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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.
About: This article is published in Parkinsonism & Related Disorders.The article was published on 2013-04-01 and is currently open access. It has received 211 citations till now. The article focuses on the topics: Parkinsonism & Parkin.

Summary (4 min read)

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

  • Three pathogenic point mutations as well as genomic duplications and triplications are known in the gene encoding alpha-synuclein (SNCA).
  • The family originates from the Basque region in Northern Spain.
  • 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] .
  • The A30P and E46K mutations have not been reported from any other family worldwide.
  • The clinical phenotype of PD patients with SNCA mutations (including multiplications) has certain characteristics.

LRRK2

  • In 2004, two groups simultaneously reported the discovery of mutations in the leucine-rich repeat kinase 2 (LRRK2, dardarin) gene in PD [26, 27] .
  • Nevertheless, the large number of PD patients with the LRRK2 G2019S mutation allowed for a clear description of the clinical phenotype attributed to a single mutation in a PD gene, and for statistical analyses [45] .
  • Based on data from 1,045 patients with this mutation, motor symptoms and non-motor symptoms of LRRK2 PD were more benign than those of a control group of patients, for example the risk for dementia was lower [45] .
  • These findings remain uncertain [46] and need to be interpreted in light of the fact that that study's control group consisted of PD patients collected in a brain bank, which may not reflect the average idiopathic PD population.

VPS35

  • The mutation was present in one family each from the United States and Tunisia, and in one family and one sporadic patient of Yemenite Jewish origin [53] .
  • An incomplete neuropathological examination of only parts of the cortex and basal ganglia (but not the brainstem) did not reveal any alphasynuclein immunoreactivity in these areas [54] .
  • Penetrance was incomplete with the oldest reported unaffected carrier at 86 years [53] .

EIF4G1

  • Five mutations in this gene, encoding eukaryotic translation initiation factor 4-gamma 1, were described in PD patients in 2011 [63] .
  • Co-segregation of a mutation with disease could only be demonstrated for the p.R1205H mutation, found initially in a French family and subsequently in patients from the USA, Canada, Ireland, Italy, and Tunisia [63] .
  • The clinical phenotype was that of mild PD with a late age of onset (50-80, mean 64 years) and preserved cognition, but this is based on the few patients described.
  • Concomitant Alzheimer pathology was present in a family with dementia and parkinsonism who had both G686C and R1197W mutations [66] .

Other dominant and x-linked disorders that may present with parkinsonism

  • Trinucleotide expansions in ATXN2 (ataxin-2) or ATXN3 (ataxin-3) usually cause spinocerebellar ataxia that may include parkinsonian features.
  • Men with premutations may develop the fragile X tremor/ataxia syndrome , typically characterized by adult-onset tremor, ataxia, neuropathy, autonomic dysfunction, cognitive decline, behavioral changes with apathy, disinhibition or irritability, and depression.
  • Some of the individuals with pathogenic MAPT mutations present with parkinsonism; signs of frontotemporal dementia may occur years later [73] .
  • The phenotype may resemble PD but there are frequently signs of dystonia as well, such as dystonic tremor [81] .
  • Two patients have been reported who had adult onset PD and TH mutations, but the association remains uncertain, although a pathophysiological connection appears reasonable [82] .

Monogenic disorders with various manifestations that may include parkinsonism

  • Mutations in mitochondrial DNA polymerase gamma (POLG, POLG1) have been reported from patients with parkinsonism, with loss of dopaminergic cells evidenced in DATscans and at least partial response to dopaminergic medication [85, 86] .
  • All these patients also had pronounced additional neurological signs such as progressive external ophthalmoplegia, ataxia, sensory neuropathy or sensorineural hearing loss, or muscle weakness with elevated creatine kinase and mitochondrial myopathy in muscle biopsy, and/or hypogonadism [85] [86] [87] [88] .
  • Most patients with hereditary leukoencephalopathy with spheroids, a disorder caused by mutations in the CSF1R gene, develop parkinsonism during the course of their disease, but parkinsonism is neither the initial nor the only symptom [89] [90] [91] .

Recessive PD genes

  • Recessive inheritance is suggested in families where several members of one generation are affected, especially siblings, but not their parents or their children.
  • Some of these have been published from several groups and have become wellestablished.
  • Others have only been found in one or a few patients, and their significance is difficult to ascertain.

PINK1

  • Homozygous mutations in phosphatase and tensin homolog-induced putative kinase1 (PINK1, PARK6) are associated with early-onset PD [105] .
  • Over 40 point mutations and rarely, large deletions, have been detected [101] .
  • The clinical phenotype seems to be similar to that of parkin mutations, but there are some indications that psychiatric symptoms may occur more commonly among patients with PINK1 mutations [101, 106] .
  • Mutations in PINK1 are rarer than parkin mutations.

