Genetics of Atypical Parkinsonism
139
9
Genetics of Atypical Parkinsonism
Implications for Nosology
Thomas Gasser
INTRODUCTION
Parkinson’s disease (PD) is traditionally defined as a clinico-pathologic entity, characterized by a
core syndrome of akinesia, rigidity, tremor, and postural instability, and pathologically by a more or
less selective degeneration of dopaminergic neurons of the substantia nigra, leading to a deficiency
of dopamine in the striatal projection areas of these neurons. Characteristic eosinophilic inclusions,
the Lewy bodies (LBs), are found in surviving dopaminergic neurons but also, although less abundantly, in other parts of the brain in most cases (1).
Approximately 20–30% of patients with parkinsonism exhibit additional clinical features and a
neuropathological picture clearly different from idiopathic PD. These disorders are collectively called
“atypical parkinsonism.” The most common clinico-pathological entities of this group are dementia
with LBs (DLB), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal
degeneration (CBD), and frontotemporal dementia with parkinsonism (FTDP). In addition, a number of
other rare familial or sporadic diseases may present with parkinsonism and different atypical features.
The nosologic classification of these entities, however, is not always easy. Considerable overlap
exists, both clinically and pathologically, between some of these syndromes, but also, for example,
between DLB and Alzheimer’s disease (AD), leading to the concept of the “neurodegenerative overlap syndromes” (2). Although the majority of cases appears to be sporadic in all atypical parkinsonian syndromes, it was the recent progress in molecular genetics that has provided an “Archimedes
point” in the search for a nosologic classification, by identifying the genetic cause of several rare,
monogenic variants.
These findings have brought several key molecules into the focus of research, particularly α-synuclein
and the microtubule-associated protein tau, providing the first rational basis for a very broad molecular
classification of neurodegenerative diseases: in those disorders associated with α-synuclein accumulation (synucleinopathies: PD, DLB, MSA, and neurodegeneration with brain iron accumulation type 1,
NBIA-1), and those characterized by an abnormal accumulation of the microtubule-associated protein
tau (MAPT), the tauopathies such as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), PSP, and CBD (3). The most common neurodegenerative disease, AD, has
possible links to both groups of disorders, as will be seen below.
Although those findings have greatly advanced our understanding of the etiology of
neurodegenerative diseases, the relationship between genes, mutations, and the associated molecular
pathways (the “genotype”) on the one hand, and the clinical and pathologic features observed in
patients and families (the “phenotype”) on the other hand, is increasingly recognized to be highly
complex.
From: Current Clinical Neurology: Atypical Parkinsonian Disorders
Edited by: I. Litvan © Humana Press Inc., Totowa, NJ
139
140
Gasser
This review will attempt to give an overview of the current knowledge on these issues, focussing
not on PD, but on atypical parkinsonian syndromes. Genetic findings in individual diseases will be
discussed, and the range of phenotypic presentations related to particular genetic causes will be
reviewed.
SYNUCLEINOPATHIES: PARKINSONISM RELATED TO α-SYNUCLEIN
AGGREGATION
α-Synuclein: Its Physiologic Function and Role in Disease
A major breakthrough in the molecular dissection of parkinsonism was the discovery of mutations
in the gene for α-synuclein on the long arm of chromosome 4 as the cause for a dominantly inherited
disorder that resembles idiopathic PD in many ways both clinically and pathologically (4).
α-Synuclein is a relatively small, natively unfolded protein that is abundantly expressed in many
parts of the brain and localized mostly to presynaptic nerve terminals. Many aspects of the normal
function of α-synuclein are still unknown. The protein may functionally be involved in brain plasticity and has been shown to bind to brain vesicles (5) and other cell membranes (6). However, knockout mice for α-synuclein show only very subtle alterations in dopamine release under certain
experimental conditions, but no other phenotype (7).
The central role of α-synuclein in the neurodegenerative process became clear when it was discovered that fibrillar aggregates of this protein are not only found in those rare families with mutations of the α-synuclein gene, but also constitute the primary component of the LB, the well-known
pathologic hallmark of idiopathic PD and in DLB. Furthermore, α-synuclein aggregates are also
found in oligodendrocytes in patients with MSA in the form of so-called “glial cytoplasmic inclusions” (GCIs) (8) and, although less consistently, in NBIA-I (9), the disorder formerly called
Hallervorden–Spatz disease. All those disorders have therefore been collectively termed
“synucleinopathies.”
The currently favored hypothesis states that through a hydrophobic 12 amino acid domain in the
center of the protein, α-synuclein has the tendency to form fibrillar structures (10), which go on to
form aggregates in a nucleation-dependent manner. It is assumed that the amino acid changes in the
α-synuclein protein associated with pathogenic mutations may favor the β-pleated sheet conformation, which in turn may lead to an increased tendency to form aggregates. This has been demonstrated
in vitro (11–13). As most cases of synucleinopathies express wt-α-synuclein and not a mutated form,
other factors must be assumed to also promote aggregate formation. In fact, this has been shown for
oxidative stress (14), which is thought to be particulary high in dopaminergic neurons, and also for
dopamine itself (15), possibly explaining the selectivity of the neurodegenerative process.
The precise relationship between the formation of aggregates and cell death is unknown. It is
possible that a failure of proteasomal degradation of α-synuclein and other proteins may lead to an
accumulation of toxic compounds, ultimately leading to cell death (16). Formation of α-synucleincontaining aggregates would then be only a secondary effect (17). However, other mechanisms of
pathogenesis may also be important. Known α-synuclein mutations appear to alter the vesicle-binding properties of the protein (5), and the functional homology of α-synuclein to the 14-3-3 protein, a
ubiquitously expressed chaperone, may indicate a more profound role for this protein in cellular
metabolism and suggests still other possible pathogenic mechanisms, which might also differ between
the various synucleinopathies.
Parkinsonism Caused by Mutations Affecting the Gene for α-Synuclein
(PARK1 and PARK4)
The first mutation of the α-synuclein gene was recognized in a large family with autosomal-dominantly inherited parkinsonism, the “Contursi-kindred.” It consisted of a point mutation leading to the
Genetics of Atypical Parkinsonism
141
exchange of the amino acid alanine to threonine at position 53 of the protein. A second point mutation (Ala39Pro) was later discovered in a small German pedigree (18). Patients suffer from Ldopa-responsive parkinsonism, and neuropathological studies in individuals with the Ala53Thr
mutation showed the characteristic pattern of neuronal degeneration with α-synuclein-positive
LBs in the substantia nigra. In the early descriptions it appeared that only the relatively early age at
onset (with a mean 44 yr in the large “Contursi” kindred) distinguished this disease from typical
sporadic PD (19). As more families with this mutation are being studied, however, it became clear
that it is associated with a broader range of phenotypes and that patients frequently also exhibit
clinical features that clearly exceed what is usually found in typical PD, including prominent dementia, hypoventilation, and severe autonomic disturbances (20). There are also differences in the pathologic picture that distinguish cases with α-synuclein mutations from typical PD. In the inherited
cases, extensive pathology with α-synuclein-positive Lewy neurites are found in brainstem pigmented
nuclei, but also in the hippocampus and the temporal neocortex (20). Unexpectedly, neuritic and less
frequent perikaryal inclusions of tau were also observed (21). Interestingly, the presence of tau
immunoreactivity has been suggested to distinguish between LBs of typical PD and those seen in
DLB (22).
Point mutations in the α-synuclein gene clearly appear to be a very rare cause of parkinsonism.
Only three mutations have been recognized (4,18,22a). The mutation that was found in the original
Contursi family (Ala53Thr) has also been identified in several Greek kindreds (4,23,24). Haplotype
analyses support the hypothesis that this is owing to a founder effect (24), pointing to a single mutational event.
