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Original Contribution |

Parkin Disease:  A Clinicopathologic Entity? FREE

Karen M. Doherty, MRCP; Laura Silveira-Moriyama, PhD; Laura Parkkinen, PhD; Daniel G. Healy, PhD; Michael Farrell, FRCPath; Niccolo E. Mencacci, MD; Zeshan Ahmed, PhD; Francesca M. Brett, FRCPath; John Hardy, PhD; Niall Quinn, MD; Timothy J. Counihan, FRCPI; Timothy Lynch, FRCPI; Zoe V. Fox, PhD; Tamas Revesz, FRCPath; Andrew J. Lees, MD; Janice L. Holton, FRCPath
[+] Author Affiliations

Author Affiliations: Reta Lila Weston Institute for Neurological Studies (Drs Doherty, Silveira-Moriyama, Hardy, Revesz, Lees, and Holton), Queen Square Brain Bank for Neurological Disorders (Drs Ahmed, Revesz, Lees, and Holton), Department of Molecular Neuroscience (Drs Doherty, Silveira-Moriyama, Mencacci, Ahmed, Hardy, Revesz, Lees, and Holton), Sobell Department of Motor Neuroscience and Movement Disorders (Dr Quinn), Institute of Neurology; Institute of Education, Institute of Neurology, and Research Support Centre Biostatistics Group, Joint Research Office (Dr Fox), University College London, London; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford (Dr Parkkinen), England; Department of Neurosciences (Dr Healy), Dublin Neurological Diseases Brain Bank, Department of Neuropathology (Drs Farrell and Brett), Beaumont Hospital; The Dublin Neurological Institute at the Mater Misericordiae University Hospital (Dr Lynch), Dublin; School of Medicine, National University of Ireland, Galway (Dr Counihan), Ireland; Department of Neurology, University of Campinas, UNICAMP, Campinas, Brazil (Dr Silveira-Moriyama); and Department of Neurology and Laboratory of Neuroscience, Università degli Studi di Milano–IRCCS Istituto Auxologico Italiano, Milan, Italy (Dr Mencacci).


JAMA Neurol. 2013;70(5):571-579. doi:10.1001/jamaneurol.2013.172.
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Importance Mutations in the gene encoding parkin (PARK2) are the most common cause of autosomal recessive juvenile-onset and young-onset parkinsonism. The few available detailed neuropathologic reports suggest that homozygous and compound heterozygous parkin mutations are characterized by severe substantia nigra pars compacta neuronal loss.

Objective To investigate whether parkin -linked parkinsonism is a different clinicopathologic entity to Parkinson disease (PD).

Design, Setting, and Participants We describe the clinical, genetic, and neuropathologic findings of 5 unrelated cases of parkin disease and compare them with 5 pathologically confirmed PD cases and 4 control subjects. The PD control cases and normal control subjects were matched first for age at death then disease duration (PD only) for comparison.

Results Presenting signs in the parkin disease cases were hand or leg tremor often combined with dystonia. Mean age at onset was 34 years; all cases were compound heterozygous for mutations of parkin. Freezing of gait, postural deformity, and motor fluctuations were common late features. No patients had any evidence of cognitive impairment or dementia. Neuronal counts in the substantia nigra pars compacta revealed that neuronal loss in the parkin cases was as severe as that seen in PD, but relative preservation of the dorsal tier was seen in comparison with PD (P = .04). Mild neuronal loss was identified in the locus coeruleus and dorsal motor nucleus of the vagus, but not in the nucleus basalis of Meynert, raphe nucleus, or other brain regions. Sparse Lewy bodies were identified in 2 cases (brainstem and cortex).

Conclusions and Relevance These findings support the notion that parkin disease is characterized by a more restricted morphologic abnormality than is found in PD, with predominantly ventral nigral degeneration and absent or rare Lewy bodies.

Figures in this Article

Autosomal recessive families of juvenile-onset or young-onset parkinsonism were reported from Japan almost 20 years ago.1 These patients had a relatively benign course, sleep benefit, and a sustained response to low doses of levodopa but with early development of interdose choreoathetosis and dystonia. Linkage studies pinpointed a locus on the long arm of chromosome 6 (6q25.2q27) and were followed by identification of a gene, which was named parkin.2,3 From the large number of parkin cases subsequently reported worldwide, a distinctive phenotype has been proposed, characterized by prominent leg tremor,4 foot dystonia,5,6 normosmia,7 and marked behavioral disturbances,5,8 although it has been hypothesized that the early age at onset rather than the presence of a parkin mutation9 is the critical determinant of the clinical picture. In some cases, there may be no detectable family history and rarely has onset in the fifth and sixth decades of life been reported.1012

The parkin gene has 12 coding exons and the subsequent protein comprises 3 RING fingers13 separated by an in-between domain at the carboxyl terminal. Parkin plays an important role in mitochondrial functioning, as well as the ubiquitin proteasome system, where it acts as a ubiquitin E3 ligase.14 Impaired autophagy and mitophagy, protein accumulation, and mitochondrial dysfunction are the main mechanisms proposed in the development of parkinsonism due to mutations of parkin.15

Parkinson disease (PD) is characterized pathologically by severe loss of dopaminergic neurons in the substantia nigra (SN), with numerous cytoplasmic inclusions containing α-synuclein, known as Lewy bodies (LBs), in the surviving neurons. Autopsy reports of patients with parkinsonism carrying 2 mutations in the parkin gene described localized severe nigral degeneration with gliosis, mild neuronal loss, and depigmentation of the locus coeruleus (LC) but an absence of LBs in most cases (Table 1 and Table 2).1627

Table Graphic Jump LocationTable 1. Pathological Reports of Published Parkin Cases

Table Graphic Jump LocationTable 2. Additional Pathological Reports of Published Parkin Cases

We conducted a detailed clinicopathologic study in 5 cases with compound heterozygous mutations of parkin to define the clinical features, late disease course, and pathologic lesion in parkin disease.

MATERIALS

Cases with 2 confirmed mutations of parkin with clinical data and pathologic material were included. Three cases were identified from the Queen Square Brain Bank and 2 from the Dublin Brain Bank, where tissue is collected using ethically approved protocols and material stored under a license issued by the Human Tissue Authority. None had received a diagnosis of parkin disease in life, but they were genetically tested following suspicion raised on review of available clinical and family history data. Five PD control cases and 4 normal control cases matched first for age at death then disease duration (PD only) were also selected for comparison.

