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Journal ArticleDOI

Monogenic Parkinson's disease and parkinsonism: Clinical phenotypes and frequencies of known mutations.

01 Apr 2013-Parkinsonism & Related Disorders (Elsevier)-Vol. 19, Iss: 4, pp 407-415

TL;DR: Clinical features of diseases caused by mutations in SNCA cause cognitive or psychiatric symptoms, parkinsonism, dysautonomia and myoclonus with widespread alpha-synuclein pathology in the central and peripheral nervous system.
Abstract: Mutations in seven genes are robustly associated with autosomal dominant (SNCA, LRRK2, EIF4G1, VPS35) or recessive (parkin/PARK2, PINK1, DJ1/PARK7) Parkinson's disease (PD) or parkinsonism. Changes in a long list of additional genes have been suggested as causes for parkinsonism or PD, including genes for hereditary ataxias (ATXN2, ATXN3, FMR1), frontotemporal dementia (C9ORF72, GRN, MAPT, TARDBP), DYT5 (GCH1, TH, SPR), and others (ATP13A2, CSF1R, DNAJC6, FBXO, GIGYF2, HTRA2, PLA2G6, POLG, SPG11, UCHL1). This review summarizes the clinical features of diseases caused by mutations in these genes, and their frequencies. Point mutations and multiplications in SNCA cause cognitive or psychiatric symptoms, parkinsonism, dysautonomia and myoclonus with widespread alpha-synuclein pathology in the central and peripheral nervous system. LRRK2 mutations may lead to a clinical phenotype closely resembling idiopathic PD with a puzzling variety in neuropathology. Mutations in parkin/PARK2, PINK1 or DJ1/PARK7 may cause early-onset parkinsonism with a low risk for cognitive decline and a pathological process usually restricted to the brainstem. Carriers of mutations in the other genes may develop parkinsonism with or without additional symptoms, but rarely a disease resembling PD. The pathogenicity of several mutations remains unconfirmed. Although some mutations occur with high frequency in specific populations, worldwide all are very rare. The genetic cause of the majority of patients with sporadic or hereditary PD remains unknown in most populations. Clinical genetic testing is useful for selected patients. Testing strategies need to be adapted individually based on clinical phenotype and estimated frequency of the mutation in the patient's population.
Topics: Parkinsonism (64%), Parkin (56%), LRRK2 (53%), Parkinson's disease (52%), TARDBP (51%)

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LUND UNIVERSITY
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221 00 Lund
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Monogenic Parkinson's disease and parkinsonism: Clinical phenotypes and
frequencies of known mutations.
Puschmann, Andreas
Published in:
Parkinsonism & Related Disorders
DOI:
10.1016/j.parkreldis.2013.01.020
2013
Link to publication
Citation for published version (APA):
Puschmann, A. (2013). Monogenic Parkinson's disease and parkinsonism: Clinical phenotypes and frequencies
of known mutations.
Parkinsonism & Related Disorders
,
19
(4), 407-415.
https://doi.org/10.1016/j.parkreldis.2013.01.020
Total number of authors:
1
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Puschmann: Review monogenic PD
Monogenic Parkinson’s disease and parkinsonism: Clinical phenotypes and frequencies
of known mutations
Andreas Puschmann*
Dept. for Neurology, Lund University and Skåne University Hospital, Sweden
* Corresponding author. Department for Neurology, Lund University Hospital, Getingevägen
4, 22185 Lund, Sweden. Tel.: +46 46 175421/+46 46 171000; fax: +46 46 177940. E-mail
address: andreas.puschmann@med.lu.se (A. Puschmann).
Keywords: Parkinson’s disease, Genetics, Single-Gene Defects; Review
Short Title: Review monogenic PD
Word Count: 4019 words.
Abstract Word Count: 248
Abstract
Mutations in seven genes are robustly associated with autosomal dominant (SNCA, LRRK2,
EIF4G1, VPS35) or recessive (parkin/PARK2, PINK1, DJ1/PARK7) Parkinson’s disease (PD)
or parkinsonism. Changes in a long list of additional genes have been suggested as causes for
parkinsonism or PD, including genes for hereditary ataxias (ATXN2, ATXN3, FMR1),
frontotemporal dementia (C9ORF72, GRN, MAPT, TARDBP), DYT5 (GCH1, TH, SPR), and
others (ATP13A2, CSF1R, DNAJC6, FBXO, GIGYF2, HTRA2, PLA2G6, POLG, SPG11,
UCHL1). This review summarizes the clinical features of diseases caused by mutations in
1

