Clinical characteristics.

VPS35-related Parkinson disease (PARK-VPS35) is indistinguishable from Parkinson disease of unknown cause representing a simplex case (also referred to as "sporadic" Parkinson disease). PARK-VPS35 is characterized by typical parkinsonism (resting tremor, bradykinesia, rigidity, disturbance of postural reflexes) presenting on average a decade earlier than in individuals with simplex Parkinson disease of unknown cause. Median age of onset is approximately 50 years, with a range of onset spanning the third to eighth decade of life. PARK-VPS35 subtypes can include tremor dominant, akinetic rigid, gait difficulty, or mixed. Asymmetric presentation is typical. The disease course is usually milder than that of simplex Parkinson disease of unknown cause, with a decreased incidence of atypical signs. Dyskinesia and motor fluctuations may occur. Neuropsychiatric manifestations (depression and schizophrenia), learning difficulties, mild cognitive impairment, and dementia have been reported, albeit with lower occurrence than in simplex Parkinson disease of unknown cause. Additional findings include impaired sense of smell and autonomic manifestations including orthostasis and constipation.

Diagnosis/testing.

The diagnosis of PARK-VPS35 is established in a proband with parkinsonism (bradykinesia with rigidity and/or resting tremor) and a heterozygous VPS35 pathogenic variant identified by molecular genetic testing.

Management.

Treatment of manifestations: To date, treatment of PARK-VPS35 does not differ from that of simplex Parkinson disease of unknown cause. Drugs to treat motor manifestations include levodopa, in combination with a peripheral dopa decarboxylase inhibitor (carbidopa, benserazide), dopamine agonists, inhibitors of catechol-O-methyltransferase or monoamine oxidase-B, anticholinergics, and amantadine. Most individuals respond well to levodopa and other dopaminergic medications. Individuals benefit from physical, occupational, and speech therapies. Due to the lower risk of atypical signs, neuropsychiatric disturbances, and dementia, individuals with PARK-VPS35 seem to be good candidates for treatment with dopamine agonists. In addition, in those with dyskinesia and motor fluctuations, subthalamic deep brain stimulation and apomorphine intermittent injections or continuous therapy with an infusion pump should be considered. Peak-dose dyskinesia may be ameliorated with amantadine and dopaminergic treatment reduction (if tolerated). Low-dose clozapine, quetiapine, or pimavanserin and reduction of dopaminergic therapy can decrease delusions and hallucinations. Standard treatments for depression; consider droxidopa for orthostasis; symptomatic treatment for constipation.

Surveillance: Neurologic evaluations to assess tremor, bradykinesia, rigidity, gait, neuropsychiatric symptoms, cognition, and treatment efficacy every six to 12 months or as needed; neuropsychiatric and cognitive assessments as needed; assess for symptoms of orthostasis, measure blood pressure, and assess for constipation at each visit; echocardiogram as needed in those treated with ergot-derived dopamine agonists; assess family and social work needs at each visit.

Agents/circumstances to avoid: Drugs that may induce or exacerbate parkinsonism include but are not limited to neuroleptics, antidepressants, calcium channel blockers, valproate, lithium, and amiodarone. Ergot-derived dopaminergic drugs should be discontinued if fibrotic heart-valve changes are identified.

Genetic counseling.

PARK-VPS35 is inherited in an autosomal dominant manner. About 90% of individuals diagnosed with PARK-VPS35 have positive family history of Parkinson disease. Each child of an individual with PARK-VPS35 has a 50% chance of inheriting the VPS35 pathogenic variant. Once the VPS35 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

VPS35-related Parkinson disease (PARK-VPS35) should be considered in individuals with the following clinical, imaging, and family history findings.

Clinical findings. The clinical manifestations of PARK-VPS35 are similar to those of Parkinson disease of unknown cause representing a simplex case (also referred to as "sporadic" Parkinson disease; see Nomenclature). However, onset for PARK-VPS35 is on average a decade earlier, progression is slower, and there is a lower risk of atypical signs, neuropsychiatric disturbances, and dementia. The cardinal sign of PARK-VPS35 is parkinsonism, defined as:

• Bradykinesia (slowness of movement AND decrement in amplitude or speed) in combination with at least one of the following:
  • Resting tremor (rhythmic tremor usually of the hands and forearms when relaxed, which disappears with active limb movement)
  • Rigidity (increased muscle tone resulting in resistance to passive movement)

Additional clinical findings of PARK-VPS35:

• Adult onset
• Typically unilateral onset
• Slow disease progression
• Good response to levodopa therapy

Imaging findings. Normal brain MRI

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of PARK-VPS35 is established in a proband with parkinsonism (bradykinesia with rigidity and/or resting tremor) and a heterozygous VPS35 pathogenic (or likely pathogenic) variant 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 any likely pathogenic variants. (2) Identification of a heterozygous VPS35 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotypes of inherited Parkinson disease are largely indistinguishable, most individuals with PARK-VPS35 are diagnosed by the following recommended testing or testing to consider.

