Vps35-Related Parkinson Disease

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2021-01-18
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Summary

Clinical characteristics.

VPS35-related Parkinson disease (VPS35-PD) is defined as Parkinson disease caused by heterozygous VPS35 pathogenic variants. Currently, the only known VPS35 variant with confirmed pathogenicity is c.1858G>A (p.Asp620Asn). Except for a younger age of onset, VPS35-PD is clinically indistinguishable from Parkinson disease of unknown cause (so-called sporadic Parkinson disease). Variability among 50 individuals reported with molecularly confirmed VPS35-PD includes age of onset (mean: 51.0±8.7 years; range: 34-68 years), Parkinson subtype (tremor, akinetic rigid, mixed), first motor symptom, course of the disease (unilateral onset and slow disease progression are typical; dyskinesia and motor fluctuations may occur), and presence/absence of neuropsychiatric manifestations (including depression, schizophrenia, learning difficulties, mild cognitive impairment, and dementia).

Diagnosis/testing.

The diagnosis of VPS35-PD is established in a proband with at least two cardinal manifestations of Parkinson disease and the heterozygous VPS35 pathogenic variant c.1858G>A (p.Asp620Asn) identified on molecular genetic testing.

Management.

Treatment of manifestations: To date, treatment of VPS35-PD does not differ from that of Parkinson disease in general. Drugs to treat motor manifestations include the precursor of dopamine, levodopa, in combination with a peripheral dopa decarboxylase inhibitor (carbidopa, benserazide), dopamine agonists, inhibitors of catechol-O-methyltransferase (COMT) or monoamine oxidase-B (MAO-B), anticholinergics, and amantadine. A good response to levodopa is usually seen. Deep brain stimulation to the subthalamic nucleus is effective in treating motor fluctuations or dyskinesia. Effective treatments for neuropsychiatric and autonomic symptoms, which may be disabling, are limited. Patients benefit from physical, occupational, and speech therapies.

Surveillance: Follow-up clinical neurologic evaluations are recommended every three to 12 months (depending on clinical scenario) to assess tremor, hypokinesia, rigidity, gait, cognition, and neuropsychiatric symptoms as well as treatment effectiveness.

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.

Pregnancy management: No reports have addressed pregnancy management in women with VPS35-PD.

Genetic counseling.

VPS35-PD is inherited in an autosomal dominant manner. About 85% of affected individuals have an affected parent. Although about 15% of affected individuals are simplex cases (i.e., a single occurrence in a family), family data are insufficient to determine if the pathogenic variant is de novo. Each child of an individual with VPS35-PD has a 50% chance of inheriting the VPS35 pathogenic variant. Once the VPS35 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Diagnosis

Diagnostic criteria for Parkinson disease have been published [Berardelli et al 2013, Postuma et al 2015].

Suggestive Findings

VPS35-related Parkinson disease (VPS35-PD) should be considered in individuals with the following clinical and imaging findings (characteristic of all forms of PD) and a family history of PD.

Clinical findings

Cardinal manifestations of Parkinson disease including:

  • Resting tremor (rhythmic tremor usually of the hands and forearms when relaxed, which disappears with active limb movement)
  • Hypokinesia (partial or complete loss of muscle movement)
  • Rigidity (increased muscle tone resulting in resistance to passive movement)
  • Disturbance of postural reflexes (which maintain posture during movement)

Additional clinical characteristics:

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

Neuroimaging. Normal cranial MRI

Family history consistent with autosomal dominant inheritance, which can also include simplex cases (i.e., a single occurrence in a family) caused by a de novo pathogenic variant

Establishing the Diagnosis

The diagnosis of VPS35-PD is established in a proband with least two cardinal manifestations of Parkinson disease and the heterozygous VPS35 pathogenic variant c.1858G>A (p.Asp620Asn) identified on molecular genetic testing (see Table 1). Note: To date, this is the only VPS35 variant with confirmed pathogenicity. Other variants have been identified in persons with Parkinson disease but their pathogenicity remains equivocal (see Molecular Genetics).

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and genomic testing (comprehensive genome sequencing).

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 VPS35-PD are diagnosed by the following recommended testing or testing to be considered.

Recommended Testing

A multigene Parkinson disease panel including VPS35 and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Given the rarity of VPS35-related Parkinson disease, some panels for Parkinson disease may not include this gene.

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

Testing to Consider

Comprehensive genome sequencing (when clinically available) includes exome sequencing and genome sequencing. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Note: Single-gene testing (sequence analysis of VPS35) is typically not recommended. Because the phenotype overlaps with that of other inherited forms of Parkinson disease, a multigene panel or exome sequencing are typically used in lieu of single-gene testing.

Table 1.

Molecular Genetic Testing Used in VPS35-Related Parkinson Disease

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
VPS35Sequence analysis 324/24 4, 5
Gene-targeted deletion/duplication analysis 6None reported 7
1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

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

4.

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]

5.

