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Parkin Type of Early-Onset Parkinson Disease

, MD and , MD.

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

Estimated reading time: 23 minutes


Clinical 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.


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. PRKN (formerly PARK2), the gene encoding the protein parkin, is the only gene in which pathogenic variants 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 pathogenic variants are identified on both alleles of PRKN (i.e., the individual is homozygous for the same pathogenic allele or compound heterozygous for two different pathogenic alleles). The variant detection frequency varies by family history and age of onset.


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 pathogenic alleles have been identified in an affected family member.


Clinical Diagnosis

Parkin type of early-onset Parkinson disease is often clinically indistinguishable from Parkinson disease of other etiologies [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


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

Molecular Genetic Testing

Gene. PRKN (formerly PARK2) is the only gene in which pathogenic variants are known to cause parkin type of early-onset Parkinson disease.

Note: The detection frequency of all pathogenic variant 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 pathogenic variants 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 pathogenic variant 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 2013].

Table 1.

Molecular Genetic Testing Used in Parkin Type of Early-Onset Parkinson Disease

Gene 1MethodPathogenic Variants Detected 2Variant Detection Frequency 3
Family History
PRKNSequence analysis 4 / Scanning for pathogenic variants 5Sequence variants≤80%-90% 6See Table 2
Deletion/duplication analysis 7Heterozygous deletions/
duplications/triplications 8

See Molecular Genetics for information on allelic variants.


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


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


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


Sequencing of the12 coding exons permits identification of the missense and nonsense variants described so far, as well as small exon 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, Muñoz et al 2000, Hedrich et al 2004].


Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


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

Table 2.

Frequency of PRKN Pathogenic Variants by Age at Onset in Individuals with Early-Onset Parkinson Disease and No Family History

Age at OnsetIndividuals w/PRKN Pathogenic VariantsTotal 1Variant Detection Frequency95% Confidence Interval
<20 yrs101567%38-88
20-24 yrs41527%8-55
25-29 yrs93824%11-40
30-34 yrs4538%2-18
35-39 yrs4716%2-14
40-45 yrs5519%3-21
Total38 2246 215%11-20

Adapted from Periquet et al [2003] with permission


Including 100 cases from Lücking et al [2000]


Age at onset was not known for two affected individuals with PRKN pathogenic variants and for one affected individual without a pathogenic variant; all three were younger than age 45 years when examined.

Interpretation of test results

  • The diagnosis of parkin type of early-onset Parkinson disease can only be confirmed when pathogenic variants are identified on both PRKN alleles (i.e., the individual is homozygous for the same pathogenic allele or a compound heterozygote for two different pathogenic alleles).
  • The finding of a single pathogenic variant 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) pathogenic variant is very high, up to 70% of parkin cases [Poorkaj et al 2004].
  • A better understanding of the mode of inheritance, penetrance, and carrier frequency is needed to interpret the significance of single (heterozygous) pathogenic variants.
  • The absence of a PRKN pathogenic variant on one or both alleles cannot completely exclude the diagnosis of parkin type of early-onset Parkinson disease.

Testing Strategy

To confirm/establish the diagnosis in a proband identification of pathogenic variants on both PRKN alleles (i.e., the individual is homozygous for the same pathogenic allele or a compound heterozygote for two different pathogenic 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 PRKN.

Multigene panel. Another strategy for molecular diagnosis of a proband suspected of having parkin type of early-onset Parkinson disease is use of a multigene panel.

Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. (5) Testing for pathogenic variants in PRKN, 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]).

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Characteristics

Clinical Description

Women and men are affected with equal frequency. Age at onset is highly variable, even in individuals with the same pathogenic variant [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 2013].

In contrast to Parkinson disease of other etiologies, the sense of smell does not appear to be impaired in affected individuals with compound heterozygous pathogenic variants, whereas individuals with Parkinson disease and a heterozygous PRKN pathogenic variant 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 Parkinson disease of other etiologies; in contrst, 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 pathogenic variant 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 pathogenic variant 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 pathogenic variant demonstrated an increase of both putaminal and pallidal gray matter volume.

Using functional MRI, asymptomatic individuals with a single heterozygous pathogenic variant 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 PRKN pathogenic variants 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 Parkinson disease of other etiologies, 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 PRKN appear to have greater pathogenicity than single-nucleotide variants or small insertions/deletions, resulting in an association with an earlier age at onset [Pankratz et al 2009, Grünewald et al 2013]. No correlation between missense or truncating PRKN variants and age at onset, clinical presentation, or disease progression has been observed [Lücking et al 2000, Grünewald et al 2013]. Missense variants in known functional domains do not result in an earlier onset than missense variants in other regions of the protein [Grünewald et al 2013].