Clinical Description

VPS35-related Parkinson disease (PARK-VPS35) is indistinguishable from Parkinson disease of unknown cause representing a simplex case (also referred to as "sporadic" Parkinson disease; see Nomenclature). PARK-VPS35 is characterized by cardinal manifestations of typical parkinsonism (resting tremor, bradykinesia, rigidity, disturbance of postural reflexes). Similar to simplex Parkinson disease of unknown cause, non-motor symptoms also occur; however, neuropsychiatric disturbances and dementia are less common. Atypical features are also of lower frequency compared to simplex Parkinson disease of unknown cause. Disturbances of postural reflexes, autonomic manifestations, and sleep disorders occur at a similar rate to simplex Parkinson disease of unknown cause. PARK-VPS35 manifestations may be variable among affected individuals within the same family. To date, approximately 150 individuals with PARK-VPS35 have been identified [Vilariño-Güell et al 2011; Zimprich et al 2011; Ando et al 2012; Kumar et al 2012; Lesage et al 2012; Sharma et al 2012; Sheerin et al 2012; Trinh et al 2018; Dulski et al 2022; Vollstedt et al 2023; Dulski et al, unpublished data].

Age of onset. Median age of onset was 52 years (interquartile range [IQR]: 45-61) in a group of 67 affected individuals [Trinh et al 2018], and 48 years (IQR: 44-56) in a group of 23 affected individuals [Vollstedt et al 2023].

Parkinson subtype. The motor manifestations do not differ from simplex Parkinson disease of unknown cause. Affected individuals may manifest tremor dominant, akinetic rigid, gait difficulty, and mixed subtypes [Dulski et al 2022].

Course of disease

• Presentation is asymmetric.
• The disease course is usually milder than that of simplex Parkinson disease of unknown cause.
• Dyskinesia and motor fluctuations may occur.
• Atypical signs are very rare. To date, atypical features were observed in only one individual, who developed classic manifestations of Parkinson disease in his early 70s, followed by bulbar symptoms, gait apraxia, falls, supranuclear gaze palsy, apraxia of eyelid opening, and dysexecutive syndrome. However, this individual also had a FBXO7 variant, and the phenotype could have been due to double heterozygosity for VPS35 and FBXO7 variants. A cousin of the affected individual also had the VPS35 variant and presented with classic late-onset Parkinson disease [Bartonikova et al 2016, Menšíková et al 2019].

Neuropsychiatric manifestations

• Depression was observed in up to 70% of individuals [Trinh et al 2018].
• Psychotic symptoms occurred in up to 25% of individuals [Trinh et al 2018].
• Anxiety is rare [Trinh et al 2018].

Cognitive issues. Impairment of cognition ranges from mild to dementia and occurs in up to 45% of individuals.

Other findings

• Impaired sense of smell was reported in most individuals. However, the reported number of affected individuals is small, and further investigation is required [Zimprich et al 2011, Sheerin et al 2012, Struhal et al 2014, Trinh et al 2018, Vollstedt et al 2023].
• Autonomic manifestations including orthostasis and gastrointestinal symptoms (constipation) affect up to 75% of individuals [Trinh et al 2018].

Functional imaging studies show presynaptic dopaminergic dysfunction, which is apparently indistinguishable from findings in other individuals with Parkinson disease.

Single photon emission computed tomography (SPECT) of cerebral blood flow was normal in one individual [Ando et al 2012, Vollstedt et al 2023].

¹⁸F-fluorodopa positron emission tomography (PET) showed asymmetrically reduced striatal ¹⁸F-fluorodopa uptake with a posterior predominance [Wider et al 2008].

[¹²³I]-FP-CIT SPECT showed asymmetric tracer uptake [Zimprich et al 2011].

Transcranial sonography. In one individual with Parkinson disease that started with resting tremor on the left side, transcranial sonography performed after a disease course of about 15 years showed normal echogenicity of the left substantia nigra, whereas the bone window was insufficient to allow visualization on the right side [Kumar et al 2012].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified [Dulski et al 2022].

Penetrance

To date, data is too limited to allow quantification of penetrance.

Nomenclature

Based on the International Parkinson and Movement Disorder Society Task Force for the Nomenclature of Genetic Movement Disorders, the recommended name for Parkinson disease caused by VPS35 pathogenic variants is "PARK-VPS35" [Lange et al 2022].

"Idiopathic Parkinson disease" and "sporadic Parkinson disease" are terms used in the Parkinson disease medical literature to describe Parkinson disease of unknown cause diagnosed in an individual with a negative family history. Because future advances in the understanding of genetic risk factors are likely to identify genetic causes /risk factors for some Parkinson disease currently considered "idiopathic" or "sporadic," these terms are generally not used in this GeneReview. Instead, the term "Parkinson disease of unknown cause representing a simplex case" is preferred because "simplex case" refers specifically to an individual with no family history of Parkinson disease without implying presence or absence of a genetic factor or a specific recurrence risk.

Prevalence

PARK-VPS35 is exceedingly rare, and to date only 150 affected individuals have been reported worldwide [Vilariño-Güell et al 2011, Zimprich et al 2011, Ando et al 2012, Kumar et al 2012, Lesage et al 2012, Sharma et al 2012, Sheerin et al 2012, Trinh et al 2018, Vollstedt et al 2023].

The largest study to date included 67 individuals with PARK-VPS35. Of these individuals, 45% were White, 35% were Asian, and 20% were Ashkenazi Jewish; more than half of the affected individuals were from Western Europe [Trinh et al 2018]. In a smaller study that included 26 individuals, all were White, and most were of Western European ancestry [Vollstedt et al 2023].

