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Movement Disorders
Contents Preface
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Joseph Jankovic Etiology and Pathogenesis of Parkinson Disease
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Anthony H.V. Schapira The etiology of Parkinson disease (PD) is multifactorial and is likely to involve different causes in different patients. Several different genes have been identified as causes of familial PD, including alpha-synuclein gene mutations and multiplications, and mutations of parkin, PINK1, DJ1, and LRRK2. The biochemical consequences of these mutations have served to reinforce the relevance of the pathways to pathogenesis previously characterized, for example, mitochondrial dysfunction, oxidative stress, and protein misfolding and aggregation. The recognition that glucocerebrosidase mutations represent a significant risk factor for PD has focused attention on lysosomal function and autophagy as relevant to PD. Several environmental factors have also been shown to influence the risk for PD, although odds ratios remain relatively modest. Specific toxins can cause dopaminergic cell death in man and animals, but they probably have limited relevance to the etiology of PD. Medical Treatment of Parkinson Disease
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Mark Stacy The cardinal characteristics of Parkinson disease (PD) include resting tremor, rigidity, and bradykinesia. Patients may also develop autonomic dysfunction, cognitive changes, psychiatric symptoms, sensory complaints, and sleep disturbances. The treatment of motor and non-motor symptoms of Parkinson disease is addressed in this article. Surgical Treatment of Movement Disorders
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Benzi M. Kluger, Olga Klepitskaya, and Michael S. Okun Surgical approaches are an important consideration in the management of many movement disorders, particularly for patients refractory to medications. In this article, we review the history, pathophysiology, risks and indications for surgical treatment. Summaries of case studies, case series and clinical trials performed using deep brain stimulation are provided for Parkinson’s disease, dystonia, essential tremor and other movement disorders. Tremor: Clinical Features, Pathophysiology, and Treatment Rodger J. Elble Tremor is not understood completely, and pharmacotherapy for all tremor disorders is inadequate. Fortunately, deep brain stimulation is effective for
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the most common and disabling tremor disorders. Our understanding of pathologic tremors has increased at an accelerating pace during the past 30 years, and this will hopefully lead to improved pharmacotherapy in the near future.
Genetics and Treatment of Dystonia
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Cordelia S. Schwarz and Susan B. Bressman The torsion dystonias encompass a broad collection of etiologic subtypes, often divided into primary and secondary classes. Tremendous advances have been made in uncovering the genetic basis of dystonia, including discovery of a gene causing early onset primary torsion dystonia—a GAG deletion in exon 5 of the DYT1 gene that encodes torsinA. Although the exact function of torsinA remains elusive, evidence suggests aberrant localization and interaction of mutated protein; this may result in an abnormal response to stress or interference with cytoskeletal events and the development of neuronal brain pathways. Breakthroughs include the discovery of a genetic modifier that protects against clinical expression in DYT1 dystonia and the identification of the gene causing DYT6, THAP1. The authors review genetic etiologies and discuss phenotypes as well as counseling of patients regarding prognosis and progression of the disease. They also address pharmacologic and surgical treatment options for various forms of dystonia.
Huntington Disease and Other Choreas
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Francisco Cardoso Chorea is defined as a syndrome characterized by brief, abrupt involuntary movements resulting from a continuous flow of random muscle contractions. There are genetic and non-genetic causes of chorea. The most common genetic cause of chorea is Huntington’s disease (HD). Non-genetic forms of chorea include vascular choreas, auto-immune choreas, metabolic and toxic choreas, and drug-induced choreas. This chapter provides an overview of clinical features, pathogenesis and management of HD, other important genetic causes of chorea, Sydenham’s chorea, other autoimmune choreas and vascular choreas.
Tourette Syndrome Joohi Jimenez-Shahed Tourette syndrome (TS) is a neuro-developmental disorder of childhood that is often associated with various psychiatric morbidities. Timely diagnosis and appropriate management can significantly impact psychosocial functioning. Morbidities may be a major source of disability, and may determine ultimate prognosis, although most children will experience significant improvement or resolution of symptoms by adulthood. Additional management considerations must be made in those with TS symptoms persisting into adulthood. The mainstay of therapy remains dopamine receptor blocking drugs, but new therapies are emerging.
