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PINK1 Type of Young-Onset Parkinson Disease

Synonym: PINK1-Related Parkinson Disease

, MD, PhD and , MD.

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

Initial Posting: ; Last Update: September 18, 2014.

Summary

Clinical characteristics.

The PINK1 type of young-onset Parkinson disease is characterized by variable combinations of rigidity, bradykinesia, and rest tremor, often making it clinically indistinguishable from idiopathic Parkinson disease.

Lower-limb dystonia may be a presenting sign. Onset usually occurs in the third or fourth decade. The disease is slowly progressive. Clinical signs vary; hyperreflexia may be present and abnormal behavior and/or psychiatric manifestations have been described. Dyskinesias as a result of treatment with levodopa frequently occur, as with all individuals with young-onset disease, regardless of the underlying genetic cause.

Diagnosis/testing.

The diagnosis of the PINK1 type of young-onset Parkinson disease is considered primarily in individuals with early-onset parkinsonism (age <40 years), particularly if autosomal recessive inheritance is suspected. PINK1, the gene encoding the protein PINK1, is the only gene in which pathogenic variants are known to cause PINK1 type of young-onset Parkinson disease. Mutation detection frequency varies by family history and age of onset.

The diagnosis of the PINK1 type of young-onset Parkinson disease can be confirmed only when pathogenic variants are identified on both alleles of PINK1 (i.e., the individual is homozygous for the same disease-causing allele or compound heterozygous for two different disease-causing alleles).

Management.

Treatment of manifestations: This disorder usually responds well to levodopa and other dopaminergic therapies. Deep brain stimulation (DBS) has been used for those experiencing difficulty with levodopa therapy. Levodopa-induced dyskinesias and fluctuations can be reduced by administering dopamine therapies and lowering the dose of levodopa.

Prevention of secondary complications: Levodopa dosage should not exceed the level required for satisfactory clinical response. Dopamine agonists should be employed if not contraindicated to possibly delay the onset of motor fluctuations, as affected individuals often require several decades of treatment.

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

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

Genetic counseling.

The PINK1 type of young-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 for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if both disease-causing alleles have been identified in an affected family member.

Diagnosis

In 2009 the European Federation of Neurological Societies published guidelines on the molecular diagnosis of Parkinson disease [Harbo et al 2009]; see Testing Strategy.

Clinical Diagnosis

The PINK1 type of young-onset Parkinson disease is often clinically indistinguishable from idiopathic Parkinson disease. Rigidity, bradykinesia, and rest tremor are variably combined in both disorders.

The following findings suggest PINK1 type of young-onset Parkinson disease (based on a systematic review of 81 individuals who have biallelic pathogenic variants):

  • Early onset (age <40 years) or juvenile onset (age <20 years), with mean age of onset 32.6±12.1 years [Kasten et al 2010a]
  • Tremor (49%), which is the most common initial sign [Kasten et al 2010a]; dystonia (often of the lower limbs), either as a presenting sign or occurring during disease progression (38%); hyperreflexia (42%)
  • Rigidity (93%), bradykinesia (91%), tremor (85%), and postural instability (65%). Signs are asymmetric in 79% [Kasten et al 2010a].
  • Marked and sustained response to oral administration of levodopa, frequently associated with levodopa-induced fluctuations and dyskinesias (abnormal involuntary movements) [Nishioka et al 2009]. Sleep benefit is observed in many (53%) [Li et al 2005, Kasten et al 2010a].
  • Slow disease progression
  • A family history consistent with autosomal recessive inheritance

Testing

No clinical investigations unambiguously distinguish individuals with the PINK1 type of young-onset Parkinson disease from those with pathogenic variants in PARK2 or DJ-1 or those with idiopathic Parkinson disease.

Molecular Genetic Testing

Gene. PINK1 is the only gene in which pathogenic variants are known to cause PINK1 type of young-onset Parkinson [Valente et al 2004b].

Clinical testing

Table 1.

Summary of Molecular Genetic Testing Used in PINK1 Type of Young-Onset Parkinson Disease

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
PINK1Sequence analysis 2>90%
Deletion/duplication analysis 3<10%
Targeted mutation analysis 4Unknown
1.

See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2.

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

3.

Testing that identifies exonic or whole-gene deletions/duplications not 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.

4.

Detecting the p.Gly309Asp pathogenic variant. Note: Pathogenic variants included in a panel may vary by laboratory.

