Dados do Trabalho

Título

AN UNUSUAL PRESENTATION OF LEVODOPA-RESPONSIVE DYSTONIA ASSOCIATED WITH A VARIANT OF UNCERTAIN SIGNIFICANCE IN THE GCH1 GENE

Apresentação do caso único

Case presentation: An 11-year-old female began experiencing a burning pain in her lower limbs at the age of 6, with walking problems. Symptoms worsened at the end of the day. Upon examination, she had slight fine tremors in her extremities, exacerbated by muscle contraction, and fatigue. At the age of 9, she underwent electromyography, which was normal, as well as dorsal and lumbar spinal cord MRIs. Her mother had previously been diagnosed with dopa-responsive dystonia (Segawa syndrome) and had been on levodopa with benserazide since then. Genetic testing for neuromuscular diseases revealed a variant of uncertain significance (VUS) in the GCH1 gene in heterozygosity, at position chr14:54,845,855, G > C variation, resulting in c.542-3> G ENST00000491895. This variant, not previously reported in the literature, was assessed as potentially deleterious with likely splice acceptor site loss. Following the initiation of levodopa, the patient consistently experienced relief from pain symptoms, though she still had significant diurnal symptom variation.

Discussão

Discussion: Dopa-responsive dystonia (DRD), also known as Segawa syndrome, is a rare treatable monogenic cause of dystonia. Diagnosis is often delayed, due to the disease being commonly mistaken for cerebral palsy, which impacts patient outcomes, as early treatment is associated with better prognosis. Therefore, early recognition of the disease is crucial. The most common subtype of DRD is the AD GCH-1 deficiency, which presents as childhood-onset dystonia, linked to mutations in the GCH1 gene with autosomal dominant inheritance. Positive diagnostic features include a good response to L-dopa therapy and diurnal fluctuation of episodes, affecting 50% or more of patients. Our patient had an atypical presentation without visible dystonia during clinical examination; pain was the main symptom, varying throughout the day and responding well to the initiation of levodopa. Although pain is not typically recognized as a major symptom in Segawa syndrome, it can be a consequence of the dystonia itself.

Comentários finais

Conclusion: As a rare disease first described in 1971, dopa-responsive dystonia may still harbor undiscovered pathogenic variants. While additional reports are needed to classify the VUS identified in this case presentation as pathogenic, this study may represent a first step towards uncovering still undescribed mutations associated with DRD.

Referências

1. Weissbach A, Pauly MG, Herzog R, Hahn L, Halmans S, Hamami F, Bolte C, Camargos S, Jeon B, Kurian MA, Opladen T, Brüggemann N, Huppertz HJ, König IR, Klein C, Lohmann K. Relationship of Genotype, Phenotype, and Treatment in Dopa-Responsive Dystonia: MDSGene Review. Mov Disord. 2022 Feb;37(2):237-252. doi: 10.1002/mds.28874. Epub 2021 Dec 15. PMID: 34908184.

2. Kim R, Jeon B, Lee WW. A Systematic Review of Treatment Outcome in Patients with Dopa-responsive Dystonia (DRD) and DRD-Plus. Mov Disord Clin Pract. 2016 Jun 6;3(5):435-442. doi: 10.1002/mdc3.12361. PMID: 30363598; PMCID: PMC6178724.

3. Wijemanne, S., Jankovic, J. Dopa-responsive dystonia—clinical and genetic heterogeneity. Nat Rev Neurol 11, 414–424 (2015). https://doi.org/10.1038/nrneurol.2015.86

Palavras Chave

Segawa; dystonia; dopa-responsive dystonia