The Parkin Gene: A Discrete Clinical Entity
THE PARKIN GENE: A DISCRETE CLINICAL ENTITY by Michael Rezak, MD, PhD
In an important article published by Doherty et al. in JAMA Neurology (vol.70,No. 5, May, 2013), 5 unrelated cases of young onset parkinsonism with the parkin gene mutation were studied in detail, and compared to 5 PD patients and 4 normal controls. What makes this study unique is that the clinical course, symptomatology, and microscopic neuropathology were obtained over the course of the lifetime of the patients (longitudinally).
The parkin genetic mutation (also known as Park 2) has long been known to be a cause of young-onset parkinsonism including some cases of juvenile parkinsonism. The abnormality appears to reside on the long arm of chromosome 6 and a number of variations can exist at this locus (alleles) resulting in parkinsonism. It is autosomal recessive so that 2 copies of the abnormality need to be present, but they do not have to be the exact same abnormality to present as the clinical entity of parkinsonism.
This article confirms and extends our knowledge base concerning those individuals affected by parkin gene abnormalities. First, parkin has a role in marking abnormal proteins for removal from cells (ubiquitin-proteasome functions), second, it is important for maintaining normal cellular mechanisms for removing dysfunctional and abnormal proteins (autophagy) and finally it appears critical for maintaining normal mitochondrial function and integrity.
The article demonstrates that parkin related parkinsonism differs from typical Parkinson’s disease based on the following findings:
1. Neuropathology: Minimal or no Lewy bodies or Lewy body neurites (little alpha synuclein staining).
2. Cellular loss: moderate to severe loss in the ventral portion of the substantia nigra, mild to moderate loss in the locus coeruleus, mild loss in the dorsal motor nucleus of the vagus and cerebellum.
3. Clinical: young onset (age at onset 25-46), presenting with dystonia or tremor as initial symptoms, development of motor fluctuations, dystonia and freezing gait as it slowly progresses, no dementia or psychiatric problems (no hallucinations), continued symptomatic benefit from l-dopa for the duration of the disease and long disease duration(25-50 years).
The authors conclude that based upon the above significant differences from typical PD, patients with this genetic type of parkinsonism should be noted to have “Parkin disease.” Parkin disease is clinically and pathologically distinct and differs from Parkinson’s disease that has widespread brain pathology with Lewy pathology and cell loss, which accounts for the myriad of non-motor features of PD and limited responsiveness of motor symptoms over time.
Dr. Rezak is the Medical Director of the APDA National Young Onset Center as well as the Director of the Movement Disorders Center and Co-Director of the Deep Brain Stimulation Program of the Neurosciences Institute at Central DuPage Hospital in Winfield, IL. Dr. Rezak is also on the Speaker's Bureau for Allergan, Novartis, Medtronic, Teva, and GlaxoSmithKline.