Clinical characteristics.

Parkin type of early-onset Parkinson disease (PARK-Parkin) is characterized by the cardinal signs of Parkinson disease (PD): bradykinesia, resting tremor, and rigidity. The median age at onset is 31 years (range: 3-81 years). The disease is slowly progressive: disease duration of more than 50 years has been reported. Clinical findings vary; hyperreflexia is common. Lower-limb dystonia may be a presenting sign and cognitive decline appears to be no more frequent than in the general population. Dyskinesia as a result of treatment with levodopa frequently occurs.

Diagnosis/testing.

The diagnosis of PARK-Parkin is established in a proband with suggestive findings and biallelic pathogenic variants in PRKN identified by molecular genetic testing.

Management.

Treatment of manifestations: Levodopa and dopamine agonists, MAO B inhibitors, COMT inhibitors, and amantadine; deep brain stimulation for those experiencing difficulty with levodopa therapy.

Surveillance: Neurologic follow up including assessment of treatment every six to 12 months.

Agents/circumstances to avoid: Use of levodopa therapy that exceeds the dose needed for satisfactory clinical response. Neuroleptic treatment may exacerbate parkinsonism.

Genetic counseling.

PARK-Parkin is inherited in an autosomal recessive manner. At conception, each sib of a proband has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Once the PRKN pathogenic variants in a family are known, carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

Parkin type of early-onset Parkinson disease (PARK-Parkin) should be suspected in individuals with the following clinical findings and family history.

Clinical findings

• Onset before age 40 years in most individuals (median age: 31 years; range: 3-81 years) or, rarely, juvenile onset (age <20 years).
• Lower-limb dystonia (may be a presenting sign or may occur during disease progression), which sometimes remains an isolated finding for years
• Slow disease progression
• Absence of dementia in most individuals (present in <3%)
• Well-preserved sense of smell
• Marked and sustained response to oral administration of levodopa, which is frequently associated with levodopa-induced motor fluctuations and dyskinesias (abnormal involuntary movements)

Family history consistent with autosomal recessive inheritance, including parental consanguinity

Establishing the Diagnosis

The diagnosis of PARK-Parkin is established in a proband with suggestive findings and biallelic pathogenic variants in PRKN identified by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (typically a multigene panel that includes deletion/duplication analysis) and gene dosage analysis (typically multiplex ligation-dependent analysis). Alternatively, PRKN variants can be assessed by exome or genome sequencing taking into account copy number variations.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas exome or genome testing does not. Because the phenotype of PARK-Parkin is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of PARK-Parkin has not been considered are more likely to be diagnosed using exome or genome testing (see Option 2).

Clinical Description

Parkin type of early-onset Parkinson disease (PARK-Parkin) is characterized by the cardinal signs of Parkinson disease (PD): bradykinesia, resting tremor, and rigidity. The median age at onset is 31 years (range: 3-81 years). The disease is slowly progressive and disease duration of more than 50 years has been reported. Clinical findings vary; hyperreflexia is common. Lower-limb dystonia may be a presenting sign and cognitive decline appears to be no more frequent than in the normal population. Dyskinesia as a result of treatment with dopaminergic drugs frequently occurs.

Women and men are affected with equal frequency. Age at onset is highly variable, even among individuals with the same pathogenic variant [Chien et al 2006]; onset is usually before age 40 years; the median age at onset is 31 years (25th %ile: 23 years; 75th %ile: 38 years; range: 3-81 years) (see www.MDSGene.org).

Clinical findings vary; however, tremor, bradykinesia, and dystonia are the most common presenting signs. Dystonia is observed in 65% (177/271) of affected individuals for whom this information is available. Almost half of affected individuals present with hyperreflexia. The diagnosis of PD may be delayed due to unusual clinical features, especially in patients with an early manifestation [Borsche et al 2019, Ruiz-Lopez et al 2019].

PARK-Parkin is not associated with specific behavioral, neuropsychological, or psychiatric manifestations [Caccappolo et al 2011, Srivastava et al 2011, Kasten et al 2018]. Cognitive impairment is uncommon, and dementia is observed very rarely [Benbunan et al 2004, Grünewald et al 2013, Kasten et al 2018].