Very recently, a different type of mutation affecting the α-synuclein gene was identified in another family with widespread synuclein pathology. One branch of this family, now called the “Iowakindred,” was originally described by Spellman, and later in more detail by Muenter and colleagues
(25). A different branch of the family was identified by Waters and Miller (26).
The clinical picture of affected family members is variable, ranging from relatively pure PD to
parkinsonism with prominent dementia, autonomic disturbances, and hypoventilation (25). Age at
onset is rather uniformly in the fourth decade and progression is rapid with a disease duration of less
than 10 yr. Pathologic examination showed nigral cell loss and LBs in pigmented brainstem nuclei,
resembling typical PD, but also extensive neuritic changes and α-synuclein inclusions with vacuolization in neocortical areas, most prominent in the superior temporal gyrus (27), remarkably similar to the findings in the Contursi kindred just described.
The gene locus had originally been mapped to the short arm of chromosome 4 (4p13, PARK4; see
ref. 28), and thus thought to be distinct from the α-synuclein locus on chromosome 4q. It is now
known that this chromosomal assignment was actually because of a typing error, and that the causative mutation is in fact a triplication of a 2 Mb region containing (in addition to 19 other genes) the
entire α-synuclein gene on chromosome 4q26 (28a). The triplication was associated with a twofold
increase of α-synuclein expression in the brain, determined at both the RNA and the protein level.
This important finding shows that not only a pathogenic alteration of the protein, but also a mere
increase in its expression level, is sufficient to cause neurodegeneration and disease with profound
Lewy pathology. The situation is therefore similar to AD, where point mutations in several genes
(APP, presenilin 1 and 2) but also an increase of expression of the normal APP gene, as in trisomy 21
(Down syndrome) can cause AD pathology.
Taken together, these findings also show that mutations affecting the α-synuclein protein or its
expression level can result, within single families, in a spectrum of phenotypes that can variably
share many clinical and pathologic features with PD (L-dopa-responsive parkinsonism with LBs and
neurodegeneration more or less restricted to brainstem nuclei) as well as with other synucleinopathies,
which should more appropriately be classified as atypical parkinsonism, particularly DLB (dementia,
Lewy pathology in limbic and cortical areas) and even MSA (orthostatic hypotension).
142
Gasser
Dementia With Lewy Bodies
Although the recognition of α-synuclein mutations has extremely important implications for the
understanding of the underlying disease process, it must be recognized that the vast majority of cases
of the common “synucleinopathies,” such as PD, DLB, and MSA, are sporadic and are not a result of
a recognized α-synuclein gene mutation. It is therefore assumed that in these cases other genetic or
non-genetic factors may lead to an abnormal processing of α-synuclein. As the tried and tested tools
of molecular genetics, such as linkage analysis and positional cloning, are not easily applied to sporadic disorders, the identification of these factors may turn out to be a major challenge of future
research. Nevertheless, recent findings have begun to shed some light also on these still enigmatic
diseases.
DLB is a disorder characterized by dementia and parkinsonism with several additional characteristic features, such as formed visual hallucinations, fluctuating levels of alertness, as well as frequent
falls and increased sensitivity to neuroleptic treatment (29). Neuropathologically, α-synuclein-positive LBs, Lewy neurites, and neuronal degeneration are found in pigmented brainstem nuclei, but
also, to a variable degree, in limbic and neocortical regions. In addition, a profound cholinergic deficit
occurs owing to degeneration of brainstem and basal forebrain cholinergic projection neurons (30).
The question whether PD and DLB are separate entities or rather different manifestations of a
single disease process has been widely debated. There is in fact considerable evidence suggesting
that PD and DLB are both parts of a continuum of LB diseases. With sensitive α-synuclein
immunostaining, cortical LBs are found in the majority of patients with typical PD (31). Furthermore, the findings in families with α-synuclein mutations described in the previous subheading indicate that the pathology associated with a single mutation can be restricted to the brainstem (clinically
pure PD) or affect limbic and cortical areas as in DLB (clinically PD plus dementia).
However, the situation in sporadic cases is more complex. Density of cortical LBs is not always
correlated with the degree of dementia (32). Pure Lewy pathology is actually found only in a minority
of patients with DLB, whereas Alzheimer’s-type changes are found, in addition to Lewy pathology,
in the majority of cases. This AD-like pathology differs to some degree from that found in “typical”
AD. Senile plaques, composed of the Aβ-fragment of the amyloid precursor protein (APP) are found
in similar density and distribution as in AD, but neurofibrillary tangles, consisting of
hyperphosphorylated tau protein are less prominent and are often not sufficient to allow the diagnosis
of AD according to accepted criteria.
It has therefore been a matter of considerable debate whether to consider DLB a “variant” of AD,
a variant of PD, or a disease entity of its own. In any case, the overlapping clinical and neuropathologic spectrum suggests that common pathogenic mechanisms may be operating. The identification
of common genetic risk factors could potentially clarify this complex relationship.
Familial DLB
Several large families with parkinsonism and dementia have been published in the literature, but
as far as can be told from the family descriptions, only a few would fulfill the clinical criteria for the
diagnosis of DLB, with dementia preceding or occurring within 1 yr of parkinsonism, and even fewer
with neuropathologic confirmation. However, as shown earlier for the families with α-synuclein
mutations, families who had originally been described as suffering from PD may actually resemble
more closely DLB, both clinically and neuropathologically. It remains to be determined whether the
less than a handful of other families, who have been described under the heading of “familial DLB”
(33,34), will prove to have α-synuclein mutations.
Families With Coexistence of AD and LB Pathology
The emergence of α-synuclein as the most sensitive histologic marker for Lewy pathology has
revealed unexpected findings in AD: Lewy bodies are found in 20–40% of cases of AD, not in
brainstem nucei, but rather in the amygdala (35). Even more striking, in more than half of the patients
Genetics of Atypical Parkinsonism
143
developing early-onset familial AD because of a mutation in the APP gene (APP717), LBs are found
in the brainstem and in the neocortex. LBs have also been found in patients with other APP mutations
and with mutations in presenilin 1 (3). The extent and distribution of Lewy pathology varies within
families with the identical APP mutation, indicating that Alzheimer and Lewy pathology are closely
related, but dependent on factors other than the primary APP mutation.
Other dominant families have been described with parkinsonism and a variable degree of dementia, who showed coexisting Lewy and Alzheimer pathology at postmortem examination (36). In two
of these families, the gene has been mapped to chromosome 2p13 (37), but not yet identified. As
affecteds from those families presented clinically with L-dopa-responsive parkinsonism (38) and developed dementia only later during the course of the disease (36), these kindreds were classified as
dominantly inherited PD (PARK3). Again, follow-up examination and postmortem analysis demonstrated that the phenotype associated with single mutations may be more variable than initially
thought, and that clinical dementia and plaque-predominant AD and LB changes occur in affecteds
and may share a common genetic susceptibility.
Taken together, family studies in dominant families with mutations in the genes for α-synuclein,
APP, and in as yet unidentified genes indicate that three possible scenarios exist (Fig. 1):
• A continuum of restricted brainstem to widespread cortical Lewy pathology without significant AD
changes in families with mutations in α-synuclein.
• The occurrence of limbic and cortical AD changes on top of a brainstem LB disorder as the consequence
of single, as yet unidentified gene mutations (e.g., PARK3).
• The appearance of LBs, in addition to AD-type changes, in patients with a primary “AD-mutation”
(APP717).
These findings indicate that the underlying mutation may be viewed as a port of entry to a disease
process, which involves different molecular pathways that lead to overlapping pathologic changes
with disease progression.
Genetic Risk Factors for DLB
As mentioned in the previous subheading, dominantly inherited monogenic cases of PD, AD, and
DLB are very rare. Therefore, no single genetic cause can be identified in the majority of cases.