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Pathophysiology and Treatment of Myoclonus
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John N. Caviness Myoclonus is defined as sudden, brief, shock-like, involuntary movements caused by muscular contractions or inhibitions. Etiologic classification organizes the myoclonus disorders and provides major categories of clinical presentation. However, classifying myoclonus according to its source provides insight about its pathophysiology. The best strategy for symptomatic treatment is derived from defining the pathophysiology by way of source physiologic classification.
Restless Legs Syndrome
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William G. Ondo Restless legs syndrome (RLS) affects many people. General population prevalence surveys usually range from 1% to 12%, but most European ancestry studies suggest 10%. The development of validated rating scales and standardized diagnostic criteria have vastly improved the quality of RLS treatment trials. Although multiple medications have shown outstanding efficacy, all of them are felt to provide only symptomatic relief, rather than any ‘‘curative’’ effect. Dopamine agonists are clearly the best investigated and probably the most effective treatments for RLS.
Psychogenic Movement Disorders
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Elizabeth L. Peckham and Mark Hallett Psychogenic movement disorders (PMDs) represent a challenging dilemma for the treating neurologist. The terminology to classify this disorder is confusing and making the diagnosis is difficult. Once the diagnosis has been established, treatment options are limited, and the patient generally does not accept the diagnosis.
Peripherally Induced Movement Disorders
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Joseph Jankovic Peripherally induced movement disorders may be defined as involuntary or abnormal movements triggered by trauma to the cranial or peripheral nerves or roots. Although patients often recall some history of trauma before the onset of a movement disorder, determining the true relationship of the disorder to the earlier trauma is often difficult. The pathophysiology of these disorders is reviewed.
Index
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Movement Disorders
Preface
Joseph Jankovic, MD Guest Editor
Few neurologic disorders have attracted more attention from the scientific and lay communities than Parkinson disease and related neurodegenerative diseases. Advances in basic research into mechanisms of neuronal death, physiology of the basal ganglia, and biochemistry and pharmacology are now being translated into clinical practice. Despite extraordinary therapeutic advances during the recent past, Parkinson disease continues to be among the most common causes of disability, particularly among the elderly. In this issue of Neurologic Clinics, dedicated entirely to movement disorders, two articles, one by Dr. Schapira and another by Dr. Stacy, focus on the pathogenesis and medical treatment of Parkinson disease. Dr. Kluger and colleagues provide an update on surgical treatment, particularly deep brain stimulation, in Parkinson disease and other movement disorders. The clinical features, pathophysiology, and treatment of tremor, the most common movement disorder encountered in a movement disorders clinic, are reviewed by Dr. Elble. The remarkable progress in the understanding of the genetics of various dystonias and their treatment, including botulinum toxin, is reviewed by Drs. Schwarz and Bressman. Huntington disease, manifested by a combination of chorea, affective disorder, and cognitive decline, is reviewed by Dr. Cardoso. Although tetrabenazine has been used in the treatment of various hyperkinetic movement disorders for several decades, this monoamine depleter has recently become the first drug approved by the Food and Drug Administration for the treatment of chorea associated with Huntington disease. Tics and other features of Tourette syndrome, along with a review of possible pathophysiologic mechanisms and medical and surgical treatment, are discussed by Dr. JimenezShahed. In Dr. Caviness’s article, the pathophysiology and treatment of myoclonus are reviewed. Restless legs syndrome is one of the most common movement disorders in the general population; its pathogenesis and treatment are reviewed by Dr. Ondo. Some of the most challenging disorders, increasingly encountered in specialty clinics, are the psychogenic movement disorders, covered in some detail by Drs. Peckham and Hallett. In the last article, I review the clinical features and presumed pathophysiologic mechanisms of peripherally induced movement disorders, including hemifacial spasm,
Neurol Clin 27 (2009) ix–x doi:10.1016/j.ncl.2009.04.012 neurologic.theclinics.com 0733-8619/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