The prevalence of PARK-VPS35 among persons with familial Parkinson disease is less than 1% [Dulski et al 2022].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PARK-VPS35, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

To date, the treatment of individuals with PARK-VPS35 does not differ from that of simplex Parkinson disease of unknown cause (also referred to as "sporadic Parkinson disease"; see Nomenclature). The following is a brief summary of recommended treatment for Parkinson disease, based on extensive existing guidelines and recommendations for pharmacotherapy of motor and non-motor manifestations of Parkinson disease as well as neurosurgical interventions for motor findings [Zesiewicz et al 2010, Oertel et al 2011a, Oertel et al 2011b, Seppi et al 2011, Ferreira et al 2013, Odin et al 2015, Trenkwalder et al 2015].

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Agents/Circumstances to Avoid

Neuroleptic drugs may increase the severity of parkinsonism in individuals with PARK-VPS35 (as in Parkinson disease in general). In general, atypical neuroleptics are less likely to exacerbate parkinsonism than typical neuroleptics; in particular clozapine, quetiapine, or pimavanserin are considered well tolerated and effective in Parkinson disease. Other drugs that may induce or exacerbate parkinsonism include but are not limited to antidepressants, calcium channel blockers, valproate, lithium, and amiodarone [Bondon-Guitton et al 2011, Bohlega & Al-Foghom 2013].

Ergot-derived dopaminergic drugs should be discontinued if fibrotic heart-valve changes are identified [Antonini & Poewe 2007].

Evaluation of Relatives at Risk

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

Pregnancy Management

Reports addressing pregnancy management in women with PARK-VPS35 are not available.

The effect of Parkinson disease of any cause on pregnancy has not been well characterized, since pregnancy is uncommon in women with Parkinson disease. In general, half of affected individuals experience improvement or no change in manifestations during pregnancy, whereas half experience worsening manifestations [Seier & Hiller 2017]. Monotherapy with levodopa seems to be the best treatment option for pregnant individuals, both in terms of safety and efficacy [Seier & Hiller 2017].

No long-term outcome data exist for children born to mothers with Parkinson disease.

• Levodopa has not been linked with a higher risk of spontaneous abortions, teratogenicity, or birth complications [Seier & Hiller 2017].
• There is insufficient evidence to determine the safety of dopamine agonists, selegiline, and rasagiline in affected individuals during pregnancy [Seier & Hiller 2017].
• Anticholinergics were associated with minor birth defects, but no other complications [Seier & Hiller 2017].
• Amantadine should be avoided during pregnancy due to teratogenicity [Seier & Hiller 2017].

Discussion of the risks and benefits of using a given medication during pregnancy should ideally take place prior to conception. 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

VPS35-related Parkinson disease (PARK-VPS35) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• About 90% of individuals diagnosed with PARK-VPS35 have a positive family history of Parkinson disease. Of note, PARK-VPS35 manifestations may be variable among affected individuals within the same family.
• About 10% of individuals with PARK-VPS35 represent simplex cases (i.e., a single occurrence in a family). However, the parents of these individuals have not been evaluated sufficiently to determine if the pathogenic variant occurred de novo in the proband; therefore, the proportion of PARK-VPS35 caused by a de novo pathogenic variant is unknown.
• If the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with PARK-VPS35 may appear to be negative because of failure to recognize the disorder in family members, age-related or reduced penetrance of the disease in a heterozygous parent, or early death of the parent before the onset of disease manifestations. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband has the VPS35 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%.
  • To date, data are too limited to allow quantification of penetrance; the likelihood that a sib who inherits a familial VPS35 pathogenic variant will develop manifestations of PARK-VPS35 is not known.
  • The manifestations of PARK-VPS35 may be variable among affected family members with the same pathogenic variant.
• If the VPS35 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the VPS35 pathogenic variant but are clinically unaffected, sibs are still presumed to be at increased risk for PARK-VPS35 because of the possibility of age-related or reduced penetrance in a parent and the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with PARK-VPS35 has a 50% chance of inheriting the VPS35 pathogenic variant.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has the VPS35 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Predictive testing (i.e., testing of asymptomatic, at-risk individuals)

• Predictive testing for at-risk relatives is possible once the VPS35 pathogenic variant has been identified in an affected family member. The utility of predictive testing for a known familial VPS35 pathogenic variant may be of limited clinical use because current data are too limited to allow quantification of penetrance (i.e., the likelihood that an asymptomatic individual found to be heterozygous for a familial VPS35 pathogenic variant will develop PARK-VPS35 is not known).
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals found to be heterozygous) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• Predictive testing may facilitate participation in research to better understand PARK-VPS35 and, in the long term, contribute to the discovery of biomarkers and therapy.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years)

• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

Note: It is appropriate to consider testing symptomatic individuals regardless of age in a family with an established diagnosis of PARK-VPS35.

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 or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the VPS35 pathogenic variant has 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 use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

VPS35 encodes vacuolar protein sorting-associated protein 35 (VPS35), which is part of the retromer, an evolutionarily conserved complex that associates with the cytosolic face of endosomes. The retromer is involved in the retrograde transport of transmembrane cargo (receptors, including dopamine receptors, transporters, adhesion molecules, and other proteins) from endosomes to the trans-Golgi network and to the plasma membrane; its cargo proteins are either recycled or degraded [Williams et al 2022].