To date, the pathogenic variant p.Asp620Asn has been found in four simplex cases (i.e., a single occurrence in a family) and 20 probands (index patients) with familial Parkinson disease.

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.

Vilariño-Güell et al [2011], Verstraeten et al [2012]

Clinical Characteristics

Clinical Description

To date, 24 probands with molecularly confirmed VPS35-related Parkinson disease (i.e., due to the p.Asp620Asn pathogenic variant) have been reported [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]; 20 were familial and four were simplex cases (a single occurrence of VPS35-PD in a family). By testing at-risk relatives in the 20 familial cases, the authors confirmed the diagnosis of VPS35-PD in 26 additional individuals worldwide, bringing to 50 the total of number of individuals with molecularly confirmed VPS35-PD.

Except for a younger age of onset, VPS35-PD is clinically undistinguishable from Parkinson disease of unknown cause. Variability within families with VPS35-PD includes age of onset, first motor symptom, prevailing motor manifestations throughout the course of the disease, and presence/absence of neuropsychiatric manifestations (e.g., depression, dementia).

Age of onset. Mean age at disease onset is 51.0±8.7 years (range: 34-68 years; n=50); 51.2% are female (22/43).

Parkinson subtype. While the tremor-dominant subtype of Parkinson disease (with leg tremor as the initial manifestation) was thought to be common [Wider et al 2008], subsequently reported families had akinetic rigid and mixed subtypes of Parkinson disease, and some individuals never developed tremor [Lesage et al 2012, Sheerin et al 2012].

Course of the disease

  • Asymmetric presentation at disease onset is typical.
  • The disease course is usually slowly progressive.
  • Dyskinesia and motor fluctuations may occur.
    Of note, atypical motor findings, cerebellar signs, or ocular motor signs have not been reported.

Neuropsychiatric manifestations

  • Depression has been reported occasionally; in one family depression was common [Zimprich et al 2011].
  • In one family with VPS35-PD, schizophrenia was reported in two family members with Parkinson disease; however, it was not explicitly stated that the two individuals had been tested for the p.Asp620Asn variant [Wider et al 2008, Vilariño-Güell et al 2011].
  • Learning difficulties, mild cognitive impairment, and dementia have been reported in several affected individuals.

Other findings reported

  • Impaired sense of smell [Zimprich et al 2011, Sheerin et al 2012, Struhal et al 2014]
  • Autonomic manifestations including orthostasis and gastrointestinal symptoms (constipation)

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

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

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 correlation is possible as p.Asp620Asn is the only confirmed pathogenic variant to date.

Penetrance

The penetrance of the p.Asp620Asn variant is high and age dependent [Trinh et al 2014, Lill 2016]. Of note, to date data are too limited to allow quantification of penetrance.

Age-dependent penetrance (onset range: 34-68 years) is most likely reflected in the following information on ten unaffected individuals heterozygous for the p.Asp620Asn variant identified in families with VPS35-PD:

  • Six were age 62 years or younger [Zimprich et al 2011, Kumar et al 2012].
  • Four were between ages 49 and 67 years [Vilariño-Güell et al 2011].

The p.Asp620Asn variant is very rare and was not found in:

  • Control groups screened for VPS35 variants, including Zimprich et al [2011], Vilariño-Güell et al [2011], and Sharma et al [2012] – of which the largest study [Sharma et al 2012] had 6,513 individuals;
  • The Genome Aggregation Database (gnomAD), which contains data for 123,136 exomes and 15,496 whole genomes [Lek et al 2016].

Nomenclature

VPS35-related Parkinson disease is also referred to as "PARK-VPS35" per the alternative nomenclature system proposed by Marras et al [2012].

Prevalence

To date 24 probands with VPS35-related Parkinson disease 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]. Twenty were familial and four were simplex cases (a single occurrence of VPS35-PD in a family). By testing relatives at risk in the 20 familial cases, the authors confirmed the diagnosis of VPS35-PD in an additional 26 individuals.

Nine studies with sample sizes greater than 500 patients with PD are available. They comprise a total of 19,294 individuals. In these nine studies, the VPS35 p.Asp620Asn variant was identified in 12 familial index cases and three simplex cases [Vilariño-Güell et al 2011, Zimprich et al 2011, Ando et al 2012, Guo et al 2012, Kumar et al 2012, Sharma et al 2012, Sheerin et al 2012, Zhang et al 2012, Chen et al 2013].

The prevalence of VPS35-PD ranged from 0.0% to 1.5% in the following specific patient populations, which only included persons with familial PD:

  • 2:131 in Austria [Zimprich et al 2011]
  • 3:246 in France [Lesage et al 2012]
  • 3:300 in Japan [Ando et al 2012]
  • 1:191 in the UK [Sheerin et al 2012]
  • 0:475 and 0:250 in Italy [Guella et al 2012, Gagliardi et al 2014]

In one study (including both familial and simplex cases) heterozygote frequencies were 2:120 in Yemenite Jews and 1:199 in Tunisians [Vilariño-Güell et al 2011].

