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 - 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. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
UR - http://www.scopus.com/inward/record.url?scp=85121354264&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/25aa6ae4-ef46-39c7-bfa5-99d311ee9536/
U2 - 10.1002/mds.28874
DO - 10.1002/mds.28874
M3 - Scientific review articles
C2 - 34908184
SN - 0885-3185
VL - 37
SP - 237
EP - 252
JO - Movement disorders : official journal of the Movement Disorder Society
JF - Movement disorders : official journal of the Movement Disorder Society
IS - 2
ER -
