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Parkin Type of Early-Onset Parkinson Disease

, MD and , MD.

Author Information
, MD
Institute of Neurogenetics and Department of Neurology
University of Luebeck
Luebeck, Germany
, MD
Institute of Neurogenetics and Department of Neurology
University of Luebeck
Luebeck, Germany

Initial Posting: ; Last Update: April 4, 2013.

Summary

Disease characteristics. Parkin type of early-onset Parkinson disease is characterized by rigidity, bradykinesia, and resting tremor. Lower-limb dystonia may be a presenting sign. Onset usually occurs between ages 20 and 40 years with an average age of onset in the early to mid-thirties. The disease is slowly progressive and disease duration of more than 50 years has been reported. Clinical signs vary; hyperreflexia is common. Dyskinesia as a result of treatment with levodopa frequently occurs.

Diagnosis/testing. The diagnosis of parkin type of early-onset Parkinson disease is considered primarily in individuals with early-onset parkinsonism (age <40 years), particularly if autosomal recessive inheritance is suspected. PARK2, the gene encoding the protein parkin, is the only gene in which mutations are known to cause parkin type of early-onset Parkinson disease. The diagnosis of parkin type of early-onset Parkinson disease can only be confirmed when disease-causing mutations are identified on both alleles of PARK2 (i.e., the individual is homozygous for the same disease-causing allele or compound heterozygous for two different disease-causing alleles). The mutation detection frequency varies by family history and age of onset.

Management. Treatment of manifestations: Levodopa and other dopaminergic agonists; deep brain stimulation (DBS) for those experiencing difficulty with levodopa therapy.

Prevention of secondary complications: Do not use levodopa therapy above the dose needed for satisfactory clinical response.

Surveillance: Neurologic follow-up including assessment of treatment every six to 12 months.

Agents/circumstances to avoid: Neuroleptic treatment may exacerbate parkinsonism.

Genetic counseling. Parkin type of early-onset Parkinson disease is inherited in an autosomal recessive manner. At conception, each sib of a proband has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Each unaffected sib has a 2/3 chance of being a carrier. Carrier testing and prenatal testing for pregnancies at increased risk are possible if both disease-causing alleles have been identified in an affected family member.

Diagnosis

Clinical Diagnosis

Parkin type of early-onset Parkinson disease is often clinically indistinguishable from idiopathic Parkinson disease [Lücking et al 2000]. Rigidity, bradykinesia, and resting tremor are variably combined in both disorders.

The following findings suggest parkin type of early-onset Parkinson disease:

  • Early onset (age <40 years) or, rarely, juvenile onset (age <20 years). Most affected individuals appear to have onset before age 40 years.
  • Lower-limb dystonia, which may be a presenting sign or occurs during disease progression. This finding can sometimes be present in isolation for years.
  • Hyperreflexia of the lower extremities
  • Well-preserved sense of smell
  • Marked and sustained response to oral administration of levodopa, which is frequently associated with levodopa-induced motor fluctuations and dyskinesias (abnormal involuntary movements)
  • Slow disease progression
  • Absence of dementia in most cases (prevalence <3%)
  • Family history consistent with autosomal recessive inheritance

Testing

No clinical investigations distinguish individuals with parkin type of early-onset Parkinson disease from those with idiopathic Parkinson disease.

Molecular Genetic Testing

Gene. PARK2 is the only gene in which mutations are known to cause parkin type of early-onset Parkinson disease.

Clinical testing

Note: The detection frequency of all mutation types varies by population and depends mostly on the presence of a positive family history and the age at onset [Abbas et al 1999, Lücking et al 2000, Periquet et al 2001, Hedrich et al 2002, West et al 2002, Lohmann et al 2003, Periquet et al 2003, Poorkaj et al 2004, Wiley et al 2004, Wu et al 2005, Marder et al 2010, Kilarski et al 2012]. The detection frequency of all types of mutations is as high as 80%-90% in familial cases with onset before age 20 years, and lower than 10% in individuals with no family history and onset around age 40 years. Otherwise, only 18%-26% of cases with a reported mutation had a juvenile onset, whereas 70% manifested the disease between the ages of 20 to 40 years, and 12% at 41 years or older (Table 2) [Periquet et al 2003, Kasten et al 2010]. A major caveat is that more than 50% of all published studies restricted their recruitment to those with young-onset disease [Grünewald et al, in press].

