mutations are believed to cause a form of neurodegenerative disease that is indistinguishable clinically5-9
from idiopathic PD. Only a few exceptions exist in the literature. First, the large German-Canadian family later associated with a LRRK2
had two members who manifested primarily with dementia. Unfortunately, very little clinical information is available for these individuals. Second, a LRRK2
intronic variant of uncertain significance from a Chinese population (IVS33 + 6 T>A) was found in one patient who developed typical parkinsonian signs after an 8-year course of isolated essential tremor.28
More recently, a LRRK2
G2019S mutation case has been reported with pathologic findings consistent with frontotemporal dementia with ubiquitin-immunoreactive inclusions.29
Clinical information is scant, but the patient had advanced dementia at the time of death.
We report here the detailed clinical findings of two LRRK2 mutation carriers who presented with cognitive difficulties, leading to clinical diagnoses of CBS and PPA, a subtype of FTD. Neither patient had PD clinically. LRRK2 mutations have not been clinically linked to either of these disorders, nor to other types of FTD. Of note, mutations in GRN or MAPT, which are associated with familial FTD, were excluded in both of these patients by DNA sequencing of the coding regions of these genes.
What might account for the relatively large proportion (2/8 or 25%) of our LRRK2
mutation patients manifesting as a non-parkinsonian clinical phenotype? Close scrutiny reveals that most of the >25 reported genetic screens have focused on patients from PD or movement disorders clinics or on kindreds with familial PD. Indeed, only a handful of studies have included other neurodegenerative diseases at all,11-14
with no LRRK2
mutations found in cohorts of patients with AD or ALS. Only one study has examined multiple neurodegenerative diseases.10
This study included 40 patients with CBD/FTD but focused exclusively on the G2019S mutation, which was not found in any of these patients. In contrast, our LRRK2
mutation screen was comprehensive both in terms of mutations screened and populations tested, which might account for the higher yield of atypical LRRK2
Our patients with CBS harbored the LRRK2
G2019S mutation, the most common LRRK2
mutation, reported to be pathogenic, with incomplete penetrance. This mutation has been previously linked to some cases of tau-predominant pathology,30
and CBD, the usual neuropathologic correlate of clinical CBS, is characterized by tau-immunoreactive inclusion bodies in gray and white matter.31
Our patient with PPA harbored the R793M mutation, a change of putative pathogenicity reported previously in two familial PD cases, one sporadic PD case, and one 40-year-old asymptomatic individual.23
This mutation occurs within the ankyrin domain of LRRK2,
which possesses no other pathogenic or putative pathogenic mutations. In keeping with the likely multifunctional nature of LRRK2,
mutations in different functional domains could manifest heterogeneously.
The diagnoses of CBS and PPA made here are clinical, with as yet no pathologic confirmation. The diagnosis of CBS as a manifestation of underlying neuropathologic CBD is further complicated by the lack of clinical consensus criteria. However, our CBS patient's combination of levodopa-resistant asymmetric akinetic-rigidity, “alien hand” phenomenon, cortical sensory loss, and cognitive decline are consistent with both classic32
and more recent31,33
clinical-pathologic studies of CBD. The radiographic pattern of atrophy, especially affecting Brodmann areas 6 and 7, is also consistent with patterns of atrophy in CBS/CBD reported by us and others.19,34
Finally, the CSF findings of normal to low tau and normal Aβ
42 corroborate the diagnosis of a non-AD dementia. As we have previously shown, in CBD and in PPA, CSF tau levels are normal to low in comparison to controls and CSF Aβ
42 levels slightly less than in controls, while in AD, tau levels tend to be increased and Aβ
42 levels decreased relative to controls.24
In the case of our patient with PPA, the clinical presentation meets several sets of consensus clinical criteria for the overlapping diagnoses of PPA, FTD, and frontotemporal lobar degeneration (FTLD) of the progressive nonfluent aphasia sub-type. These include the McKhann criteria for FTD of the language deficit variety,35
the Neary criteria for progressive nonfluent aphasia as a subtype of FTLD,36
and the Mesulam criteria for PPA.37
In addition, the striking frontal and temporal atrophy seen on MRI strongly suggests a diagnosis of FTD or FTLD. Finally, as for our patient with CBS, CSF findings of low tau and normal Aβ
42 corroborate a diagnosis of non-AD dementia.
LRRK2 mutations have been associated with pleomorphic pathology, leading some to speculate on an “upstream” role for LRRK2 in the cascade of events leading to disease. In this article, we provide a potential clinical accompaniment to this heterogeneous pathology and extend the clinical spectrum of LRRK2-associated disease.