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dystonia (with or without complex regional pain syndrome, previously referred to as reflex sympathetic dystrophy), tremor, and other disorders following peripheral injury. This comprehensive volume, written by a team of leading movement disorder neurologists, should be of interest not only to clinicians concerned with the care of those afflicted with Parkinson disease and other movement disorders, but also to clinical and basic investigators pursuing answers to some of the unanswered questions about the pathogenesis of this challenging group of disorders. The authors provide a broad and well-balanced review of the progress made in the understanding of this group of neurologic disorders. I would like to take this opportunity to thank Randolph Evans, MD, for his initial invitation and encouragements to edit this issue. I also thank Donald Mumford, Senior Developmental Editor and Editor of Neurologic Clinics at Elsevier, for his hard work, guidance, and professionalism. Finally, I wish to express my deep appreciation to all the authors who shared their knowledge and expertise by providing authoritative and comprehensive reviews of the assigned topics. Joseph Jankovic, MD Professor of Neurology Distinguished Chair in Movement Disorders Director Parkinson’s Disease Center and Movement Disorders Clinic Department of Neurology Baylor College of Medicine Houston, Texas 77030, USA E-mail address:
[email protected] (J. Jankovic)
Etiology and Patho genesis of Parkinson Dis eas e Anthony H.V. Schapira, MD, DSc, FRCP, FMedSci KEYWORDS Parkinson disease Alpha-synuclein Mitochondria Oxidative stress Proteosome Lewy body
Defining the epidemiology of Parkinson disease (PD) is confounded by several variables, which include the difficulty in diagnosis and the age dependence of the disease. Several studies have sought to define incidence. In the United States, the ageadjusted figure is 13.5 to 13.9 per 100,000 person years.1,2 The age-adjusted prevalence is approximately 115 per 100,000 and is estimated as 1.3 per 100,000 under age 45 years and 1192.9 per 100,000 in patients aged 75 to 85 years.1 A prevalence study in Holland found 3100 cases per 100,000 aged 75 to 85 years and 4300 per 100,000 for those older than 85 years.3 The geographic distribution of the disease appears similar across the United States and Japan, but failure to adjust population figures for age can lead to widely discrepant results, for example, prevalence of 10 per 100,000 in Nigeria.4 PD pathology is part of a multicentric neurodegenerative disease in which it is suggested that the appearance of morphologic abnormalities follows a specific sequence, beginning in the dorsal motor nucleus and in the olfactory bulbs and nucleus, followed by Lewy body formation in the locus ceruleus, and subsequently in the substantia nigra pars compacta (SNc).5 However, the relationship of the presence of the Lewy body to cell death is not yet defined. Neuronal cell loss in PD appears first in the dopaminergic cells of the SNc. This is associated with the appearance of the early motor features of PD and is the point at which a clinical diagnosis of PD becomes possible. It has been estimated that dopamine levels in the striatum are reduced to approximately 60% to 70% of normal values at the time of diagnosis. Imaging studies using positron emission tomography (PET) or single photon emission computerized tomography may demonstrate the asymmetric loss of posterior putaminal fluorodopa or dopamine transporter, respectively. Sequential imaging of PD patients suggests
University Department of Clinical Neurosciences, Institute of Neurology, University College London, Rowland Hill Street, London NW3 2PF, UK E-mail address:
[email protected] Neurol Clin 27 (2009) 583–603 doi:10.1016/j.ncl.2009.04.004 neurologic.theclinics.com 0733-8619/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
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that the preclinical period of cell loss is around 8 years, with the greatest rate of decline in the early stages of the disease.6 Thus, consideration of the etiology of PD must take into account the apparent latent period of the disease and the relative early selectivity of the pathology to the substantia nigra, the distribution of Lewy bodies not withstanding. Degeneration of nondopaminergic neurons also occurs in PD, but it usually occurs later in the course of the disease. The cholinergic nucleus basalis of Meynert, the serotoninergic neurons of the raphe nucleus, and the hypocretin-containing neurons of the hypothalamus suffer neuron loss with advanced disease. The noradrenergic dorsal vagal nucleus shows comparatively mild neuron loss despite marked deposition of alpha-synuclein. There is relatively mild cell loss in the amygdala, even at end-stage disease. The pattern and severity of cell loss in PD are thus not directly related to alpha-synuclein deposition, which has implications for understanding the contribution of this protein to pathology in different neurotransmitter pathways. The loss of nondopaminergic neurons contributes to the nonmotor features of PD.7 Inflammatory change has been identified as a common and important feature of PD pathology. Reactive microglia are found in the substantia nigra, particularly around pigmented neurons. Microglia have also been demonstrated in the putamen and cerebral cortex of PD. The extent of microglial activation in the substantia nigra correlates with the degree of alpha-synuclein deposition. Although the cause of PD is not known, both genetic and environmental factors are considered important.8 Several single gene mutations have now been identified in familial PD, other loci await characterization, and a number of putative association loci that might influence the development of PD have been described. A consistent pathogenetic profile is beginning to emerge from the study of familial and sporadic PD.9 Gene mutations are present in proteins involved in protein handling, oxidative stress, and mitochondrial function. These processes are closely interlinked. Environmental toxins used to model PD in animals inhibit mitochondrial function, increase free radical formation, and, in some cases, cause protein aggregation.