DJ1

  • Mutations in oncogene DJ1 (parkinson protein 7, PARK7) are well-established but very rare causes for recessive PD [107] .
  • Only a few patients homozygous for DJ1 mutations have been described.

Aspects common to parkin, PINK1, DJ1

  • Mutations in these three genes are associated with a similar clinical phenotype, which is distinct from the average patient with idiopathic PD.
  • Accompanying non-motor symptoms, if present, remain mild in most cases.
  • Apart from the tendency to develop dyskinesias and dystonia common to all patients with early-onset PD irrespective of genetic background [112] , no specific features reliably distinguish these forms.
  • An important criterion for the pathogenicity of a mutation is that of co-segregation within families, meaning that mutation carriers develop disease whereas their relatives without mutations remain unaffected.
  • Stringent large-scale studies exploring the association of reported mutations with disease have not been performed, and the pathogenicity of a considerable number of mutations in these three genes remains unconfirmed.

Detailed information about clinical characteristics of carriers of certain mutations in parkin,

  • PINK1 and DJ1 is also limited: Although a large number of different mutations are known, each one is comparatively rare.
  • Grouping together patients with different mutations in the same gene may overcome this problem but has limitations when different biological effects of the various mutations are assumed.
  • It has been suggested that certain mutations cause early-onset PD when they are present on both alleles, but cause late-onset PD in heterozygote carriers [115] .
  • The overall frequency of mutations in these three genes is lower than previously estimated; a systematic review of publications covering more than 5,800 EOPD patients reported proportions of 8.6% with mutations in parkin, 3.7% in PINK1 and 0.4% in DJ1 [103] .

Recessive disorders that may include parkinsonism

  • Mutations in ATPase type 13A2 (ATP13A2; PARK9) were found to cause the rare Kufor-Rakeb syndrome in a Chilean family.
  • ATP13A2 mutations appear to be exceedingly rare.
  • Both are severe neuro-pediatric disorders that bear no resemblance to PD.
  • Three years later, mutations in this gene were reported from patients who also developed what was called adult-onset levodopa-responsive dystonia-parkinsonism [125, 126] .

Conclusions

  • The genetic causes of a considerable number of monogenic disorders with parkinsonism are known today.
  • In most populations, the known pathogenic mutations are exceptionally rare, and can only explain a very minor part [8, 24, 44, 103, 132] of the estimated 10% of PD patients with one or more affected first-degree relatives [133] .
  • In general, the probability to find a pathogenic mutation in a given patient with parkinsonism remains low [44, 103, 132] , but varies widely, depending on factors including the patient's age at onset, family history, origin, and clinical phenotype.
  • Table 4 shows which genetic tests may be useful.
  • Clinical genetic analysis should only be performed when adequate genetic counseling before, during and after testing can be provided.

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Citations
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Journal ArticleDOI
TL;DR: It was found that over half of the reported cases with SNCA duplication had early-onset parkinsonism and non-motor features, such as dysautonomia, rapid eye movement sleep behavior disorder (RBD), hallucinations, and cognitive deficits leading to dementia.

131 citations


Cites background from "Monogenic Parkinson's disease and p..."

  • ...Twenty-one PARK loci have been identified for familial PD, including autosomal dominant, autosomal recessive, and X-linked forms, and causative genes have been discovered for a majority of them [2]....

    [...]

Journal ArticleDOI
TL;DR: The neuropsychiatric comorbidity provides additional support for the idea that DAT missense mutations are an ADHD risk factor and suggests that complex DAT genotype and phenotype correlations contribute to different dopaminergic pathologies.
Abstract: Parkinsonism and attention deficit hyperactivity disorder (ADHD) are widespread brain disorders that involve disturbances of dopaminergic signaling. The sodium-coupled dopamine transporter (DAT) controls dopamine homeostasis, but its contribution to disease remains poorly understood. Here, we analyzed a cohort of patients with atypical movement disorder and identified 2 DAT coding variants, DAT-Ile312Phe and a presumed de novo mutant DAT-Asp421Asn, in an adult male with early-onset parkinsonism and ADHD. According to DAT single-photon emission computed tomography (DAT-SPECT) scans and a fluoro-deoxy-glucose-PET/MRI (FDG-PET/MRI) scan, the patient suffered from progressive dopaminergic neurodegeneration. In heterologous cells, both DAT variants exhibited markedly reduced dopamine uptake capacity but preserved membrane targeting, consistent with impaired catalytic activity. Computational simulations and uptake experiments suggested that the disrupted function of the DAT-Asp421Asn mutant is the result of compromised sodium binding, in agreement with Asp421 coordinating sodium at the second sodium site. For DAT-Asp421Asn, substrate efflux experiments revealed a constitutive, anomalous efflux of dopamine, and electrophysiological analyses identified a large cation leak that might further perturb dopaminergic neurotransmission. Our results link specific DAT missense mutations to neurodegenerative early-onset parkinsonism. Moreover, the neuropsychiatric comorbidity provides additional support for the idea that DAT missense mutations are an ADHD risk factor and suggests that complex DAT genotype and phenotype correlations contribute to different dopaminergic pathologies.

