Characterize the cervical dystonia pattern: Specifically note whether anterocollis, retrocollis, laterocollis, or torticollis predominates 1
• Assess for apraxia of eyelid opening: This frequently accompanies blepharospasm in this subphenotype 1
• Obtain detailed family history: Document any movement disorders in first- and second-degree relatives 1, 2
• Examine for spread beyond craniocervical region: The absence of limb or truncal involvement supports this specific subphenotype 1

Genetic Testing Considerations

• Current genetic testing has limited yield for this specific subphenotype, as the causative gene(s) remain unmapped 1, 2
• Testing for known dystonia genes (DYT1, THAP1) is unlikely to be informative based on available evidence 1
• Genetic counseling should emphasize: The likely genetic contribution given familial clustering, but acknowledge that specific genetic testing is not yet available 1, 2

Therapeutic Challenges

This subphenotype presents specific treatment difficulties:

• Blepharospasm component is particularly refractory: Often requires both surgical myectomy and substantial botulinum toxin doses to pretarsal orbicularis oculi muscles 1
• Deep brain stimulation may benefit the cervical component: One reported case showed marked improvement in anterocollis with DBS 1
• Standard botulinum toxin protocols may be insufficient: Higher doses and more frequent injections are typically needed compared to isolated blepharospasm 1

Pathophysiological Considerations

While the specific gene remains unknown, the clinical features suggest:

• Network disorder involving multiple brain regions: Beyond isolated basal ganglia dysfunction, evidence points to involvement of brainstem, cerebellum, and cortical areas 4, 5
• Basal ganglia and mesencephalic/diencephalic dysfunction: Secondary cases from focal lesions in these regions support their role in pathophysiology 5
• Distinct from other adult-onset focal dystonias: The specific pattern of spread and therapeutic resistance suggests unique underlying mechanisms 1, 2

The identification of this as a distinct subphenotype is clinically important for prognostication and treatment planning, even though the specific genetic etiology remains to be discovered. 1, 2