Nevertheless it is assumed that genetic risk factors are modulating the susceptibility to and the
course of these disorders even in sporadic cases. If common genetic risk factors could be identified
for AD, PD, and DLB, this would strengthen the argument for a common molecular disease process.
The ε4-allele of the apolipoprotein E gene (ApoE4) is the only confirmed risk factor for sporadic
AD. ApoE4 has been shown to increase the risk for, and decrease the age of onset of AD (39). This
has been confirmed in a large number of studies. By contrast, the majority of studies does not find an
association of PD with the ApoE4 allele (40,41).
Studies on the influence of ApoE4 on DLB have produced conflicting results, which can in part be
explained by differences in the study design and small sample sizes (42–46). Koller (44) and
Egensperger (47) did not find a difference between PD patients with or without dementia, as compared to controls, whereas in the study of Hardy et al. (43) ApoE4 allele frequencies in patients with
DLB were intermediate between controls and AD. A higher proportion of ApoE4 alleles was also
found in patients with PD and concomitant AD changes (“B and C” according to the CERAD [Consortium to Establish a Registry for Alzheimer’s Disease] criteria) as compared to PD patients without
such changes (48). The association of neuritic plaques with ApoE4 was confirmed by Olechney (49),
whereas another study supported a role of the ApoE4 allele in the density of cortical LBs, but not AD
changes (50).
A single formal meta-analysis has been published (51) that confirmed a higher rate of ApoE4
alleles in DLB, but did not distinguish between “pure” DLB and DLB with AD-plaques (which would
144
Gasser
Fig. 1. Hypothetical scheme of the evolution of inherited PD, DLB, and AD. The underlying mutation and
mostly modifying factors act together to determine distribution and type of pathology.
also be very difficult in a meta-analysis because of the heterogeneity of the populations examined
and ambiguous descriptions in the original populations).
Overall the studies seem to indicate that ApoE4 is likely to be a risk factor for dementia in patients
with parkinsonism, although not quite as clearly as in “pure” AD. It remains unresolved whether this
is because of an increase of AD changes or to the cortical or limbic LB load.
Another risk factor for DLB may be an as yet unidentified gene in the pericentromeric region of
chromosome 12. Linkage with this locus was identified in a genome-wide screen in a group of families with late-onset AD (52). Further analysis of this region showed that much of the evidence was
derived from a subset of families with affected individuals with the neuropathologic diagnosis of
DLB (53). Interestingly, linkage to this region was also found in a Japanese family with autosomaldominant parkinsonism (PARK8; see ref. 54), and this locus has been confirmed in other families
with dominant parkinsonism (54a). The clinical and neuropathologic spectrum in these families is
variable, including brainstem and diffuse Lewy pathology, again indicating that mutations in a single
gene can cause a range of phenotypes that may be determined more specifically by other genetic or
nongenetic factors.
Multiple System Atrophy (MSA)
MSA is the second most common parkinsonian syndrome after idiopathic PD. In a majority of
patients with MSA, parkinsonism predominates (MSA-P), whereas a smaller proportion have prominent cerebellar disturbances (MSA-C). Regardless of the predominant clinical picture, MSA has been
classified among the synucleinopathies, since it was discovered that a key pathologic feature is the
aggregation of α-synuclein in the form of flame-shaped cytoplasmic inclusions in oligondendrocytes
and in neurons. It is still enigmatic why α-synuclein should accumulate in oligodendrocytes, as these
cells usually express only very low levels of this protein.
By contrast to all other atypical parkinsonian syndromes, no clearly familial cases with MSA have
been described in the literature. It is still conceivable that genetic factors may influence the susceptibility to the disease. Only a few association studies have been performed with polymorphisms in
Genetics of Atypical Parkinsonism
145
genes, which were considered candidate genes for MSA, including dopamine beta hydroxylase (55),
apolipoprotein E (56), and debrisoquine hydroxylase (57), without any consistent positive findings.
TAU-RELATED DISORDERS
Several neurodegenerative disorders appear to be related to the abnormal deposition of the microtubule-associated protein tau (MAPTau). A detailled discussion of this complex group of disorders is
beyond the scope of this chapter. Excellent reviews on the clinical (58) and molecular (59) aspects of
tauopathies have been published. The brief discussion here will be restricted to aspects directly related
to their presentation as atypical parkinsonian syndromes.
Tau: Normal Function and Role in Disease
The normal function of tau is to bind to tubulin, to promote its polymerization, and to maintain the
stability of microtubules. As also explained in other chapters of this book, the tau gene gives rise to
six isoforms of the tau protein, generated by alternative splicing of exons 2, 3, and 10. Tau contains
four imperfect repeat sequences in the carboxy terminal part of the protein, referred to as the microtubule binding domains. The fourth domain is encoded by exon 10. Therefore, alternative splicing of
exon 10 determines whether the protein contains three or four copies of repeated sequence. Under
normal conditions, three-repeat and four-repeat tau are present in roughly equal amounts in the brain.
Tau is found as fibrillar aggregates in AD (then called neurofibrillary tangles), but also in a number of other neurodegenerative disorders, such as PSP, CBD, the parkinsonism dementia complex of
Guam, postencephalitic and posttraumatic parkinsonism, and others. The analysis of mutations of the
tau gene and their functional consequences in inherited tauopathies has provided important information on the molecular mechanisms of tau-associated neurodegeneration.
Inherited Tauopathies With Mutations in the MAPTau Gene
The term “frontotemporal dementia with parkinsonism linked to chromosome 17,” or FTDP-17,
has been adopted for a familial disorder characterized by behavioral and cognitive disturbances, usually beginning between the ages of 40 and 50, progressing to dementia, and a variable degree of
extrapyramidal, pyramidal, oculomotor, and lower motorneuron signs. Pathologically, atrophy of frontal and temporal lobes is most prominent, together with involvement of the substantia nigra, the
amygdala, and the striatum (60). Only about 10% of all cases of frontotemporal dementia are inherited in an autosomal-dominant manner, but of these, a substantial subset of 10–40% turned out to be
genetically linked to a locus on the long arm of chromosome 17 (17q21-22) (60,61). As the tau gene
is located in this region, it had to be considered a primary candidate gene, and in fact, mutations in
this gene have been identified (62) in many families with FTDP-17 (63).
Mutations are clustered around the part of the gene encoding the microtubule binding domain and
have been found in exons 9, 10, 12, and 13, or in adjacent intronic sequences. The variability of the
clinical phenotype is accounted for, at least in part, by the fact that tau mutations appear to lead to
pathology by different mechanisms.
Intronic mutations flanking exon 10, as well as some exonic exon 10 mutations affect the alternative splicing of this exon, and as a consequence alter the relative abundance of three-repeat and fourrepeat tau, the two major classes of the protein present in the brain (62). Other exon 10 and exon 9
mutations seem to impair the ability of tau to bind microtubules or to promote microtubule assembly,
as shown by functional in vitro assays (64). Whereas mutations affecting exon 10 splicing lead to the
deposition of predominantly four-repeat tau, non-exon 10 coding mutations result in tau aggregates
consisting of three-repeat and four-repeat tau (65).
To some extent, the different functional consequences of the mutations result in a characteristic
clinical picture. If mutations affect exon 10 splicing (and thus lead to the deposition of predominantly
four-repeat tau) L-dopa unresponsive parkinsonism tends to be a a prominent clinical feature (66–68)
146
Gasser
(reviewed in ref. 58). This is particularly striking in the family described by Wszolek et al. clinically
and pathologically as pallido-ponto-nigral degeneration (PPND) (69). Affected subjects present with
rapidly progressive L-dopa-unresponsive parkinsonism with supranuclear gaze palsy, with dementia,
frontal-lobe release signs, and perseverative vocalizations developing later. This family was found to
harbor a mutation (N279K) increasing the activity of an exoning splice enhancer of exon 10, thus
leading to increased production of four-repeat tau (70,71).
