Targeted gene under study:
Genes PTPS/PTS (OMIM *612719), SR/SPR (*182125), DHPR/QDPR (*612676), PCBD1 (*126090), PCBD2 (*609836), TH (*191290)
Abstract
Dopamine synthesis disorders are caused by variants in genes implicated in cofactor biosynthesis or recycling (GTP cyclohydrolase 1 [GCH1], 6-pyruvoyl-tetrahydropterin synthase [PTPS/PTS], sepiapterin reductase [SR/SPR], carbinolamine-4α-dehydratase [PCBD1, PCBD2], dihydropteridine reductase [DHPR/QDPR]) and monoamine synthesis (tyrosine hydroxylase [TH], aromatic L‑amino acid decarboxylase [DDC]).
Perturbations in this metabolic pathway cause systemic hyperphenylalaninemia and neurological phenotypes due to monoamine neurotransmitter deficiencies. The phenotypic spectrum encompasses extrapyramidal manifestations (dystonia, parkinsonism, chorea), oculogyric crises, epilepsy, autonomic dysfunction and cognitive decline. While GCH1- and DDC-related disorders have been better studies (with the latter being currently investigated in a gene therapy trial), phenotypic features and long-term follow-up of disorders caused by mutation(s) in PTS, SPR, QDPR, PCBD1, PCBD2 and TH are less characterised.
We aim to conduct deep phenotyping and define the natural history of these disorders in a large, international patient cohort.
Coordinating clinician
Dr Francesca Magrinelli – f.magrinelli@ucl.ac.uk
Institution
Department of Clinical and Movement, Neurosciences, UCL Queen Square Institute of Neurology, University College London.
Specific requirements beyond clinical data and genotype data sharing:
1- Re-analysis of DNA samples: if possible
2- Resampling of patients: if possible
3- Linked to a translational/basic research project: Possibly in the future