Penetrance appears to be nearly complete in individuals who have two PRKN pathogenic variants.


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).


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 PRKN pathogenic variants. 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, Muñoz et al 2000, Biswas et al 2006, Vinish et al 2010, Guerrero Camacho et al 2012, Semenova et al 2012].

Differential Diagnosis

Parkinson disease multigene 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 Parkinson disease of other etiologies 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.

Pathogenic variants in PINK1 are the second most common cause of early-onset Parkinson disease, after PRKN. Cases associated with pathogenic variants in PRKN and PINK1 are clinically indistinguishable on an individual basis [Ibáñez 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 pathogenic variants in GCH1.


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 consultation with a clinical geneticist and/or genetic counselor.

Treatment of Manifestations

To date, the treatment of parkin type of early-onset Parkinson disease is not different from that of Parkinson disease of other etiologies. 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 Parkinson disease of other etiologies, 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.


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 in the US and EU Clinical Trials Register in Europe 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 (Heterozygote) Detection

Carrier testing using molecular genetic techniques is possible if the pathogenic variants 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the PRKN pathogenic variants have been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.


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
  • National Library of Medicine Genetics Home Reference

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 from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

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


Gene structure. PRKN (formerly PARK2) is the second largest human gene spanning approximately 1.35 Mb. It consists of 12 coding exons separated by large intronic regions. See Table A, Gene for a detailed summary of gene and protein information.

Benign variants. Many exon and intron variants have been detected; four of them cause amino acid changes (Table 3). The frequency of the particular benign variants varies by geographic location [Abbas et al 1999, Wang et al 1999, Lincoln et al 2003, Lücking et al 2003].

Table 3.

PRKN Selected Benign Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.

Pathogenic variants. More than 180 pathogenic variants of PRKN have been described; half are situated in the region spanning exons 2 to 4 [Corti et al 2011, Grünewald et al 2013]. Several of the pathogenic variants 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, Muñoz et al 2000, Hedrich et al 2002, Periquet et al 2003, Rawal et al 2003, Grünewald & Klein 2012]. Different types of PRKN variants are found at variable frequencies. Changes have been identified in the homozygous, compound heterozygous, and heterozygous state.

  • PRKN exon rearrangements (deletions or duplications; rarely triplications) of single or multiple exons account for more than 50% of all PRKN pathogenic variants [Hedrich et al 2004, Marder et al 2010, Grünewald et al 2013]. The frequency of exon rearrangements is likely even underestimated given that early variant screening studies did not include methods that aimed at identifying these types of variants. Gene dosage alterations lead to internal deletions or premature protein truncation [Lücking et al 2000]. The deletion of exon 3 is the most frequent pathogenic variant in PRKN. Importantly, heterozygous exon rearrangements cannot be detected by conventional sequencing.
  • Most of the PRKN single-nucleotide variants are missense variants. The most common single-nucleotide variant is the c.924C>T, in exon 7. Nonsense variants, one- or two-base pair deletions, or small insertions result in a frameshift that either predicts or is known to cause truncated parkin.

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 PRKN pathogenic variants produce a loss of function of normal E3 ubiquitin ligase activity by the absence of the protein (truncating variants) or its inactivation (missense variants). PRKN pathogenic variants impair the ubiquitination of mitofusins, which are highly relevant mitochondrial fusion and fission factors [Rakovic et al 2011]. The pathogenic variants 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 PRKN. In addition, in vitro studies have shown that the consequences of pathogenic variants 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, PRKN pathogenic variants 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.


Published Guidelines / Consensus Statements

  • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 7-2-19. [PubMed: 23428972]
  • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2018. Accessed 7-2-19.