GENETIC, NEUROPATHOLOGIC, AND CLINICAL METHODS

Genomic DNA was extracted using standard methods from frozen brain tissue in all suspected cases. Parkin coding region and splice sites were screened for point mutations by polymerase chain reaction and subsequent bidirectional sequencing using BigDye Terminator version 3.1 (Applied Biosystems) sequencing chemistry. Exon rearrangements were detected by multiplex ligation-dependent probe amplification using the P051 and P052 Salsa MLPA Parkinson probe sets, according to the manufacturer's instructions (MRC-Holland).

Brain tissue fixed with 10% buffered formalin was sampled, processed for histology, and stained according to standard protocols. Formalin-fixed paraffin-embedded tissue sections from cortical, subcortical, brainstem, and cerebellar regions were stained using routine histologic stains (hematoxylin and eosin and Luxol fast blue/cresyl violet) and supplemented by immunohistochemical staining using the following primary antibodies: glial fibrillary acidic protein, α-synuclein, tau (AT8), amyloid-β, ubiquitin, p62, neurofilaments, IC2, fused in sarcoma (FUS), and TAR DNA-binding protein 43 (full details are in eAppendix 1). All cases were assessed by an experienced neuropathologist who was blind to the diagnosis and graded regional neuronal loss and gliosis using a 4-point semiquantitative scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe, based on previously published studies).28 α-Synuclein, tau, ubiquitin, p62, and amyloid-β immunoreactive structures were analyzed in selected brain areas. Lewy body pathology was assessed according to the recommendations of the third report of the Dementia with Lewy Bodies Consortium29 and also by Braak stage.30 Concomitant pathologies were assessed (eAppendix 1).

Detailed study of the severity of nigral neuronal loss was carried out in the PD and parkin cases only. A single, transverse 7-μm thick section of midbrain was taken at the level where the fascicles of the third cranial nerve emerge from the midbrain, allowing evaluation of pertinent nuclear groups at a defined level. These sections were stained with the Luxol fast blue/cresyl violet method; single-section counts of all neuromelanin-containing neurons, with or without a visible nucleus, in the SN pars compacta were obtained by using Image-Pro Plus software package (Media Cybernetics). All the counts were performed twice by the same investigator blinded to clinical data. Each SN pars compacta was outlined and further divided into ventral and dorsal tiers as described in detail elsewhere.31 Pars lateralis was excluded from the analysis because, in this region, there is a considerable mixing of neuronal types. The software automatically divided each examined area into a number of nonoverlapping counting squares of equal size of 300 μm × 300 μm, where all pigmented neurons were counted at ×200 magnification. The number of these squares was used to determine the surface area and, finally, the neuronal density was expressed as neurons per square millimeter. Single-section counting has been shown to be as reliable as the dissector method in evaluating the neuronal loss from SN.32

Clinical record review was undertaken in the parkin, PD, and control cases for details of disease presentation, response to medication, progression, and late features. Full case descriptions were summarized for the parkin cases.

STATISTICAL METHODS

Using a semiquantitative approach, we first compared the severity (ie, none, mild, moderate, or severe) of neuronal loss and gliosis among the 3 groups: parkin disease (5 cases), PD (5 cases), and control (4 cases). In each case, 9 brain areas were selected for examination. The grades of neuronal loss (or gliosis) in each brain area were pooled and an ordinal logistic regression model with a robust variance estimator was used to assess the increased odds of having more severe neuronal loss (or gliosis) and take into account clustering among individuals.

In the second analysis, only parkin and PD groups were compared with regard to the neuronal densities in the ventral, dorsal, and total (ventral and dorsal combined) nigral tiers. Neuronal counts in the SN were performed twice on each case (5 parkin and 5 PD). Intrarater reliability for the nigral neuronal counts was assessed with intraclass correlation. Intraclass correlation coefficients were greater than 0.80 for all the ratings performed, reflecting high reliability. The means of the 2 counts for each given nigral area were then plotted and assessed for normality. Independent-sample t tests or Mann-Whitney U tests were used depending on the distribution. P values of less than .05 were considered to indicate a significant trend. Linear regression was used to assess what proportion of the variation of each outcome variable was explained by each predictor variable (R2) and to quantify differences between individuals with parkin disease and those with PD. SPSS version 19 (SPSS Inc) and STATA version 11.2 (StataCorp) statistical programs were used to analyze the data.

The clinical features and genetic mutations in the 5 parkin cases are summarized in Table 3. The clinical description of the first parkin case is detailed here (descriptions of cases 2-5 are available in eAppendix 2 and Video 1 and Video 2 of case 5 in the online-only material).

Table Graphic Jump LocationTable 3. Clinical and Genetic Details of Parkin Disease Cases
CASE 1: CLINICAL SUMMARY

At age 36 years, this woman noticed the toes on her left foot turning up. Initial examination revealed involuntary dorsiflexion of her left great toe associated with a coarse tremor of her left foot and leg. Focal dystonia was diagnosed, and she was treated with anticholinergic medication to good effect. Ten years later, a diagnosis of PD was considered when reduced arm swing and arm tremor were noted; however, levodopa treatment was not started until the age of 56 years, when she had an excellent response. While in her 70s, she began to experience falls and freezing of gait, but she still walked unaided when taking medication. Examination in the year she died revealed occasional tremor of both hands with bilateral rigidity and bradykinesia, and she reported that her medication (combined levodopa/carbidopa/entacapone, 150/37.5/200 mg, 4 times per day, and selegiline hydrochloride, 5 mg, twice daily) still improved her symptoms. In her last year of life, she had an episode of confusion and disorientation and experienced some visual hallucinations, but these were short lived. She was not demented and denied any memory problems. She died of ischemic heart disease 4 days following repair of a fractured neck of femur at age 86 years.

