Anne Weissbach1,2, Martje G Pauly1,2,3, Rebecca Herzog2,3, Lisa Hahn1,2, Sara Halmans2, Feline Hamami2, Christina Bolte2, Sarah Camargos4, Beomseok Jeon5, Manju A Kurian6, Thomas Opladen7, Norbert Brüggemann1,3, Hans-Jürgen Huppertz8, Inke R König9, Christine Klein1, Katja Lohmann1. 1. Institute of Neurogenetics, University of Lübeck, Lübeck, Germany. 2. Institute of Systems Motor Science, University of Lübeck, Lübeck, Germany. 3. Department of Neurology, University Hospital Schleswig Holstein, Lübeck, Germany. 4. Department of Internal Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. 5. Department of Neurology, Seoul National University College of Medicine, Seoul, South Korea. 6. Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, United Kingdom. 7. Division of Child Neurology and Metabolic Disorders, University Children's Hospital, Heidelberg, Germany. 8. Swiss Epilepsy Center, Klinik Lengg AG, Zurich, Switzerland. 9. Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck, Germany.
Abstract
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.
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.
Authors: Ailton C Alves Júnior; Maurício V Daker; Alexei M C Machado; Alan S Luna; Dirceu C Valladares Neto; Eugenia R Valadares Journal: Mol Genet Metab Rep Date: 2022-04-18
Authors: Lazzaro di Biase; Alessandro Di Santo; Maria Letizia Caminiti; Pasquale Maria Pecoraro; Simona Paola Carbone; Vincenzo Di Lazzaro Journal: J Clin Med Date: 2022-07-19 Impact factor: 4.964