Clinical characteristics.

PINK1 type of young-onset Parkinson disease is characterized by early onset (median age at onset 32 years) of tremor, bradykinesia, and rigidity that are often indistinguishable from other causes of Parkinson disease. Lower-limb dystonia may be a presenting sign. Postural instability, hyperreflexia, abnormal behavior, and psychiatric manifestations have been described. The disease is usually slowly progressive. Individuals have a marked and sustained response to oral administration of levodopa (L-dopa), frequently associated with L-dopa-induced fluctuations and dyskinesias.

Diagnosis/testing.

The diagnosis of PINK1 type of young-onset Parkinson disease is established by the identification of biallelic PINK1 pathogenic variants on molecular genetic testing.

Management.

Treatment of manifestations: PINK1 type of young-onset Parkinson disease usually responds well to L-dopa and/or other dopamine agonists, which may be used in combination with catechol-O-methyltransferase inhibitors or monoamine oxidase-B inhibitors, anticholinergics, and amantadine. Physical therapy and/or occupational therapy to improve and/or maintain gross motor and fine motor skills as well as speech therapy. Invasive therapies include intrajejunal L-dopa-carbidopa pump, subcutaneous apomorphine pump, or deep brain stimulation. L-dopa-induced dyskinesias can be treated by reducing L-dopa dose, switching to dopamine receptor agonists, deep brain stimulation, or continuous treatment with L-dopa or apomorphine. Atypical neuroleptic agents can be used for neuropsychiatric manifestations; standard treatments for depression. Cholinesterase inhibitors can be used to treat dementia. Consider droxidopa, midodrine, fludrocortisone, and/or supportive measures for orthostasis. Symptomatic treatment for constipation.

Surveillance: Neurologic evaluation every three to 12 months to assess motor and non-motor manifestations and treatment efficacy; in addition, assess for atypical manifestations and therapy needs at each visit. Neuropsychiatric evaluation in those with mood disorder / psychotic symptoms or as needed. Cognitive assessment annually or as needed. At each visit, assess nutrition and safety of feeding; assess for symptoms of orthostasis and measure supine and standing blood pressure and pulse; assess for constipation, urinary urgency, or urge incontinence; and assess family needs.

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

Genetic counseling.

PINK1 type of young-onset Parkinson disease is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a PINK1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial PINK1 pathogenic variants. Once the PINK1 pathogenic variants have been identified in an affected family member, heterozygote testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.

Suggestive Findings

PINK1 type of young-onset Parkinson disease should be suspected in individuals with the following clinical and family history findings.

Clinical findings

• Early onset. Onset is age <40 years in 57%; late onset (27%) and juvenile onset (16%) can also occur.
• Parkinsonism (bradykinesia, resting tremor, rigidity)
• Dyskinesia
• Motor fluctuations
• Dystonia
• Cognitive decline
• Psychiatric manifestations
• Good response to levodopa (L-dopa) treatment (in 98% of individuals with a reported L-dopa response)

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of PINK1 type of young-onset Parkinson disease is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in PINK1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision-making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic PINK1 variants of uncertain significance (or of one known PINK1 pathogenic variant and one PINK1 variant of uncertain significance) does not establish or rule out the diagnosis.

Because the phenotype of PINK1 type of young-onset Parkinson disease is indistinguishable from many other inherited causes of Parkinson disease, recommended molecular genetic testing approaches include the use of a multigene panel or comprehensive genomic testing (exome sequencing, genome sequencing). A multigene panel requires that the clinician determine which genes are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Note: (1) PINK1 single-exon and multiexon deletions/duplications have been identified in individuals with PINK1 type of young-onset Parkinson disease; molecular genetic testing should include deletion/duplication analysis (see Table 1). (2) Single-gene testing (sequence analysis of PINK1, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

Clinical Description

PINK1 type of young-onset Parkinson disease is characterized by typically early-onset Parkinson disease that is often clinically indistinguishable from other genetic causes of Parkinson disease or idiopathic Parkinson disease. Typical features include bradykinesia, rigidity, dyskinesia, motor fluctuations, and dystonia. Some individuals have cognitive decline and psychiatric manifestations. The following information is based on a systematic review of published reports including 205 individuals with PINK1 type of young-onset Parkinson disease from 136 families (see www.mdsgene.org and references therein).

Onset. The majority of individuals (57%) have early onset (age at onset <40 years), 27% have late onset, and 16% have juvenile onset (age at onset <21 years). Note: The age of onset was not specified in 10% of individuals. The median age of onset is 32 years (interquartile range: age 24-40 years; range: age 9-67 years) (see www.mdsgene.org).