GENETIC FACTORS
Several recent case control studies have confirmed that PD is more common in relatives of PD cases compared with matched controls.10–13 Overall, the relative risk in first-degree relatives of PD cases has increased approximately 2 to 3-fold.14 A large PD twin study showed no significant concordance for PD among monozygotic twins, suggesting no significant genetic contribution to PD.15 However, for those with onset before age 50 years, the concordance rate was significant, implying that young-onset PD is more likely genetically determined. Another albeit smaller twin study using fluorodopa PET to image dopaminergic function in both affected and unaffected mono- and dizygotic twin pairs demonstrated an increased concordance for PD among identical twins, supporting a role for genetics in etiology.16 All of the twins were environmentally concordant in early life. At follow-up, the combined concordance levels for subclinical dopaminergic dysfunction and clinical PD were 75% in the 12 monozygotic twins and 22% in the 9 dizygotic twins evaluated twice. There have been numerous reports of familial aggregations of PD where inheritance has followed autosomal dominant or recessive inheritance. Several gene mutations and chromosomal loci have now been identified (Table 1).
Etiology and Pathogenesis of Parkinson Disease
Table 1 Causes of familial Parkinson disease Inheritance
Chromosomal locus
PARK 114
AuD
Protein Alpha-synuclein
Chr 4q
PARK 2
AuR
Parkin
Chr 6q
PARK 6
AuR
PINK1
Chr 1p
PARK 7
AuR
DJ1
Chr 1p
PARK 8
AuD
LRRK2
Chr 12q
PARK 9
AuR
ATP13A2
Chr 1p
Others UCHL1 Omi/HtrA2 Nurr1 mtDNA polymerase gamma Glucocerebrosidase Abbreviations: AuD, autosomal dominant; AuR, autosomal recessive.
Alpha-synuclein (Park 1)
The first familial cause of PD described involved mutations in the alpha-synuclein gene (PARK 1).17,18 More recently, multiplications of the wild-type alpha-synuclein gene have been described. A triplication of the gene was identified in a large autosomaldominant kindred with PD and tremor.19 Duplication of the gene was found in 1 of 42 familial probands of early onset PD.20 A third alpha-synuclein point mutation (E46K) has been reported in an autosomal-dominant family with parkinsonism and Lewy body dementia.21 The clinical spectrum associated with these mutations includes classical late-onset PD without prominent cognitive features, for example, the family carrying the A30P mutation, and early onset disease with dementia and rapid progression, for example, the A53T mutation. In the E46K family, there were features of early dementia and prominent autonomic dysfunction reminiscent of dementia with Lewy bodies, rather than typical PD. The discovery that multiplications of the normal (wild-type [WT]) gene cause autosomal-dominant parkinsonism with extensive LB inclusions is a potentially more important and relevant discovery than alpha-synuclein point mutations as a cause of PD. Not only are multiplications more common than point mutations of alpha-synuclein, but the fact that overexpression of WT alpha-synuclein protein is toxic to dopaminergic neurons and can reproduce the clinical and pathologic features of typical PD is of major importance to sporadic PD. A triplication of the alpha-synuclein gene was first identified in the so-called ‘‘Iowa-kindred,’’ a family with early onset parkinsonism, dementia, and prominent autonomic dysfunction.22,23 Postmortem examination of brains showed wide-spread aggregates of different shapes, with severe neuritic abnormalities and vacuolar changes in the temporal cortex.24 Duplications have been described in apparently sporadic patients with late-onset disease.25 There appears to be a gene dose effect in terms of age of onset: the greater the alpha-synuclein expression, the earlier the age of onset of PD.26 Polymorphisms of the promoter region of the alpha-synuclein gene have also been associated with increased protein production and enhanced risk for PD,27–29 although not all studies have been able to replicate these observations.30,31 The allele-specific