The disease is slowly progressive: disease duration of greater than 50 years has been reported. In later disease stages, freezing of gait, postural deformities, and motor fluctuations may be common features, whereas dementia usually does not develop [Doherty et al 2013].

Genotype-Phenotype Correlations

No clear-cut genotype-phenotype correlations have been observed.

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 PRKN pathogenic variants is "PARK-Parkin" [Marras et al 2016].

Families with PARK-Parkin were mostly described in Japan in the 1970s as having "autosomal recessive juvenile parkinsonism" (AR-JP).

Prevalence

The population-based prevalence of PARK-Parkin is largely unknown. However, in Europe, PARK-Parkin accounts for approximately 50% of autosomal recessive parkinsonism and 18% of parkinsonism in simplex cases (i.e., a single occurrence of parkinsonism in a family) with onset before age 45 years [Lücking et al 2000].

The percentage of PARK-Parkin rapidly decreases with increasing age at onset: After age 30 years, only a few percent of simplex cases have biallelic PRKN pathogenic variants. However, in families with a clear-cut autosomal recessive mode of inheritance, the age-related decrease is less pronounced [Periquet et al 2003].

Prevalence of PARK-Parkin appears to be similar in all populations. Individuals with PARK-Parkin from many different regions have been reported [Kasten et al 2018].

Early-Onset Parkinson Disease

Parkin type of early-onset Parkinson disease (PARK-Parkin) is often clinically indistinguishable from Parkinson disease of other etiologies (see Parkinson Disease Overview). Rigidity, bradykinesia, and resting tremor are variably combined in both disorders.

PARK-Parkin and early-onset Parkinson disease of other etiologies (see Table 3) are difficult to distinguish by clinical examination.

Dopa-Responsive Dystonia

For individuals with juvenile-onset parkinsonism, especially those with prominent dystonia, dopa-responsive dystonia should be considered:

• GTP cyclohydrolase 1-deficient dopa-responsive dystonia caused by heterozygous pathogenic variants in GCH1
• Tyrosine hydroxylase-deficient dopa-responsive dystonia caused by biallelic pathogenic variants in TH
• Sepiapterin reductase-deficient dopa-responsive dystonia caused by biallelic pathogenic variants in SPR

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Parkin type early-onset Parkinson disease (PARK-Parkin), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Assess the presence and the severity of parkinsonian signs, non-motor features, and treatment-related complications using the Unified Parkinson's disease rating scale (UPDRS) [Fahn & Elton 1987] or the Movement Disorder Society (MDS) UPDRS [Goetz et al 2008].
• Assess the presence of atypical signs, such as hyperreflexia and dystonia.
• Evaluate the degree of response to treatment.
• Assess for cognitive or behavioral problems.
• Consider consultation with a clinical geneticist and/or genetic counselor.

Treatment of Manifestations

To date, the treatment of PARK-Parkin does not differ from that of Parkinson disease of other etiologies. No specific guidelines are currently available.

• The motor impairment usually responds very well to low doses of dopaminergic medication; the response is typically sustained even after long disease duration. To reduce or delay side effects, levodopa doses should not exceed the levels required for satisfactory clinical response.
  On average, the response to low doses of levodopa is excellent and sustained. The likelihood of developing levodopa-induced dyskinesias is higher than in individuals with parkinsonism resulting from other etiologies.
• The most relevant treatment-related problem is the early occurrence of levodopa-induced dyskinesias (abnormal involuntary movements) and motor fluctuations. The management of treatment-related complications is not different from the strategies applied in Parkinson disease of other etiologies, and includes deep brain stimulation (DBS) in selected cases. Given its rarity, PARK-Parkin appears to be overrepresented in patient populations undergoing DBS.
• The response to DBS is favorable, including in patients with a long disease duration [Ligaard et al 2019].

Surveillance

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

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

Pregnancy is rare in women with Parkinson disease. Only one instance of a successful pregnancy in a woman with PARK-Parkin has been reported [Serikawa et al 2011]. The woman successfully gave birth to spontaneously conceived dichorionic/diamnionic male twins at age 27 years. Exacerbation of her motor disabilities occurred during late pregnancy. She was treated with levodopa/carbidopa only during the period of organogenesis. Both babies were born healthy, without any evidence of psychomotor impairment at age two years.