However, behavioral disturbances may also be prominent in families with this class of mutations.
In the first family linked to chromosome 17 (and in whom the disease had been named “disinhibitiondementia-parkinsonism-amyotrophy complex; see ref. 61) personality changes begin at an average
age of 45, accompanied by hypersexuality and hyperphagia. L-dopa-unresponsive parkinsonism is a
consistent feature. This family bears an intronic mutation adjacent to exon 10.
In other families, a more typical picture of frontotemporal dementia with cognitive and behavioral
disturbances predominates, followed by parkinsonism, and other neurological disturbances such as
supranuclear gaze palsy, pyramidal tract dysfunction, and urinary incontinence to a variable degree
during the later course of the disease. These phenotypes are more commonly associated with missense mutations in the constitutively spliced exons 9, 12, and 13 (58). Other mutations have been
associated with dementia with epilepsy (72), progressive subcortical sclerosis (73), or “familial multiple system tauopathy” (74).
The same mutation may lead to different clinical manifestations in different families and also
within single pedigrees. The most common mutation, P301L, has been found to be associated with a
variety of clinical phenotypes, more or less closely resembling Pick’s disease (75), CBD (76), or
PSP. The considerable variability within single families (77,78) indicates that other factors in addition to tau mutations are influencing the clinical characteristics of the disease in a given patient.
Although a reduced penetrance of tau mutations has been reported (62), heterozygous (dominant)
mutations are almost exclusively found in individuals with a clearly positive dominant family history
and are very rare in series of patients with sporadic dementing syndromes (< 0.2%) (79). However,
recent evidence raises the possibility of autosomal-recessive mutations causing an apparently sporadic PSP-like phenotype (80) (see below).
The relationship between the tau gene, FTDP-17, and PSP is particularly interesting. As will be
discussed below, typical PSP is nearly always a sporadic disorder, but the prominent accumulation of
four-repeat tau strongly suggests that the tau protein, and hence possibly also the tau gene, is intimately involved in the disease process. Given the high variability of the clinical picture in families
with tau mutations and the predominance of extrapyramidal symptoms associated with some of them,
it is not too surprising that, as noted above, some tau mutations lead to a phenotype more or less
resembling typical PSP. One interesting mutation causing a PSP-like phenotype, the S305S-mutation, is located in exon 10 of the tau gene and forms part of a stem-loop structure at the 5' splice donor
site (81). Although the mutation does not give rise to an amino acid change in the tau protein, functional exon-trapping experiments show that it results in a significant 4.8-fold increase in the splicing
of exon 10, resulting in the overproduction of tau containing four microtubule-binding repeats.
Although the clinical phenotype in this family, as well as in other families with mutations that
affect splicing of exon 10, share features of PSP, both clinically and neuropathologically, others have
emphazised the differences that distinguish those families from typical PSP and have questioned
whether the disorder should be called “familial PSP” (82). Regardless of terminology, this finding
emphasizes the close relationship between FTDP-17 and PSP.
Another interesting observation strengthening this link is that in rare cases, homozygous or compound heterozygous mutations of the tau gene can cause a PSP-like syndrome (80,83), whereas heterozygous mutation carriers were either unaffected or showed only mild parkinsonism with late onset.
Again, although this “recessive” form of FTDP-17 shared several features with PSP, both cases also
differed from typical PSP by their early onset (40 yr or less) and by the presence of additional neurologic deficits, such as apraxia, cortical sensory deficits, or speech disturbances.
Genetics of Atypical Parkinsonism
147
Other Diseases Associated With Tau Deposits
As in the synucleinopathies, the majority of cases of neurodegeneration with tau deposition is
sporadic. Two disease entities are usually distinguished, but as will become apparent, are probably
closely related: PSP and CBD.
Progressive Supranuclear Palsy (PSP)
PSP is a disease characterized by predominantly axial, L-dopa-unresponsive parkinsonism, early
postural instability, supranuclear gaze palsy, and subcortical dementia (84).
PSP is, with exception of the cases described above, a sporadic disorder. It is pathologically characterized by the deposition of abnormally phosphorylized tau protein as neurofibrillary tangles and
neuropil threads, consisting predominantly of four-repeat tau. Tangles are also present in astrocytes
(“tufted astrocytes”) and oligodendroglia (coiled bodies). Based on this pathologic pattern and on the
insights gained into the molecular mechansisms from the inherited tauopathies described in the previous subheading, it seems likely that an abnormality of the splicing of the tau gene may be the
underlying molecular defect.
Although no coding region or splice site mutations in the tau gene can be identified in typical PSP,
there appears to be a genetic susceptibility to the disease that is related to the tau gene. Initially,
Conrad and coworkers observed that one particular allele (which they called the “A0” allele) of a
dinucleotide repeat marker within the tau gene is highly associated, in homozygous form, with PSP
(85). This allele was later found to be part of an extended haplotype (the H1-haplotype) of more than
100 kb, that is usually inherited en bloc (86,87). It is unclear why no recombinations occur within this
region in the human population.
As the H1-haplotype is common in the general population (~ 60% of chromosomes) it does per se
not carry a high risk for the development of a tau-related disorder. It is possible, however, that a more
recent mutation that has occurred on the background of this haplotype is responsible, or that the H1haplotype is merely “permissive” for the development of typical PSP, although the ultimate cause
remains unknown.
Corticobasal Degeneration
Much of what has been said for PSP also holds true for CBD. CBD is in most instances a sporadic
syndrome that shares with PSP the relentless progression of L-dopa-unresponsive parkinsonism and
predominantly subcortical cognitive disturbances, but differs in the additional presence of a usually
marked asymmetry of signs, dystonia and irregular reflex myoclonus in the most affected limb, as
well as cortical sensory loss and, in about 40% of cases, the characteristic “alien limb sign.” In addition to the subcortical changes, asymmetric cortical atrophy is often observed. Neuropathology reveals
characteristic tau accumulation in the form of neuropil threads throughout gray and white matter. Tau
filaments in CBD include both paired helical filament (PHF)-like filaments and straight tubules (59).
As in PSP, the filaments are composed predominantly of four-repeat tau.
As was also described for PSP, in a few families with dominant tau mutations, the disease
resembles CBD (76). It is probably a matter of semantics whether the disease in these cases should
be called “familial CBD” or “FTDP resembling CBD,” as long as it is kept in mind that there are
similarities and differences: sporadic CBD is not caused by detectable exonic or splice site mutations
in the tau gene, but it shares the same tau-related genetic background with PSP, the homozygocity for
the H1-haplotype, supporting the close relationship between these two disorders (88,89).
TAUOPATHIES, SYNUCLEINOPATHIES, AND BEYOND
Although recent genetic and pathologic evidence lead to the distinction of two major groups of
neurodegenerative disorders, the tauopathies and the synucleinopathies, based on the predominant
pathology and on mutations of the respective genes in rare familial forms of these diseases, there is
also evidence accumulating that the pathogenic mechanisms may in fact be related.
148
Gasser
As detailed above, there appears to be considerable overlap both clinically and pathologically
between PD, DLB, and AD. Various combinations of Lewy pathology and AD-type pathology are
found even in monogenically inherited forms.
However, there is also neuropathologic and genetic evidence linking Lewy pathology to alterations of tau: LBs in DLB have been distinguished from LBs in PD by tau staining (22). Similarly,
some LBs found in the brain of patients with the α-synuclein mutation A53T could be stained with
antibodies to the tau protein (21).
An association of the H1 haplotype, which is present in homozygous form in the great majority of
PSP-patients, with idiopathic PD has been reported (90) but not confirmed (91). However, in a total
genome screen in a large number of sib pairs and small families with PD, the tau locus on chromosome 17 was identified as one of the five loci with suggestive lod scores (although not reaching
statistical significance) (92).