Parkinsonian features are usually asymmetric; in some individuals the manifestations at onset are symmetric. PINK1 type of Parkinson disease clinically resembles other monogenic causes of Parkinson disease, especially those with recessive inheritance, and Parkinson disease of unknown cause. Individuals frequently present with all the typical features of Parkinson disease, including bradykinesia, rigidity, tremor, and postural instability. Tremor and bradykinesia are the most common presenting signs. The disease is slowly progressive. Rigidity and postural instability (60%) frequently occur with disease progression. Sleep benefit was reported for 40% of individuals (see www.mdsgene.org). A clinical presentation resembling atypical parkinsonism is very rare.

Non-motor Parkinson features are frequently reported (92%) in individuals with PINK1 type of young-onset Parkinson disease and commonly include psychiatric involvement, cognitive impairment, and autonomic dysfunction.

Psychiatric involvement. Abnormal behavior and/or psychiatric manifestations – in particular, depression (51%), anxiety (56%), and psychotic symptoms (33%) (see www.mdsgene.org) – can occur in affected individuals. Related sleep impairment (e.g., falling and staying asleep) is also common in individuals with PINK1 type of young-onset Parkinson disease [Ricciardi et al 2014].

Cognitive decline, ranging from mild cognitive impairment to dementia, has been reported for a subset of individuals.

Information on the occurrence of hyposmia is scarce (www.mdsgene.org; only available for 24 individuals in total and present in ten).

Autonomic dysfunction was reported for 48% of individuals (see www.mdsgene.org) and most commonly include urinary urgency, urge incontinence, constipation, and orthostatic hypotension.

Other additional neurologic manifestations. Dystonia (often of the lower limbs) and hyperreflexia may also be present or develop as the disease progresses [Bonifati et al 2005]. Dystonia has also been reported as the initial sign in a subset of individuals (18% of individuals with available data).

Neuroimaging. CT and MRI neuroimaging of individuals with PINK1 type of young-onset Parkinson disease is usually normal. Imaging of dopamine function (using DaTscan) generally demonstrated relatively symmetric loss of radioligand uptake in the striatum, similar to the pattern seen in the Parkin type of young-onset Parkinson disease, LRRK2 (Gly2019Ser) type of Parkinson disease, and SNCA type of Parkinson disease [McNeill et al 2013].

Response to treatment. In general, the vast majority of individuals with PINK1 type of young-onset Parkinson disease have a good response to L-dopa therapy [Over et al 2021]; it was suggested to be even better than in Parkinson disease of unknown cause [Valente & Ferraris 2010]. Usually, this positive response persists over time, although no systematic longitudinal assessment is available. L-dopa primarily addresses motor features of the disease; additional medication might be needed to address non-motor features, especially psychiatric involvement. Side effects of L-dopa are common and most frequently include L-dopa-induced dyskinesias; motor fluctuations are also reported, and rarely dystonia. Response to non-L-dopa therapies including dopamine agonists, catechol-O-methyltransferase (COMT) inhibitors, monoamine oxidase-B (MAO-B) inhibitors, anticholinergics, and/or amantadine is also good, but information is limited [Over et al 2021]. Surgical therapies, including deep brain stimulation and thalamotomy, have only been reported in a small number of individuals with usually a moderate-to-good response; however, the sample size is too small to draw meaningful conclusions.

Prognosis. Progression is slower compared to Parkinson disease of unknown cause [Kasten et al 2018]. However, detailed and systematic data on disease progression is limited [Kasten et al 2018]. Large, multicenter studies with longitudinal and systematic data collection are needed. In general, the expected life span in individuals with PINK1 type of young-onset Parkinson disease is similar to Parkinson disease of unknown cause. Common causes of an earlier death include complications related to Parkinson disease (e.g., pneumonia due to severe dysphagia and aspiration, falls resulting in serious injuries due to gait difficulties, or immobility).

Genotype-Phenotype Correlations

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

Modifiers. Recently, it has been shown that somatic mitochondrial variant load is a disease-onset modifier for PINK1 (and Parkin) type of young-onset Parkinson disease. By investigating mitochondrial DNA (mtDNA) integrity in individuals with biallelic (n=84) and heterozygous (n=170) PINK1 or PRKN pathogenic variants compared to individuals with Parkinson disease of unknown cause (n=67) and controls (n=90), it was shown that affected and unaffected individuals with a heterozygous PINK1 or PRKN pathogenic variant can be distinguished by heteroplasmic mtDNA variant load; and individuals with biallelic PINK1 or PRKN pathogenic variants contain more heteroplasmic mtDNA variants in blood than individuals with a heterozygous PINK1 or PRKN variant [Trinh et al 2023].