Interpretation of test results

  • The diagnosis of the PINK1 type of young-onset Parkinson disease can be confirmed only when pathogenic variants are identified on both PINK1 alleles (i.e., the individual is homozygous for the same disease-causing allele or compound heterozygous for two different disease-causing alleles).
  • The finding of a single pathogenic variant is only suggestive (i.e., not diagnostic) of the PINK1 type of young-onset Parkinson disease. While the affected individual may be a heterozygote, the cause of parkinsonism may be unrelated to the genetic change and it is not yet clear to what degree individuals with a single (heterozygous) pathogenic variant are predisposed to developing parkinsonian features. A better understanding of the mode of inheritance, penetrance, and carrier frequency is needed to interpret the significance of single (heterozygous) pathogenic variants.
  • Apparently autosomal dominant forms of inheritance have also been noted [Criscuolo et al 2006].
  • Absence of a PINK1 pathogenic variant on one or both alleles cannot completely exclude the diagnosis of the PINK1 type of young-onset Parkinson disease.

Testing Strategy

Testing for mutations in PINK1 and other genes in which pathogenic variants cause autosomal recessive PD (PARK2, DJ-1) is recommended in families in which autosomal recessive inheritance is suspected (affected sib pairs) or in simplex cases with very early onset (<35 years) [Harbo et al 2009].

To confirm/establish the diagnosis in a proband. Identification of pathogenic variants on both PINK1 alleles (i.e., the individual is homozygous for the same disease-causing allele or compound heterozygous for two different disease-causing alleles) is required (see Molecular Genetic Testing, Interpretation of test results).

One genetic testing strategy is molecular genetic testing of PINK1, the only gene in which pathogenic variants are known to cause PINK1 type of young-onset Parkinson disease.

An alternative genetic testing strategy is use of a multi-gene panel that includes PINK1 and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

Genomic testing. If single gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an individual with features of Parkinson disease, genomic testing may be considered. Such testing may include whole-exome sequencing (WES), whole-genome sequencing (WGS), and whole-mitochondrial sequencing (WMitoSeq).

Notes regarding WES and WGS: (1) False negative rates vary by genomic region; therefore, genomic testing may not be as accurate as targeted single gene testing or multi-gene molecular genetic testing panels; (2) most laboratories confirm positive results using a second, well-established method; (3) nucleotide repeat expansions and epigenetic alterations cannot be detected; (4) deletions/duplications larger than 8-10 nucleotides are not reliably detected [Biesecker & Green 2014].

Clinical Characteristics

Clinical Description

Women and men are affected equally. Age at onset is highly variable, even in individuals with the same pathogenic variant [Hedrich et al 2006]; onset is usually in the third or fourth decade [Bonifati et al 2005, Ishihara-Paul et al 2008, Marongiu et al 2008, Valente & Ferraris 2010]. In the study by Marongiu et al [2008] the average age at onset in those with two PINK1 pathogenic variants was 41 years.

Bradykinesia and tremor are the most common presenting signs. In some individuals the symptoms at onset are symmetric. Dystonia and hyperreflexia may also be present [Bonifati et al 2005].

In addition to parkinsonism, individuals with the PINK1 type of young-onset Parkinson disease may be prone to psychiatric involvement. Abnormal behavior and/or psychiatric manifestations (in particular depression and anxiety) occur in about 30% and 15% of affected individuals, respectively. Other features include hallucinations and dementia [Kasten et al 2010a, Ricciardi et al 2014]. Nonmotor symptoms are also frequent [Ricciardi et al 2014].

Overall, the clinical signs at examination are also variable.

On average, the response to levodopa is better than in other forms of Parkinson disease [Valente & Ferraris 2010]; however, the incidence of levodopa-induced dyskinesias may be greater in individuals with PINK1-associated young-onset Parkinson disease than in those with parkinsonism of different etiologies [Nishioka et al 2009].

The disease is slowly progressive.

Neuroimaging. CT and MRI neuroimaging are usually normal.

MR spectroscopy (MRS) demonstrated raised myoinositol levels in the basal ganglia of the two individuals who were imaged, reflecting possible astroglial proliferation [Prestel et al 2008].

For asymptomatic heterozygotes with a single mutant PINK1 allele, voxel-based morphometry revealed an increase of putaminal and pallidal gray matter volume –findings generally similar to those in the Parkin type of young-onset Parkinson disease [Binkofski et al 2007, Reetz et al 2010].

Reduced presynaptic striatal uptake was seen on 18F-dopa-PET studies in four homozygous individuals and three asymptomatic heterozygous relatives: 85% reduction and 20%-30% reduction in uptake, respectively [Khan et al 2002]. In another study PET imaging with a dopamine D2 receptor ligand 11C-raclopride in one affected case with a homozygous missense mutation revealed that postsynaptic 11C-raclopride uptake was normal in the bilateral putamen [Yamashita et al 2008].