127 citations

01 Aug 2008
TL;DR: A detailed clinical evaluation of 34 patients (19 women, 15 men) with confirmed mutations in the guanosine triphosphate cyclohydrolase 1 (GTPCH1) gene was presented in this paper.
Abstract: Background: An autosomal dominantly inherited defect in the GCH1 gene that encodes guanosine triphosphate cyclohydrolase 1 (GTPCH1) is the most common cause of dopa-responsive dystonia (DRD). A classic phenotype of young-onset lower-limb dystonia, diurnal fluctuations and excellent response to levodopa has been well recognised in association with GCH1 mutations, and rare atypical presentations have been reported. However, a number of clinical issues remain unresolved including phenotypic variability, long-term response to levodopa and associated non-motor symptoms, and there are limited data on long-term follow-up of genetically proven cases. Methods: A detailed clinical evaluation of 34 patients (19 women, 15 men), with confirmed mutations in the GCH1 gene, is presented. Results and conclusions: The classic phenotype was most frequent (n = 23), with female predominance (F:M = 16:7), and early onset (mean 4.5 years) with involvement of legs. However, a surprisingly large number of patients developed craniocervical dystonia, with spasmodic dysphonia being the predominant symptom in two subjects. A subset of patients, mainly men, presented with either a young-onset (mean 6.8 years) mild DRD variant not requiring treatment (n = 4), or with an adult-onset (mean 37 years) Parkinson disease-like phenotype (n = 4). Two siblings were severely affected with early hypotonia and delay in motor development, associated with compound heterozygous GCH1 gene mutations. The study also describes a number of supplementary features including restless-legs-like symptoms, influence of female sex hormones, predominance of tremor or parkinsonism in adult-onset cases, initial reverse reaction to levodopa, recurrent episodes of depressive disorder and specific levodopa-resistant symptoms (writer’s cramp, dysphonia, truncal dystonia). Levodopa was used effectively and safely in 20 pregnancies, and did not cause any fetal abnormalities.

121 citations

Journal ArticleDOI
TL;DR: The graded risk concept of the most recently identified PARK loci and some susceptibility variants in GBA, LRRK2 and SNCA and the emerging concept of rare genetic variants in candidates genes for PD, such as HSPA9, TRAP1 and RHOT1 complete the picture of the complex genetic architecture of PD.
Abstract: Mitochondrial impairment is a well-established pathological pathway implicated in Parkinson’s disease (PD). Defects of the complex I of the mitochondrial respiratory chain have been found in post-mortem brains from sporadic PD patients. Furthermore, several disease-related genes are linked to mitochondrial pathways, such as PRKN, PINK1, DJ-1 and HTRA2 and are associated with mitochondrial impairment. This phenotype can be caused by the dysfunction of mitochondrial quality control machinery at different levels: molecular, organellar or cellular. Mitochondrial unfolded protein response represents the molecular level and implicates various chaperones and proteases. If the molecular level of quality control is not sufficient, the organellar level is required and involves mitophagy and mitochondrial-derived vesicles to sequester whole dysfunctional organelle or parts of it. Only when the impairment is too severe, does it lead to cell death via apoptosis, which defines the cellular level of quality control. Here, we review how currently known PD-linked genetic variants interfere with different levels of mitochondrial quality control. We discuss the graded risk concept of the most recently identified PARK loci (PARK 17–23) and some susceptibility variants in GBA, LRRK2 and SNCA. Finally, the emerging concept of rare genetic variants in candidates genes for PD, such as HSPA9, TRAP1 and RHOT1, complete the picture of the complex genetic architecture of PD that will direct future precision medicine approaches.