Literature Cited

  • Abbas N, Lücking CB, Ricard S, Durr A, Bonifati V, De Michele G, Bouley S, Vaughan JR, Gasser T, Marconi R, Broussolle E, Brefel-Courbon C, Harhangi BS, Oostra BA, Fabrizio E, Bohme GA, Pradier L, Wood NW, Filla A, Meco G, Denefle P, Agid Y, Brice A. A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. French Parkinson's Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson's Disease. Hum Mol Genet. 1999;8:567–74. [PubMed: 10072423]
  • Alcalay RN, Clark LN, Marder KS, Bradley WE. Lack of association between cancer history and PARKIN genotype: a family based study in PARKIN/Parkinson's families. Genes Chromosomes Cancer. 2012;51:1109–13. [PMC free article: PMC3465486] [PubMed: 22927236]
  • Alcalay RN, Siderowf A, Ottman R, Caccappolo E, Mejia-Santana H, Tang MX, Rosado L, Louis E, Ruiz D, Waters C, Fahn S, Cote L, Frucht S, Ford B, Orbe-Reilly M, Ross B, Verbitsky M, Kisselev S, Comella C, Colcher A, Jennings D, Nance M, Bressman S, Scott WK, Tanner C, Mickel S, Rezak M, Novak KE, Friedman JH, Pfeiffer R, Marsh L, Hiner B, Clark LN, Marder K. Olfaction in Parkin heterozygotes and compound heterozygotes: the CORE-PD study. Neurology. 2011;76:319–26. [PMC free article: PMC3034420] [PubMed: 21205674]
  • Anders S, Sack B, Pohl A, Münte T, Pramstaller P, Klein C, Binkofski F. Compensatory premotor activity during affective face processing in subclinical carriers of a single mutant Parkin allele. Brain. 2012;135:1128–40. [PMC free article: PMC3326258] [PubMed: 22434215]
  • Benbunan BR, Korczyn AD, Giladi N. Parkin mutation associated parkinsonism and cognitive decline, comparison to early onset Parkinson's disease. J Neural Transm. 2004;111:47–57. [PubMed: 14714215]
  • Biswas A, Gupta A, Naiya T, Das G, Neogi R, Datta S, Mukherjee S, Das SK, Ray K, Ray J. Molecular pathogenesis of Parkinson's disease: identification of mutations in the Parkin gene in Indian patients. Parkinsonism Relat Disord. 2006;12:420–6. [PubMed: 16793319]
  • Bonifati V, Lücking CB, Fabrizio E, Periquet M, Meco G, Brice A. Three parkin gene mutations in a sibship with autosomal recessive early onset parkinsonism. J Neurol Neurosurg Psychiatry. 2001;71:531–4. [PMC free article: PMC1763498] [PubMed: 11561042]
  • Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science. 2003;299:256–9. [PubMed: 12446870]
  • Brooks J, Ding J, Simon-Sanchez J, Paisan-Ruiz C, Singleton AB, Scholz SW. Parkin and PINK1 mutations in early-onset Parkinson's disease: comprehensive screening in publicly available cases and control. J Med Genet. 2009;46:375–81. [PMC free article: PMC4767009] [PubMed: 19351622]
  • Caccappolo E, Alcalay RN, Mejia-Santana H, Tang MX, Rakitin B, Rosado L, Louis ED, Comella CL, Colcher A, Jennings D, Nance MA, Bressman S, Scott WK, Tanner CM, Mickel SF, Andrews HF, Waters C, Fahn S, Cote LJ, Frucht S, Ford B, Rezak M, Novak K, Friedman JH, Pfeiffer RF, Marsh L, Hiner B, Siderowf AD, Ross BM, Verbitsky M, Kisselev S, Ottman R, Clark LN, Marder KS. Neuropsychological Profile of Parkin Mutation Carriers with and without Parkinson Disease: The CORE-PD Study. J Int Neuropsychol Soc. 2011;17:91–100. [PMC free article: PMC3366462] [PubMed: 21092386]
  • Chien HF, Rohe CF, Costa MD, Breedveld GJ, Oostra BA, Barbosa ER, Bonifati V. Early-onset Parkinson's disease caused by a novel parkin mutation in a genetic isolate from northeastern Brazil. Neurogenetics. 2006;7:13–9. [PubMed: 16328510]
  • Corti O, Lesage S, Brice A. What genetics tells us about the causes and mechanisms of Parkinson's disease. Physiol Rev. 2011;91:1161–218. [PubMed: 22013209]
  • De Rosa A, Volpe G, Marcantonio L, Santoro L, Brice A, Filla A, Perretti A, De Michele G. Neurophysiological evidence of corticospinal tract abnormality in patients with Parkin mutations. J Neurol. 2006;253:275–9. [PubMed: 16502212]