Further, one individual with biallelic PINK1 pathogenic variants and homoplasmy for pathogenic variants in two mitochondrial genes encoding subunits of complex I (MT-ND5 and MT-ND6) was reported with very early-onset Parkinson disease [Piccoli et al 2008]; thus, it was hypothesized that the combination of pathogenic variants in MT-ND5 and MT-ND6 accelerated the disease onset.

Penetrance

Biallelic PINK1 pathogenic variants are considered fully penetrant [Höglinger et al 2024]. Penetrance of heterozygous variants is under debate (see Heterozygotes).

Nomenclature

Based on the International Parkinson and Movement Disorder Society Task Force for Nomenclature of Genetic Movement Disorders, the recommended name for Parkinson disease caused by PINK1 pathogenic variants is "PARK-PINK1" [Marras et al 2016, Lange et al 2022].

Prevalence

The prevalence is not known. PINK1 pathogenic variants are a rare cause of early-onset Parkinson disease but are the second most common form of autosomal recessive Parkinson disease [Jia et al 2022].

The proportion of women among individuals with PINK1 type of young-onset Parkinson disease is 54%. The majority of families are of Asian (36%), White/European (31%), or mixed (21%) ancestry; reports of individuals of Arab, African, or Indian ancestry are rare (see www.mdsgene.org).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PINK1 type of young-onset Parkinson disease, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

To date, the treatment of PINK1 type of young-onset Parkinson disease does not differ from that of Parkinson disease of other etiologies (e.g., other monogenic forms, Parkinson disease of unknown etiology), and no gene-specific guidelines or recommendations have been developed. Updated treatment guidelines for Parkinson disease have been published by national and international neurologic societies, such as the European or American Academy of Neurology (EAN or AAN), often in cooperation with the Movement Disorder Society (MDS).

To date, no therapy can slow or stop the progression of Parkinson disease; available treatment options are purely symptomatic. In general, optimal management should begin at diagnosis and involve a multidisciplinary team approach, including pharmacologic and non-pharmacologic interventions [Bloem et al 2021].

Surveillance

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

There is only a single case report of a woman with biallelic PINK1 pathogenic variants who became pregnant [Li et al 2021]. During pregnancy, symptoms neither worsened nor improved, and the individual continued to take very low doses of L-dopa. The pregnancy and birth were without complications.

In general, data on pregnancy in individuals with Parkinson disease is rare, since age of onset is often after the childbearing years. Historically, it was reported that parkinsonian symptoms may exacerbate during pregnancy, but this may be because antiparkinsonian medications were not recommended or were underdosed [Seier & Hiller 2017]. Reviewing data from case reports and drug registries, L-dopa seems to be the safest option in pregnancy. Amantadine should be avoided in women who are pregnant or trying to become pregnant [Seier & Hiller 2017]. Data on other pharmacologic and surgical treatments is limited. To date, there is no evidence that women with Parkinson disease have higher rates of birth or fetal complications [Seier & Hiller 2017].

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

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 presumed to be heterozygous for a PINK1 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a PINK1 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• The risk to heterozygotes of developing symptoms is not yet determined; however, several individuals with parkinsonism who have a single PINK1 pathogenic variant have been reported (see Clinical Description, Heterozygotes).

Sibs of a proband

• If both parents are known to be heterozygous for a PINK1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial PINK1 pathogenic variants.
• The risk to heterozygotes of developing symptoms is not yet determined; however, several individuals with parkinsonism who have a single PINK1 pathogenic variant have been reported (see Clinical Description, Heterozygotes).

Offspring of a proband. The offspring of an individual with PINK1 type of young-onset Parkinson disease are obligate heterozygotes for a pathogenic variant in PINK1.

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for a PINK1 pathogenic variant.

Heterozygote Detection

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

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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 heterozygous, or are at risk of being heterozygous.

Prenatal Testing and Preimplantation Genetic Testing

Once the PINK1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider decisions use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

PINK1 encodes serine/threoninep-protein kinase PINK1, mitochondrial (also called PTEN-induced putative kinase 1, or PINK1). PINK1 spans the outer mitochondrial membrane, with the C-terminal kinase domain facing the cytoplasm and the N-terminal inside the mitochondria. PINK1 presumably exerts its neuroprotective effect by phosphorylating specific mitochondrial proteins and modulating their functions [Sim et al 2006]. PINK1 and E3 ubiquitin-protein ligase parkin (parkin; see Parkinson Disease Overview) have been mapped to a shared pathway, with PINK1 acting upstream of parkin. PINK1 detects mitochondrial dysfunction, initiates the translocation of parkin to mitochondria, and signals parkin to ubiquitinate the damaged mitochondria, leading to their removal by autophagy [Pickrell & Youle 2015]. Thus, PINK1 and parkin acting together constitute a mitochondrial quality control function.

