DYT-GNAL

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.