The p.Asp620Asn variant was not found in 11 studies involving individuals with sporadic and familial Parkinson disease from Europe, the US, South Africa, China (4 studies), and India [Deng et al 2012, Guo et al 2012, Verstraeten et al 2012, Zhang et al 2012, Chen et al 2013, Nuytemans et al 2013, Sudhaman et al 2013, Blanckenberg et al 2014, Kalinderi et al 2015, Bandrés-Ciga et al 2016, Török et al 2016].

The frequency of the VPS35 p.Asp620Asn variant in the general (control) population is very low, and not exactly determined.

Differential Diagnosis

The differential diagnosis of VPS35-related Parkinson disease (VPS35-PD) includes Parkinson disease of unknown cause (sometimes referred to as idiopathic or sporadic Parkinson disease). Apart from a younger age at onset, the phenotype of VPS35-PD (onset at age 50.2±8.9 years) is clinically indistinguishable from sporadic Parkinson disease (average onset at 60 years). Thus, the differential diagnosis of VPS35-PD is the same as it is for PD in general (see Parkinson Disease Overview). In addition, an extensive list of differential diagnosis of familial parkinsonism can be found in the book chapter by Fujioka & Wszolek [2014].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with VPS35-related Parkinson disease, the following evaluations are recommended:

  • Perform neurologic examination including assessment of tremor, hypokinesia, rigidity, postural reflexes, gait (propulsion, arm swing, stride length), and autonomic findings (e.g., orthostasis).
  • Assess cognitive function and psychiatric manifestations (e. g., hallucinations, delusions, depression, anxiety, sleep disorders).
  • Evaluate levodopa response.
  • Consider consultation with a clinical geneticist and/or genetic counselor.

Treatment of Manifestations

To date, the treatment of individuals with VPS35-PD does not differ from that of Parkinson disease in general. The following is a brief summary of recommended treatment for PD, based on extensive existing guidelines and recommendations for pharmacotherapy of motor and non-motor manifestations of PD 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].

Pharmacotherapy. Drugs to treat motor manifestations include the precursor of dopamine, levodopa, in combination with a peripheral dopa decarboxylase inhibitor (carbidopa, benserazide), dopamine agonists, inhibitors of catechol-O-methyltransferase (COMT) or monoamine oxidase-B (MAO-B), anticholinergics, and amantadine. A good levodopa response was seen in nearly all reported individuals with VPS35-PD.

General recommendations for treatment of Parkinson disease of unknown cause include the following:

  • To reduce or delay side effects (e.g., dyskinesias, hallucinations, impulse control disorder) of levodopa and dopaminergic medication, doses should not exceed the levels required for a satisfactory clinical response. In younger patients, dopamine agonists should be given a preference.
  • Dyskinesias can be treated with reduction of levodopa doses, use of dopamine receptor agonists, deep-brain stimulation, and continuous application of levodopa or apomorphine.
  • Patients treated with ergot-derived dopamine agonists require periodic echocardiograms. Ergot-derived dopaminergic drugs should be discontinued if fibrotic heart-valve changes are revealed [Antonini & Poewe 2007].

Deep brain stimulation to the subthalamic nucleus was repeatedly reported to be effective in the treatment of disabling motor fluctuations or dyskinesia in persons with VPS35-PD.

Other. Overall, effective treatment for neuropsychiatric and autonomic symptoms (which may be disabling) is limited. Atypical neuroleptic agents such as low-dose clozapine and reduction of dopaminergic therapy can decrease delusions and hallucinations. If depression occurs, it should be treated according to guidelines. Droxidopa may be used to treat orthostasis.

Patients also benefit from physical, occupational, and speech therapy.

Surveillance

For VPS35-PD (as well as in Parkinson disease in general), follow-up clinical neurologic evaluations are recommended every three to 12 months (depending on the clinical scenario and the needs of the individual) to assess tremor, hypokinesia, rigidity, gait, cognition, and neuropsychiatric symptoms as well as treatment effectiveness.

Agents/Circumstances to Avoid

Neuroleptic drugs may increase the severity of parkinsonism in VPS35-PD (as in Parkinson disease in general). In general, atypical neuroleptics are less likely to exacerbate parkinsonism than typical neuroleptics. 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].

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 VPS35-PD are not available. The effect of PD in general on pregnancy has not been well characterized, since pregnancy is uncommon in women with PD. While most reports indicate that disease manifestations worsen during pregnancy, improvement has also been described (for a review see Robottom et al [2008], Kranick et al [2010]).

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

  • Levodopa crosses the placenta and some animal models have shown that high doses of levodopa administered during pregnancy may induce skeletal and visceral malformations; however, in more than 30 cases reported in the literature, levodopa treatment during human pregnancy did not result in adverse fetal outcome [Scott & Chowdhury 2005].
  • Amantadine should be avoided during pregnancy, if possible, since adverse pregnancy outcomes have been reported in rats.

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.