  • Fahn S, Elton RL. UPDRS program members: Unified Parkinsons Disease Rating Scale. In: Fahn S, Marsden CD, Goldstein M, Calne DB, eds. Recent Developments in Parkinson’s Disease. Vol 2. Florham Park, NJ: Macmillan Healthcare Information; 1987:153-63.
  • Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S, Zhang H, Estes A, Brune CW, Bradfield JP, Imielinski M, Frackelton EC, Reichert J, Crawford EL, Munson J, Sleiman PM, Chiavacci R, Annaiah K, Thomas K, Hou C, Glaberson W, Flory J, Otieno F, Garris M, Soorya L, Klei L, Piven J, Meyer KJ, Anagnostou E, Sakurai T, Game RM, Rudd DS, Zurawiecki D, McDougle CJ, Davis LK, Miller J, Posey DJ, Michaels S, Kolevzon A, Silverman JM, Bernier R, Levy SE, Schultz RT, Dawson G, Owley T, McMahon WM, Wassink TH, Sweeney JA, Nurnberger JI, Coon H, Sutcliffe JS, Minshew NJ, Grant SF, Bucan M, Cook EH, Buxbaum JD, Devlin B, Schellenberg GD, Hakonarson H. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature. 2009;459:569–73. [PMC free article: PMC2925224] [PubMed: 19404257]
  • Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, Poewe W, Sampaio C, Stern MB, Dodel R, Dubois B, Holloway R, Jankovic J, Kulisevsky J, Lang AE, Lees A, Leurgans S, LeWitt PA, Nyenhuis D, Olanow CW, Rascol O, Schrag A, Teresi JA, van Hilten JJ, LaPelle N., Movement Disorder Society UPDRS Revision Task Force. Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord. 2008;23:2129–70. [PubMed: 19025984]
  • Grünewald A, Kasten M, Ziegler A, Klein C. Next generation phenotyping using the Parkin example: Time to catch up with genetics. JAMA Neurol. 2013;70:1186–91. [PubMed: 23835509]
  • Grünewald A, Klein C. Parkin-associated Parkinson’s disease. In: Pfeiffer RF, Wszolek ZK, Ebadi M, eds: Parkinson’s Disease. 2 ed. Chap 14. Boca Raton, FL: CRC Press; 2012.
  • Guerrero Camacho JL, Monroy Jaramillo N, Yescas Gómez P, Rodríguez Violante M, Boll Woehrlen C, Alonso Vilatela ME, López López M. High frequency of Parkin exon rearrangements in Mexican-mestizo patients with early-onset Parkinson's disease. Mov Disord. 2012;27:1047–51. [PubMed: 22777964]
  • Harbo HF, Finsterer J, Baets J, Van Broeckhoven C, Di Donato S, Fontaine B, De Jonghe P, Lossos A, Lynch T, Mariotti C, Schöls L, Spinazzola A, Szolnoki Z, Tabrizi SJ, Tallaksen C, Zeviani M, Burgunder JM, Gasser T. EFNS. EFNS guidelines on the molecular diagnosis of neurogenetic disorders: general issues, Huntington's disease, Parkinson's disease and dystonias. Eur J Neurol. 2009;16:777–85. [PubMed: 19469830]
  • Hattori N, Kitada T, Matsumine H, Asakawa S, Yamamura Y, Yoshino H, Kobayashi T, Yokochi M, Wang M, Yoritaka A, Kondo T, Kuzuhara S, Nakamura S, Shimizu N, Mizuno Y. Molecular genetic analysis of a novel Parkin gene in Japanese families with autosomal recessive juvenile parkinsonism: evidence for variable homozygous deletions in the Parkin gene in affected individuals. Ann Neurol. 1998a;44:935–41. [PubMed: 9851438]
  • Hattori N, Matsumine H, Asakawa S, Kitada T, Yoshino H, Elibol B, Brookes AJ, Yamamura Y, Kobayashi T, Wang M, Yoritaka A, Minoshima S, Shimizu N, Mizuno Y. Point mutations (Thr240Arg and Gln311Stop) [correction of Thr240Arg and Ala311Stop] in the Parkin gene. Biochem Biophys Res Commun. 1998b;249:754–8. [PubMed: 9731209]
  • Hedrich K, Eskelson C, Wilmot B, Marder K, Harris J, Garrels J, Meija-Santana H, Vieregge P, Jacobs H, Bressman SB, Lang AE, Kann M, Abbruzzese G, Martinelli P, Schwinger E, Ozelius LJ, Pramstaller PP, Klein C, Kramer P. Distribution, type, and origin of Parkin mutations: review and case studies. Mov Disord. 2004;19:1146–57. [PubMed: 15390068]