120 citations

Journal ArticleDOI
TL;DR: Evidence that phosphorylation of Parkin at Ser65 is critical for its activation is provided and evidence that Miro1 is a direct Parkin substrate is provided, indicating an essential role for the catalytic cysteine Cys431.
Abstract: Mutations in PINK1 and Parkin are associated with early-onset Parkinson's disease. We recently discovered that PINK1 phosphorylates Parkin at serine65 (Ser65) within its Ubl domain, leading to its activation in a substrate-free activity assay. We now demonstrate the critical requirement of Ser65 phosphorylation for substrate ubiquitylation through elaboration of a novel in vitro E3 ligase activity assay using full-length untagged Parkin and its putative substrate, the mitochondrial GTPase Miro1. We observe that Parkin efficiently ubiquitylates Miro1 at highly conserved lysine residues, 153, 230, 235, 330 and 572, upon phosphorylation by PINK1. We have further established an E2-ubiquitin discharge assay to assess Parkin activity and observe robust discharge of ubiquitin-loaded UbcH7 E2 ligase upon phosphorylation of Parkin at Ser65 by wild-type, but not kinase-inactive PINK1 or a Parkin Ser65Ala mutant, suggesting a possible mechanism of how Ser65 phosphorylation may activate Parkin E3 ligase activity. For the first time, to the best of our knowledge, we report the effect of Parkin disease-associated mutations in substrate-based assays using full-length untagged recombinant Parkin. Our mutation analysis indicates an essential role for the catalytic cysteine Cys431 and reveals fundamental new knowledge on how mutations may confer pathogenicity via disruption of Miro1 ubiquitylation, free ubiquitin chain formation or by impacting Parkin's ability to discharge ubiquitin from a loaded E2. This study provides further evidence that phosphorylation of Parkin at Ser65 is critical for its activation. It also provides evidence that Miro1 is a direct Parkin substrate. The assays and reagents developed in this study will be important to uncover new insights into Parkin biology as well as aid in the development of screens to identify small molecule Parkin activators for the treatment of Parkinson's disease.

119 citations


Cites background from "Monogenic Parkinson's disease and p..."

  • ...genetic breakthroughs have uncovered nearly 20 genes or loci associated with familial Parkinson’s disease (PD) that provide a solid biochemical platform to uncover the molecular origins and mechanisms underlying this devastating disorder [2]....

    [...]

References
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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.

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

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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’.

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TL;DR: In this article, the α-synuclein was identified as the major component of Lewy bodies, the pathological hallmark of Parkinson's disease, and of glial cell cytoplasmic inclusions.
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

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TL;DR: In this paper, the authors 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
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)

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Related Papers (5)
Frequently Asked Questions (12)
Q1. What are the contributions mentioned in the paper "Monogenic parkinson’s disease and parkinsonism: clinical phenotypes and frequencies of known mutations" ?

This review summarizes the clinical features of diseases caused by mutations in 

More than 100 different parkin mutations have been reported from PD patients, including copy number variations (deletions, insertions, multiplications), missense and truncating mutations [101]. 

In a recently published international multicenter study, only 49 of 8,371 (0.58%) PD patients of European and Asian origin carried a LRRK2 G2019S mutation [44]. 

Other studies found homozygous or compound heterozygous parkin mutations in a lower percentage of patients with early onset-PD (before 40 or 45 years), ranging from 8.2% in Italy, 2.7% in Korea, 2.5% in Poland, to 1.4% in Australia [8, 98-100]. 

In rare patients, parkinsonism has been the presenting or predominant clinical manifestation of GRN mutation [77], but mutations in MAPT or GRN are not considered a major cause of familial parkinsonism, especially in the absence of other clinical signs and symptoms. 

In families with recessive patterns of inheritance, cosegregation analysis is often limited to a few siblings, but siblings have a 25% chance probability to have inherited the identical allele. 

12Puschmann: Review monogenic PDFeatures common to patients with parkin mutations and PD, aside from young or very young age at onset, are probably a good and lasting effect of levodopa, albeit with the occurrence of dyskinesias during the disease course, and a lower risk for non-motor symptoms such as cognitive decline and dysautonomia [102]. 

The phenotypes caused by mutations in SNCA or the recessive PD genes (parkin, PINK1, DJ1) represent characteristic subtypes of PD. 

Given the prevalence of D620N of 0.14% among PD patients in the two initial studies and of 0.4% in the multicentre study [58], and the fact that replication studies in Belgium [61] or China [62] have not identified additional cases, this mutation is rare. 

Late-onset PD was reported in the Austrian family, one member had only developed depression and tremor with a pathological DATscan indicating incipient PD [55]. 

Genetic testing can today be offered to a subset of patients with unusually young onset, dominant inheritance, and/or a clinical phenotype suggesting a defined monogenic form of parkinsonism. 

Carriers of mutations in the other genes may develop parkinsonism with or without additional symptoms, but rarely a disease resembling PD.