Neuropathology. Neuropathologic data in individuals who carry a PINK1 pathogenic variant are limited [Poulopoulos et al 2012]. Brain autopsy data are available only for one individual who was a compound heterozygote (deletion and a splicing mutation in exon 7) with onset of disease at age 31 [Samaranch et al 2010, Poulopoulos et al 2012]. Pathology study revealed significant presence of Lewy bodies and neuronal loss in the substantia nigra pars compacta with sparing of the locus coeruleus, which would be atypical for idiopathic Parkinson disease (PD). The brain stem reticular formation and the nucleus basalis of Meynert were also affected. There were no tau- or TDP43-positive inclusions. In a PD brain bank study Gandhi et al [2006] identified four individuals with PD and heterozygous PINK1 mutations who showed pathologic findings consistent with classical PD with Lewy bodies distributed in the brain stem and cortical areas, and neuronal loss affecting the substantia nigra pars compacta and neurofibrillary tangles stage I to V.

Genotype-Phenotype Correlations

No correlation between the type of mutation and age at onset, clinical presentation, or disease progression has yet been observed.

Individuals with both PINK1 and mitochondrial DNA (mtDNA) mutations who have very early onset of symptoms have been reported [Piccoli et al 2008]. It is possible that the combination of mutations in both genes may have accelerated the disease onset.

Penetrance

Penetrance is age dependent but appears to be complete in individuals who have two PINK1 pathogenic variants.

Prevalence

The prevalence is not known. However, in Europe and Africa, PINK1-associated Parkinson disease is rare.

Overall, PINK1 represents a rare cause of early-onset parkinsonism [Marongiu et al 2008].

To date, PINK1 homozygotes and compound heterozygotes (i.e., affected individuals) and PINK1 heterozygotes who appear to be healthy carriers have been reported from many different regions [Healy et al 2004, Valente et al 2004a, Bonifati et al 2005, Li et al 2005, Chishti et al 2006, Fung et al 2006, Hiller et al 2007, Guo et al 2008, Ishihara-Paul et al 2008, Piccoli et al 2008, Camargos et al 2009, Biswas et al 2010, Keyser et al 2010, Zhang et al 2011].

Differential Diagnosis

Clinically, the PINK1 type of young-onset Parkinson disease and idiopathic Parkinson disease are difficult to differentiate (see Parkinson Disease Overview). More than 80% of individuals with Parkinson disease have no family history of the disorder. Several monogenic forms account for some of the cases with a positive family history.

PARK2-related juvenile parkinsonism is more common than PINK1 type of young-onset Parkinson disease [Marongiu et al 2008, Grünewald et al 2013]. The clinical findings in individuals with pathogenic variants in PARK2 and PINK1 are indistinguishable.

Another disorder in the differential diagnosis is the DJ1 (PARK7)-type of young-onset Parkinson disease (OMIM 606324), which also presents as early-onset disorder with a phenotype overall similar to that of the PINK1 type of young-onset Parkinson disease [Bonifati et al 2003, Li et al 2005].

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 the GTP cyclohydrolase I gene (GCH1).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with the PINK1 type of young-onset Parkinson disease, the following evaluations are recommended:

  • Assessment for presence/severity of atypical signs using the Unified Parkinson’s Disease Rating Scale (UPDRS) rating scale [Goetz et al 2008]
  • Evaluation of the degree of response to treatment and its potential complications
  • Assessment for cognitive or behavioral problems
  • Medical genetics consultation

Treatment of Manifestations

To date, the treatment of PINK1 type of young-onset Parkinson disease is not different from that of idiopathic Parkinson disease and no specific guidelines or recommendations have been developed.

Individuals with PINK1 type of young-onset Parkinson disease have a mild form of Parkinson disease that responds well to levodopa and to other dopaminergic agonists.

  • Response is usually significant and is sustained for low doses of levodopa even after long disease duration. The response may be even better in PINK1 type of young-onset Parkinson disease than in idiopathic Parkinson disease [Valente & Ferraris 2010].
  • The major problem is the early occurrence of severe levodopa-induced dyskinesias (abnormal involuntary movements) and fluctuations. Fluctuations can be reduced by the combination of dopamine therapies with low doses of levodopa.
  • The use of deep brain stimulation (DBS) in PINK1 type Parkinson disease has been described [Moro et al 2008, Johansen et al 2011].

Prevention of Primary Manifestations

No measures that eliminate disease manifestations in a symptomatic person or prevent them from appearing in an asymptomatic person have been identified.

Prevention of Secondary Complications

To reduce or delay side effects, levodopa dosage should not exceed the level required for satisfactory clinical response. Dopamine agonists should be employed if not contraindicated to possibly delay the onset of motor fluctuations, as affected individuals often require several decades of treatment.