The retromer comprises two assembling subunits: one consists of a trimeric complex of VPS35, VPS26, and VPS29 proteins and is also termed a cargo-selective complex, and the other consists of a sortin nexin dimer (SNX). VPS35 forms a horseshoe-shaped alpha-helical solenoid predicted to contain 33 helices [Lucas et al 2016]. It functions as the central platform for binding to other retromer proteins. VPS35 also mediates the association with the WASH complex, which includes FAM21. FAM21 binds to VPS35 through its extended unstructured "tail" domain, thereby allowing WASH-dependent retromer-mediated sorting of proteins (reviewed in Burd & Cullen [2014]).

VPS35 pathogenic variants have been shown to:

• Increase the activation of the LRRK2 kinase, thus exerting similar effects as LRRK2 pathogenic variants [Mir et al 2018, Williams et al 2022];
• Affect VPS35 binding to FAM21 of the WASH complex, resulting in impairment of recruitment of the WASH complex to endosomes, retromer-mediated sorting of proteins, and autophagy [Follett et al 2014, McGough et al 2014, Zavodszky et al 2014a, Zavodszky et al 2014b, Williams et al 2022];
• Redistribute endosomes to a perinuclear localization [Follett et al 2014];
• Enlarge endosomes [Follett et al 2014];
• Lead to lysosomal dysfunction through abnormal sorting of cathepsin D [Follett et al 2014, Williams et al 2022];
• Impair VPS35 interaction with dopamine receptor D1 (DRD1), causing dysregulation of DRD1 trafficking and impairment of DRD1-mediated dopamine signaling [Wang et al 2016];
• Damage dopaminergic pathways, including loss of dopaminergic neurons and axonal degeneration [Williams et al 2022];
• Lead to lysosomal dysfunction through abnormal sorting of cathepsin D [Williams et al 2022];
• Cause mitochondrial dysfunction [Williams et al 2022];
• Induce tau pathology and accumulation of total alpha-synuclein in animal models [Williams et al 2022].

Mechanism of disease causation. Gain of function or partial loss of function; the exact mechanism remains to be elucidated [Williams et al 2022].

Author Notes

Jaroslaw Dulski, MD, PhD, is Visiting Research Fellow at the Department of Neurology, Mayo Clinic, Florida. He is a board-certified neurologist and an assistant professor at the Medical University of Gdansk and St Adalbert Hospital in Gdansk, Poland. Since the beginning of his professional and scientific career, he has been interested in the genetics of Parkinson disease. In 2020 he received an award from the Chancellor of the Medical University of Gdansk for an outstanding PhD dissertation. In 2021, he received the Joseph Babinski Award from the Polish Neurological Society for the best original publication in the years from 2017-2021. He has received scholarships from the European Academy of Neurology, the Polish National Agency for Academic Exchange, the Polish Neurological Society, the Medical University of Gdansk, and the Haworth Family Professorship in Neurodegenerative Diseases Fund. Email: ude.oyam@walsoraj.ikslud; lp.ude.demug@ikslud.walsoraj

Owen A Ross, PhD, obtained his PhD in the genetics of aging from the University of Ulster and Queens University Belfast in Ireland. In 2010, Dr Ross started his independent lab at the Department of Neuroscience at the Mayo Clinic College of Medicine in Jacksonville, Florida. He now pursues the role of LRRK2, VPS35, and other genes in Parkinson disease. He received an honorable mention for the Moore Award in clinicopathology research for his work on LRRK2 variant p.Gly2019Ser with Professor Dennis W Dickson. Dr Ross has published over 350 articles in the fields of aging and neurodegeneration and is presently an associate professor of neuroscience at the Mayo Clinic College of Medicine. He also served on the editorial board of Parkinsonism and Related Disorders, PloS ONE, and American Journal of Neurodegenerative Disease. His research is supported by several active grants from the National Institutes of Health, among other foundations. His primary research interests are in the genetics of neurodegeneration, specifically in Parkinson disease and related movement disorders. Email: ude.oyam@newo.ssor

Zbigniew Wszolek, MD, is a consultant in the Department of Neurology at Mayo Clinic in Jacksonville, Florida, and the Haworth Family Professor in Neurodegenerative Diseases. Dr Wszolek has contributed to discoveries related to the genetic basis of Parkinson disease and parkinsonism-related disorders. He has amassed vast clinical information about family pedigrees. Dr Wszolek has published more than 600 journal articles, reviews, editorials, and chapters, and 740 abstracts and letters. He is co-editor-in-chief of the Polish Journal of Neurology and Neurosurgery, and former co-editor-in chief of Parkinsonism and Related Disorders. He is a founding officer of the International Association of Parkinsonism and Related Disorders. Email: ude.oyam@weingibz.kelozsw

Dr Zbigniew Wszolek (ude.oyam@weingibz.kelozsw) and Dr Jaroslaw Dulski (ude.oyam@walsoraj.ikslud) are actively involved in clinical research regarding individuals with PARK-VPS35. They would be happy to communicate with persons who have any questions regarding the diagnosis of PARK-VPS35 or other considerations.

Contact Dr Zbigniew Wszolek (ude.oyam@weingibz.kelozsw) to inquire about the review of VPS35 variants of uncertain significance.

Acknowledgments

The authors would like to thank the patients and their families for participating in research and their contributions to the field.

JD is partially supported by the Polish National Agency for Academic Exchange (BPN/WAL/2022/1/00007/U/00001), and the Haworth Family Professorship in Neurodegenerative Diseases Fund.