Table 1. Summary of Molecular Genetic Testing Used in Parkin Type of Early-Onset Parkinson Disease

Gene SymbolTest Method Mutations DetectedMutation Detection Frequency 1
Family History
Positive Negative
PARK2Sequence / mutation scanning analysis 2Sequence variants 3≤80%-90% 4See Table 2
Deletion / duplication analysis 5Heterozygous deletions / duplications / triplications 6

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably between laboratories depending on the specific protocol used.

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

4. Sequencing of the12 coding exons permits identification of the missense and nonsense mutations described so far, as well as small exonic rearrangements (1- or 2-base pair deletions or insertions) [Hattori et al 1998a, Hattori et al 1998b, Kitada et al 1998, Leroy et al 1998, Lücking et al 1998, Abbas et al 1999, Nisipeanu et al 1999, Maruyama et al 2000, Munoz et al 2000, Hedrich et al 2004].

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment (alias array comparative genomic hybridization (aGCH).

6. Exon rearrangements (i.e. deletions, duplications, and rarely, triplications of single or multiple exons) account for more than 50% of mutations [Hedrich et al 2004, Marder et al 2010]. The frequency of exon rearrangements is likely even underestimated given that early mutation screening studies did not include methods that aimed at identifying these types of mutations. Deletions or duplications are frequently found in the heterozygous state [Lücking et al 2000].

Table 2. Frequency of PARK2 Mutations by Age at Onset in Individuals with Early-Onset Parkinson Disease and No Family History

Age at Onset Individuals with PARK2 Mutations Total 1 Mutation Detection Frequency 95% Confidence Interval
<20 yrs10 15 67% 38-88
20-24 yrs4 15 27% 8-55
25-29 yrs9 38 24% 11-40
30-34 yrs4 53 8% 2-18
35-39 yrs4 71 6% 2-14
40-45 yrs5 51 9% 3-21
Total 38 2 246 2 15% 11-20

Adapted from Periquet et al [2003] with permission

1. Including 100 cases from Lücking et al [2000]

2. Age at onset was not known for two affected individuals with PARK2 mutations and for one affected individual without a mutation; all three were younger than age 45 years when examined.

Interpretation of test results

  • For issues to consider in interpretation of sequence analysis results, click here.
  • The diagnosis of parkin type of early-onset Parkinson disease can only be confirmed when disease-causing mutations are identified on both PARK2 alleles (i.e., the individual is homozygous for the same disease-causing allele or a compound heterozygote for two different disease-causing alleles).
  • The finding of a single disease-causing mutation is only suggestive (i.e., not diagnostic) of parkin type of early-onset Parkinson disease; the affected individual may truly be a heterozygote and have parkinsonism from some other cause. In some series, even with individuals with early-onset Parkinson disease, the proportion of individuals with a single (heterozygous) mutation is very high, up to 70% of parkin cases [Poorkaj et al 2004].
    • Those affected individuals with a single heterozygous PARK2 mutation have on average about a nine year higher age at onset (39.9±13.3 years, n=232) than affected individuals with homozygous or compound heterozygous mutations in PARK2 (30.9±11.2 years, n=378) [Grünewald et al, in press].
  • A better understanding of the mode of inheritance, penetrance, and carrier frequency is needed to interpret the significance of single (heterozygous) mutations.
  • The absence of a PARK2 mutation on one or both alleles cannot completely exclude the diagnosis of parkin type of early-onset Parkinson disease.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband identification of disease-causing mutations on both PARK2 alleles (i.e., the individual is homozygous for the same disease-causing allele or a compound heterozygote for two different disease-causing alleles) is required.

Single gene testing. One strategy for molecular diagnosis of a proband suspected of having parkin type of early-onset Parkinson disease is molecular genetic testing of PARK2.

Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having parkin type of early-onset Parkinson disease is use of a multi-gene panel. The genes included and the methods used in multi-gene panels vary by laboratory and over time; a panel may not include a specific gene of interest. See Differential Diagnosis.

Note: Testing for mutations in PARK2, PINK1, and DJ-1 is recommended in families with a recessive mode of inheritance or in sporadic cases in which an affected individual has an early age at onset (<35 years [Harbo et al 2009] or <40 years [Klein & Schlossmacher 2006]).