GENETIC ANALYSIS

Four different parkin mutations were detected: 2 missense changes (c.823C>T p.R275W; c.1289G>A, p.G430D), 1 frameshift deletion causing the premature introduction of a stop codon (c.337_376del; p.Pro113fs), and 1 whole-exon rearrangement (exon 6 deletion). All the identified mutations have been previously described and shown (when homozygous or compound heterozygous) to be associated with early-onset parkinsonism.

NEUROPATHOLOGY
Parkin -Linked Cases

Macroscopically, the changes in the parkin cases appeared identical to that of PD, with marked nigral (all cases) and LC (2 of the 5 cases) pallor. Table 4, Figure 1, and Figure 2 provide a summary of the histologic findings in the parkin cases, the most striking feature being the loss of pigmented neurons in the SN (moderate to severe); in all cases, the pattern was one of the ventral tier being most severely affected (Figure 1A and B). This was accompanied by mild to moderate cell loss in the LC with pigment incontinence. Other structures affected by neuronal loss included the dorsal motor nucleus of the vagus (DMV) (mild in 2 of 3 cases examined) and the cerebellar cortex (examined at the level of the dentate nucleus and the superior cerebellar peduncle), which showed mild Purkinje cell loss with empty baskets. In no other region examined was any appreciable neuronal loss evident including the nucleus basalis of Meynert (NBM) (4 cases examined; Figure 2A). Mild to moderate gliosis accompanied the neuronal loss previously described, but there was also evidence of gliosis (in the absence of detectable neuronal loss) in the raphe nucleus, NBM, striatum, globus pallidus, dentate nucleus, amygdala, hippocampus, and cerebral cortices (Figure 2B). None of the parkin disease cases looked similar to PD when immunochemistry for α-synuclein was performed. The results from 2 cases were negative for α-synuclein (cases 1 and 2): 1 had sparse Lewy neurites in the SN but no LBs (case 4) and 1 had sparse Lewy neurites and a total of 2 LBs (midbrain periaquaductal gray matter and transentorhinal cortex) (case 3). Case 5 had brainstem-predominant LB disease according to McKeith et al criteria29 but was unusual for PD because the severe loss of pigmented nigral neurons was accompanied by only very sparse LBs (Figure 1C and D). Mild neuronal loss in the LC was associated with moderate numbers of LBs (Figure 1E and F). Only 1 or 2 LBs were identified in the NBM, transentorhinal cortex, amygdala, and cingulate cortex sections, and the pattern of pathology did not conform well to the Braak PD staging scheme as the density of brainstem LBs did not show the expected increase when LB pathology extended beyond the brainstem.30

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Graphic Jump Location

Figure 1. Histologic findings in the parkin cases. Case 2 substantia nigra illustrates the more severe neuronal loss in the ventral tier (white arrow) compared with the dorsal tier (black arrow) (A), accompanied by severe gliosis (white arrow) in the ventral tier compared with the dorsal tier (black arrow) (B). Case 5 showed severe neuronal loss in the ventrolateral substantia nigra (C) and only sparse α-synuclein pathology (arrows) (D), with mild cell dropout in the locus coeruleus (E) accompanied by moderate numbers of Lewy bodies (arrows) and Lewy neurites (F). The scale bar represents 260 μm in parts A and B, 50 μm in parts C and D, 100 μm in parts E and F, and 25 μm in the inset in part F. Hematoxylin-eosin staining in parts A, C, and E; glial fibrillary acidic protein in part B; and α-synuclein in parts D and F.

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Graphic Jump Location

Figure 2. Regional neuronal loss (A) and gliosis (B) in parkin, Parkinson disease (PD), and control cases. A, The severity of neuronal loss in various brain regions in the 5 parkin, 5 PD, and 4 control cases (not all structures were available for examination in all cases [eg, the raphe was only available for examination in 3 parkin, 2 PD, and 3 control cases]). B, The severity of gliosis in various brain regions in the parkin, PD, and control cases. GP indicates globus pallidus; DMV, dorsal motor nucleus of the vagus; LC, locus coeruleus; NBM, nucleus basalis of Meynert; SN, substantia nigra.

Table Graphic Jump LocationTable 4. Neuropathology of Parkin Disease Cases

There was either no (2 cases) or only mild (3 cases) deposition of hyperphosphorylated tau, which did not exceed Braak and Braak stage II pathology. Sparse tau immunoreactive neuropil threads were identified in the SN in 2 cases (cases 1 and 4) and in the LC in case 5. Tau pathology characteristic of other tauopathies, such as tufted astrocytes or astrocytic plaques, was not observed.

Ubiquitin and p62 stains highlighted small irregular neuronal intracytoplasmic inclusions in the cytoplasm of pigmented nigral neurons in 3 cases. These inclusions were not recognized in immunohistochemical preparations for α-synuclein, tau, IC2 (recognizing polyglutamine repeat–containing proteins), neurofilaments, TAR DNA-binding protein 43, or FUS, and they were also observed in 3 of 4 control cases, indicating that they are not disease specific.

PD and Control Cases

The pathologically confirmed PD cases were retrospectively reviewed, and the demographics and mean SN neuronal density measurements are given in Table 5. The clinical details were consistent with PD and none of the cases had a positive family history of parkinsonism. The pathologic findings were also classic for PD in all cases without the finding of other significant pathology.

Table Graphic Jump LocationTable 5. Comparison of Parkin and Parkinson Disease Cases

The causes of death in the control cases were metastatic bowel cancer in 2 and myocardial infarction in 2. None had experienced any symptoms suggestive of parkinsonism or other neurodegenerative diseases. One control case was found to have sparse cortical and brainstem LBs without significant SN or LC neuronal loss. There was no clinical correlate to these findings; the patient was 81 years old at death and the pathologic diagnosis of incidental LB disease was made.

STATISTICAL ANALYSES

Figure 2 shows the distribution and severity of neuronal loss and gliosis in the 3 groups. The PD group had the greatest severity of neuronal loss and the control group had the least severe: after adjusting for age at death, the odds ratios of having an increased severity of neuronal loss were 1.2 (95% CI, 0.8-1.8) and 0.5 (95% CI, 0.4-0.7) for PD and control cases, respectively, relative to parkin disease (global P < .001, averaged over all brain areas examined). Gliosis also differed significantly between the 3 diagnoses (P = .02), with a 1.4 increased odds ratio (95% CI, 0.6-3.1) of having more severe gliosis in PD compared with parkin disease cases and a 0.4 decreased odds ratio (95% CI, 0.1-0.9) for control compared with parkin disease cases. Detailed statistical analysis in each region was limited by small case number, but the largest differences in severity were observed in the SN, LC, and DMV for neuronal loss (Figure 2A), as well as in the SN, LC, and NBM for gliosis (Figure 2B).