  • Hedrich K, Marder K, Harris J, Kann M, Lynch T, Meija-Santana H, Pramstaller PP, Schwinger E, Bressman SB, Fahn S, Klein C. Evaluation of 50 probands with early-onset Parkinson's disease for Parkin mutations. Neurology. 2002;58:1239–46. [PubMed: 11971093]
  • Ibáñez P, Lesage S, Lohmann E, Thobois S, De Michele G, Borg M, Agid Y, Durr A, Brice A. Mutational analysis of the PINK1 gene in early-onset parkinsonism in Europe and North Africa. Brain. 2006;129:686–94. [PubMed: 16401616]
  • Imai Y, Soda M, Takahashi R. Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. J Biol Chem. 2000;275:35661–4. [PubMed: 10973942]
  • Kasten M, Kertelge L, Bruggemann N, van der Vegt J, Schmidt A, Tadic V, Buhmann C, Steinlechner S, Behrens MI, Ramirez A, Binkofski F, Siebner H, Raspe H, Hagenah J, Lencer R, Klein C. Nonmotor symptoms in genetic Parkinson disease. Arch Neurol. 2010;67:670–676. [PubMed: 20558386]
  • Kay DM, Stevens CF, Hamza TH, Montimurro JS, Zabetian CP, Factor SA, Samii A, Griffith A, Roberts JW, Molho ES, Higgins DS, Gancher S, Moses L, Zareparsi S, Poorkaj P, Bird T, Nutt J, Schellenberg GD, Payami H. A comprehensive analysis of deletions, multiplications, and copy number variations in PARK2. Neurology. 2010;75:1189–94. [PMC free article: PMC3013490] [PubMed: 20876472]
  • Kilarski LL, Pearson JP, Newsway V, Majounie E, Knipe MD, Misbahuddin A, Chinnery PF, Burn DJ, Clarke CE, Marion MH, Lewthwaite AJ, Nicholl DJ, Wood NW, Morrison KE, Williams-Gray CH, Evans JR, Sawcer SJ, Barker RA, Wickremaratchi MM, Ben-Shlomo Y, Williams NM, Morris HR. Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ-1) and LRRK2 in early-onset Parkinson's disease. Mov Disord. 2012;27:1522–9. [PubMed: 22956510]
  • Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998;392:605–8. [PubMed: 9560156]
  • Klein C, Lohmann-Hedrich K, Rogaeva E, Schlossmacher MG, Lang AE. Deciphering the role of heterozygous mutations in genes associated with parkinsonism. Lancet Neurol. 2007;6:652–62. [PubMed: 17582365]
  • Klein C, Pramstaller PP, Kis B, Page CC, Kann M, Leung J, Woodward H, Castellan CC, Scherer M, Vieregge P, Breakefield XO, Kramer PL, Ozelius LJ. Parkin deletions in a family with adult-onset, tremor-dominant parkinsonism: expanding the phenotype. Ann Neurol. 2000;48:65–71. [PubMed: 10894217]
  • Klein C, Schlossmacher MG. The genetics of Parkinson disease: Implications for neurological care. Nat Clin Pract Neurol. 2006;2:136–46. [PubMed: 16932540]
  • Kobayashi T, Matsumine H, Zhang J, Imamichi Y, Mizuno Y, Hattori N. Pseudo-autosomal dominant inheritance of PARK2: two families with parkin gene mutations. J Neurol Sci. 2003;207:11–7. [PubMed: 12614925]
  • Leroy E, Anastasopoulos D, Konitsiotis S, Lavedan C, Polymeropoulos MH. Deletions in the Parkin gene and genetic heterogeneity in a Greek family with early onset Parkinson's disease. Hum Genet. 1998;103:424–7. [PubMed: 9856485]
  • Lincoln SJ, Maraganore DM, Lesnick TG, Bounds R, de Andrade M, Bower JH, Hardy JA, Farrer MJ. Parkin variants in North American Parkinson's disease: cases and controls. Mov Disord. 2003;18:1306–11. [PubMed: 14639672]
  • Lohmann E, Periquet M, Bonifati V, Wood NW, De Michele G, Bonnet AM, Fraix V, Broussolle E, Horstink MW, Vidailhet M, Verpillat P, Gasser T, Nicholl D, Teive H, Raskin S, Rascol O, Destee A, Ruberg M, Gasparini F, Meco G, Agid Y, Durr A, Brice A. How much phenotypic variation can be attributed to parkin genotype? Ann Neurol. 2003;54:176–85. [PubMed: 12891670]
  • Lücking CB, Abbas N, Durr A, Bonifati V, Bonnet AM, de Broucker T, De Michele G, Wood NW, Agid Y, Brice A. Homozygous deletions in parkin gene in European and North African families with autosomal recessive juvenile parkinsonism. The European Consortium on Genetic Susceptibility in Parkinson's Disease and the French Parkinson's Disease Genetics Study Group. Lancet. 1998;352:1355–6. [letter] [PubMed: 9802278]
