Clinical Diagnosis

The PINK1 type of juvenile 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:

• Early onset (age <40 years) or juvenile onset (age <20 years). Most affected individuals appear to have onset before age 40 years.

• Lower-limb dystonia can be a presenting sign or occurs during disease progression

• 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 some [Li et al 2005].

• Slow disease progression

• A family history consistent with autosomal recessive inheritance

• Neuropathologic details not known

Testing

No clinical investigations unambiguously distinguish individuals with the PINK1 type of young-onset Parkinson disease from those with idiopathic Parkinson disease.

Molecular Genetic Testing

Gene. The PINK1 type of young-onset Parkinson disease is caused by mutations in the PINK1 gene [Valente et al 2004b].

Clinical testing

• Sequence analysis. Sequencing of eight coding exons permit identification of various missense and nonsense mutations described so far [Bonifati et al 2005, Klein et al 2005, Hedrich et al 2006, Ibáñez et al 2006, Klein et al 2006].

• Deletion/duplication analysis. Various techniques can be used to detect heterozygous deletions. Exonic, multiexonic, [Li et al 2005], and whole-gene deletions [Marongiu et al 2007] are very rare but have also been reported for PINK1.

Table 1. Summary of Molecular Genetic Testing Used in PINK1 Type of Young-Onset Parkinson Disease

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
PINK1	Sequence analysis	Sequence variants	>90%	Clinical
	Deletion/duplication analysis 2	Exonic or whole-gene deletions	<10%

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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

2. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

Interpretation of test results

• For issues to consider in interpretation of sequence analysis results, click here.

• The diagnosis of the PINK1 type of young-onset Parkinson disease can only be confirmed when disease-causing mutations are identified on both PINK1 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 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 yet unclear to what degree individuals with a single (heterozygous) mutation 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) mutations.

• Apparently dominant forms of inheritance have also been noted [Criscuolo et al 2006].

• Absence of a PINK1 mutation on one or both alleles cannot completely exclude the diagnosis of the PINK1 type of young-onset Parkinson disease.

Testing Strategy

Confirmation of the diagnosis in a proband requires identification of disease-causing mutations on both PINK1 alleles (i.e., the individual is homozygous for the same disease-causing allele or a compound-heterozygote for two different disease-causing alleles).

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

Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutations in the family.

Genetically Related (Allelic) Disorders

A few reports suggest that PINK1 mutations could manifest in heterozygotes and could result in autosomal dominant Parkinson disease or constitute a risk factor for Parkinson disease [Criscuolo et al 2006]. In a Parkinson disease study by Marongiu et al [2008], the average age at onset in persons with a single PINK1 pathologic allelic variant (i.e., heterozygotes) was 52 years. However, whether and to what extent a single mutation may be pathogenic remains to be proven.

Natural History

Women and men are affected equally. Age at onset is highly variable, even in individuals with the same mutation [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 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, abnormal behavior and/or psychiatric manifestations are common, in particular depression and anxiety, which occur in about 30% and 15%, respectively. Other features include hallucinations and dementia [Karsten et al, in press].

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].

18F-Dopa-PET studies revealed reduced presynaptic striatal uptake [Khan et al 2002].

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 PARK2 mutations and very early onset 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 disease-causing PINK1 mutations.

Prevalence

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

PINK1 represents the second most frequent cause of early-onset parkinsonism, after PARK2-related juvenile parkinsonism (Parkin type of juvenile parkinson disease) in which homozygous and compound-heterozygous mutations account for about 4%-5% of autosomal recessive and 1%-2% of simplex cases (i.e., single occurrence in a family) [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].

Evaluations Following Initial Diagnosis

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

• Assess severity and presence of atypical signs using the Unified Parkinson’s Disease Rating Scale (UPDRS) rating scale [Goetz et al 2008].

• Evaluate the degree of response to treatment and its potential complications.

• Check for cognitive or behavioral problems.

Treatment of Manifestations

To date, the treatment of the PINK1 type of young-onset Parkinson disease is not different from that of idiopathic Parkinson disease.

Individuals with the 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 even be better in PINK1 type of young-onset Parkinson disease than 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 the PINK1 type Parkinson disease has been described [Moro et al 2008].

Prevention of Secondary Complications

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

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.

Testing 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.

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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

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

• The parents of an affected individual are obligate heterozygotes.

• The risk to heterozygotes of developing symptoms is not yet determined; however, several individuals with parkinsonism who have a single PINK1 mutation have been reported [Hedrich et al 2006, Klein & Lohmann-Hedrich 2007, Klein et al 2007, Ishihara-Paul et al 2008, Lesage & Brice 2009, Tan et al 2009].

Sibs of a proband

• At conception, each sib of an affected individual 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.

• Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.

• The risk to heterozygotes of developing symptoms is not yet determined, although several individuals with parkinsonism who have a single PINK1 mutation have been reported [Hedrich et al 2006, Klein & Lohmann-Hedrich 2007, Klein et al 2007, Ishihara-Paul et al 2008, Lesage & Brice 2009, Tan et al 2009].

Offspring of a proband

• The offspring of an individual with the PINK1 type of young-onset Parkinson disease are obligate heterozygotes.

• The risk to offspring of being affected depends on the frequency of heterozygotes (which is unknown) in the general population. 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 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 an affected family member.

Related Genetic Counseling Issues

Family planning. The optimal time for determination of genetic risk and clarification of carrier status is before pregnancy.

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. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

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 available for families in which the disease-causing mutations have been identified in an affected family member. For laboratories offering PGD, see .

Literature Cited

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Revision History

• 16 March 2010 (me) Review posted live

• 1 December 2009 (ck) Original submission