Genetic and clinical profile of a Brazilian cohort of dopa-responsive dystonia

Abstract

Background

Dopa-responsive dystonia (DRD) is a rare genetic and neurotransmitter disorder also known as Segawa Disease. The guanosine triphosphate cyclohydrolase 1 (GCH1) gene variants, inherited in an autosomal dominant pattern, are the most common cause of DRD.

Objectives

To describe the genetic and clinical profile of a Brazilian cohort of DRD patients.

Methods

Twenty-two patients were recruited from the SARAH Network of Rehabilitation Hospitals. A retrospective analysis of phenotype-genotype correlation from the next generation sequencing (NGS) genetic test alongside clinical features and evolution were performed. Clinical measures included: age at the disease onset, gender, time of diagnosis, response to Levodopa medication, behavioral symptoms related to psychiatric disorders.

Results

Variants in genes associated with DRD were detected in 17 patients (77 %), of which 16 (94 %) presented variants in the GCH1 gene (pathogenic variants, n = 10; likely pathogenic variants, n = 6) and, 1 (5 %) in the tyrosine hydroxylase (TH) gene. The average age at disease onset was 7.8 years, with a predominant diagnosis in females, accompanied by a significant delay. A moderate positive response to a low dosage of Levodopa was observed. Patients also reported severe behavioral symptoms related to psychiatric disorders and use of medication.

Conclusions

The autosomal dominant DYT/PARK-GCH1 was the most prevalent subtype. Not all patients were characterized with typical phenotypes contributing to the significant diagnosis delay. Uncommon occurrences of behavioral symptoms and Levodopa-induced dyskinesias were also found. Particular attention is suggested to the autosomal recessive form of the GCH1.