Can We Identify Pre-Motor Parkinson's Disease in LRRK2 Carriers?

Abstract & Commentary

By Claire Henchcliffe, MD, Associate Professor of Neurology and Neuroscience, Weill Cornell Medical Center. Dr. Henchcliffe reports she is on the speakers bureau and advisory board for Allergan and Teva; speakers bureau for Boehringer-Ingelheim, GlaxoSmithKline, and Novartis; advisory board for Merz; and is a consultant for Gerson Lehman Group and Guidpoint Global.

Synopsis: Evaluation of non-Parkinsonian carriers of the LRRK2 mutation associated with Parkinson's disease supports a model of pre-motor symptomatology, including impaired color discrimination and constipation, that could be related to pathology developing prior to that in the substantia nigra.

Source: Marras C, et al. Phenotype in Parkinsonian and nonparkinsonian LRRK2 G2019S mutation carriers. Neurology 2011;77:325-333.

This international study focuses on individuals with parkinson's disease (PD) due to the G2019S LRRK2 mutation, a cause of both familial and sporadic PD, and provides the most detailed description to date of their motor and non-motor phenotypes. Fifteen unrelated probands (from sites in Canada, the United States, Brazil, and Germany) were compared with 54 first-degree relatives with identical LRRK2 mutations (25 of whom had PD), 53 relatives without the mutation and without PD, 84 individuals with idiopathic PD (iPD), and 112 unrelated controls (the iPD and control groups were recruited at German sites only). Enrolled subjects underwent neurologic exam, but also a careful assessment of features believed to constitute a premotor constellation of symptoms related to possible early PD pathology outside of the substantia nigra. Premotor symptoms include impaired olfaction and color vision, anxiety, and depression. In terms of motor features, those with LRRK2-PD had a tremor presentation more often than iPD. They also had better olfactory identification, worse color discrimination as judged by the Farnsworth-Munsell 100-Hue test, and higher depression scores on the Beck Depression Inventory scale. The most fascinating finding, however, is that LRRK2 G2019S non-manifesting carriers also were found to have significant differences in non-motor features compared with control subjects, including worse constipation and visual color discrimination, as well as mildly higher scores on the Unified Parkinson's Disease Rating Scale that objectively evaluates PD signs and symptoms (UPDRS). This was also true of family members who did not carry the LRRK2 gene mutation, raising the question of other as yet unknown factors contributing to PD risk in these families.

Commentary

LRRK2 mutations account for approximately 4% of familial and 1% of sporadic cases of PD, although in certain populations they may be more important: For example, in North African Arabs, LRRK2 mutations have been detected in approximately 40% of individuals with sporadic PD. Penetrance is incomplete, and age-dependent. Both phenotypic and pathologic heterogeneity due to this mutation remain a field of intense interest, and Marras and colleagues therefore provide a significant contribution in their detailed phenotypic descriptions. Importantly, the authors demonstrate that despite minor phenotypic differences, the LRRK2 G2019S mutation (which is the most common pathogenic LRRK2 mutation) leads to a phenotype largely indistinguishable on a clinical basis from idiopathic PD. It is therefore hoped that this population will provide information that may be extended to the larger population with "idiopathic" PD, and in particular that studying non-parkinsonian LRRK2 G2019S carriers will shed light upon development of clinical PD. Therefore, the most intriguing finding is that non-manifesting LRRK2 G2019S carriers have subtle but measurable differences from controls in color discrimination, constipation, and in UPDRS scores. These could potentially represent a "pre-motor" or "pre-diagnostic" phenotype, of use for risk stratification in the future. Unfortunately, differences in recruitment sites between subject groups (and therefore potential differences in examiners and assessments) limits interpretation of findings. In addition, the authors had to make statistical adjustments for age and disease duration, since those with LRRK2-associated PD were younger and had a shorter disease duration than enrollees with iPD. However, a companion article by Saunders-Pullman and colleagues examining 31 individuals with LRRK2 G2019S-related PD recruited within New York City provides data supporting the possibility of a "pre-motor" phenotype detectable in a subset of mutation carriers, in this case olfactory dysfunction.1 Longitudinal data will be important to see which of these carriers goes on to develop PD (or another) phenotype, but the present data support the notion that assessment of non-motor features may eventually provide a logical data-driven screening strategy for individuals at risk for PD. Identification of such a group is imperative if we are to test preventive interventions (for example, exercise, diet, and pharmacologic neuroprotectants). Finally, with efforts to provide broad public access to genetic testing, including the LRRK2 gene, the clinician will be increasingly faced with worried individuals seeking guidance on their neurologic risk. It is therefore important that expanded and longitudinal studies be pursued, in order to provide meaningful information on risk to our patients.

References

1. Saunders-Pullman R, et al. Olfactory dysfunction in LRRK2 G2019S mutation carriers. Neurology 2011;77:319-324.