Síndrome de Segawa: aprimoramento do fenótipo e proposta de gestão de casos

Abstract

Introduction: The ultra-rare Segawa syndrome, or dopa-responsive dystonia (DRD) caused by heterozygous variants in the GTP cyclohydrolase 1 gene (AD DYT/PARK-GCH1), shows known motor manifestations and non-motor symptoms (NMS) less studied. Objectives: To expand the knowledge of the clinical and laboratory manifestations of this syndrome, helping to define its incomplete penetrance and the relevance of levodopa/other psychotropic drugs in its phenotype. Propose case management technology for affected individuals. Methods: 1) Relatives with the clinical and/or genetic diagnosis of the IVS5+3insT variant in heterozygosity in the GTP cyclohydrolase 1 gene (n = 16-23) and intrafamilial control group (n = 12-21); 2) Historical review of NMS in AD DYT/PARK-GCH1; 3) Investigation of NMS, by validated forms, and related drugs in individuals with the variant; 4) Investigation of serum levels of amino acids (and their estimated brain inflows), serotonin and daytime/nighttime melatonins, considering the use of levodopa/other psychotropic drugs, interfaced with related master's evaluations; 5) Investigation of mixed anxiety-depressive disorder and restless legs syndrome (RLS), by validated forms; 6) Case management of individuals with AD DYT/PARK-GCH1, through systematized tools, including pregnant women with RLS. Results: Depressive symptoms stood out in the review and thesis. Considered NMS, they increased the estimated penetrance of AD DYT/PARK-GCH1 from 58.80 to 88.20% in this family. In individuals with the genetic variant, the average estimated brain influx of phenylalanine was higher (p = 0.015), and, if levodopa users, the mean level of tryptophan was lower (p = 0.046). Levodopa use was correlated with lower nocturnal melatonin levels compared to the other individuals with the variant (p = 0.031), being able to change other studied correlations between pairs of variables. There was no clear association between individuals with the AD DYT/PARK-GCH1 and mixed anxiety-depressive disorder or RLS, possibly due to confounding factors. Two primiparous women with DRD and RLS using levodopa had babies with head circumference at the 5.59th percentile, caught up in the first month, with proper development, and breastfeeding. The case management of other individuals, named "Management of Rare Lives" (MRL), reduced the motor symptoms of DRD (only one case maintained poor response) and RLS (in 50% of those reevaluated in the first monitoring and in 100% in the second one; with mean severity 44.87% lower in the fourth monitoring compared to the beginning). Regarding the initial assessment, the MRL also reduced depressive symptoms (in 53.85% of the individuals and 17.20% of the mean score), anergy/abulia/apathy (in 38.38/31.55/81.75%), and the percentage of individuals with altered impulsivity scale (33.33 to 15.38%). Conclusions: Depressive symptoms increased incomplete penetrance. Levodopa use influenced proposed laboratory and clinical evaluations (such as RLS and NMS). The increased cerebral influx of phenylalanine may be a diagnostic biochemical marker in individuals with the variant. In these, associations such as the use of levodopa and lower nocturnal serum melatonin should be deeper investigated, by supposed benefits such as melatonin intake for a better quality of life. Case management proved to be effective, including in pregnant/nursing women with RLS using levodopa, and applicable to other rare diseases.