  • Lücking CB, Bonifati V, Periquet M, Vanacore N, Brice A, Meco G. Pseudo-dominant inheritance and exon 2 triplication in a family with parkin gene mutations. Neurology. 2001;57:924–7. [PubMed: 11552035]
  • Lücking CB, Chesneau V, Lohmann E, Verpillat P, Dulac C, Bonnet AM, Gasparini F, Agid Y, Durr A, Brice A. Coding polymorphisms in the parkin gene and susceptibility to Parkinson disease. Arch Neurol. 2003;60:1253–6. [PubMed: 12975291]
  • Lücking CB, Durr A, Bonifati V, Vaughan J, De Michele G, Gasser T, Harhangi BS, Meco G, Denefle P, Wood NW, Agid Y, Brice A. Association between early-onset Parkinson's disease and mutations in the parkin gene. French Parkinson's Disease Genetics Study Group. N Engl J Med. 2000;342:1560–7. [PubMed: 10824074]
  • Marder KS, Tang MX, Mejia-Santana H, Rosado L, Louis ED, Comella CL, Colcher A, Siderowf AD, Jennings D, Nance MA, Bressman S, Scott WK, Tanner CM, Mickel SF, Andrews HF, Waters C, Fahn S, Ross BM, Cote LJ, Frucht S, Ford B, Alcalay RN, Rezak M, Novak K, Friedman JH, Pfeiffer RF, Marsh L, Hiner B, Neils GD, Verbitsky M, Kisselev S, Caccappolo E, Ottman R, Clark LN. Predictors of parkin mutations in early-onset Parkinson disease: the consortium on risk for early-onset Parkinson disease study. Arch Neurol. 2010;67:731–8. [PMC free article: PMC3329757] [PubMed: 20558392]
  • Maruyama M, Ikeuchi T, Saito M, Ishikawa A, Yuasa T, Tanaka H, Hayashi S, Wakabayashi K, Takahashi H, Tsuji S. Novel mutations, pseudo-dominant inheritance, and possible familial affects in patients with autosomal recessive juvenile parkinsonism. Ann Neurol. 2000;48:245–50. [PubMed: 10939576]
  • Mira MT, Alcais A, Nguyen VT, Moraes MO, Di Flumeri C, Vu HT, Mai CP, Nguyen TH, Nguyen NB, Pham XK, Sarno EN, Alter A, Montpetit A, Moraes ME, Moraes JR, Dore C, Gallant CJ, Lepage P, Verner A, Van De Vosse E, Hudson TJ, Abel L, Schurr E. Susceptibility to leprosy is associated with PARK2 and PACRG. Nature. 2004;427:636–40. [PubMed: 14737177]
  • Moore DJ. Parkin: a multifaceted ubiquitin ligase. Biochem Soc Trans. 2006;34:749–753. [PubMed: 17052189]
  • Moro E, Volkmann J, Konig IR, Winkler S, Hiller A, Hassin-Baer S, Herzog J, Schnitzler A, Lohmann K, Pinsker MO, Voges J, Djarmatic A, Seibler P, Lozano AM, Rogaeva E, Lang AE, Deuschl G, Klein C. Bilateral subthalamic stimulation in Parkin and PINK1 parkinsonism. Neurology. 2008;70:1186–91. [PubMed: 18378882]
  • Muñoz E, Pastor P, Marti MJ, Oliva R, Tolosa E. A new mutation in the parkin gene in a patient with atypical autosomal recessive juvenile parkinsonism. Neurosci Lett. 2000;289:66–8. [PubMed: 10899410]
  • Narendra D, Walker JE, Youle R. Mitochondrial quality control mediated by PINK1 and Parkin: links to parkinsonism. Cold Spring Harb Perspect Biol. 2012;4(11) [PMC free article: PMC3536340] [PubMed: 23125018]
  • Nisipeanu P, Inzelberg R, Blumen SC, Carasso RL, Hattori N, Matsumine H, Mizuno Y. Autosomal-recessive juvenile parkinsonism in a Jewish Yemenite kindred: mutation of Parkin gene. Neurology. 1999;53:1602–4. [PubMed: 10534280]
  • Oliveira SA, Scott WK, Martin ER, Nance MA, Watts RL, Hubble JP, Koller WC, Pahwa R, Stern MB, Hiner BC, Ondo WG, Allen FH Jr, Scott BL, Goetz CG, Small GW, Mastaglia F, Stajich JM, Zhang F, Booze MW, Winn MP, Middleton LT, Haines JL, Pericak-Vance MA, Vance JM. Parkin mutations and susceptibility alleles in late-onset Parkinson's disease. Ann Neurol. 2003;53:624–9. [PubMed: 12730996]
  • Pankratz N, Kissell DK, Pauciulo MW, Halter CA, Rudolph A, Pfeiffer RF, Marder KS, Foroud T, Nichols WC. Parkin dosage mutations have greater pathogenicity in familial PD than simple sequence mutations. Neurology. 2009;73:279–86. [PMC free article: PMC2715211] [PubMed: 19636047]