Finally, in a recent report, Wszolek et al. describe a family with autosomal-dominant inheritance,
initially presenting with pure L-dopa-responsive parkinsonism (93). Some affecteds progressed to
show symptoms of atypical parkinsonism, including supranuclear gaze palsy. Interestingly, pathology in different members of this family varied, from typical brainstem LB disease to diffuse LB
disease to a tauopathy resembling PSP (106). The gene locus in this family most likely maps to the
PARK8 locus on chromosome 12. If in fact the disease in all affected subjects of this family is owing
to a mutation in a single gene, this would bridge the gap between the two major categories of
neurodegenerative disease recognized today, and strongly argue for a common pathogenic process.
OTHER GENETIC DISEASES OCCASIONALLY PRESENTING
WITH ATYPICAL PARKINSONISM
Huntington’s Disease
Huntington’s disease (HD) is an autosomal-dominantly inherited disorder, usually characterized
by a hyperkinetic movement disorder, personality changes, and dementia. It is caused by the pathologic expansion of a CAG-trinucleotide repeat sequence in the gene for Huntingtin on chromosome 4
(94). The fact that particularly cases of early onset frequently present with dystonia and parkinsonism, rather than with chorea, has long been recognized (95). In addition, the widespread use of
molecular diagnosis for HD has shown that the phenotypic spectrum may even include late-onset
levodopa-responsive parkinsonism (96) and atypical parkinsonian syndromes (97).
Spinocerebellar Ataxias
Like HD, the spinocerebellar ataxias (SCAs) are caused by expansions of CAG repeat sequences.
The core syndrome is usually that of a progressive cerebellar ataxia with or without additional neurologic features. Particularly in SCA1, 2, and 3, extrapyramidal symptoms are relatively common, and
have been described in 10–50% of patients (98). Patients with SCA3 have occasionally been found to
present with parkinsonism (99). This has recently been confirmed in another family (100) and
extended to a family with SCA2 (101). It is therefore not unlikely that other forms of SCA might
also, occasionally, mimic parkinsonian syndromes. The reason for the variable expressivity of the
genes with expanded CAG repeat expansion is still largely unknown.
Neurodegeneration With Brain Iron Accumulation Type 1 (NBIA-1)
NBIA-1 (formerly called Hallervorden–Spatz disease) is an autosomal-recessive disorder presenting during childhood or adolescence with a progressive syndrome of parkinsonism, dystonia, spasticity, epileptic seizures, and cognitive decline. The characteristic iron accumulations in the basal ganglia
are visible on magnetic resonance imaging (MRI) as hypointensities with a central region of
hyperintensity reflecting gliosis (eye of the tiger sign). The disease gene maps to chromosome 20,
and has been identified to code for pantothenate kinase 2 (PANK2), an enzyme catalyzing an impor-
Name
Chromosomal
Region
Gene Mutation
Range of Age
of Disease Onset
(Mean), in Years
Phenotype
Response
to Levodopa
Pathology
Autosomal dominant
PARK 1/4
4q21
α-synuclein
20–85 (46)
three missense mutations
one triplication
PD, some cases with dementia
Good
Lewy bodies in
brainstem, Lewy
neurite, and vacuolization
in temporal cortex
PARK 3
2p13
Unknown
36–89 (58)
PD, some cases with dementia
Good
Lewy bodies and amyloid
plaques
PARK 8
12p11.2- q13.11 Unknown
38–68 (51)
PD
Good
Variable: pure nigral
degeneration, Lewy body,
tau pathology
FTDP-17
17q21-22
tau/multiple mutations
25–76 (49)
FTD, PD, PSP, CBgD, ALS
Poor
Tau pathology
DYT12
19q13
Unknown
12–45 (23)
Rapid-onset dystonia-parkinsonism
Poor
Unknown
Genetics of Atypical Parkinsonism
Table 1
Genes and Mutations Associated With Atypical Parkinsonian Syndromes
Autosomal recessive
NBIA I
20p12.3
Pantothenate kinase/
multiple mutations
4–64
Parkinsonism, dystonia, spasticity,
dementia
Poor
Iron accumulation, Lewy
bodies
PARK 9
1p36
Unknown
11–16 (10’s)
PD, dementia, gaze palsy
Good
Unknown
DYT3
Xq13.1
Unknown
Dystonia-parkinsonism
Poor
No Lewy bodies
X-linked recessive
12–48 (35)
149
150
Gasser
tant step in the acyl-CoA-metabolism (102). As with many other diseases, the discovery of the gene
led to the appreciation of a broader phenotype, including cases of adult-onset atypical parkinsonism.
It seems that all cases show the typical MRI changes, leading to the correct diagnosis.
CONCLUSIONS: IMPACT OF GENETICS ON NOSOLOGY
The identification of several genes that lead to monogenic forms of the major neurodegenerative
disorders has greatly advanced our understanding of the molecular mechanisms involved. However,
the careful analysis of their clinical and pathologic features reveals that, although they share many
features with the respective sporadic diseases, there are clearly also important differences. Therefore,
those disorders should be viewed as natural models, recapitulating some, but certainly not all features
of their molecular pathogenesis. Perhaps most remarkably, both the variability of the phenotypes
associated with single gene mutations, as well as the similarities and overlap between disorders caused
by alterations in different genes appear to indicate that we are dealing in fact not with strictly distinct
pathways, but rather with a complex metabolic network, consisting of pathogenic mutations, genetic
modifiers, and probably also environmental influences, which defines the course of the disease in a
given patient.
FUTURE RESEARCH
In order to better understand the relationship between genetic alterations on one hand, and pathologic and clinical phenotypes on the other, further research will be needed: (1) To identify additional
loci and genes in large informative pedigrees with monogenically inherited forms of parkinsonism.
(2) To study the role of genes identified in monogenic forms also in large, well-characterized patient
populations. (3) To identify the metabolic pathways involved in the disease process in monogenic
forms, in order to identify new candidate genes for the sporadic disease.
REFERENCE
1. Gibb WR, Lees AJ. The significance of the Lewy body in the diagnosis of idiopathic Parkinson’s disease. Neuropathol
Appl Neurobiol 1989;15(1):27–44.
2. Perl DP, Olanow CW, Calne D. Alzheimer’s disease and Parkinson’s disease: distinct entities or extremes of a spectrum of neurodegeneration? Ann Neurol 1998;44(3 Suppl 1):S19–S31.
3. Hardy J, Duff K, Hardy KG, Perez-Tur J, Hutton M. Genetic dissection of Alzheimer’s disease and related dementias:
amyloid and its relationship to tau. Nat Neurosci 1998;1(5):355–358.
4. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, et al. Mutation in the α-synuclein gene identified in families with Parkinson’s disease. Science 1997;276:2045–2047.
5. Jensen PH, Nielsen MS, Jakes R, Dotti CG, Goedert M. Binding of alpha-synuclein to brain vesicles is abolished by
familial Parkinson’s disease mutation. J Biol Chem 1998;273(41):26292–26294.
6. McLean PJ, Kawamata H, Ribich S, Hyman BT. Membrane association and protein conformation of alpha-synuclein in
intact neurons. Effect of Parkinson’s disease–linked mutations. J Biol Chem 2000;275(12):8812–8816.
7. Abeliovich A, Schmitz Y, Farinas I, Choi-Lundberg D, Ho WH, Castillo PE et al. Mice lacking alpha-synuclein display
functional deficits in the nigrostriatal dopamine system. Neuron 2000;25(1):239–252.
8. Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PL, Goedert M. Filamentous alpha-synuclein inclusions link
multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci Lett 1998;251(3):205–208.
9. Neumann M, Adler S, Schluter O, Kremmer E, Benecke R, Kretzschmar HA. Alpha-synuclein accumulation in a case
of neurodegeneration with brain iron accumulation type 1 (NBIA-1, formerly Hallervorden–Spatz syndrome) with
widespread cortical and brainstem-type Lewy bodies. Acta Neuropathol (Berl) 2000;100(5):568–574.