Table 5 and Figure 3 illustrate the neuronal densities in the different tiers of the SN in the PD and parkin disease cases. Analysis revealed a significantly greater mean cell density in the dorsal tier of the parkin disease cases (19.16 neurons/mm2) than in the PD cases (14.28 neurons/mm2) (P = .04; Table 5). The neuronal density of the ventral nigra did not differ between parkin and PD cases (P = .89). An unadjusted standard linear regression model found that diagnosis (parkin or PD) predicted a mean 4.88 neurons/mm2 (95% CI, 0.36-9.41; P = .04) higher dorsal SN density in parkin compared with PD cases.

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Graphic Jump Location

Figure 3. Clustered box plot illustrating neuronal density in ventral, dorsal, and combined (total) nigral tiers in the parkin and Parkinson disease (PD) cases. The asterisk indicates an extreme score (ie, the value is more than 3 box lengths from the upper quartile) and the black dot indicates an outlier (ie, the value is more than 1.5 box lengths from the lower quartile).

Parkin disease has recently been described as a nigropathy owing to its restricted pathology.33 Previous neuropathologic reports described marked SN neuronal loss (5 noted that the ventrolateral tier was most severely affected1618,21,23), mild to moderate neuronal loss of the LC (11 of 13 cases), limited tau pathology27 (few neurofibrillary tangles17,18 and occasional tau-positive astrocytes19), and LBs staining positively with α-synuclein in only 3 cases.20,24,27 To our knowledge, this is the largest and most detailed neuropathologic study of parkin disease to date, and our comparison with PD and control cases led us to consider parkin disease as a ventral-predominant nigropathy with additional involvement of the LC. In contrast to PD, marked neuronal loss of the DMV, NBM, and the midbrain raphe was not found; LBs were rare and, when observed, were sparse.

Lewy bodies have been observed in other genetic forms of parkinsonism: neurodegeneration with brain iron accumulation associated with the PLA2G6 mutation (NBIA type 2 or PARK14)34 and recently in a young patient (age, 39 years) with compound heterozygous PINK1 mutations.35 In PARK8 (leucine-rich repeat kinase 2), LBs appear to be more commonly found than in parkin disease36 (especially in those with the G2019S mutation); however, limited nigral and LC neuronal loss in the absence of other pathology is also described. Tau pathology has been reported in a large proportion of leucine-rich repeat kinase 2 cases,37 whereas our series combined with existing reported cases would suggest there is much less tau burden in parkin disease.

The disparity between the severity of nigral loss with sparse or no LBs that we observed supports the notion that abnormal α-synuclein deposition is not an integral component of the pathology of parkin disease; therefore, it is innately different from PD. It can be argued that the LBs we identified were incidental owing to their paucity in comparison with PD. Case 5 died at age 82 years, an age at which the finding of incidental LB disease post mortem is known to occur in at least 15% of normal control subjects,3841 and case 3 died at age 61 years and only 2 LBs were identified after thorough study. Incidental LBs were also identified in 1 of our control cases with age at death of 81 years. Incidental LB disease may also explain 2 of the LB-positive parkin cases described in the literature.24,27 Age at disease onset is another possible factor that has been linked to the finding of LBs post mortem in parkin disease (Christine Klein, MD, oral communication, June 2012). Combining our 5 cases with those previously reported and comparing those that had LBs at post mortem with those that did not, there was a significant difference in age at disease onset between the groups (mean age at onset: LB-positive cases, 46 years; LB-negative cases, 27 years; P < .001; t test). Parkin cases with LBs discovered at pathologic examination were on average 19 years older at presentation.

An incomplete loss of ubiquitin ligase activity, recognized to occur with certain missense mutations of parkin,42 might permit the formation of LBs. In vitro studies have shown that different mutant parkin isoforms have different levels of enzymatic activity, with certain point mutations exhibiting only partial loss of function or possibly toxic gain of function.42 This is exemplified by the p.R275W mutation, which retains a functional RING domain (critical for E3 ligase activity) and has preserved ubiquitylation activity42 and the capacity to produce aggresomes.43 Alternatively, it has been proposed that parkin mutations resulting in loss of RING domain function are unable to form LBs as α-synuclein cannot be ubiquitinated.44 The p.R275W missense mutation was present in 4 of our cases (2 of which had LBs) and also in the case with LBs reported by Farrer and colleagues.20 We postulate that if the p.R275W-mutated protein is able to ubiquitinate some of its substrates to form an aggresome, then LBs could occur.

Another consideration is that 2 of the LB-positive cases20,24 descended from pedigrees not reflective of simple autosomal recessive inheritance—parkinsonism was seen in consecutive generations.

All of our cases had the characteristic clinical features felt to be particular for parkin disease—early-onset tremor often combined with dystonia and sustained response to dopaminergic medication. All experienced troublesome severe l-dopa–induced motor fluctuations. Freezing of gait and painful off-period dystonia were other common features. Three patients were described as having abnormal postures, either stooped forward or laterally flexed (scoliotic), which may reflect the chronicity of truncal dystonia throughout their disease course. The lack of cognitive and psychiatric features experienced in our patients might reflect sparing of the NBM and cerebral cortex. Only 1 patient experienced brief visual hallucinations at the end of her life (while taking levodopa and selegiline therapy), and no patients were reported as having delirium, amnesia, or dementia, despite their long disease duration (range, 27-50 years). This is important for clinical practice and may allay some patient fears in considering the long-term aspects of their parkin disease and its management.

In conclusion, parkin disease appears clinically and pathologically distinct from PD. It can be conceptualized as an early-onset, slowly progressive, levodopa-responsive parkinsonism without hallucinations or dementia due to neuronal loss in the ventral SN.