OAR is supported by NIH (RF1 NS085070; U01 NS100620; R01 AG056366; U19 AG071754), DOD (W81XWH-17-1-0249), The Michael J Fox Foundation, American Brain Foundation, and the Mayo Clinic LBD Center without Walls (U54-NS110435). Mayo Clinic is an American Parkinson Disease Association (APDA) Mayo Clinic Information and Referral Center, an APDA Center for Advanced Research, and a Lewy Body Dementia Association (LBDA) Research Center of Excellence.

ZKW is partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, gifts from the Donald G and Jodi P Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases Fund, and The Albertson Parkinson's Research Foundation. He serves as PI or co-PI on Biohaven Pharmaceuticals, Inc (BHV4157-206), Neuraly, Inc (NLY01-PD-1), and Vigil Neuroscience, Inc (VGL101-01.002, VGL101-01.201, PET tracer development protocol, and Csf1r biomarker and repository project) grants. He serves as co-PI of the Mayo Clinic APDA Center for Advanced Research and as an external advisory board member for the Vigil Neuroscience, Inc.

Author History

Angela Deutschländer, MD; Mayo Clinic (2017-2023)
Jaroslaw Dulski, MD, PhD (2023-present)
Owen A Ross, PhD (2017-present)
Zbigniew K Wszolek, MD (2017-present)

Revision History

• 23 March 2023 (sw) Comprehensive updated posted live
• 10 August 2017 (bp) Review posted live
• 15 December 2016 (ad) Original submission

