TY - JOUR
T1 - Relationship of Genotype, Phenotype, and Treatment in Dopa-Responsive Dystonia
T2 - MDSGene Review
AU - Weissbach, Anne
AU - Pauly, Martje G
AU - Herzog, Rebecca
AU - Hahn, Lisa
AU - Halmans, Sara
AU - Hamami, Feline
AU - Bolte, Christina
AU - Camargos, Sarah
AU - Jeon, Beomseok
AU - Kurian, Manju A
AU - Opladen, Thomas
AU - Brüggemann, Norbert
AU - Huppertz, Hans-Jürgen
AU - König, Inke R
AU - Klein, Christine
AU - Lohmann, Katja
N1 - Funding Information: : The study was supported by the Movement Disorder Society to C.K. and K.L.; by the Deutsche Forschungsgemeinschaft (FOR 2488) to C.K., I.R.K., M.A.K., K.L., and N.B., (SFB936 project C5) to C.K., and (WE 5919/2‐1) to A.W.; and by the Else Kröner‐Fresenius Foundation (EKFS, 2018_A55) to A.W. Funding agencies Publisher Copyright: © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
PY - 2022/2
Y1 - 2022/2
N2 - Background: Pathogenic variants in 5 genes (GCH1, TH, PTS, SPR, and QDPR), involved in dopamine/tetrahydrobiopterin biosynthesis or recycling, have been linked to Dopa-responsive dystonia (DRD). Diagnosis and treatment are often delayed due to high between- and within-group variability. Objectives: Comprehensively analyzed individual genotype, phenotype, treatment response, and biochemistry information. Methods: 734 DRD patients and 151 asymptomatic GCH1 mutation carriers were included using an MDSGene systematic literature review and an automated classification approach to distinguish between different forms of monogenic DRDs. Results: Whereas dystonia, L-Dopa responsiveness, early age at onset, and diurnal fluctuations were identified as red flags, parkinsonism without dystonia was rarely reported (11%) and combined with dystonia in only 18% of patients. While sex was equally distributed in autosomal recessive DRD, there was female predominance in autosomal dominant DYT/PARK-GCH1 patients accompanied by a lower median age at onset and more dystonia in females compared to males. Accordingly, the majority of asymptomatic heterozygous GCH1 mutation carriers (>8 years of age) were males. Multiple other subgroup-specific characteristics were identified, showing high accuracy in the automated classification approach: Seizures and microcephaly were mostly seen in DYT/PARK-PTS, autonomic symptoms appeared commonly in DYT/PARK-TH and DYT/PARK-PTS, and sleep disorders and oculogyric crises in DYT/PARK-SPR. Biochemically, homovanillic acid and 5-hydroxyindoleacetic acid in CSF were reduced in most DRDs, but neopterin and biopterin were increased only in DYT/PARK-PTS and DYT/PARK-SPR. Hyperphenylalaninemia was seen in DYT/PARK-PTS, DYT/PARK-QDPR, and rarely reported in autosomal recessive DYT/PARK-GCH1. Conclusions: Our indicators will help to specify diagnosis and accelerate start of treatment.
AB - Background: Pathogenic variants in 5 genes (GCH1, TH, PTS, SPR, and QDPR), involved in dopamine/tetrahydrobiopterin biosynthesis or recycling, have been linked to Dopa-responsive dystonia (DRD). Diagnosis and treatment are often delayed due to high between- and within-group variability. Objectives: Comprehensively analyzed individual genotype, phenotype, treatment response, and biochemistry information. Methods: 734 DRD patients and 151 asymptomatic GCH1 mutation carriers were included using an MDSGene systematic literature review and an automated classification approach to distinguish between different forms of monogenic DRDs. Results: Whereas dystonia, L-Dopa responsiveness, early age at onset, and diurnal fluctuations were identified as red flags, parkinsonism without dystonia was rarely reported (11%) and combined with dystonia in only 18% of patients. While sex was equally distributed in autosomal recessive DRD, there was female predominance in autosomal dominant DYT/PARK-GCH1 patients accompanied by a lower median age at onset and more dystonia in females compared to males. Accordingly, the majority of asymptomatic heterozygous GCH1 mutation carriers (>8 years of age) were males. Multiple other subgroup-specific characteristics were identified, showing high accuracy in the automated classification approach: Seizures and microcephaly were mostly seen in DYT/PARK-PTS, autonomic symptoms appeared commonly in DYT/PARK-TH and DYT/PARK-PTS, and sleep disorders and oculogyric crises in DYT/PARK-SPR. Biochemically, homovanillic acid and 5-hydroxyindoleacetic acid in CSF were reduced in most DRDs, but neopterin and biopterin were increased only in DYT/PARK-PTS and DYT/PARK-SPR. Hyperphenylalaninemia was seen in DYT/PARK-PTS, DYT/PARK-QDPR, and rarely reported in autosomal recessive DYT/PARK-GCH1. Conclusions: Our indicators will help to specify diagnosis and accelerate start of treatment.
KW - GCH1
KW - MDSGene
KW - PTS
KW - QDPR
KW - SPR
KW - TH
KW - automated classification
KW - dopa-responsive dystonia
KW - genetics
UR - http://www.scopus.com/inward/record.url?scp=85121354264&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/mds.28874
DO - https://doi.org/10.1002/mds.28874
M3 - Review article
C2 - 34908184
SN - 0885-3185
VL - 37
SP - 237
EP - 252
JO - Movement disorders
JF - Movement disorders
IS - 2
ER -