Correspondence: Janice L. Holton, FRCPath, Department of Molecular Neuroscience, University College London Institute of Neurology, Queen Square, London, WC1N 3BG, England (janice.holton@ucl.ac.uk).

Accepted for Publication: January 21, 2013.

Published Online: March 4, 2013. doi:10.1001/jamaneurol.2013.172

Author Contributions:Study concept and design: Doherty, Silveira-Moriyama, Healy, Ahmed, Hardy, Lynch, Revesz, Lees, and Holton. Acquisition of data: Doherty, Parkkinen, Farrell, Mencacci, Brett, Quinn, Counihan, Lynch, Revesz, and Holton. Analysis and interpretation of data: Doherty, Silveira-Moriyama, Parkkinen, Healy, Mencacci, Quinn, Lynch, Fox, Lees, and Holton. Drafting of the manuscript: Doherty, Brett, Hardy, Lynch, and Fox. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Doherty, Parkkinen, Lynch, and Fox. Obtained funding: Hardy. Administrative, technical, and material support: Parkkinen, Farrell, Ahmed, and Lees. Study supervision: Silveira-Moriyama, Healy, Counihan, Revesz, Lees, and Holton.

Conflict of Interest Disclosures: Dr Doherty's work is funded by the Reta Lila Weston Trust for Medical Research. She is the beneficiary of an innovation grant from Parkinson's UK, and in the past 3 years, she has received travel compensation to attend scientific meetings from Teva Pharmaceuticals, Ipsen, Novartis, GlaxoSmithKline, and Orion. Dr Silveira-Moriyama has received honoraria from Britannia Pharmaceuticals; grants from Parkinson's UK, the Parkinson Disease Foundation, the Reta Lila Weston Trust, FAPESP, and the University of Campinas; and travel support from UCB Pharmaceuticals, Genus Pharmaceuticals, and Abbott Laboratories. She is employed by the Reta Lila Weston Institute of Neurological Studies and the University of Campinas. Dr Parkkinen is a career development fellow funded by the Monumental Trust Award from Parkinson's UK. Dr Lynch has received honorarium from Abbott Laboratories, Boehringer Ingelheim, Lundbeck, and Orion; educational grants from Bayer-Schering, Biogen Idec, Lundbeck, and Medtronic; and grants from the Irish Institute of Clinical Neuroscience, and Mater College, as well as PRTL1 funding. He serves on advisory boards for Abbott Laboratories, Novartis, UCB Pharmaceuticals, Teva Pharmaceuticals, Merck Serono, and Biogen Idec. Dr Revesz's work is supported by grants from the Multiple System Atrophy Trust, Parkinson's UK, and Alzheimer's Research UK. Dr Lees serves as a consultant for Genus Pharmaceuticals and advisory board member for Novartis, Teva Pharmaceuticals, Boehringer Ingelheim, GlaxoSmithKline, Ipsen, Lundbeck, Allergan, Orion, BIAL Pharmaceuticals, Noscira, and Roche. Dr Lees has received honoraria from Novartis, Teva Pharmaceuticals, Meda, Boehringer Ingelheim, GlaxoSmithKline, Ipsen, Lundbeck, Allergan, Orion, BIAL Pharmaceuticals, Noscira, and Roche, as well as grants from the PSP Association and the Reta Lila Weston Trust for Medical Research. Dr Holton's work is supported by the Reta Lila Weston Trust for Medical Research, Parkinson's UK, the Multiple System Atrophy Trust, Alzheimer's Research UK, and the National Institute for Health Research Biomedical Research Unit at University College London Hospitals, University College London.

Funding/Support: This work was supported by the Reta Lila Weston Trust for Medical Research, the Dublin Brain Bank, the Wellcome Trust/MRC Joint Call in Neurodegeneration award, Parkinson's UK, the Multiple System Atrophy Trust, and Alzheimer's Research UK, as well as partly supported by the National Institute for Health Research Biomedical Research Unit based at University College London Hospitals, University College London.

Disclaimer: The views expressed are those of the authors and not necessarily those of the UK National Health Service, the National Institute for Health Research, or the Department of Health.

Previous Presentation: This paper was presented at the 16th International Congress of Parkinson's Disease and Movement Disorders; June 20, 2012; Dublin, Ireland.

Additional Contributions: We thank Catherine Strand, MSc, Tammaryn Lashley, PhD, and Karen Shaw, RMN, for their assistance in this project.

Online-Only Material: The video is available here.