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

Unlike in idiopathic Parkinson disease, women and men are affected with equal frequency. Age at onset is highly variable, even in individuals with the same mutation [Chien et al 2006]; onset is usually before age 40 years, but some individuals may not develop disease until age 60 or 70 years [Klein et al 2000, Lohmann et al 2003].

Clinical signs vary; however, bradykinesia and tremor are the most common presenting signs. Dystonia is observed in 42% of affected individuals. Almost half of affected individuals present with hyperreflexia. A prolongation of the central motor conduction time points to involvement of the corticospinal tract [De Rosa et al 2006, Schneider et al 2008, Perretti et al 2011] corresponding to the clinically observed hyperreflexia.

On average, the response to low doses of levodopa is excellent and sustained. The likelihood of developing levodopa-induced dyskinesias is higher than in individuals with parkinsonism resulting from other etiologies.

Parkin type of early-onset Parkinson disease is not associated with specific behavioral, neuropsychological, or psychiatric symptoms [Caccappolo et al 2011, Srivastava et al 2011]. Cognitive impairment is uncommon, and dementia is observed very rarely [Benbunan et al 2004; Grünewald et al, in press].

In contrast to idiopathic Parkinson disease, the sense of smell does not appear to be impaired in affected individuals with compound heterozygous mutations, whereas individuals with Parkinson disease and a heterozygous PARK2 mutation demonstrate typical hyposmia [Alcalay et al 2011].

The disease is slowly progressive and disease duration of longer than 50 years has been reported.

Neuroimaging. Routine cranial CT and MRI scans are usually normal.

PET/SPECT studies have revealed a reduced striatal 18F-DOPA uptake and a reduced presynaptic dopamine transporter density in individuals with parkin type of early-onset Parkinson disease [van der Vegt et al 2009]. The putamen is predominantly affected, consistent with the findings in idiopathic Parkinson disease. Unlike the idiopathic form, however, the loss of dopaminergic striatal innervation is rather symmetric and the progression rate is considerably slower. The postsynaptic D2 receptor density as assessed with 11C-raclopride PET has been shown to be upregulated in untreated affected individuals and downregulated in affected individuals who receive dopaminergic medication.

Asymptomatic individuals who have a heterozygous mutation show a slight and subclinical impairment of dopaminergic neurotransmission. A longitudinal PET study demonstrated a very subtle progression rate, indicating that only a marginal number of asymptomatic individuals with a heterozygous mutation may develop clinically overt parkinsonism if no other risk factors are present [Pavese et al 2009].

Voxel-based morphometry revealed a decrease of putaminal gray matter volume and a slight increase of gray matter in the right pallidum in affected individuals (those with two mutated alleles), whereas asymptomatic individuals with a single heterozygous mutation demonstrated an increase of both putaminal and pallidal gray matter volume.

Using functional MRI, asymptomatic individuals with a single heterozygous mutation showed an increased activation of motor-related brain regions when they performed repetitive finger movements [van Nuenen et al 2009]. The same mechanism of an increased neuronal recruitment has been illustrated for a facial emotion recognition task [Anders et al 2012].

Neuropathology. To date, detailed post mortem studies of nine individuals with homozygous and compound heterozygous PARK2 mutations have been published [Poulopoulos et al 2012]. The most prominent and most common feature was the finding of neuronal loss in pigmented nuclei of the brain stem. Unlike idiopathic Parkinson disease, the neuronal loss was stronger in the substantia nigra pars compacta than in the locus coeruleus (see Parkinson Disease Overview). Typical alpha-synuclein-containing Lewy bodies were identified in only two affected individuals, whereas one affected individual had basophilic Lewy body-like pathology of the pedunculopontine nucleus. Tau-containing neurofibrillary tangles were observed in two affected individuals. In conclusion, the spectrum of post mortem findings is broad and thus reminiscent of the situation in LRRK2-related Parkinson disease.

Genotype-Phenotype Correlations

Exon rearrangements of PARK2 appear to have greater pathogenicity than point mutations or small insertions/deletions, resulting in an association with an earlier age at onset [Pankratz et al 2009; Grünewald et al, in press]. No correlation between missense or truncating PARK2 mutations and age at onset, clinical presentation, or disease progression has been observed [Lücking et al 2000; Grünewald et al, in press]. Missense mutations in known functional domains do not result in an earlier onset than missense mutations in other regions of the protein [Grünewald et al, in press].