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binding of the transcriptional regulator poly-(ADP-ribose) transferase/polymerase-1 has been suggested as important.32 Although regulation of alpha-synuclein transcription and translation is likely to be complex, the emerging consensus that factors that upregulate this protein’s production contribute to PD risk provides a direct link between inherited and sporadic PD. Several models of abnormal alpha-synuclein expression have been developed over the past few years. Knockout of the gene in mice resulted in no detectable abnormality other than an alteration of dopamine release in response to rapid stimulation, although this has no clear functional correlate.33 Overexpression of WT human alpha-synuclein in mice resulted in loss of dopaminergic terminals; intranuclear and cytoplasmic ubiquitin-rich nonfibrillar a-synuclein inclusions in the substantia nigra, hippocampus, and cortex; and a rotor-rod motor deficit at 1 year.34 Overexpression of human WT and mutant a-synuclein in flies caused a loss of dopaminergic neurons, Lewy body-like inclusions with fibrillar a-synuclein, and a motor deficit with no significant difference between WT and mutant a-synuclein.35 Additional mouse models of a-synuclein expression have demonstrated inclusion formation and spinal cord pathology but no dopaminergic cell loss or motor deficit at late stage.36 Viral-mediated overexpression of alpha-synuclein induces nigral degeneration in rodents.37 The long-term expression of WT and mutant alpha-synuclein using recombinant adeno-associated viral vectors delivered to the ventral midbrain of marmosets induced parkinsonism with motor incoordination. Pathologic examination demonstrated the accumulation of pathologically phosphorylated alpha-synuclein, ubiquitinated aggregates, and dopamine cell degeneration.38 The A53T alpha-synuclein mutation enhances protofibrillar and fibrillar protein formation, which is considered the more toxic form of the protein.39 Catecholamines, including dopamine, and levodopa, inhibit fibril formation in vitro, and this is reversed by antioxidants, that is, catechol oxidation promotes protofibril formation.40 This observation would support a protective role for Lewy bodies in PD. An important observation revealing a potential toxic mechanism for alpha-synuclein is that the mutant form increases toxicity to dopamine, increasing cell death and free radical–mediated damage.41 The authors proposed that the mutation impaired vesicular uptake of dopamine, resulting in higher cytoplasmic or extravesicular synaptic concentrations of dopamine, which would in turn cause free radical–mediated damage. Phosphorylation at the Ser129 residue is required to mediate the toxicity of alpha-synuclein and increases the formation of inclusions in SHSY-5Y cells.42 This phosphorylated form of alpha-synuclein is present in Lewy bodies.43 Prevention of this phosphorylation by substitution of an alanine residue reduced inclusion formation in the SHSY-5Y model, and in the Drosophila model, this same mutation at 129, which prevents phosphorylation, protected against dopaminergic neuronal loss.44 Parkin (Park 2)
PARK2 gene mutations were first identified in autosomal recessive juvenile onset parkinsonism (ARJPD).45 ARJPD has been most commonly seen in the Japanese population and is characterized by onset before age 40 years, symptomatic improvement following sleep, mild dystonia, and a good response to levodopa.46 Resting tremor is seen less frequently than it is in idiopathic PD, and patients may have brisk tendon reflexes but no other pyramidal features. Progression is generally slower than that in sporadic PD. However, a broader clinical phenotype is also recognized with later onset and tremor, which more closely resembles sporadic PD. Pathologic changes include dopaminergic cell loss in the SNc and
Etiology and Pathogenesis of Parkinson Disease
locus ceruleus but no Lewy body deposition.47 The gene responsible for ARJPD was mapped to 6q25.2-q27,48 and in 1998, the gene was discovered and named parkin.45 Affected patients carry deletions or point mutations in various parts of the parkin gene.49,50 The relationship of parkin mutations to idiopathic PD has been highlighted by the identification of parkin mutations in apparently sporadic cases of PD. The role of single parkin gene mutations in determining the risk for PD remains controversial but of considerable interest. Parkin is ubiquitously transcribed, and intracellular localization studies have described association of the parkin protein with the endoplasmic reticulum, Golgi apparatus, synaptic vesicles, and mitochondria.51–53 The function of parkin is not known, but the protein contains a number of different domains for protein-protein interactions and E3 ligase activity. The latter involves a function within the ubiquitin proteasomal pathway, and several substrates for parkin ubiquitin ligase activity have been identified, including a 22 kD glycosylated form of alpha-synuclein, parkin-associated endothelin receptor-like receptor (Pael-R), and CDCrel-1. Overexpression of Pael-R causes it to become ubiquinated, insoluble, and unfolded and