Clinical and molecular phenotype of PTRHD1-associated juvenile parkinsonism

Title : Clinical and molecular phenotype of PTRHD1-associated juvenile parkinsonism

Abstract:

Objective: Although Parkinson’s Disease is the most common movement disorder in adults, juvenile parkinsonism is rare. It is often dominated by rigidity, hypokinesia, and postural instability and less commonly features a resting tremor. Despite its rarity, several important scientific insights have come from studies of early-onset parkinsonism. We describe 6 previously unreported patients with mutations in PTRHD1, an orphan gene of unknown function. Although mutations in this gene have recently been reported in a few families with juvenile parkinsonism and intellectual disability, clinical phenotypes have been incompletely characterized. We sought to identify genotype-phenotype correlations in patients with frameshift deletion, missense, or genomic loss of function mutations in PTRHD1. 
Methods: Each family provided written informed consent for participation according to local ethics guidelines. Clinical phenotypes, MRI images, patient photographs, and videos were collected from 6 patients with homozygous mutations in the PTRHD1 gene. When possible, blood and/or skin punch biopsies were also performed for transcriptomic and proteomic analysis.
Results: Clinical presentations included dysarthria, rigidity, postural instability, gait dysfunction, and mild intellectual disability. Resting tremor was observed in several patients. There was no evidence of oculomotor abnormalities. Anatomic MRI imaging was normal. Patients responded to carbidopa-levodopa but developed peak-dose dyskinesias and wearing-off effects early in the treatment course. Outlier analysis of RNA sequencing revealed underexpression of PTGR1 and UFSP2. Outlier analysis of proteomics revealed significantly decreased expression of the following proteins: ATP6V1C1, CNOT3, CPSF1, PTGR1, PTRHD1, SPC24, THUMPD3, and TSPAN10. These analyses highlight the genotype-phenotype correlations. Proteomic results suggest a potential role for the orphan protein PTRHD1 in RNA metabolism and translational control.
Conclusions: Biallelic PTRHD1 mutations represent a newly-recognized form of parkinsonism that should be considered in patients presenting in childhood or adolescence.

Biography:

Bhavan A. Modi, MD is a PGY-5 in Child Neurology at Barrow Neurological Institute at Phoenix Children’s Hospital. A native of Birmingham, Alabama, he earned his Doctor of Medicine from the University of Alabama at Birmingham School of Medicine. He also completed both his Master of Science in Biomedical and Health Sciences and his Bachelor of Science in Molecular Biology and Psychology, with a focus in Neuroscience, at the University of Alabama at Birmingham. He will be pursuing Epilepsy fellowship at the Barrow Neurological Institute at Phoenix Children's upon completion of residency. Bhavan A. Modi, MD is a PGY-5 in Child Neurology at Barrow Neurological Institute at Phoenix Children’s Hospital. A native of Birmingham, Alabama, he earned his Doctor of Medicine from the University of Alabama at Birmingham School of Medicine. He also completed both his Master of Science in Biomedical and Health Sciences and his Bachelor of Science in Molecular Biology and Psychology, with a focus in Neuroscience, at the University of Alabama at Birmingham. He will be pursuing Epilepsy fellowship at the Barrow Neurological Institute at Phoenix Children's upon completion of residency.