Penetrance

Penetrance appears to be nearly complete in individuals who have two disease-causing PARK2 mutations.

Nomenclature

Families with parkin type of early-onset Parkinson disease were mostly described in Japan in the 1970s as having "autosomal recessive juvenile parkinsonism" (AR-JP).

Prevalence

The population-based prevalence is largely unknown. However, in Europe, parkin type of early-onset Parkinson disease accounts for approximately 50% of autosomal recessive parkinsonism and 18% of parkinsonism in individuals without a family history and an onset before age 45 years [Lücking et al 2000]. The percentage of parkin type of early-onset Parkinson disease cases rapidly decreases with increasing age at onset. After age 30 years, only a few percent of individuals representing simplex cases (parkinsonism in a single individual in a family) are found to have PARK2 mutations. However, in families with a clear-cut autosomal recessive mode of inheritance, the age-related decrease is less pronounced [Periquet et al 2003].

Prevalence of parkin type of early-onset Parkinson disease appears to be similar in all populations. Individuals with parkin type of early-onset Parkinson disease from many different regions have been reported [Hattori et al 1998a, Hattori et al 1998b, Leroy et al 1998, Lücking et al 1998, Abbas et al 1999, Nisipeanu et al 1999, Klein et al 2000, Maruyama et al 2000, Munoz et al 2000, Biswas et al 2006, Vinish et al 2010, Guerrero Camacho et al 2012, Semenova et al 2012].

Differential Diagnosis

Parkinson disease multi-gene panels may include testing for a number of the genes associated with disorders discussed in this section.

Parkin type of early-onset Parkinson disease and idiopathic Parkinson disease are difficult to distinguish by clinical examination (see Parkinson Disease Overview). More than 80% of individuals with Parkinson disease have no family history of the disorder. Several monogenic forms account for a number of cases with a positive family history.

Mutations in PINK1 are the second most common cause of early-onset Parkinson disease, after PARK2. Cases associated with mutations in PARK2 and PINK1 are clinically indistinguishable on an individual basis [Ibanez et al 2006] (see PINK1 Type of Young-Onset Parkinson Disease).

Another disorder in the differential diagnosis is the DJ1- type of early-onset Parkinson disease, which also presents as an early-onset disorder with an overall similar phenotype to that of the parkin type of early-onset Parkinson disease [Bonifati et al 2003].

For individuals with juvenile-onset Parkinson disease, especially those with prominent dystonia, dopa-responsive dystonia should be considered; for example, GTP cyclohydrolase 1-deficient dopa-responsive dystonia, caused by mutations in GCH1.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with parkin type of early-onset Parkinson disease, the following evaluations are recommended:

  • Assess the presence and the severity of parkinsonian signs, non-motor features and treatment-related complications using the Unified Parkinson’s disease rating scale (UPDRS) [Fahn & Elton 1987] or the Movement Disorder Society (MDS) UPDRS [Goetz et al 2008].
  • Assess the presence of atypical signs, such as hyperreflexia and dystonia.
  • Evaluate the degree of response to treatment.
  • Assess for cognitive or behavioral problems.
  • Consider medical genetics consultation.

Treatment of Manifestations

To date, the treatment of parkin type of early-onset Parkinson disease is not different from that of idiopathic Parkinson disease. No specific guidelines are currently available.

  • The motor impairment usually responds very well to low doses of dopaminergic medication and is typically sustained even after long disease duration.
  • The most relevant treatment-related problem is the early occurrence of levodopa-induced dyskinesias (abnormal involuntary movements) and motor fluctuations. The management of treatment-related complications is not different from the strategies applied in idiopathic Parkinson disease and includes deep brain stimulation in selected cases [Moro et al 2008].

Prevention of Secondary Complications

To reduce or delay side effects, levodopa doses should not exceed the levels required for satisfactory clinical response.

Surveillance

Neurologic follow-up every six to 12 months to modify treatment as needed is appropriate.