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Lücking CB, Dürr A, Bonifati V,  et al; French Parkinson's Disease Genetics Study Group; European Consortium on Genetic Susceptibility in Parkinson's Disease.  Association between early-onset Parkinson's disease and mutations in the parkin gene.  N Engl J Med. 2000;342(21):1560-1567
PubMed   |  Link to Article
Klein C, Pramstaller PP, Kis B,  et al.  Parkin deletions in a family with adult-onset, tremor-dominant parkinsonism: expanding the phenotype.  Ann Neurol. 2000;48(1):65-71
PubMed   |  Link to Article
Nichols WC, Pankratz N, Uniacke SK,  et al.  Linkage stratification and mutation analysis at the Parkin locus identifies mutation positive Parkinson's disease families.  J Med Genet. 2002;39(7):489-492
PubMed   |  Link to Article
Hristova VA, Beasley SA, Rylett RJ, Shaw GS. Identification of a novel Zn2+-binding domain in the autosomal recessive juvenile Parkinson-related E3 ligase parkin.  J Biol Chem. 2009;284(22):14978-14986
PubMed   |  Link to Article
Yao Z, Wood NW. Cell death pathways in Parkinson's disease: role of mitochondria.  Antioxid Redox Signal. 2009;11(9):2135-2149
PubMed   |  Link to Article
Deas E, Wood NW, Plun-Favreau H. Mitophagy and Parkinson's disease: the PINK1-parkin link.  Biochim Biophys Acta. 2011;1813(4):623-633
PubMed   |  Link to Article
Yamamura Y, Kuzuhara S, Kondo K,  et al.  Clinical, pathologic and genetic studies on autosomal recessive early-onset parkinsonism with diurnal fluctuation.  Parkinsonism Relat Disord. 1998;4(2):65-72
PubMed   |  Link to Article
Mori H, Kondo T, Yokochi M,  et al.  Pathologic and biochemical studies of juvenile parkinsonism linked to chromosome 6q.  Neurology. 1998;51(3):890-892
PubMed   |  Link to Article
Hayashi S, Wakabayashi K, Ishikawa A,  et al.  An autopsy case of autosomal-recessive juvenile parkinsonism with a homozygous exon 4 deletion in the parkin gene.  Mov Disord. 2000;15(5):884-888
PubMed   |  Link to Article
van de Warrenburg BPC, Lammens M, Lücking CB,  et al.  Clinical and pathologic abnormalities in a family with parkinsonism and parkin gene mutations.  Neurology. 2001;56(4):555-557
PubMed   |  Link to Article
Farrer M, Chan P, Chen R,  et al.  Lewy bodies and parkinsonism in families with parkin mutations.  Ann Neurol. 2001;50(3):293-300
PubMed   |  Link to Article
Mori H, Hattori N, Mizuno Y. Genotype-phenotype correlation: familial Parkinson disease.  Neuropathology. 2003;23(1):90-94
PubMed   |  Link to Article
Gouider-Khouja N, Larnaout A, Amouri R,  et al.  Autosomal recessive parkinsonism linked to parkin gene in a Tunisian family: clinical, genetic and pathological study.  Parkinsonism Relat Disord. 2003;9(5):247-251
PubMed   |  Link to Article
Sasaki S, Shirata A, Yamane K, Iwata M. Parkin-positive autosomal recessive juvenile Parkinsonism with alpha-synuclein-positive inclusions.  Neurology. 2004;63(4):678-682
PubMed   |  Link to Article
Pramstaller PP, Schlossmacher MG, Jacques TS,  et al.  Lewy body Parkinson's disease in a large pedigree with 77 Parkin mutation carriers.  Ann Neurol. 2005;58(3):411-422
PubMed   |  Link to Article
Orimo S, Amino T, Yokochi M,  et al.  Preserved cardiac sympathetic nerve accounts for normal cardiac uptake of MIBG in PARK2.  Mov Disord. 2005;20(10):1350-1353
PubMed   |  Link to Article
Torres L CM, Mata I, Mazzetti PE,  et al.  A novel PARK2 mutation in a Peruvian family: clinical and pathological characteristics.  Mov Disord. 2011;26:((suppl 2):)  S311-S312
Miyakawa S, Ogino M, Funabe S,  et al.  Lewy body pathology in a patient with a homozygous parkin deletion.  Mov Disorddoi:10.1002/mds.25346
Ozawa T, Paviour D, Quinn NP,  et al.  The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations.  Brain. 2004;127(pt 12):2657-2671
PubMed   |  Link to Article
McKeith IG, Dickson DW, Lowe J,  et al; Consortium on DLB.  Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.  Neurology. 2005;65(12):1863-1872
PubMed   |  Link to Article
Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease.  Neurobiol Aging. 2003;24(2):197-211
PubMed   |  Link to Article
Halliday G. Substantia nigra and locus coeruleus. In: Paxinos G, Juergen KM, eds. The Human Nervous System. 2nd ed. London, England: Elsevier Academic Press; 2004:449-463
Ma SY, Collan Y, Röyttä M, Rinne JO, Rinne UK. Cell counts in the substantia nigra: a comparison of single section counts and disector counts in patients with Parkinson's disease and in controls.  Neuropathol Appl Neurobiol. 1995;21(1):10-17
PubMed   |  Link to Article
Ahlskog JE. Parkin and PINK1 parkinsonism may represent nigral mitochondrial cytopathies distinct from Lewy body Parkinson's disease.  Parkinsonism Relat Disord. 2009;15(10):721-727
PubMed   |  Link to Article
Paisán-Ruiz C, Li A, Schneider SA,  et al.  Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations.  Neurobiol Aging. 2012;33(4):814-823
PubMed   |  Link to Article
Samaranch L, Lorenzo-Betancor O, Arbelo JM,  et al.  PINK1-linked parkinsonism is associated with Lewy body pathology.  Brain. 2010;133(pt 4):1128-1142
PubMed   |  Link to Article
Cookson MR, Hardy J, Lewis PA. Genetic neuropathology of Parkinson's disease.  Int J Clin Exp Pathol. 2008;1(3):217-231
PubMed
Poulopoulos M, Levy OA, Alcalay RN. The neuropathology of genetic Parkinson's disease.  Mov Disord. 2012;27(7):831-842
PubMed   |  Link to Article
Gibb WRG, Lees AJ. The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease.  J Neurol Neurosurg Psychiatry. 1988;51(6):745-752
PubMed   |  Link to Article
Fearnley JM, Lees AJ. Ageing and Parkinson's disease: substantia nigra regional selectivity.  Brain. 1991;114(pt 5):2283-2301
PubMed   |  Link to Article
Parkkinen L, Soininen H, Laakso M, Alafuzoff I. Alpha-synuclein pathology is highly dependent on the case selection.  Neuropathol Appl Neurobiol. 2001;27(4):314-325
PubMed   |  Link to Article
Markesbery WR, Jicha GA, Liu H, Schmitt FA. Lewy body pathology in normal elderly subjects.  J Neuropathol Exp Neurol. 2009;68(7):816-822
PubMed   |  Link to Article
Sriram SR, Li X, Ko HS,  et al.  Familial-associated mutations differentially disrupt the solubility, localization, binding and ubiquitination properties of parkin.  Hum Mol Genet. 2005;14(17):2571-2586
PubMed   |  Link to Article
Cookson MR, Lockhart PJ, McLendon C, O’Farrell C, Schlossmacher M, Farrer MJ. RING finger 1 mutations in Parkin produce altered localization of the protein.  Hum Mol Genet. 2003;12(22):2957-2965
PubMed   |  Link to Article
Klein C, Lohmann-Hedrich K, Rogaeva E, Schlossmacher MG, Lang AE. Deciphering the role of heterozygous mutations in genes associated with parkinsonism.  Lancet Neurol. 2007;6(7):652-662
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Histologic findings in the parkin cases. Case 2 substantia nigra illustrates the more severe neuronal loss in the ventral tier (white arrow) compared with the dorsal tier (black arrow) (A), accompanied by severe gliosis (white arrow) in the ventral tier compared with the dorsal tier (black arrow) (B). Case 5 showed severe neuronal loss in the ventrolateral substantia nigra (C) and only sparse α-synuclein pathology (arrows) (D), with mild cell dropout in the locus coeruleus (E) accompanied by moderate numbers of Lewy bodies (arrows) and Lewy neurites (F). The scale bar represents 260 μm in parts A and B, 50 μm in parts C and D, 100 μm in parts E and F, and 25 μm in the inset in part F. Hematoxylin-eosin staining in parts A, C, and E; glial fibrillary acidic protein in part B; and α-synuclein in parts D and F.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Regional neuronal loss (A) and gliosis (B) in parkin, Parkinson disease (PD), and control cases. A, The severity of neuronal loss in various brain regions in the 5 parkin, 5 PD, and 4 control cases (not all structures were available for examination in all cases [eg, the raphe was only available for examination in 3 parkin, 2 PD, and 3 control cases]). B, The severity of gliosis in various brain regions in the parkin, PD, and control cases. GP indicates globus pallidus; DMV, dorsal motor nucleus of the vagus; LC, locus coeruleus; NBM, nucleus basalis of Meynert; SN, substantia nigra.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 3. Clustered box plot illustrating neuronal density in ventral, dorsal, and combined (total) nigral tiers in the parkin and Parkinson disease (PD) cases. The asterisk indicates an extreme score (ie, the value is more than 3 box lengths from the upper quartile) and the black dot indicates an outlier (ie, the value is more than 1.5 box lengths from the lower quartile).