Literature Cited

• Ando M, Funayama M, Li Y, Kashihara K, Murakami Y, Ishizu N, Toyoda C, Noguchi K, Hashimoto T, Nakano N, Sasaki R, Kokubo Y, Kuzuhara S, Ogaki K, Yamashita C, Yoshino H, Hatano T, Tomiyama H, Hattori N. VPS35 mutation in Japanese patients with typical Parkinson's disease. Mov Disord. 2012;27:1413-7. [PubMed: 22991136]
• Antonini A, Poewe W. Fibrotic heart-valve reactions to dopamine-agonist treatment in Parkinson's disease. Lancet Neurol. 2007;6:826-9. [PubMed: 17706566]
• Bartonikova T, Mensikova K, Mikulicova L, Vodicka R, Vrtel R, Godava M, Vastik M, Kaiserova M, Otruba P, Dolinova I, Nevrly M, Kanovsky P. Familial atypical parkinsonism with rare variant in VPS35 and FBXO7 genes: A case report. Medicine (Baltimore). 2016;95:e5398. [PMC free article: PMC5120934] [PubMed: 27861377]
• Bohlega SA, Al-Foghom NB. Drug-induced Parkinson's disease: a clinical review. Neurosciences (Riyadh). 2013;18:215-21. [PubMed: 23887211]
• Bondon-Guitton E, Perez-Lloret S, Bagheri H, Brefel C, Rascol O, Montastruc JL. Drug-induced parkinsonism: a review of 17 years' experience in a regional pharmacovigilance center in France. Mov Disord. 2011;26:2226-31. [PubMed: 21674626]
• Burd C, Cullen PJ. Retromer: a master conductor of endosome sorting. Cold Spring Harb Perspect Biol. 2014;6. [PMC free article: PMC3941235] [PubMed: 24492709]
• Deng HX, Shi Y, Yang Y, Ahmeti KB, Miller N, Huang C, Cheng L, Zhai H, Deng S, Nuytemans K, Corbett NJ, Kim MJ, Deng H, Tang B, Yang Z, Xu Y, Chan P, Huang B, Gao XP, Song Z, Liu Z, Fecto F, Siddique N, Foroud T, Jankovic J, Ghetti B, Nicholson DA, Krainc D, Melen O, Vance JM, Pericak-Vance MA, Ma YC, Rajput AH, Siddique T. Identification of TMEM230 mutations in familial Parkinson's disease. Nat Genet. 2016;48:733-9. [PMC free article: PMC6047531] [PubMed: 27270108]
• Dulski J, Uitti RJ, Ross OA, Wszolek ZK. Genetic architecture of Parkinson's disease subtypes -review of the literature. Front Aging Neurosci. 2022;14:1023574. [PMC free article: PMC9632166] [PubMed: 36337703]
• Ferreira JJ, Katzenschlager R, Bloem BR, Bonuccelli U, Burn D, Deuschl G, Dietrichs E, Fabbrini G, Friedman A, Kanovsky P, Kostic V, Nieuwboer A, Odin P, Poewe W, Rascol O, Sampaio C, Schüpbach M, Tolosa E, Trenkwalder C, Schapira A, Berardelli A, Oertel WH. Summary of the recommendations of the EFNS/MDS-ES review on therapeutic management of Parkinson's disease. Eur J Neurol. 2013;20:5-15. [PubMed: 23279439]
• Follett J, Norwood SJ, Hamilton NA, Mohan M, Kovtun O, Tay S, Zhe Y, Wood SA, Mellick GD, Silburn PA, Collins BM, Bugarcic A, Teasdale RD. The Vps35 D620N mutation linked to Parkinson's disease disrupts the cargo sorting function of retromer. Traffic. 2014;15:230-44. [PubMed: 24152121]
• Kumar KR, Weissbach A, Heldmann M, Kasten M, Tunc S, Sue CM, Svetel M, Kostić VS, Segura-Aguilar J, Ramirez A, Simon DK, Vieregge P, Münte TF, Hagenah J, Klein C, Lohmann K. Frequency of the D620N mutation in VPS35 in Parkinson disease. Arch Neurol. 2012;69:1360-4. [PubMed: 22801713]
• Lange LM, Gonzalez-Latapi P, Rajalingam R, Tijssen MAJ, Ebrahimi-Fakhari D, Gabbert C, Ganos C, Ghosh R, Kumar KR, Lang AE, Rossi M, van der Veen S, van de Warrenburg B, Warner T, Lohmann K, Klein C, Marras C, et al. Nomenclature of Genetic Movement Disorders: recommendations of the International Parkinson and Movement Disorder Society Task Force - an update. Mov Disord. 2022;37:905-35. [PubMed: 35481685]
• Lesage S, Condroyer C, Klebe S, Honoré A, Tison F, Brefel-Courbon C, Dürr A, Brice A, et al. Identification of VPS35 mutations replicated in French families with Parkinson disease. Neurology. 2012;78:1449-50. [PubMed: 22517097]
• Lucas M, Gershlick DC, Vidaurrazaga A, Rojas AL, Bonifacino JS, Hierro A. Structural mechanism for cargo recognition by the retromer complex. Cell. 2016;167:1623-35.e14. [PMC free article: PMC5147500] [PubMed: 27889239]
• McGough IJ, Steinberg F, Jia D, Barbuti PA, McMillan KJ, Heesom KJ, Whone AL, Caldwell MA, Billadeau DD, Rosen MK, Cullen PJ. Retromer binding to FAM21 and the WASH complex is perturbed by the Parkinson disease-linked VPS35(D620N) mutation. Curr Biol. 2014;24:1670-6. [PMC free article: PMC4110399] [PubMed: 24980502]
• Menšíková K, Tučková L, Kolařiková K, Bartoníková T, Vodička R, Ehrmann J, Vrtěl R, Procházka M, Kaňovský P, Kovacs GG. Atypical parkinsonism of progressive supranuclear palsy-parkinsonism (PSP-P) phenotype with rare variants in FBXO7 and VPS35 genes associated with Lewy body pathology. Acta Neuropathol. 2019;137:171-3. [PubMed: 30374525]
• Mir R, Tonelli F, Lis P, Macartney T, Polinski NK, Martinez TN, Chou MY, Howden AJM, König T, Hotzy C, Milenkovic I, Brücke T, Zimprich A, Sammler E, Alessi DR. The Parkinson's disease VPS35[D620N] mutation enhances LRRK2-mediated Rab protein phosphorylation in mouse and human. Biochem J. 2018;475:1861-83. [PMC free article: PMC5989534] [PubMed: 29743203]