Puschmann: Review monogenic PD
these genes and their frequency. Point mutations and multiplications in SNCA cause cognitive
or psychiatric symptoms, parkinsonism, dysautonomia and myoclonus with widespread alpha-
synuclein pathology in the central and peripheral nervous system. LRRK2 mutations may lead
to a clinical phenotype closely resembling idiopathic PD with a puzzling variety in
neuropathology. Mutations in parkin/PARK2, PINK1 or DJ1/PARK7 may cause early-onset
parkinsonism with a low risk for cognitive decline and a pathological process usually
restricted to the brainstem. Carriers of mutations in the other genes may develop parkinsonism
with or without additional symptoms, but rarely a disease resembling PD. The pathogenicity
of several mutations remains unconfirmed. Although some mutations occur with high
frequency in specific populations, worldwide all are very rare. The genetic cause of the
majority of patients with sporadic or hereditary PD remains unknown in most populations.
Clinical genetic testing is useful for selected patients. Testing strategies need to be adapted
individually based on clinical phenotype and estimated frequency of the mutation in the
patient’s population.
Table of Contents:
Introduction .............................................................................................................................. 3
Dominant PD genes .................................................................................................................. 3
SNCA .................................................................................................................................... 3
LRRK2 .................................................................................................................................. 5
VPS35 ................................................................................................................................... 7
EIF4G1 ................................................................................................................................. 8
Other dominant and x-linked disorders that may present with parkinsonism ...................... 9
Monogenic disorders with various manifestations that may include parkinsonism ........... 11
Recessive PD genes ................................................................................................................. 11
Parkin ................................................................................................................................. 12
PINK1 ................................................................................................................................. 13
2

Puschmann: Review monogenic PD
DJ1 ...................................................................................................................................... 13
Aspects common to parkin, PINK1, DJ1 ............................................................................ 13
Recessive disorders that may include parkinsonism .......................................................... 15
Conclusions ............................................................................................................................. 17
References ............................................................................................................................... 18
Introduction
The first mutation causing Parkinson’s disease (PD) was discovered in the SNCA gene in
1997 [1]. Since then, intensive research efforts have established a total of seven genes
containing causal mutations for parkinsonism clinically resembling PD, with autosomal
dominant or recessive modes of inheritance. For mutations in at least 19 additional genes, a
disease-causing role was postulated (Table 1), but subsequent studies either could not confirm
that mutations in these genes are associated with parkinsonism or PD, or showed that they in
most or all cases cause a clinical phenotype that is clearly distinguishable from PD. This
article reviews the present knowledge on these monogenic disorders, with an emphasis on
their clinical phenotype and their frequency.
Dominant PD genes
Today, there is good evidence that mutations in four dominant PD genes may cause
parkinsonism. The first two, SNCA and LRRK2, have been studied in detail, whereas EIF4G1
and VPS35 have only been identified recently.
SNCA
3

Puschmann: Review monogenic PD
Three pathogenic point mutations as well as genomic duplications and triplications are known
in the gene encoding alpha-synuclein (SNCA). The first point mutation, A53T (p.Ala53Thr,
c.209G >A) was discovered in 1997 in members of the large Italian-American Contursi
kindred [2] and in three families from Greece [1]. A very similar clinical phenotype had been
described in the Greek-American Family H [3], which was soon found to harbor the same
mutation [4]. Subsequently, the A53T mutation was identified in a number of families of
Greek origin, with a regional common founder haplotype [5-7]. A Korean family with a
different haplotype [8, 9] was reported, as well as one sporadic case of Polish origin [10]. The
mutation occurred de novo within a Swedish family [11].
In 1998, the A30P (p.Ala30Pro, c.88G>C) mutation was identified in one German family with
three clearly affected members and two additional mutation carriers who only showed subtle
neurological symptoms [12, 13]. The E46K (p.Glu46Lys, c.188G>A) mutation was found in
2004 in one large kindred with 5 affected individuals spanning two generations [14]. The
family originates from the Basque region in Northern Spain. The phenotype is characterized
by fluctuating impairment of frontal lobe functions, memory dysfunction and parkinsonism as
initial symptoms, and subsequent development of profound dementia [15]. The severity of the
clinical symptoms and the response to levodopa were variable [14], and studies of mutation
carriers without PD symptoms revealed sleep abnormalities [16] and cardiac sympathetic
denervation [17]. Despite extensive efforts in many genetic screening studies, the A30P and
E46K mutations have not been reported from any other family worldwide.
Triplications of the SNCA genomic locus in families with parkinsonism were reported in 2003
[18] and duplications in 2004 [19, 20]. In contrast to the rare occurrence of A53T, A30P and
E46K point mutations, these multiplications in SNCA have meanwhile been reported from 31
families worldwide [18, 19, 21-24].
4

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References
More filters

Journal ArticleDOI
27 Jun 1997-Science
TL;DR: A mutation was identified in the α-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype.
Abstract: Parkinson's disease (PD) is a common neurodegenerative disorder with a lifetime incidence of approximately 2 percent. A pattern of familial aggregation has been documented for the disorder, and it was recently reported that a PD susceptibility gene in a large Italian kindred is located on the long arm of human chromosome 4. A mutation was identified in the α-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype. This finding of a specific molecular alteration associated with PD will facilitate the detailed understanding of the pathophysiology of the disorder.