leads to endoplasmic reticulum stress and cell death.54 It has been demonstrated to accumulate in its insoluble form in the brains of patients with parkin mutations, suggesting a possible toxic mechanism. CDCrel-1 is a protein involved in cytokinesis and may influence synaptic vesicle function.55,56 Parkin is constitutively phosphorylated, and this can be modulated by proteasomal dysfunction and endocytoplasmic reticulum stress.57 The ability of parkin to ubiquinate proteins may be impaired by S-nitrosylation, which in turn may be a consequence of excitotoxic-mediated damage.58 Parkin has been reported to have an intramitochondrial localization in dividing cells.59 Parkin protein was released into the cytosol when cells were exposed to uncouplers or inhibitors of respiratory chain activity, including rotenone. Cell cycle blockers induced a similar redistribution of parkin. In contrast to undifferentiated, dividing SHSY-5Y cells, differentiation was associated with only a cytosolic distribution of parkin. The transfer of parkin from mitochondria to cytosol appeared to involve the mitochondrial permeability transition pore. Parkin protein could be imported into mitochondria and, interestingly, mutant forms less so than WT. The overexpression of parkin in SHSY-5Y cells induced increased transcription and translation of mitochondrial DNA (mtDNA) in dividing cells, which was mediated via an interaction with mtDNA transcription factor A. A parkin knockout mouse showed an increase in striatal extracellular dopamine, a reduction in synaptic excitability, and a mild nonprogressive motor deficit at 2 to 4 months.60 There was no loss of dopaminergic neurons and no inclusion formation. These mice had decreased striatal mitochondrial respiratory chain function and reductions in specific respiratory chain and antioxidant proteins.61 Parkin knockout flies developed muscle pathology, mitochondrial abnormalities, and apoptotic cell death.62 Overexpression of parkin in PC12 cells indicated that it is associated with the mitochondrial outer membrane.63 Parkin-positive patients have decreased lymphocyte complex I activity.64 The ability of parkin to ubiquinate proteins may be impaired by S-nitrosylation, which in turn may be a consequence of excitotoxic-mediated damage.58 UCH-L1 (Park 5)
A missense mutation in the gene encoding ubiquitin carboxyhydrolase L1 has been described in 2 siblings with typical PD.65 UCH-LI is an enzyme that hydrolyzes the C-terminus of ubiquitin to generate ubiquitin monomers that can be recycled to clear
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other proteins. The mutant form of UCH-L1 was shown to have reduced enzyme activity, resulting in impaired protein clearance through the ubiquitin-proteasome pathway. However, no other mutations in this gene have been identified in other families, suggesting that it is a rare cause of PD.66,67 PINK1 (Park 6)
Recessive mutations in PTEN-induced kinase 1 (PINK1) were found to be responsible for a familial form of early onset parkinsonism, previously mapped to chromosome 1p36.68 Several homozygous mutations have been described in familial PD patients, indicating that loss of function is the cause of disease pathogenesis. The majority of PINK1 mutation-positive patients have onset of parkinsonism below age 40 years, with relatively typical features of PD, good response to levodopa, slow progression, but early motor complications. Postmortem examination of brains of carriers with PINK1 mutations showed nigrostriatal cell loss and Lewy body formation.69 PINK1 protein has been observed in a small proportion (5%–10%) of Lewy bodies in PD brains and also localizes to the aggrosome under conditions of proteasomal inhibition, when there is also increased cleavage of the protein.70 Mutant PINK1 shows a similar distribution to Lewy bodies and aggrosomes under the same conditions. PINK1 mutations are relatively rare, and sequence variations are not considered an important factor influencing common forms of sporadic PD.71,72 In one European study, 2 of 100 young-onset PD patients had causative mutations, 1 homozygous and the other compound heterozygous.73 An additional 5 patients had 1 PINK1 mutation, that is, they were heterozygous compared with 2 of 200 controls. The heterozygote PINK1 carriers had mean age of onset of 44 years (range, 37–47 years), but the cohort only comprised PD cases with onset before age 50 years and so does not indicate the mean age of onset of carriers in the general PD population. These PINK1 carrier patients had features relatively typical of young-onset PD. In a study of 80 early onset (