Agents/Circumstances to Avoid

Neuroleptic treatment may exacerbate parkinsonism.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancy in women with Parkinson disease is a rare event. Only one case of a successful pregnancy in a woman with parkin type of early-onset Parkinson disease has been reported [Serikawa et al 2011]. The 27-year old woman successfully gave birth to spontaneously conceived dichorionic/diamnionic male twins. Exacerbation of her motor disabilities was noted during late pregnancy. She was treated with levodopa/carbidopa only during the period of organogenesis. Both babies were born healthy, without any evidence of psychomotor impairment two years after birth.

Worsening of parkinsonian symptoms could in part be explained by the reduction of dopaminergic replacement therapy. If possible, dopaminergic medication should be limited to levodopa/decarboxylase inhibitor to minimize the potential risk for teratogenicity at least over the course of the embryonic phase.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Parkin type of early-onset Parkinson disease is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

Offspring of a proband

  • The offspring of an individual with parkin type of early-onset Parkinson disease are obligate heterozygotes.
  • The risk to offspring of being affected depends on the frequency of heterozygotes, which is 0%-3.7% in the general population [Grünewald & Klein 2012], thus generating a risk of 0%-1% to offspring of being affected. As for other autosomal recessive disorders, the risk is higher when the proband and his/her reproductive partner are related.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing using molecular genetic techniques is possible if the disease-causing mutations have been identified in the proband.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified in an affected family member.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Parkinson Disease Association (APDA)
    135 Parkinson Avenue
    Staten Island NY 10305
    Phone: 800-223-2732 (toll-free); 718-981-8001
    Fax: 718-981-4399
    Email: apda@apdaparkinson.org
  • National Library of Medicine Genetics Home Reference
  • Parkinson's Disease Foundation (PDF)
    1359 Broadway
    Suite 1509
    New York NY 10018
    Phone: 800-457-6676 (Toll-free Helpline); 212-923-4700
    Fax: 212-923-4778
    Email: info@pdf.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Parkin Type of Early-Onset Parkinson Disease: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Parkin Type of Early-Onset Parkinson Disease (View All in OMIM)

600116PARKINSON DISEASE 2, AUTOSOMAL RECESSIVE JUVENILE; PARK2
602544PARKIN; PARK2

Normal allelic variants. PARK2 is the second largest human gene spanning approximately 1.35 Mb. It consists of 12 coding exons separated by large intronic regions. Many exonic and intronic variants have been detected; four of them cause amino acid changes (Table 3). The frequency of the particular normal allelic variants varies by geographic location [Abbas et al 1999, Wang et al 1999, Lincoln et al 2003, Lücking et al 2003].

Pathologic allelic variants. More than 180 pathologic allelic variants of PARK2 have been described with half of them being situated in the region spanning exons 2 to 4 [Corti et al 2011; Grünewald et al, in press]. Several of the mutations are recurrent [Hattori et al 1998a, Hattori et al 1998b, Leroy et al 1998, Lücking et al 1998, Abbas et al 1999, Nisipeanu et al 1999, Klein et al 2000, Maruyama et al 2000, Munoz et al 2000, Hedrich et al 2002, Periquet et al 2003, Rawal et al 2003, Grünewald & Klein 2012]. Different types of PARK2 mutations are found at variable frequencies. Changes have been identified in the homozygous, compound heterozygous, and heterozygous state.

  • PARK2 exon rearrangements (deletions or duplications; rarely triplications) of single or multiple exons account for more than 50% of all PARK2 mutations [Hedrich et al 2004; Marder et al 2010; Grünewald et al, in press]. The frequency of exon rearrangements is likely even underestimated given that early mutation screening studies did not include methods that aimed at identifying these types of mutations. Gene dosage alterations lead to internal deletions or premature protein truncation [Lücking et al 2000]. The deletion of exon 3 is the most frequent mutation in PARK2. Importantly, heterozygous exon rearrangements cannot be detected by conventional sequencing.
  • Most of the PARK2 point mutations are missense mutations. The most common point mutation is the c.924C>T single nucleotide mutation in exon 7. Nonsense mutations, one- or two-base pair deletions, or small insertions result in a frameshift that either predicts or is known to cause truncated parkin.