6,834 citations


"Monogenic Parkinson's disease and p..." refers background in this paper

  • ...Introduction The first mutation causing Parkinson’s disease (PD) was discovered in the SNCA gene in 1997 [1]....

    [...]

  • ...209G >A) was discovered in 1997 in members of the large Italian-American Contursi kindred [2] and in three families from Greece [1]....

    [...]


Journal ArticleDOI
09 Apr 1998-Nature
TL;DR: Mutations in the newly identified gene appear to be responsible for the pathogenesis of Autosomal recessive juvenile parkinsonism, and the protein product is named ‘Parkin’.
Abstract: Parkinson's disease is a common neurodegenerative disease with complex clinical features1. Autosomal recessive juvenile parkinsonism (AR-JP)2,3 maps to the long arm of chromosome 6 (6q25.2-q27) and is linked strongly to the markers D6S305 and D6S253 (ref. 4); the former is deleted in one Japanese AR-JP patient5. By positional cloning within this microdeletion, we have now isolated a complementary DNA clone of 2,960 base pairs with a 1,395-base-pair open reading frame, encoding a protein of 465 amino acids with moderate similarity to ubiquitin at the amino terminus and a RING-finger motif at the carboxy terminus. The gene spans more than 500 kilobases and has 12 exons, five of which (exons 3–7) are deleted in the patient. Four other AR-JP patients from three unrelated families have a deletion affecting exon 4 alone. A 4.5-kilobase transcript that is expressed in many human tissues but is abundant in the brain, including the substantia nigra, is shorter in brain tissue from one of the groups of exon-4-deleted patients. Mutations in the newly identified gene appear to be responsible for the pathogenesis of AR-JP, and we have therefore named the protein product ‘Parkin’.

4,613 citations


"Monogenic Parkinson's disease and p..." refers background in this paper

  • ...The initial patients with EPDF experienced marked alleviation of their parkinsonism after a night’s sleep, at least during the first years of their illness [96]....

    [...]

  • ...In 1998, mutations in the parkin gene (PARK2, encoding parkinson protein 2, E3 ubiquitin protein ligase) were discovered in several siblings from consanguineous families in Japan and Turkey, who shared a peculiar clinical syndrome initially designated Early-Onset Parkinsonism with Diurnal Fluctuation (EPDF) [95, 96]....

    [...]

  • ...Parkin In 1998, mutations in the parkin gene (PARK2, encoding parkinson protein 2, E3 ubiquitin protein ligase) were discovered in several siblings from consanguineous families in Japan and Turkey, who shared a peculiar clinical syndrome initially designated Early-Onset Parkinsonism with Diurnal Fluctuation (EPDF) [95, 96]....

    [...]


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31 Oct 2003-Science
Abstract: Mutations in the α-synuclein gene ( SNCA ) in the Contursi kindred ([ 1 ][1]) implicated this gene in Parkinson's disease (PD). Subsequently, α-synuclein was identified as the major component of Lewy bodies, the pathological hallmark of PD, and of glial cell cytoplasmic inclusions ([ 2 ][2]). We

3,662 citations


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Rejko Krüger1, Wilfried Kuhn1, Thomas Müller1, Dirk Woitalla1  +6 moreInstitutions (2)

3,384 citations


Journal ArticleDOI
Mike Hutton1, Corinne Lendon2, Patrizia Rizzu3, Matt Baker1  +48 moreInstitutions (13)
18 Jun 1998-Nature
Abstract: Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)(1-9), historically termed Pick's disease(10) Most FTDP-17 cases show neuronal and/or glial inclusions that stain positively with antibodies raised against the microtubule-associated protein Tau, although the Tau pathology varies considerably in both its quantity (or severity) and characteristics(1-8,12) Previous studies have mapped the FTDP-17 locus to a 2-centimorgan region on chromosome 17q2111; the tau gene also lies within this region We have now sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5' splice site of exon in The splice-site mutations all destabilize a potential stem-loop structure which is probably involved in regulating the alternative splicing of exon10 (ref 13) This causes more frequent usage of the 5' splice site and an increased proportion of tan transcripts that include exon 10 The increase in exon 10(+) messenger RNA will increase the proportion of Tau containing four microtubule-binding repeats, which is consistent with the neuropathology described in several families with FTDP-17 (refs 12, 14)

3,193 citations


"Monogenic Parkinson's disease and p..." refers background in this paper

  • ...or without parkinsonism and with tau pathology [72]....

    [...]


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