Neuropsychiatric and sleep study in autosomal dominant dopa-responsive dystonia

Abstract

Introduction: Although the diurnal fluctuation of motor dysfunction, reversible with small doses of dopamine, is a cornerstone for the phenotype of the autosomal dominant Segawa syndrome, the non-motor symptoms of this neurotransmitter deficiency have still received limited attention.

Objective: This study aims to evaluate non-motor symptoms of this dopa-responsive dystonia through an intrafamilial comparative cross-sectional study.

Methods: Seventeen individuals with a c.IVS5 + 3insT (c.626 + 3insT) variation in the GTP cyclohydrolase-1 gene (GCH1, HGNC: 4193) and 34 intrafamilial controls were studied using the Beck Depression Inventory-II, the Wiener Matrizen Test 2, the Epworth Sleepiness Scale, the Pittsburgh Sleep Quality Index, the MINI/MINI PLUS Questionnaires, the World Health Organization Quality of Life - BREF Instrument and a drug use assessment questionnaire.

Results: No significant difference was found between the groups in the prevalence of sleep disorders and in cognitive function. Nevertheless, generalized anxiety disorder (p = 0.050) and attention-deficit/hyperactivity disorder in childhood (p = 0.011) were observed only in individuals without the molecular variation. The group with the GCH1 variation presented a worse perception about how safe they feel in their daily lives (p = 0.034), less satisfaction with themselves (p = 0.049) and with their relationships (p = 0.029), and a higher prevalence of past major depressive episodes before use of L-Dopa (p = 0.046).

Conclusion: Low dopamine could have been protective against generalized anxiety disorder and attention-deficit/hyperactivity disorder in childhood in Segawa group individuals. The prevalence of depression was higher in individuals with the molecular variant prior to the L-Dopa treatment. Considering it, the penetrance estimates for the variant carriers increased from 58.8% to up to 88% in this large studied family. Additionally, neuropsychiatric tests of all individuals with a molecular diagnosis in an affected family are a valuable instrument for its clinical management.

Keywords: ADHD CHD, Attention deficit/hyperactivity disorder in childhood.; Autosomal dominant GPCH1 deficiency; Autosomal dominant familial dystonia; BDI-II, Beck Depression Inventory – II.; BH4, Tetrahydrobiopterin cofactor.; DRD, Dopa-responsive dystonia.; DYT/PARK-GCH1, Dopa-responsive dystonia syndrome caused by GTP cyclohydrolase-1 gene variation.; DYT5a, Autosomal dominant Segawa syndrome.; Dystonia, Dopa-responsive; Dystonic disorders; ESS, Epworth Sleepiness Scale.; GAD, Generalized Anxiety Disorder.; GCH1, The official gene symbol approved by the HGNC for GTP cyclohydrolase-1 gene.; GTP Cyclohydrolase-1, guanosine triphosphate cyclohydrolase-1 enzyme.; HGNC 4193, HGNC ID for gene of the GTP cyclohydrolase-1.; L-Dopa, Levodopa.; MDE PAST, Past major depressive episode.; MDE, Major depressive episode.; MINI/MINI PLUS, Mini International Neuropsychiatric Interview.; Mental disorders; NMS, non-motor symptoms; NSG, Non-Segawa group.; PSQI, Pittsburgh Sleep Quality Index.; SG, Segawa group.; Sleep-wake disorders; WHOQOL-BREF, World Health Organization Quality of Life - BREF instrument.; WMT-2, Vienna Matrix Test 2..