Table 3. PARK2 Normal Allelic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.500G>Ap.Ser167Asn NM_004562​.1
NP_004553​.1
c.1096C>Tp.Arg366Trp
c.1138G>Cp.Val380Leu
c.1182G>Ap.Asp394Asn

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The normal gene product, parkin, is a 465-amino acid protein, which contains a ubiquitin-like domain at the N terminus and a RING (Really Interesting New Gene) domain composed of three RING finger motifs (RING0, 1, and 2). RING1 and 2 are separated by a sequence without any recognizable domain structure (in between-RING (IBR). Parkin is mainly localized in the cytoplasm under basal conditions. Like other RING finger proteins, parkin exhibits E3 ubiquitin ligase activity [Imai et al 2000, Shimura et al 2000, Zhang et al 2000] and mediates the ubiquitination of a number of proteins, thus targeting them for proteasomal degradation. Parkin can additionally mediate non-degradative modes of ubiquitination, which appear to be required for the survival of nigrostriatal dopaminergic neurons [Moore 2006]. More than twenty of its substrates have yet been identified. In addition to its role as E3 ligase, parkin is also involved in the maintenance of mitochondrial function and integrity, and protection from multiple stressors, hence acting as neuroprotectant. In the context of its role in mitochondrial metabolism, parkin interacts with PINK1, another protein linked to autosomal recessive, early-onset parkinsonism [Valente et al 2004]. PINK1 promotes the mitochondrial translocation of parkin, thus enabling parkin to ubiquinate mitochondrial proteins, to selectively identify impaired mitochondria, and to trigger their degradation by mitophagy [Narendra et al 2012, Rakovic et al 2013].

Abnormal gene product. It is postulated that the vast majority of PARK2 mutations produce a loss of function of normal E3 ubiquitin ligase activity by the absence of the protein (truncating mutations) or its inactivation (missense mutations). PARK2 mutations impair the ubiquitination of mitofusins, which are highly relevant mitochondrial fusion and fission factors [Rakovic et al 2011]. The mutations could also result in the accumulation of its substrates because they are no longer appropriately targeted to the proteasome system for their degradation. However, this hypothesis has not been confirmed in appropriate experimental models. As an example, degeneration does not occur in the substantia nigra of different lines of mice with inactivation of PARK2. In addition, in vitro studies have shown that the consequences of mutations may vary according to their nature and their location (e.g., decreased expression, abnormal aggregation, decreased interaction with substrates and/or E2 ubiquitin transferases). According to their involvement in mitochondrial integrity, PARK2 mutations were demonstrated to result in reduction of mitochondrial complex I activity, disruption of the mitochondrial morphology, and impairment of protection of mitochondrial genomic integrity from oxidative stress.

References

Published Guidelines/Consensus Statements

  1. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. Accessed 3-26-13. [PMC free article: PMC1801355] [PubMed: 7485175]
  2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 3-26-13.

Literature Cited

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Suggested Reading

  1. Lohmann E, Thobois S, Lesage S, Broussolle E, du Montcel ST, Ribeiro MJ, Remy P, Pelissolo A, Dubois B, Mallet L, Pollak P, Agid Y, Brice A. A multidisciplinary study of patients with early-onset PD with and without parkin mutations. Neurology. 2009;72:110–6. [PMC free article: PMC2677494] [PubMed: 18987353]
  2. Mortiboys H, Thomas KJ, Koopman WJ, Klaffke S, Abou-Sleiman P, Olpin S, Wood NW, Willems PH, Smeitink JA, Cookson MR, Bandmann O. Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts. Annals of neurology. 2008;64:555–65. [PMC free article: PMC2613566] [PubMed: 19067348]

Chapter Notes

Author History

Alexis Brice, MD; Hôpital de la Pitié-Salpêtrière (2001-2013)
Norbert Brüggemann, MD (2013-present)
Alexandra Dürr, MD, PhD; Hôpital de la Pitié-Salpêtrière (2001-2013)
Christine Klein, MD (2013-present)
Christoph Lücking, MD; Ludwig-Maximilians University (2001-2013)

Revision History

  • 4 April 2013 (me) Comprehensive update posted live
  • 1 October 2007 (me) Comprehensive update posted to live Web site
  • 6 November 2006 (cd) Revision: prenatal diagnosis available
  • 8 July 2005 (me) Comprehensive update posted to live Web site
  • 14 November 2003 (ab) Revisions
  • 3 October 2003 (cd) Revision: change in test availability
  • 6 June 2003 (ca) Comprehensive update posted to live Web site
  • 17 April 2001 (me) Review posted to live Web site
  • November 2000 (ab) Original submission
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    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

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