• Odin P, Ray Chaudhuri K, Slevin JT, Volkmann J, Dietrichs E, Martinez-Martin P, Krauss JK, Henriksen T, Katzenschlager R, Antonini A, Rascol O, Poewe W, et al. Collective physician perspectives on non-oral medication approaches for the management of clinically relevant unresolved issues in Parkinson's disease: consensus from an international survey and discussion program. Parkinsonism Relat Disord. 2015;21:1133-44. [PubMed: 26233582]
• Oertel WH, Berardelli A, Bloem BR, Bonuccelli U, Burn D, Deuschl G, Dietrichs E, Fabbrini G, Ferreira JJ, Friedman A, Kanovsky P, Kostic V, Nieuwboer A, Odin P, Poewe W, Rascol O, Sampaio C, Schüpbach M, Tolosa E, Trenkwalder C. Early (uncomplicated) Parkinson's disease. In: Gilhus NE, Barnes M, Brainin M, eds. European Handbook of Neurological Management. Vol 1. 2 ed. Oxford: Blackwell Publishing Ltd; 2011a:217-36.
• Oertel WH, Berardelli A, Bloem BR, Burn D, Deuschl G, Dietrichs E, Fabbrini G, Ferreira JJ, Friedman A, Kanovsky P, Kostic V, Nieuwboer A, Odin P, Poewe W, Rascol O, Sampaio C, Schüpbach M, Tolosa E, Trenkwalder C. Late (complicated) Parkinson's disease. In: Gilhus NE, Barnes M, Brainin M, eds. European Handbook of Neurological Management. Vol 1. 2 ed. Oxford: Blackwell Publishing Ltd; 2011b:237-67.
• Orme T, Hernandez D, Ross OA, Kun-Rodrigues C, Darwent L, Shepherd CE, Parkkinen L, Ansorge O, Clark L, Honig LS, Marder K, Lemstra A, Rogaeva E, St George-Hyslop P, Londos E, Zetterberg H, Morgan K, Troakes C, Al-Sarraj S, Lashley T, Holton J, Compta Y, Van Deerlin V, Trojanowski JQ, Serrano GE, Beach TG, Lesage S, Galasko D, Masliah E, Santana I, Pastor P, Tienari PJ, Myllykangas L, Oinas M, Revesz T, Lees A, Boeve BF, Petersen RC, Ferman TJ, Escott-Price V, Graff-Radford N, Cairns NJ, Morris JC, Pickering-Brown S, Mann D, Halliday G, Stone DJ, Dickson DW, Hardy J, Singleton A, Guerreiro R, Bras J. Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies. Acta Neuropathol Commun. 2020;8:5. [PMC free article: PMC6990558] [PubMed: 31996268]
• Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Al Turki S, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126-33. [PMC free article: PMC4731925] [PubMed: 26656846]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Rovelet-Lecrux A, Charbonnier C, Wallon D, Nicolas G, Seaman MN, Pottier C, Breusegem SY, Mathur PP, Jenardhanan P, Le Guennec K, Mukadam AS, Quenez O, Coutant S, Rousseau S, Richard AC, Boland A, Deleuze JF, Frebourg T, Hannequin D, Campion D, et al. De novo deleterious genetic variations target a biological network centered on Aβ peptide in early-onset Alzheimer disease. Mol Psychiatry. 2015;20:1046-56. [PubMed: 26194182]
• Seier M, Hiller A. Parkinson's disease and pregnancy: an updated review. Parkinsonism Relat Disord. 2017;40:11-7. [PubMed: 28506531]
• Seppi K, Weintraub D, Coelho M, Perez-Lloret S, Fox SH, Katzenschlager R, Hametner EM, Poewe W, Rascol O, Goetz CG, Sampaio C. The Movement Disorder Society Evidence-Based Medicine Review Update: treatments for the non-motor symptoms of Parkinson's disease. Mov Disord. 2011;26:S42-80. [PMC free article: PMC4020145] [PubMed: 22021174]
• Sharma M, Ioannidis JP, Aasly JO, Annesi G, Brice A, Bertram L, Bozi M, Barcikowska M, Crosiers D, Clarke CE, Facheris MF, Farrer M, Garraux G, Gispert S, Auburger G, Vilariño-Güell C, Hadjigeorgiou GM, Hicks AA, Hattori N, Jeon BS, Jamrozik Z, Krygowska-Wajs A, Lesage S, Lill CM, Lin JJ, Lynch T, Lichtner P, Lang AE, Libioulle C, Murata M, Mok V, Jasinska-Myga B, Mellick GD, Morrison KE, Meitnger T, Zimprich A, Opala G, Pramstaller PP, Pichler I, Park SS, Quattrone A, Rogaeva E, Ross OA, Stefanis L, Stockton JD, Satake W, Silburn PA, Strom TM, Theuns J, Tan EK, Toda T, Tomiyama H, Uitti RJ, Van Broeckhoven C, Wirdefeldt K, Wszolek Z, Xiromerisiou G, Yomono HS, Yueh KC, Zhao Y, Gasser T, Maraganore D, Krüger R, et al. A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants. J Med Genet. 2012;49:721-6. [PMC free article: PMC3488700] [PubMed: 23125461]
• Sheerin UM, Charlesworth G, Bras J, Guerreiro R, Bhatia K, Foltynie T, Limousin P, Silveira-Moriyama L, Lees A, Wood N. Screening for VPS35 mutations in Parkinson's disease. Neurobiol Aging. 2012;33:838.e1-5. [PMC free article: PMC3629567] [PubMed: 22154191]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Struhal W, Presslauer S, Spielberger S, Zimprich A, Auff E, Bruecke T, Poewe W, Ransmayr G, et al. VPS35 Parkinson's disease phenotype resembles the sporadic disease. J Neural Transm (Vienna). 2014;121:755-9. [PubMed: 24557499]
• Trenkwalder C, Chaudhuri KR, García Ruiz PJ, LeWitt P, Katzenschlager R, Sixel-Döring F, Henriksen T, Sesar Á, Poewe W, Baker M, Ceballos-Baumann A, Deuschl G, Drapier S, Ebersbach G, Evans A, Fernandez H, Isaacson S, van Laar T, Lees A, Lewis S, Martínez Castrillo JC, Martinez-Martin P, Odin P, O'Sullivan J, Tagaris G, Wenzel K, et al. Expert Consensus Group report on the use of apomorphine in the treatment of Parkinson's disease: clinical practice recommendations. Parkinsonism Relat Disord. 2015;21:1023-30. [PubMed: 26189414]