Tables

Table Graphic Jump LocationTable 1. Pathological Reports of Published Parkin Cases
Table Graphic Jump LocationTable 2. Additional Pathological Reports of Published Parkin Cases
Table Graphic Jump LocationTable 3. Clinical and Genetic Details of Parkin Disease Cases
Table Graphic Jump LocationTable 4. Neuropathology of Parkin Disease Cases
Table Graphic Jump LocationTable 5. Comparison of Parkin and Parkinson Disease Cases

References

Ishikawa A, Tsuji S. Clinical analysis of 17 patients in 12 Japanese families with autosomal-recessive type juvenile parkinsonism.  Neurology. 1996;47(1):160-166
PubMed   |  Link to Article
Matsumine H, Saito M, Shimoda-Matsubayashi S,  et al.  Localization of a gene for an autosomal recessive form of juvenile parkinsonism to chromosome 6q25.2-27.  Am J Hum Genet. 1997;60(3):588-596
PubMed
Kitada T, Asakawa S, Hattori N,  et al.  Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism.  Nature. 1998;392(6676):605-608
PubMed   |  Link to Article
Khan NL, Brooks DJ, Pavese N,  et al.  Progression of nigrostriatal dysfunction in a parkin kindred: an [18F]dopa PET and clinical study.  Brain. 2002;125(pt 10):2248-2256
PubMed   |  Link to Article
Khan NL, Graham E, Critchley P,  et al.  Parkin disease: a phenotypic study of a large case series.  Brain. 2003;126(pt 6):1279-1292
PubMed   |  Link to Article
Khan NL, Horta W, Eunson L,  et al.  Parkin disease in a Brazilian kindred: manifesting heterozygotes and clinical follow-up over 10 years.  Mov Disord. 2005;20(4):479-484
PubMed   |  Link to Article
Khan NL, Katzenschlager R, Watt H,  et al.  Olfaction differentiates parkin disease from early-onset parkinsonism and Parkinson disease.  Neurology. 2004;62(7):1224-1226
PubMed   |  Link to Article
Lohmann E, Periquet M, Bonifati V,  et al; French Parkinson's Disease Genetics Study Group; European Consortium on Genetic Susceptibility in Parkinson's Disease.  How much phenotypic variation can be attributed to parkin genotype?  Ann Neurol. 2003;54(2):176-185
PubMed   |  Link to Article
Kim HJ, Kim HJ, Lee JY,  et al.  Phenotype analysis in patients with early onset Parkinson's disease with and without parkin mutations.  J Neurol. 2011;258(12):2260-2267
PubMed   |  Link to Article
Lücking CB, Dürr A, Bonifati V,  et al; French Parkinson's Disease Genetics Study Group; European Consortium on Genetic Susceptibility in Parkinson's Disease.  Association between early-onset Parkinson's disease and mutations in the parkin gene.  N Engl J Med. 2000;342(21):1560-1567
PubMed   |  Link to Article
Klein C, Pramstaller PP, Kis B,  et al.  Parkin deletions in a family with adult-onset, tremor-dominant parkinsonism: expanding the phenotype.  Ann Neurol. 2000;48(1):65-71
PubMed   |  Link to Article
Nichols WC, Pankratz N, Uniacke SK,  et al.  Linkage stratification and mutation analysis at the Parkin locus identifies mutation positive Parkinson's disease families.  J Med Genet. 2002;39(7):489-492
PubMed   |  Link to Article
Hristova VA, Beasley SA, Rylett RJ, Shaw GS. Identification of a novel Zn2+-binding domain in the autosomal recessive juvenile Parkinson-related E3 ligase parkin.  J Biol Chem. 2009;284(22):14978-14986
PubMed   |  Link to Article
Yao Z, Wood NW. Cell death pathways in Parkinson's disease: role of mitochondria.  Antioxid Redox Signal. 2009;11(9):2135-2149
PubMed   |  Link to Article
Deas E, Wood NW, Plun-Favreau H. Mitophagy and Parkinson's disease: the PINK1-parkin link.  Biochim Biophys Acta. 2011;1813(4):623-633
PubMed   |  Link to Article
Yamamura Y, Kuzuhara S, Kondo K,  et al.  Clinical, pathologic and genetic studies on autosomal recessive early-onset parkinsonism with diurnal fluctuation.  Parkinsonism Relat Disord. 1998;4(2):65-72
PubMed   |  Link to Article
Mori H, Kondo T, Yokochi M,  et al.  Pathologic and biochemical studies of juvenile parkinsonism linked to chromosome 6q.  Neurology. 1998;51(3):890-892
PubMed   |  Link to Article
Hayashi S, Wakabayashi K, Ishikawa A,  et al.  An autopsy case of autosomal-recessive juvenile parkinsonism with a homozygous exon 4 deletion in the parkin gene.  Mov Disord. 2000;15(5):884-888
PubMed   |  Link to Article
van de Warrenburg BPC, Lammens M, Lücking CB,  et al.  Clinical and pathologic abnormalities in a family with parkinsonism and parkin gene mutations.  Neurology. 2001;56(4):555-557
PubMed   |  Link to Article
Farrer M, Chan P, Chen R,  et al.  Lewy bodies and parkinsonism in families with parkin mutations.  Ann Neurol. 2001;50(3):293-300
PubMed   |  Link to Article
Mori H, Hattori N, Mizuno Y. Genotype-phenotype correlation: familial Parkinson disease.  Neuropathology. 2003;23(1):90-94
PubMed   |  Link to Article