10. Giasson BI, Uryu K, Trojanowski JQ, Lee VM. Mutant and wild type human alpha-synucleins assemble into elongated
filaments with distinct morphologies in vitro. J Biol Chem 1999;274(12):7619–7622.
11. Biere AL, Wood SJ, Wypych J, Steavenson S, Jiang Y, Anafi D, et al. Parkinson’s disease-associated alpha-synuclein
is more fibrillogenic than beta- and gamma-synuclein and cannot cross-seed its homologs. J Biol Chem
2000;275(44):34574–34579.
12. Conway KA, Lee SJ, Rochet JC, Ding TT, Williamson RE, Lansbury PTJ. Acceleration of oligomerization, not
fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson’s disease: implications for pathogenesis and therapy. Proc Natl Acad Sci USA 2000;97(2):571–576.
Genetics of Atypical Parkinsonism
151
13. Conway KA, Harper JD, Lansbury PT. Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to
early-onset Parkinson disease. Nat Med 1998;4(11):1318–1320.
14. Hashimoto M, Hsu LJ, Xia Y, Takeda A, Sisk A, Sundsmo M, et al. Oxidative stress induces amyloid-like aggregate
formation of NACP/alpha-synuclein in vitro. Neuroreport 1999;10(4):717–721.
15. Conway KA, Rochet JC, Bieganski RM, Lansbury PT, Jr. Kinetic stabilization of the alpha-synuclein protofibril by a
dopamine-alpha-synuclein adduct. Science 2001;294(5545):1346–1349.
16. McNaught KS, Olanow CW, Halliwell B, Isacson O, Jenner P. Failure of the ubiquitin-proteasome system in Parkinson’s
disease. Nat Rev Neurosci 2001;2(8):589–594.
17. McNaught KS, Jenner P. Proteasomal function is impaired in substantia nigra in Parkinson’s disease. Neurosci Lett
2001;297(3):191–194.
18. Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, Kösel S, et al. Ala39Pro mutation in the gene encoding α-synuclein
in Parkinson’s disease. Nat Genet 1998;18:106–108.
19. Golbe LI, Di Iorio G, Sanges G, Lazzarini A, LaSala S, Bonavita V, et al. Clinical genetic analysis of Parkinson’s
disease in the Contursi kindred. Ann Neurol 1996;40:767–775.
20. Spira PJ, Sharpe DM, Halliday G, Cavanagh J, Nicholson GA. Clinical and pathological features of a Parkinsonian
syndrome in a family with an Ala53Thr alpha-synuclein mutation. Ann Neurol 2001;49(3):313–319.
21. Duda JE, Giasson BI, Mabon ME, Miller DC, Golbe LI, Lee VM et al. Concurrence of alpha-synuclein and tau brain
pathology in the Contursi kindred. Acta Neuropathol (Berl) 2002;104(1):7–11.
22. Galloway PG, Bergeron C, Perry G. The presence of tau distinguishes Lewy bodies of diffuse Lewy body disease from
those of idiopathic Parkinson disease. Neurosci Lett 1989;100(1–3):6–10.
22a. Zarranz JJ, Alegre J, Gomez-Esteban JC, et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and
Lewy body dementia. Ann Neurol 2004;55(2):164–173.
23. Markopoulou K, Wszolek ZK, Pfeiffer RF. A Greek-American kindred with autosomal dominant, levodopa-responsive
parkinsonism and anticipation. Ann Neurol 1995;38(3):373–378.
24. Papadimitriou A, Veletza V, Hadjigeorgiou GM, Patrikiou A, Hirano M, Anastasopoulos I. Mutated alpha-synuclein
gene in two Greek kindreds with familial PD: incomplete penetrance? Neurology 1999;52(3):651–654.
25. Muenter MD, Forno LS, Hornykiewicz O, Kish SJ, Maraganore DM, Caselli RJ et al. Hereditary form of parkinsonism—dementia. Ann Neurol 1998;43(6):768–781.
26. Waters CH, Miller CA. Autosomal dominant Lewy body parkinsonism in a four-generation family. Ann Neurol
1994;35(1):59–64.
27. Gwinn-Hardy K, Mehta ND, Farrer M, Maraganore D, Muenter M, Yen SH, et al. Distinctive neuropathology revealed
by alpha-synuclein antibodies in hereditary parkinsonism and dementia linked to chromosome 4p. Acta Neuropathol
(Berl) 2000;99(6):663–672.
28. Farrer M, Gwinn-Hardy K, Muenter M, Wavrant DF, Crook R, Perez-Tur J, et al. A chromosome 4p haplotype segregating with Parkinson’s disease and postural tremor. Hum Mol Genet 1999;8(1):81–85.
28a. Singleton AB, Farrer M, Johnson J, et al. Alpha-synuclein locus triplication causes Parkinson's disease. Science
2003;302(5456):841.
29. McKeith IG. Dementia with Lewy bodies. Br J Psychiatry 2002;180(2):144–147.
30. Dickson DW, Davies P, Mayeux R, Crystal H, Horoupian DS, Thompson A, et al. Diffuse Lewy body disease. Neuropathological and biochemical studies of six patients. Acta Neuropathol (Berl) 1987;75(1):8–15.
31. Hughes AJ, Daniel SE, Blankson S, Lees AJ. A clinicopathologic study of 100 cases of Parkinson’s disease. Arch
Neurol 1993;50(2):140–148.
32. Colosimo C, Hughes AJ, Kilford L, Lees AJ. Lewy body cortical involvement may not always predict dementia in
Parkinson’s disease. J Neurol Neurosurg Psychiatry 2003;74(7):852–856.
33. Tsuang DW, Dalan AM, Eugenio CJ, Poorkaj P, Limprasert P, La Spada AR, et al. Familial dementia with lewy bodies:
a clinical and neuropathological study of 2 families. Arch Neurol 2002;59(10):1622–1630.
34. Wakabayashi K, Hayashi S, Ishikawa A, Hayashi T, Okuizumi K, Tanaka H, et al. Autosomal dominant diffuse Lewy
body disease. Acta Neuropathol (Berl) 1998;96(2):207–210.
35. Arai Y, Yamazaki M, Mori O, Muramatsu H, Asano G, Katayama Y. Alpha-synuclein-positive structures in cases with
sporadic Alzheimer’s disease: morphology and its relationship to tau aggregation. Brain Res 2001;888(2):287–296.
36. Wszolek K, Gwinn-Hardy K, Wszolek K, Muenter D, Pfeiffer F, Rodnitzky L, et al. Neuropathology of two members of
a German-American kindred (Family C) with late onset parkinsonism. Acta Neuropathol (Berl) 2002;103(4):344–350.
37. Gasser T, Müller-Myhsok B, Wszolek ZK, Oehlmann R, Calne DB, Bonifati V, et al. A susceptibility locus for
Parkinson’s disease maps to chromosome 2p13. Nat Genet 1998;18:262–265.
38. Wszolek ZK, Cordes M, Calne DB, Munter MD, Cordes I, Pfeifer RF. Hereditary Parkinson disease: report of 3 families with dominant autosomal inheritance. Nervenarzt 1993;64(5):331–335.
39. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein
E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993;261(5123):921–923.
40. Apolipoprotein E genotype in familial Parkinson’s disease. The French Parkinson’s Disease Genetics Study Group. J
Neurol Neurosurg Psychiatry 1997;63(3):394–395.
152
Gasser
41. Benjamin R, Leake A, Edwardson JA, McKeith IG, Ince PG, Perry RH, et al. Apolipoprotein E genes in Lewy body and
Parkinson’s disease [letter]. Lancet 1994;343(8912):1565–1565.
