A number sign (#) is used with this entry because of evidence that dystonia-33 (DYT33) can be caused by heterozygous mutation in the EIF2AK2 gene (176871) on chromosome 2p22. One patient with a homozygous mutation has been reported.

Dystonia-33 (DYT33) is a neurologic disorder characterized by onset of focal or generalized dystonia in the first decades of life (from early childhood to adolescence). The disorder is slowly progressive and may result in ambulation difficulties, dysarthria, or dysphagia. There is variable expressivity even with a family, as well as incomplete penetrance of the phenotype. Most mutations are in the heterozygous state, but a homozygous mutation with autosomal recessive inheritance has been reported, indicating variable patterns of transmission of DYT33. Some patients may have a more complex neurologic disorder with motor delay, lower limb spasticity, mild developmental delay with cognitive impairments, and nonspecific brain imaging abnormalities. There may be an exacerbation of the symptoms coinciding with viral infection or stress. Deep brain stimulation (DBS) may be therapeutic (summary by Kuipers et al., 2021).

Kuipers et al. (2021) reported a large multigenerational consanguineous Taiwanese family (family A) in which 7 individuals had onset of focal or generalized dystonia between 4 and 18 years of age. The dystonia was inherited in an autosomal dominant pattern. The site of onset was usually in the hands or feet, later affecting the trunk, limbs, and occasionally the larynx. An unrelated German boy (family B) had a similar pure dystonia phenotype. There was evidence of variable expressivity, as some patients had only focal dystonia and others had generalized dystonia. Brain imaging in these patients was normal, and none had additional neurologic signs or symptoms. Three patients were treated with DBS.

Musacchio et al. (2021) reported a 3-generation German family in which 4 individuals had DYT33. The phenotype and severity were variable. The most severely affected patient was the 10-year-old proband who developed leg dystonia at age 2 years that rapidly progressed to generalized dystonia with involvement of all 4 extremities, the trunk, and the larynx. At 3 years and 9 months of age, she underwent bilateral DBS electrode implantation in the globus pallidus internus, leading to sustained symptom relief. The proband's mother and maternal uncle had onset of dystonia in childhood or adolescence, sometimes requiring wheelchair use in the mother. Symptoms were progressive in the mother after birth of the proband, with spreading of dystonia to the trunk, neck, and orofacial region, resulting in anarthria. DBS implantation in the symptomatic mother and maternal uncle resulted in significant clinical improvement. The proband's grandmother had onset of blepharospasm and spasmodic dysphonia in late adulthood; she did not require treatment.

Magrinelli et al. (2021) reported a 28-year-old Algerian man who had onset of dystonic hand posturing and head tremor at 17 years of age. Other features included gait difficulties, abnormal trunk posture or extension while walking, dysphagia, myopia, and scoliosis. No pyramidal, cerebellar, or cognitive signs were observed. The dystonia did not respond to levodopa treatment, but showed a 40% improvement with DBS of the globus pallidus over a 3-year period.

Clinical Variability

Kuipers et al. (2021) reported 3 unrelated patients with DYT33 associated with additional neurologic findings, including spasticity with hyperreflexia and extensor plantar responses. A 6-year-old Canadian boy (family C) had axial hypotonia, developmental delay, and mild cognitive deficits. He had onset of hand tremor at age 3.5 years, followed by generalized dystonic posturing ultimately resulting in loss of ambulation. There was a stepwise exacerbation of symptoms following viral infections and/or surgical intervention. Other features included dysarthria, dysphagia, language delay, and proximal muscle weakness. Brain imaging showed abnormal lesions at the bulbomedullary junction. He carried a heterozygous missense variant in the EIF2AK2 gene (G130R) that was also present in unrelated patients with pure dystonia without additional neurologic features. An 18-year-old man of Ashkenazi and Moroccan descent (family D) had onset of dystonia in the first year of life. It became generalized and he had walking difficulties. He also had spasticity, pes cavus, and nonspecific hyperintense foci on brain imaging. His mother reported mild transient muscle cramps and numbness. These patients carried a heterozygous G138A variant in the EIF2AK2 gene.

Kuipers et al. (2021) also reported a 42-year-old man, born of consanguineous Italian parents (family E), with a complicated form of DYT33 associated with a homozygous mutation in the EIF2AKA2 gene. He had delayed motor development with walking at age 3 years, seizures in the first years of life that resolved, and impaired intellectual development. At age 5 years, he developed slowly progressive generalized dystonia with severe retrocollis after a febrile illness. He lost independent ambulation as an adult; he also had lower limb spasticity with extensor plantar responses, dysarthria, dysphagia, and reduced vertical upgaze. Brain imaging showed frontal-parietal atrophy and signal abnormalities in the posterior periventricular white matter.

The transmission pattern of DYT33 in 3 of the families reported by Kuipers et al. (2021) was consistent with autosomal dominant inheritance with incomplete penetrance and variable expressivity. One patient (family C) carried a heterozygous de novo mutation in the EIF2AK2 gene. Another family (family E) showed autosomal recessive inheritance of DYT33.

In 9 patients from 3 unrelated families with DYT33, Kuipers et al. (2021) identified a heterozygous G130R mutation in the EIF2AK2 gene (176871.0006). The mutation, which was found by a combination of linkage analysis (in 1 family) and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families, although there was evidence of incomplete penetrance. It was not present in public databases, including gnomAD. The mutation was inherited in an autosomal dominant pattern in 1 family, was inherited from an unaffected parent in a second family, and occurred de novo in the third family. Analysis of other patient cohorts identified a different heterozygous missense variant (G138A) in a mother and son with the disorder. Functional studies of this variant were not performed. The authors also identified a homozygous missense variant (N32T; 176871.0007) in a patient with DYT33 who had additional neurologic abnormalities. Fibroblasts derived from patients with the G130R and N32T variants stimulated with poly(I:C) showed sustained and significantly increased levels of phosphorylated EIF2AK2 and EIF2A (609234) compared to controls, consistent with persistent activation of this pathway and prolonged activation of the integrated stress response (ISR). The findings indicated variable inheritance patterns and variable expressivity of the disorder, which may be due to environmental factors. The G130R and N32T substitutions occurred at residues in the dsRNA-binding domain that are not well conserved, and the authors emphasized that in silico analysis did not predict the variants to be functionally damaging. The authors concluded that this gene lacks evolutionary conservation, suggesting that it has acquired special functions in the recent evolution of primates. The accelerated evolution and species specificity may be related to the involvement of this protein in the cellular response to viral infections and its coevolution with infecting viruses.

In 3 members of a 3-generation German family with DYT33, Musacchio et al. (2021) identified a heterozygous G130R mutation in the EIF2AK2 gene using exome sequencing. The authors stated that it was the same mutation identified by Kuipers et al. (2021) in several of their families. Functional studies and studies of patient cells were not performed by Musacchio et al. (2021), but the authors noted that Kuipers et al. (2021) demonstrated a gain-of-function effect for the variant.

In a 28-year-old Algerian man with adolescent-onset DYT33, Magrinelli et al. (2021) identified a de novo heterozygous c.388G-C transversion in the EIF2AK2 gene, resulting in a gly130-to-arg substitution (G130R; 176871.0008). The mutation, which was found by whole-exome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the same amino acid substitution (G130R) resulting from a different nucleotide change (c.388G-A) had been reported in other DYT33 patients (G130R; 176871.0006).