Genetic Screening of a Hungarian Cohort with Focal Dystonia Identified Several Novel Putative Pathogenic Gene Variants

Abstract

Dystonia is a rare movement disorder which is characterized by sustained or intermittent muscle contractions causing abnormal and often repetitive movements, postures, or both. The two most common forms of adult-onset focal dystonia are cervical dystonia (CD) and benign essential blepharospasm (BSP). A total of 121 patients (CD, 74; BSP, 47) were included in the study. The average age of the patients was 64 years. For the next-generation sequencing (NGS) approach, 30 genes were selected on the basis of a thorough search of the scientific literature. Assessment of 30 CD- and BSP-associated genes from 121 patients revealed a total of 209 different heterozygous variants in 24 genes. Established clinical and genetic validity was determined for nine heterozygous variations (three likely pathogenic and six variants of uncertain significance). Detailed genetic examination is an important part of the work-up for focal dystonia forms. To our knowledge, our investigation is the first such study to be carried out in the Middle-European region.

Genetic Update and Treatment for Dystonia

“…However, in the Hungarian cohort study, it was found in a higher prevalence than previously reported. All three mutations identified there (c.677G>T (p.Cys226Phe), c.1315G>A (p.Val439Met) and c.1288G>A (p.Ala430Thr)) are thought to be pathogenic, and the clinical profile fits the characteristics already linked with GNAL variants [46]. (e) ANO3 (anoctamin-engaged in calcium homeostasis) ANO3-linked dystonia has an autosomal-dominant inheritance pattern, yet only heterozygous variations have been identified.…”

Focal Dystonia – an Update of Genetic Background and Novel Treatment

“…The GNAL c.677G>T (p.Cys226Phe) variant was discovered in a male patient who has had leftsided neck pain, right-directed laterocollis, torticollis, and mild retrocollis since the age of 27 [42].…”

“…The symptoms of a female patient with another GNAL c.1315G>A (p.Val439Met) variation began when she was 30 years old. The patient complained that her head began to move slightly to the left and that it became more and more challenging for her to keep it in a neutral position [42].…”

“…She tried BoNT and deep cerebral stimulation but neither worked. The patient's concerns indicate that the disease progresses [42].…”

“…Since the age of 41, one male patient with the c.2276-6T>C ANO3 splice region mutation has developed focal dystonia, left-sided torticollis, right-sided laterocaput, and dysarthria, but it was a variant of uncertain significance. There were no family members available for testing [42].…”