42. Arai H, Higuchi S, Muramatsu T, Iwatsubo T, Sasaki H, Trojanowski JQ. Apolipoprotein E gene in diffuse Lewy body
disease with or without co-existing Alzheimer’s disease [letter]. Lancet 1994;344(8932):1307–1307.
43. Hardy J, Crook R, Prihar G, Roberts G, Raghavan R, Perry R. Senile dementia of the Lewy body type has an
apolipoprotein E epsilon 4 allele frequency intermediate between controls and Alzheimer’s disease. Neurosci Lett
1994;182(1):1–2.
44. Koller WC, Glatt SL, Hubble JP, Paolo A, Troster AI, Handler MS, et al. Apolipoprotein E genotypes in Parkinson’s
disease with and without dementia. Ann Neurol 1995;37(2):242–245.
45. Lippa CF, Smith TW, Saunders AM, Crook R, Pulaski Salo D, Davies P, et al. Apolipoprotein E genotype and Lewy
body disease. Neurology 1995;45(1):97–103.
46. St Clair D, Norrman J, Perry R, Yates C, Wilcock G, Brookes A. Apolipoprotein E epsilon 4 allele frequency in patients
with Lewy body dementia, Alzheimer’s disease and age-matched controls. Neurosci Lett 1994;176(1):45–46.
47. Egensperger R, Bancher C, Kosel S, Jellinger K, Mehraein P, Graeber MB. The apolipoprotein E epsilon 4 allele in
Parkinson’s disease with Alzheimer lesions. Biochem Biophys Res Commun 1996;224(2):484–486.
48. Mattila PM, Koskela T, Roytta M, Lehtimaki T, Pirttila TA, Ilveskoski E, et al. Apolipoprotein E epsilon4 allele
frequency is increased in Parkinson’s disease only with co-existing Alzheimer pathology. Acta Neuropathol (Berl)
1998;96(4):417–420.
49. Olichney JM, Hansen LA, Galasko D, Saitoh T, Hofstetter CR, Katzman R, et al. The apolipoprotein E epsilon 4 allele
is associated with increased neuritic plaques and cerebral amyloid angiopathy in Alzheimer’s disease and Lewy body
variant. Neurology 1996;47(1):190–196.
50. Wakabayashi K, Kakita A, Hayashi S, Okuizumi K, Onodera O, Tanaka H, et al. Apolipoprotein E epsilon4 allele and
progression of cortical Lewy body pathology in Parkinson’s disease. Acta Neuropathol (Berl) 1998;95(5):450–454.
51. Bang OY, Kwak YT, Joo IS, Huh K. Important link between dementia subtype and apolipoprotein E: a meta-analysis.
Yonsei Med J 2003;44(3):401–413.
52. Pericak-Vance MA, Bass MP, Yamaoka LH, Gaskell PC, Scott WK, Terwedow HA, et al. Complete genomic screen in
late-onset familial Alzheimer disease. Evidence for a new locus on chromosome 12. JAMA 1997;278(15):1237–1241.
53. Scott WK, Grubber JM, Conneally PM, Small GW, Hulette CM, Rosenberg CK, et al. Fine mapping of the chromosome
12 late-onset Alzheimer disease locus: potential genetic and phenotypic heterogeneity. Am J Hum Genet
2000;66(3):922–932.
54. Funayama M, Hasegawa K, Kowa H, Saito M, Tsuji S, Obata F. A new locus for Parkinson’s disease (PARK8) maps to
chromosome 12p11.2-q13.1. Ann Neurol 2002;51(3):296–301.
54a. Zimprich A, Muller-Myhsok B, Farrer M, et al. The PARK8 locus in autosomal dominant Parkinsonism: confirmation
of linkage and further delineation of the disease-containing interval. Am J Hum Genet 2004;74(1):11–19.
55. Cho S, Kim CH, Cubells JF, Zabetian CP, Hwang DY, Kim JW, et al. Variations in the dopamine beta-hydroxylase
gene are not associated with the autonomic disorders, pure autonomic failure, or multiple system atrophy. Am J Med
Genet 2003;120A(2):234–236.
56. Morris HR, Schrag A, Nath U, Burn D, Quinn NP, Daniel S et al. Effect of ApoE and tau on age of onset of progressive
supranuclear palsy and multiple system atrophy. Neurosci Lett 2001;312(2):118–120.
57. Plante-Bordeneuve V, Bandmann O, Wenning G, Quinn NP, Daniel SE, Harding AE. CYP2D6-debrisoquine hydroxylase gene polymorphism in multiple system atrophy. Mov Disord 1995;10(3):277–278.
58. Reed LA, Wszolek ZK, Hutton M. Phenotypic correlations in FTDP-17. Neurobiol Aging 2001;22(1):89–107.
59. Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci 2001;24:1121–59.:1121–1159.
60. Foster NL, Wilhelmsen K, Sima AA, Jones MZ, D’Amato CJ, Gilman S. Frontotemporal dementia and parkinsonism
linked to chromosome 17: a consensus conference. Conference Participants. Ann Neurol 1997;41(6):706–715.
61. Wilhelmsen KC, Lynch T, Pavlou E, Higgins M, Nygaard TG. Localization of disinhibition-dementia-parkinsonismamyotrophy complex to 17q21-22. Am J Hum Genet 1994;55(6):1159–1165.
62. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, et al. Association of missense and 5'-splice-site
mutations in tau with the inherited dementia FTDP-17. Nature 1998;393(6686):702–705.
63. Hutton M. Missense and splice site mutations in tau associated with FTDP-17: multiple pathogenic mechanisms. Neurology 2001;56(11 Suppl 4):S21–S25.
64. Hong M, Zhukareva V, Vogelsberg-Ragaglia V, Wszolek Z, Reed L, Miller BI, et al. Mutation-specific functional
impairments in distinct tau isoforms of hereditary FTDP-17. Science 1998;282(5395):1914–1917.
65. Spillantini MG, Bird TD, Ghetti B. Frontotemporal dementia and Parkinsonism linked to chromosome 17: a new group
of tauopathies. Brain Pathol 1998;8(2):387–402.
66. Yasuda M, Takamatsu J, D’Souza I, Crowther RA, Kawamata T, Hasegawa M, et al. A novel mutation at position +12
in the intron following exon 10 of the tau gene in familial frontotemporal dementia (FTD-Kumamoto). Ann Neurol
2000;47(4):422–429.
Genetics of Atypical Parkinsonism
153
67. Delisle MB, Murrell JR, Richardson R, Trofatter JA, Rascol O, Soulages X, et al. A mutation at codon 279 (N279K) in
exon 10 of the Tau gene causes a tauopathy with dementia and supranuclear palsy. Acta Neuropathol (Berl)
1999;98(1):62–77.
68. Tsuboi Y, Uitti RJ, Delisle MB, Ferreira JJ, Brefel-Courbon C, Rascol O, et al. Clinical features and disease haplotypes
of individuals with the N279K tau gene mutation: a comparison of the pallidopontonigral degeneration kindred and a
French family. Arch Neurol 2002;59(6):943–950.
69. Wszolek ZK, Pfeiffer RF, Bhatt MH, Schelper RL, Cordes M, Snow BJ, et al. Rapidly progressive autosomal dominant
parkinsonism and dementia with pallido-ponto-nigral degeneration. Ann Neurol 1992;32(3):312–320.
70. Clark LN, Poorkaj P, Wszolek Z, Geschwind DH, Nasreddine ZS, Miller B, et al. Pathogenic implications of mutations
in the tau gene in pallido-ponto- nigral degeneration and related neurodegenerative disorders linked to chromosome 17.
Proc Natl Acad Sci USA 1998;95(22):13103–13107.
71. Reed LA, Schmidt ML, Wszolek ZK, Balin BJ, Soontornniyomkij V, Lee VM, et al. The neuropathology of a chromosome 17-linked autosomal dominant parkinsonism and dementia (“pallido-ponto-nigral degeneration”). J Neuropathol
Exp Neurol 1998;57(6):588–601.