Gouider-Khouja N, Larnaout A, Amouri R,  et al.  Autosomal recessive parkinsonism linked to parkin gene in a Tunisian family: clinical, genetic and pathological study.  Parkinsonism Relat Disord. 2003;9(5):247-251
PubMed   |  Link to Article
Sasaki S, Shirata A, Yamane K, Iwata M. Parkin-positive autosomal recessive juvenile Parkinsonism with alpha-synuclein-positive inclusions.  Neurology. 2004;63(4):678-682
PubMed   |  Link to Article
Pramstaller PP, Schlossmacher MG, Jacques TS,  et al.  Lewy body Parkinson's disease in a large pedigree with 77 Parkin mutation carriers.  Ann Neurol. 2005;58(3):411-422
PubMed   |  Link to Article
Orimo S, Amino T, Yokochi M,  et al.  Preserved cardiac sympathetic nerve accounts for normal cardiac uptake of MIBG in PARK2.  Mov Disord. 2005;20(10):1350-1353
PubMed   |  Link to Article
Torres L CM, Mata I, Mazzetti PE,  et al.  A novel PARK2 mutation in a Peruvian family: clinical and pathological characteristics.  Mov Disord. 2011;26:((suppl 2):)  S311-S312
Miyakawa S, Ogino M, Funabe S,  et al.  Lewy body pathology in a patient with a homozygous parkin deletion.  Mov Disorddoi:10.1002/mds.25346
Ozawa T, Paviour D, Quinn NP,  et al.  The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations.  Brain. 2004;127(pt 12):2657-2671
PubMed   |  Link to Article
McKeith IG, Dickson DW, Lowe J,  et al; Consortium on DLB.  Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.  Neurology. 2005;65(12):1863-1872
PubMed   |  Link to Article
Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease.  Neurobiol Aging. 2003;24(2):197-211
PubMed   |  Link to Article
Halliday G. Substantia nigra and locus coeruleus. In: Paxinos G, Juergen KM, eds. The Human Nervous System. 2nd ed. London, England: Elsevier Academic Press; 2004:449-463
Ma SY, Collan Y, Röyttä M, Rinne JO, Rinne UK. Cell counts in the substantia nigra: a comparison of single section counts and disector counts in patients with Parkinson's disease and in controls.  Neuropathol Appl Neurobiol. 1995;21(1):10-17
PubMed   |  Link to Article
Ahlskog JE. Parkin and PINK1 parkinsonism may represent nigral mitochondrial cytopathies distinct from Lewy body Parkinson's disease.  Parkinsonism Relat Disord. 2009;15(10):721-727
PubMed   |  Link to Article
Paisán-Ruiz C, Li A, Schneider SA,  et al.  Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations.  Neurobiol Aging. 2012;33(4):814-823
PubMed   |  Link to Article
Samaranch L, Lorenzo-Betancor O, Arbelo JM,  et al.  PINK1-linked parkinsonism is associated with Lewy body pathology.  Brain. 2010;133(pt 4):1128-1142
PubMed   |  Link to Article
Cookson MR, Hardy J, Lewis PA. Genetic neuropathology of Parkinson's disease.  Int J Clin Exp Pathol. 2008;1(3):217-231
PubMed
Poulopoulos M, Levy OA, Alcalay RN. The neuropathology of genetic Parkinson's disease.  Mov Disord. 2012;27(7):831-842
PubMed   |  Link to Article
Gibb WRG, Lees AJ. The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease.  J Neurol Neurosurg Psychiatry. 1988;51(6):745-752
PubMed   |  Link to Article
Fearnley JM, Lees AJ. Ageing and Parkinson's disease: substantia nigra regional selectivity.  Brain. 1991;114(pt 5):2283-2301
PubMed   |  Link to Article
Parkkinen L, Soininen H, Laakso M, Alafuzoff I. Alpha-synuclein pathology is highly dependent on the case selection.  Neuropathol Appl Neurobiol. 2001;27(4):314-325
PubMed   |  Link to Article
Markesbery WR, Jicha GA, Liu H, Schmitt FA. Lewy body pathology in normal elderly subjects.  J Neuropathol Exp Neurol. 2009;68(7):816-822
PubMed   |  Link to Article
Sriram SR, Li X, Ko HS,  et al.  Familial-associated mutations differentially disrupt the solubility, localization, binding and ubiquitination properties of parkin.  Hum Mol Genet. 2005;14(17):2571-2586
PubMed   |  Link to Article
Cookson MR, Lockhart PJ, McLendon C, O’Farrell C, Schlossmacher M, Farrer MJ. RING finger 1 mutations in Parkin produce altered localization of the protein.  Hum Mol Genet. 2003;12(22):2957-2965
PubMed   |  Link to Article
Klein C, Lohmann-Hedrich K, Rogaeva E, Schlossmacher MG, Lang AE. Deciphering the role of heterozygous mutations in genes associated with parkinsonism.  Lancet Neurol. 2007;6(7):652-662
PubMed   |  Link to Article

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Supplemental Content

Doherty KM, Silveira-Moriyama L, Parkkinen L, et al. Parkin disease: a clinicopathologic entity?. JAMA Neurol.. Published online March 4, 2013. doi:10.1001/jamaneurol.2013.172.

eAppendix 1. Full details of the antibodies used in the study including dilution and manufacturer

eAppendix 2. Clinical summaries

eReferences

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