Surveillance

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

Agents/Circumstances to Avoid

Neuroleptic treatment may exacerbate parkinsonism.

Evaluation of Relatives at Risk

Owing to the absence of preventive treatment or measures, presymptomatic genetic diagnosis is not medically justified.

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

Pregnancy Management

There are no reports specifically addressing pregnancy management in women with PINK1 type Parkinson disease. However, in general, pregnancy may either exacerbate or improve symptoms of Parkinson disease [Shulman et al 2000, Scott & Chowdhury 2005]. L-dopa crosses the placenta and (theoretically) may have an adverse effect on fetal development, as some animal models have shown that high doses of L-dopa administered during pregnancy may induce stillbirth and birth defects including skeletal malformations [Scott & Chowdhury 2005]. However, based on more than 30 cases recorded in the literature levodopa treatment during human pregnancy has not resulted in adverse fetal outcome [Scott & Chowdhury 2005].

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

The PINK1 type of young-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 the PINK1 type of young-onset Parkinson disease are obligate heterozygotes (carriers) for a pathogenic variant in PINK1.
  • The risk to offspring of being affected depends on the frequency of heterozygotes in the general population, which is unknown; however, based on current knowledge, the proportion of heterozygotes is probably less than 1%, generating a risk of less than 0.25% to offspring of being affected. As with 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 of a PINK1 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the PINK1 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

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

If the PINK1 pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Requests for prenatal testing for conditions which (like PINK1 type of young-onset Parkinson disease) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variants have been identified.

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
  • Michael J. Fox Foundation for Parkinson's Research
    Church Street Station
    PO Box 780
    New York NY 10008-0780
    Phone: 800-708-7644 (toll-free)
    Email: info@michaeljfox.org
  • National Library of Medicine Genetics Home Reference
  • National Parkinson Foundation
    1501 Northwest 9th Avenue
    Bob Hope Road
    Miami FL 33136-1494
    Phone: 800-327-4545 (toll-free); 305-243-6666
    Fax: 305-243-6073
    Email: contact@parkinson.org
  • 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.

PINK1 Type of Young-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 PINK1 Type of Young-Onset Parkinson Disease (View All in OMIM)

605909PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET; PARK6
608309PTEN-INDUCED PUTATIVE KINASE 1; PINK1

Gene structure. PINK1 contains eight exons (NM_032409.2) spanning about 18 kb. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Abnormal allelic variants. Changes have been identified in the homozygous, compound-heterozygous, and heterozygous state. Mutations include missense, nonsense, and splice site mutations and small insertions. Rarely, exonic, multiexonic [Li et al 2005, Cazeneuve et al 2009], and whole-gene deletions [Marongiu et al 2007] have been described.

Normal gene product. The gene encodes a 581-amino acid serine/threonine kinase, PTEN-induced putative kinase 1 (NP_115785.1). This kinase is located in the mitochondria spanning the outer mitochondrial membrane with the C-terminal kinase domain facing the cytoplasm and the N-terminal end inside the mitochondria. PINK1 presumably exerts its neuroprotective effect by phosphorylating specific mitochondrial proteins and, in turn, modulating their functions [Sim et al 2006]. PINK1 thereby promotes elimination of dysfunctional mitochondria by autophagy. Notably, PINK1 and parkin have been mapped to a shared pathway, with PINK1 acting upstream of parkin, where it can initiate the translocation of parkin to mitochondria [Hoepken et al 2007, Gandhi et al 2009, Narendra et al 2010, Vives-Bauza et al 2010, Rakovic et al 2013].

Abnormal gene product. Most of the known pathogenic variants are localized within the serine/threonine kinase domain of PINK1 as expected [Valente et al 2004a]. PINK1 pathogenic variants or PINK1 silencing result in reduced mtDNA levels, defective ATP production, impaired mitochondrial calcium handling, and increased free radical generation. This in turn results in a reduction in mitochondrial membrane potential and an increased susceptibility to apoptosis in neuronal cells, animal models, and patient-derived fibroblasts [Valente et al 2004a, Gegg et al 2009, Abramov et al 2011].

Overexpression of the parkin protein can rescue the effects of a PINK1 pathogenic variant in Drosophila and mammalian cells. Studies in fibroblasts from human Parkinson disease patients revealed impaired ubiquitination of mitofusins and confirmed the link between the PINK1 and parkin pathways [Rakovic et al 2010, Rakovic et al 2011, Seibler et al 2011, Rakovic et al 2013, Koyano et al 2014].

References

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Chapter Notes

Revision History

  • 18 September 2014 (me) Comprehensive update posted live
  • 6 September 2012 (me) Comprehensive update posted live
  • 16 March 2010 (me) Review posted live
  • 1 December 2009 (ck) Original submission
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