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

Overexpression of parkin can rescue the effects of a PINK1 pathogenic variant in Drosophila and mammalian cells [Pickrell & Youle 2015]. Studies in fibroblasts from individuals with Parkinson disease 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]. A link with leucine-rich repeat serine/threonine-protein kinase 2 (LRRK2) [Azkona et al 2018] and alpha-synuclein levels [Chung et al 2016] has also been demonstrated. PINK1-patient-specific induced pluripotent stem cell-derived midbrain dopamine neurons exhibit mitochondrial dysfunction with increased susceptibility to mitochondrial toxins [Chung et al 2016]. Animal studies of Pink1 knockout mice showed defects in mitochondrial depolarization and synaptic transmission that were rescued by phosphomimetic NdufA10 in knockout mouse cells and in pink^B9-null mutated Drosophila [Morais et al 2014]. Complex I deficits and adenosine triphosphate synthesis were also rescued in cells derived from individuals with PINK1 type of young-onset Parkinson disease [Morais et al 2014]. Heterozygous Pink1 knockout (Pink^+/-) mice show subtle alterations of dopamine-dependent striatal synaptic plasticity [Madeo et al 2014]. While chronic exposure to low doses of rotenone was not sufficient to alter mitochondrial integrity and ATP production in this model, the rotenone led to profound impairment in expression of long-term plasticity at corticostriatal synapses, suggesting that disruption of synaptic plasticity may represent an early feature of a premanifesting state of the disease [Martella et al 2016]. Findings of possible translational and treatment relevance include the role of vitamin K₂ as a mitochondrial electron carrier rescuing PINK1 deficiency [Vos et al 2012] and the observation that cardiolipin promotes electron transport between ubiquinone and complex I to rescue PINK1 deficiency [Vos et al 2017].

Mechanism of disease causation. Loss of function

Neuropathology. Data in individuals with PINK1 type of young-onset Parkinson disease is limited [Samaranch et al 2010, Poulopoulos et al 2012]. Brain autopsy data are available for four individuals with biallelic PINK1 pathogenic variants [Samaranch et al 2010, Poulopoulos et al 2012, Steele et al 2015, Takanashi et al 2016, Nybø et al 2020], all of which had characteristic neuronal loss in the substantia nigra. Lewy bodies were present in on histopathology in three of four individuals, although distribution varied. One individual had Lewy bodies in the substantia nigra, the temporal cortex, and locus coeruleus [Nybø et al 2020]; the second in the reticular nuclei in the brain stem, substantia nigra, and basal nucleus of Meynert, with sparing of the locus coeruleus and amygdala [Samaranch et al 2010]; and the third only in the amygdala, with only minimal neurites in the substantia nigra [Steele et al 2015]. A fourth individual had no Lewy body pathology [Takanashi et al 2016]. In addition, tau depositions were present in two individuals [Steele et al 2015, Nybø et al 2020]. In a Parkinson disease brain bank study, four individuals with Parkinson disease and heterozygous PINK1 pathogenic variants had pathologic findings consistent with typical Parkinson disease, with Lewy bodies distributed in the brain stem and cortical areas, neuronal loss affecting the substantia nigra pars compacta, and neurofibrillary tangles stage I to V [Gandhi et al 2006].

Author Notes

Lara M Lange, MD ([email protected]), and Christine Klein, MD ([email protected]), are actively involved in clinical and genetic research regarding individuals with Parkinson disease. They would be happy to communicate with persons who have any questions regarding the diagnosis of Parkinson disease or other considerations.

Lara M Lange and Christine Klein are also interested in hearing from clinicians treating families affected by Parkinson disease in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Contact Dr Lara M Lange or Prof Christine Klein to inquire about the review of PINK1 variants of uncertain significance.

Acknowledgments

Lara M Lange and Christine Klein would like to thank Susanne Schneider for her previous engagement in the PINK1 GeneReviews and Johanna Junker and Maria Leila M Doquenia for their work on the MDSGene PINK1 update.

Lara M Lange acknowledges support from the Bachmann-Strauss Dystonia and Parkinson Foundation.

Christine Klein acknowledges support from the Aligning Science Across Parkinson's (ASAP) Global Parkinson's Genetics Program (GP2), The Michael J Fox Foundation (MJFF), and the German Research Foundation (FOR2488).

Author History

Christine Klein, MD (2010-present)
Lara M Lange, MD (2024-present)
Susanne A Schneider, MD, PhD; Ludwig Maximilian University Munich (2010-2024)

Revision History

• 25 April 2024 (sw) Comprehensive update posted live
• 24 May 2018 (sw) Comprehensive update posted live
• 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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