72. Sperfeld AD, Collatz MB, Baier H, Palmbach M, Storch A, Schwarz J, et al. FTDP-17: an early-onset phenotype with
parkinsonism and epileptic seizures caused by a novel mutation. Ann Neurol 1999;46(5):708–715.
73. Goedert M, Spillantini MG, Crowther RA, Chen SG, Parchi P, Tabaton M, et al. Tau gene mutation in familial progressive subcortical gliosis. Nat Med 1999;5(4):454–457.
74. Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B. Mutation in the tau gene in familial multiple
system tauopathy with presenile dementia. Proc Natl Acad Sci U S A 1998;95(13):7737–7741.
75. Rizzini C, Goedert M, Hodges JR, Smith MJ, Jakes R, Hills R, et al. Tau gene mutation K257T causes a tauopathy
similar to Pick’s disease. J Neuropathol Exp Neurol 2000;59(11):990–1001.
76. Bugiani O, Murrell JR, Giaccone G, Hasegawa M, Ghigo G, Tabaton M, et al. Frontotemporal dementia and corticobasal
degeneration in a family with a P301S mutation in tau. J Neuropathol Exp Neurol 1999;58(6):667–677.
77. Mirra SS, Murrell JR, Gearing M, Spillantini MG, Goedert M, Crowther RA, et al. Tau pathology in a family with
dementia and a P301L mutation in tau. J Neuropathol Exp Neurol 1999;58(4):335–345.
78. Nasreddine ZS, Loginov M, Clark LN, Lamarche J, Miller BL, Lamontagne A, et al. From genotype to phenotype: a
clinical pathological, and biochemical investigation of frontotemporal dementia and parkinsonism (FTDP-17) caused
by the P301L tau mutation. Ann Neurol 1999;45(6):704–715.
79. Houlden H, Baker M, Adamson J, Grover A, Waring S, Dickson D, et al. Frequency of tau mutations in three series of
non-Alzheimer’s degenerative dementia. Ann Neurol 1999;46(2):243–248.
80. Pastor P, Pastor E, Carnero C, Vela R, Garcia T, Amer G, et al. Familial atypical progressive supranuclear palsy
associated with homozigosity for the delN296 mutation in the tau gene. Ann Neurol 2001;49(2):263–267.
81. Stanford PM, Halliday GM, Brooks WS, Kwok JB, Storey CE, Creasey H, et al. Progressive supranuclear palsy pathology caused by a novel silent mutation in exon 10 of the tau gene: Expansion of the disease phenotype caused by tau
gene mutations. Brain 2000;123(Pt 5):880–893.
82. Wszolek ZK, Tsuboi Y, Uitti RJ, Reed L, Hutton ML, Dickson DW. Progressive supranuclear palsy as a disease phenotype caused by the S305S tau gene mutation. Brain 2001;124(Pt 8):1666–1670.
83. Morris HR, Osaki Y, Holton J, Lees AJ, Wood NW, Revesz T, et al. Tau exon 10 +16 mutation FTDP-17 presenting
clinically as sporadic young onset PSP. Neurology 2003;61(1):102–104.
84. Litvan I, Agid Y, Calne D, Campbell G, Dubois B, Duvoisin RC, et al. Clinical research criteria for the diagnosis of
progressive supranuclear palsy (Steele–Richardson–Olszewski syndrome): report of the NINDS-SPSP international
workshop. Neurology 1996;47(1):1–9.
85. Conrad C, Andreadis A, Trojanowski JQ, Dickson DW, Kang D, Chen X, et al. Genetic evidence for the involvement of
tau in progressive supranuclear palsy. Ann Neurol 1997;41(2):277–281.
86. Baker M, Litvan I, Houlden H, Adamson J, Dickson D, Perez-Tur J, et al. Association of an extended haplotype in the
tau gene with progressive supranuclear palsy. Hum Mol Genet 1999;8(4):711–715.
87. Pastor P, Ezquerra M, Tolosa E, Munoz E, Marti MJ, Valldeoriola F, et al. Further extension of the H1 haplotype
associated with progressive supranuclear palsy. Mov Disord 2002;17(3):550–556.
88. Di Maria E, Tabaton M, Vigo T, Abbruzzese G, Bellone E, Donati C, et al. Corticobasal degeneration shares a common
genetic background with progressive supranuclear palsy. Ann Neurol 2000;47(3):374–377.
89. Houlden H, Baker M, Morris HR, MacDonald N, Pickering-Brown S, Adamson J, et al. Corticobasal degeneration and
progressive supranuclear palsy share a common tau haplotype. Neurology 2001;56(12):1702–1706.
90. Pastor P, Ezquerra M, Munoz E, Marti MJ, Blesa R, Tolosa E, et al. Significant association between the tau gene A0/A0
genotype and Parkinson’s disease. Ann Neurol 2000;47(2):242–245.
91. de Silva R, Hardy J, Crook J, Khan N, Graham E, Morris C, et al. The tau locus is not significantly associated with
pathologically confirmed sporadic Parkinson’s disease. Neurosci Lett 2002;330(2):201.
154
Gasser
92. Scott WK, Nance MA, Watts RL, Hubble JP, Koller WC, Lyons K, et al. Complete genomic screen in Parkinson
disease: evidence for multiple genes. JAMA 2001;286(18):2239–2244.
93. Wszolek ZK, Pfeiffer B, Fulgham JR, Parisi JE, Thompson BM, Uitti RJ, et al. Western Nebraska family (family D)
with autosomal dominant parkinsonism. Neurology 1995;45(3 Pt 1):502–505.
94. Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded
and unstable on Huntington’s disease chromosomes. Cell 1993;72(6):971–983.
95. van Dijk JG, van der Velde EA, Roos RA, Bruyn GW. Juvenile Huntington disease. Hum Genet 1986;73(3):235–239.
96. Racette BA, Perlmutter JS. Levodopa responsive parkinsonism in an adult with Huntington’s disease. J Neurol
Neurosurg Psychiatry 1998;65(4):577–579.
97. Reuter I, Hu MT, Andrews TC, Brooks DJ, Clough C, Chaudhuri KR. Late onset levodopa responsive Huntington’s
disease with minimal chorea masquerading as Parkinson plus syndrome. J Neurol Neurosurg Psychiatry
2000;68(2):238–241.
98. Schols L, Amoiridis G, Buttner T, Przuntek H, Epplen JT, Riess O. Autosomal dominant cerebellar ataxia: phenotypic
differences in genetically defined subtypes? Ann Neurol 1997;42(6):924–932.
99. Tuite PJ, Rogaeva EA, St George Hyslop PH, Lang AE. Dopa-responsive parkinsonism phenotype of Machado–Joseph
disease: confirmation of 14q CAG expansion. Ann Neurol 1995;38(4):684–687.
100. Gwinn-Hardy K, Singleton A, O’Suilleabhain P, Boss M, Nicholl D, Adam A, et al. Spinocerebellar ataxia type 3
phenotypically resembling Parkinson disease in a black family. Arch Neurol 2001;58(2):296–299.
101. Gwinn-Hardy K, Chen JY, Liu HC, Liu TY, Boss M, Seltzer W, et al. Spinocerebellar ataxia type 2 with parkinsonism
in ethnic Chinese. Neurology 2000;55(6):800–805.
102. Zhou B, Westaway SK, Levinson B, Johnson MA, Gitschier J, Hayflick SJ. A novel pantothenate kinase gene (PANK2)
is defective in Hallervorden–Spatz syndrome. Nat Genet 2001;28(4):345–349.
103. Wszolek ZK, Pfeiffer RF, Tsuboi Y, et al. Autosomal dominant Parkinsonism associated with variable synuclein and
tau pathology. Neurology 2004, in press.