  • Pavese N, Khan NL, Scherfler C, Cohen L, Brooks DJ, Wood NW, Bhatia KP, Quinn NP, Lees AJ, Piccini P. Nigrostriatal dysfunction in homozygous and heterozygous parkin gene carriers: an 18F-dopa PET progression study. Mov Disord. 2009;24:2260–6. [PubMed: 19845000]
  • Pellecchia MT, Varrone A, Annesi G, Amboni M, Cicarelli G, Sansone V, Annesi F, Rocca FE, Vitale C, Pappatà S, Quattrone A, Barone P. Parkinsonism and essential tremor in a family with pseudo-dominant inheritance of PARK2: an FP-CIT SPECT study. Mov Disord. 2007;22:559–63. [PubMed: 17149727]
  • Periquet M, Latouche M, Lohmann E, Rawal N, De Michele G, Ricard S, Teive H, Fraix V, Vidailhet M, Nicholl D, Barone P, Wood NW, Raskin S, Deleuze JF, Agid Y, Durr A, Brice A. Parkin mutations are frequent in patients with isolated early-onset parkinsonism. Brain. 2003;126:1271–8. [PubMed: 12764050]
  • Periquet M, Lücking C, Vaughan J, Bonifati V, Dürr A, De Michele G, Horstink M, Farrer M, Illarioshkin SN, Pollak P, Borg M, Brefel-Courbon C, Denefle P, Meco G, Gasser T, Breteler MM, Wood N, Agid Y, Brice A, et al. The European Consortium on Genetic Susceptibility in Parkinson's Disease. Origin of the mutations in the parkin gene in Europe: exon rearrangements are independent recurrent events, whereas point mutations may result from Founder effects. Am J Hum Genet. 2001;68:617–26. [PMC free article: PMC1274475] [PubMed: 11179010]
  • Perretti A, De Rosa A, Marcantonio L, Iodice V, Estraneo A, Manganelli F, Garavaglia B, Filla A, Santoro L, De Michele G. Neurophysiological evaluation of motor corticospinal pathways by TMS in idiopathic early-onset Parkinson's disease. Clin Neurophysiol. 2011;122:546–9. [PubMed: 20797900]
  • Poorkaj P, Nutt JG, James D, Gancher S, Bird TD, Steinbart E, Schellenberg GD, Payami H. parkin mutation analysis in clinic patients with early-onset Parkinson [corrected] disease. Am J Med Genet A. 2004;129A:44–50. [PubMed: 15266615]
  • Poulopoulos M, Levy OA, Alcalay RN. The neuropathology of genetic Parkinson's disease. Mov Disord. 2012;27:831–42. [PMC free article: PMC3383342] [PubMed: 22451330]
  • Rakovic A, Grunewald A, Kottwitz J, Bruggemann N, Pramstaller PP, Lohmann K, Klein C. Mutations in PINK1 and Parkin impair ubiquitination of Mitofusins in human fibroblasts. PLoS One. 2011;6:e16746. [PMC free article: PMC3050809] [PubMed: 21408142]
  • Rakovic A, Shurkewitsch K, Seibler P, Grünewald A, Zanon A, Hagenah J, Krainc D, Klein C. Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1)-dependent ubiquitination of endogenous Parkin attenuates mitophagy: study in human primary fibroblasts and induced pluripotent stem cell-derived neurons. J Biol Chem. 2013;288:2223–37. [PMC free article: PMC3554895] [PubMed: 23212910]
  • Rawal N, Periquet M, Lohmann E, Lücking CB, Teive HA, Ambrosio G, Raskin S, Lincoln S, Hattori N, Guimaraes J, Horstink MW, Dos Santos Bele W, Brousolle E, Destee A, Mizuno Y, Farrer M, Deleuze JF, De Michele G, Agid Y, Durr A, Brice A. New parkin mutations and atypical phenotypes in families with autosomal recessive parkinsonism. Neurology. 2003;60:1378–81. [PubMed: 12707451]
  • Schneider SA, Talelli P, Cheeran BJ, Khan NL, Wood NW, Rothwell JC, Bhatia KP. Motor cortical physiology in patients and asymptomatic carriers of parkin gene mutations. Mov Disord. 2008;23:1812–9. [PubMed: 18759365]
  • Semenova EV, Shadrina MI, Slominsky PA, Ivanova-Smolenskaya IA, Bagyeva G, Illarioshkin SN, Limborska SA. Analysis of PARK2 gene exon rearrangements in Russian patients with sporadic Parkinson's disease. Mov Disord. 2012;27:139–42. [PubMed: 21915905]
  • Serikawa T, Shimohata T, Akashi M, Yokoseki A, Tsuchiya M, Hasegawa A, Haino K, Koike R, Takakuwa K, Tanaka K, Nishizawa M. Successful twin pregnancy in a patient with parkin-associated autosomal recessive juvenile parkinsonism. BMC neurology. 2011;11:72. [PMC free article: PMC3135525] [PubMed: 21682904]
  • Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K, Suzuki T. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet. 2000;25:302–5. [PubMed: 10888878]
  • Srivastava A, Tang MX, Mejia-Santana H, Rosado L, Louis ED, Caccappolo E, Comella C, Colcher A, Siderowf A, Jennings D, Nance M, Bressman S, Scott WK, Tanner C, Mickel S, Andrews H, Waters C, Fahn S, Cote L, Frucht S, Ford B, Alcalay RN, Ross B, Orbe Reilly M, Rezak M, Novak K, Friedman JH, Pfeiffer RD, Marsh L, Hiner B, Merle D, Ottman R, Clark LN, Marder K. The relation between depression and parkin genotype: the CORE-PD study. Parkinsonism Relat Disord. 2011;17:740–4. [PMC free article: PMC3221786] [PubMed: 21856206]
  • Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, Gonzalez-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science. 2004;304:1158–60. [PubMed: 15087508]
  • van der Vegt JP, van Nuenen BF, Bloem BR, Klein C, Siebner HR. Imaging the impact of genes on Parkinson's disease. Neuroscience. 2009;164:191–204. [PubMed: 19409223]
  • van Nuenen BF, van Eimeren T, van der Vegt JP, Buhmann C, Klein C, Bloem BR, Siebner HR. Mapping preclinical compensation in Parkinson's disease: an imaging genomics approach. Mov Disord. 2009;24 Suppl 2:S703–10. [PubMed: 19877238]
  • Veeriah S, Taylor BS, Meng S, Fang F, Yilmaz E, Vivanco I, Janakiraman M, Schultz N, Hanrahan AJ, Pao W, Ladanyi M, Sander C, Heguy A, Holland EC, Paty PB, Mischel PS, Liau L, Cloughesy TF, Mellinghoff IK, Solit DB, Chan TA. Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies. Nature genetics. 2010;42:77–82. [PMC free article: PMC4002225] [PubMed: 19946270]
  • Vinish M, Prabhakar S, Khullar M, Verma I, Anand A. Genetic screening reveals high frequency of PARK2 mutations and reduced Parkin expression conferring risk for Parkinsonism in North West India. Journal of neurology, neurosurgery, and psychiatry. 2010;81:166–70. [PubMed: 19734163]
  • Wang M, Hattori N, Matsumine H, Kobayashi T, Yoshino H, Morioka A, Kitada T, Asakawa S, Minoshima S, Shimizu N, Mizuno Y. Polymorphism in the parkin gene in sporadic Parkinson's disease. Ann Neurol. 1999;45:655–8. [see comments] [PubMed: 10319889]
  • West A, Periquet M, Lincoln S, Lücking CB, Nicholl D, Bonifati V, Rawal N, Gasser T, Lohmann E, Deleuze JF, Maraganore D, Levey A, Wood N, Durr A, Hardy J, Brice A, Farrer M. Complex relationship between Parkin mutations and Parkinson disease. Am J Med Genet. 2002;114:584–91. [PubMed: 12116199]
  • Wiley J, Lynch T, Lincoln S, Skipper L, Hulihan M, Gosal D, Bisceglio G, Kachergus J, Hardy J, Farrer MJ. Parkinson's disease in Ireland: clinical presentation and genetic heterogeneity in patients with parkin mutations. Mov Disord. 2004;19:677–81. [PubMed: 15197707]
  • Wu RM, Bounds R, Lincoln S, Hulihan M, Lin CH, Hwu WL, Chen J, Gwinn-Hardy K, Farrer M. Parkin mutations and early-onset parkinsonism in a Taiwanese cohort. Arch Neurol. 2005;62:82–7. [PubMed: 15642853]
  • Zhang Y, Gao J, Chung KK, Huang H, Dawson VL, Dawson TM. Parkin functions as an E2-dependent ubiquitin-protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc Natl Acad Sci U S A. 2000;97:13354–9. [PMC free article: PMC27228] [PubMed: 11078524]

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 live
  • 6 November 2006 (cd) Revision: prenatal diagnosis available
  • 8 July 2005 (me) Comprehensive update posted live
  • 14 November 2003 (ab) Revisions
  • 3 October 2003 (cd) Revision: change in test availability
  • 6 June 2003 (ca) Comprehensive update posted live
  • 17 April 2001 (me) Review posted live
  • November 2000 (ab) Original submission
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