Deciphering the role of single mutation carriage in recessive Parkinson’s disease: Temporal Discrimination Threshold (TDT) as an endophenotype.
The vast majority of typical Parkinson’s disease is not due to an underlying primary genetic or inherited problem. There are however several rare ‘monogenetic forms’ of Parkinson’s disease that are primarily due to a mutation in a gene, usually inherited from one or both parents. In the recessive forms (in which an abnormal gene needs to be passed on by each parent in order to lead to disease in their offspring), parents and some siblings of affected patients are often referred to as ‘carriers’ meaning that that they only carry one of the two required genes that lead to Parkinson’s disease. Patients with certain recessive genetic forms of Parkinson’s disease tend to develop symptoms before the age of 35 and tend to have an excellent and sustained response to treatment, without the development of memory or cognitive problems over the years. Some experts believe that having one abnormal gene (in a recessive form) can predispose to the development of later-onset Parkinson’s disease and this notion has created much debate in the medical literature.
At the DNI and in collaboration at St Vincent’s University Hospital Dublin, the Belfast City Hospital and the Mayo Clinic Jacksonville USA, we have been undertaking a 2 year study, looking at the potential use of TDT in unaffected relatives of patients with young-onset Parkinson’s disease (who are at higher risk of recessive forms such as PARK2), in order to identify if TDT is abnormal in those who carry a single abnormal gene. If this were the case then it would strengthen the argument that having a single abnormal gene may be contributing to the development of late-onset Parkinson’s disease, as TDT is known to be abnormal due to dysfunction of the basal ganglia which are responsible for automatic movement control.
The identification of a group of individuals who are at greater risk of developing Parkinson’s disease, perhaps many decades before symptom onset would be extremely important as current research is focused on individuals who already have the condition. By the time someone presents with Parkinson’s symptoms, many of the dopamine producing cells of the brain are already lost and thus identifying a group of individuals many decades before disease onset, would offer the potential to study disease modifying/preventative therapies and in identifying potential environmental factors which in addition to genetic factors may be contributing to the development of Parkinson’s disease.
We would like to thank the patients and families who gave their time to this study, as without their valuable contribution this work would not be possible.
Dr John McKinley, DAMC Fellow in Movement Disorders, Dublin Neurological Institute at the Mater Misericordiae University Hospital and St Vincent’s University Hospital.