• Trinh J, Zeldenrust FMJ, Huang J, Kasten M, Schaake S, Petkovic S, Madoev H, Grünewald A, Almuammar S, König IR, Lill CM, Lohmann K, Klein C, Marras C. Genotype-phenotype relations for the Parkinson's disease genes SNCA, LRRK2, VPS35: MDSGene systematic review. Mov Disord. 2018;33:1857-70. [PubMed: 30357936]
• Vilariño-Güell C, Rajput A, Milnerwood AJ, Shah B, Szu-Tu C, Trinh J, Yu I, Encarnacion M, Munsie LN, Tapia L, Gustavsson EK, Chou P, Tatarnikov I, Evans DM, Pishotta FT, Volta M, Beccano-Kelly D, Thompson C, Lin MK, Sherman HE, Han HJ, Guenther BL, Wasserman WW, Bernard V, Ross CJ, Appel-Cresswell S, Stoessl AJ, Robinson CA, Dickson DW, Ross OA, Wszolek ZK, Aasly JO, Wu RM, Hentati F, Gibson RA, McPherson PS, Girard M, Rajput M, Rajput AH, Farrer MJ. DNAJC13 mutations in Parkinson disease. Hum Mol Genet. 2014;23:1794-801. [PMC free article: PMC3999380] [PubMed: 24218364]
• Vilariño-Güell C, Wider C, Ross OA, Dachsel JC, Kachergus JM, Lincoln SJ, Soto-Ortolaza AI, Cobb SA, Wilhoite GJ, Bacon JA, Behrouz B, Melrose HL, Hentati E, Puschmann A, Evans DM, Conibear E, Wasserman WW, Aasly JO, Burkhard PR, Djaldetti R, Ghika J, Hentati F, Krygowska-Wajs A, Lynch T, Melamed E, Rajput A, Rajput AH, Solida A, Wu RM, Uitti RJ, Wszolek ZK, Vingerhoets F, Farrer MJ. VPS35 mutations in Parkinson disease. Am J Hum Genet. 2011;89:162-7. [PMC free article: PMC3135796] [PubMed: 21763482]
• Vollstedt EJ, Schaake S, Lohmann K, Padmanabhan S, Brice A, Lesage S, Tesson C, Vidailhet M, Wurster I, Hentati F, Mirelman A, Giladi N, Marder K, Waters C, Fahn S, Kasten M, Brüggemann N, Borsche M, Foroud T, Tolosa E, Garrido A, Annesi G, Gagliardi M, Bozi M, Stefanis L, Ferreira JJ, Correia Guedes L, Avenali M, Petrucci S, Clark L, Fedotova EY, Abramycheva NY, Alvarez V, Menéndez-González M, Jesús Maestre S, Gómez-Garre P, Mir P, Belin AC, Ran C, Lin CH, Kuo MC, Crosiers D, Wszolek ZK, Ross OA, Jankovic J, Nishioka K, Funayama M, Clarimon J, Williams-Gray CH, Camacho M, Cornejo-Olivas M, Torres-Ramirez L, Wu YR, Lee-Chen GJ, Morgadinho A, Pulkes T, Termsarasab P, Berg D, Kuhlenbäumer G, Kühn AA, Borngräber F, de Michele G, De Rosa A, Zimprich A, Puschmann A, Mellick GD, Dorszewska J, Carr J, Ferese R, Gambardella S, Chase B, Markopoulou K, Satake W, Toda T, Rossi M, Merello M, Lynch T, Olszewska DA, Lim SY, Ahmad-Annuar A, Tan AH, Al-Mubarak B, Hanagasi H, Koziorowski D, Ertan S, Genç G, de Carvalho Aguiar P, Barkhuizen M, Pimentel MMG, Saunders-Pullman R, van de Warrenburg B, Bressman S, Toft M, Appel-Cresswell S, Lang AE, Skorvanek M, Boon AJW, Krüger R, Sammler EM, Tumas V, Zhang BR, Garraux G, Chung SJ, Kim YJ, Winkelmann J, Sue CM, Tan EK, Damásio J, Klivényi P, Kostic VS, Arkadir D, Martikainen M, Borges V, Hertz JM, Brighina L, Spitz M, Suchowersky O, Riess O, Das P, Mollenhauer B, Gatto EM, Petersen MS, Hattori N, Wu RM, Illarioshkin SN, Valente EM, Aasly JO, Aasly A, Alcalay RN, Thaler A, Farrer MJ, Brockmann K, Corvol JC, Klein C, et al. Embracing monogenic Parkinson's disease: the MJFF Global Genetic PD cohort. Mov Disord. 2023;38:286-303. [PubMed: 36692014]
• Wang C, Niu M, Zhou Z, Zheng X, Zhang L, Tian Y, Yu X, Bu G, Xu H, Ma Q, Zhang YW. VPS35 regulates cell surface recycling and signaling of dopamine receptor D1. Neurobiol Aging. 2016;46:22-31. [PMC free article: PMC5018432] [PubMed: 27460146]
• Wider C, Skipper L, Solida A, Brown L, Farrer M, Dickson D, Wszolek ZK, Vingerhoets FJ. Autosomal dominant dopa-responsive parkinsonism in a multigenerational Swiss family. Parkinsonism Relat Disord. 2008;14:465-70. [PubMed: 18342564]
• Williams ET, Chen X, Otero PA, Moore DJ. Understanding the contributions of VPS35 and the retromer in neurodegenerative disease. Neurobiol Dis. 2022;170:105768. [PMC free article: PMC9233057] [PubMed: 35588987]
• Zavodszky E, Seaman MN, Moreau K, Jimenez-Sanchez M, Breusegem SY, Harbour ME, Rubinsztein DC. Mutation in VPS35 associated with Parkinson's disease impairs WASH complex association and inhibits autophagy. Nat Commun. 2014a;5:3828. [PMC free article: PMC4024763] [PubMed: 24819384]
• Zavodszky E, Seaman MN, Rubinsztein DC. VPS35 Parkinson mutation impairs autophagy via WASH. Cell Cycle. 2014b;13:2155-6. [PMC free article: PMC4111667] [PubMed: 24963965]
• Zesiewicz TA, Sullivan KL, Arnulf I, Chaudhuri KR, Morgan JC, Gronseth GS, Miyasaki J, Iverson DJ, Weiner WJ, et al. Practice parameter: treatment of nonmotor symptoms of Parkinson disease: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2010;74:924-31. [PubMed: 20231670]
• Zimprich A, Benet-Pagès A, Struhal W, Graf E, Eck SH, Offman MN, Haubenberger D, Spielberger S, Schulte EC, Lichtner P, Rossle SC, Klopp N, Wolf E, Seppi K, Pirker W, Presslauer S, Mollenhauer B, Katzenschlager R, Foki T, Hotzy C, Reinthaler E, Harutyunyan A, Kralovics R, Peters A, Zimprich F, Brücke T, Poewe W, Auff E, Trenkwalder C, Rost B, Ransmayr G, Winkelmann J, Meitinger T, Strom TM. A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am J Hum Genet. 2011;89:168-75. [PMC free article: PMC3135812] [PubMed: 21763483]