Both levodopa and carbidopa have the ability to cross the placenta. Limited data from case reports and pregnancy registries do not suggest an increased risk of major malformations in fetuses exposed to levodopa [Seier & Hiller 2017]. Currently, levodopa is considered a first-line therapy for pregnant women with PD who experience progressive motor symptoms during pregnancy.

Data on the risk of adverse fetal outcome from the use of other medications (e.g., dopamine agonists and anticholinergics) to treat PD manifestations during pregnancy are limited, but generally reassuring [Seier & Hiller 2017]. Some reports have suggested an increased risk of adverse fetal outcome with the use of amantadine during pregnancy; therefore, this medication is generally avoided.

Worsening of parkinsonian manifestations could in part be explained by the reduction of dopaminergic replacement therapy. If possible, dopaminergic medication should be limited to levodopa/decarboxylase inhibitor to minimize the potential risk for teratogenicity at least over the course of the embryonic phase.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

PRKN variants result in impaired mitochondrial function and clearance of dysfunctional mitochondria. Thus, individuals PARK-Parkin may preferentially benefit from mitochondrial enhancers that are currently being tested in clinical trial in a gene-targeted fashion [Prasuhn et al 2019].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Parkin type of early-onset Parkinson disease (PARK-Parkin) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one PRKN pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm the genetic status of each parent and to allow reliable recurrence risk assessment. Although the parents of a proband with PARK-Parkin are typically heterozygous, in rare families:
  • Only one parent is heterozygous for a PRKN pathogenic variant and the proband has PARK-Parkin as the result of one inherited and one de novo PRKN pathogenic variant [Williams et al 2018].
  • One parent is affected (based on the presence of biallelic PRKN pathogenic variants) and the other parent is heterozygous for one PRKN pathogenic variant [Maruyama et al 2000, Bonifati et al 2001, Lücking et al 2001, Kobayashi et al 2003, Pellecchia et al 2007]. This occurrence in any autosomal recessive disorder is termed pseudodominant inheritance.
• The risk to heterozygotes of developing manifestations is not yet conclusively determined (see Genetically Related Disorders, Role of heterozygous PRKN pathogenic variants).

Sibs of a proband

• If each parent is known to be heterozygous for a PRKN 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 PRKN pathogenic variant. Age of onset is highly variable; sibs who inherit two pathogenic variants may have an earlier or later age of onset than the proband.
• The risk to heterozygotes of developing symptoms is not yet conclusively determined (see Genetically Related Disorders, Role of heterozygous PRKN pathogenic variants).

Offspring of a proband

• Unless an individual with PARK-Parkin has children with an affected individual or heterozygote, his/her offspring will be obligate heterozygotes (carriers) for a pathogenic variant in PRKN.
• The empiric recurrence risk to offspring of a proband depends on the frequency of heterozygotes, which is ≤3.7% in the general population [Grünewald & Klein 2012], thus generating a risk of ≤1% to offspring of being affected. As for other autosomal recessive disorders, the risk is higher when the proband and his/her reproductive partner are related.

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

Heterozygote Detection

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

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of genetic status, 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, heterozygous, or at risk of being heterozygous.

Prenatal Testing and Preimplantation Genetic Testing

Once the PRKN pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk 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

PRKN encodes parkin, which comprises a ubiquitin-like domain at the N terminus and a RING (really interesting new gene) domain composed of three RING finger motifs (RING0, 1, and 2). Like other RING finger proteins, parkin exhibits E3 ubiquitin ligase activity [Imai et al 2000, Shimura et al 2000, Zhang et al 2000] targeting a number of proteins for proteasomal degradation. Parkin can additionally mediate nondegradative modes of ubiquitination, which appear to be required for the survival of nigrostriatal dopaminergic neurons [Moore 2006].

Parkin is also involved in the maintenance of mitochondrial function and integrity, and protection from multiple stressors, hence acting as neuroprotectant. Parkin works in a pathway with its companion protein PINK1, another protein associated with autosomal recessive early-onset parkinsonism [Valente et al 2004]. They are jointly responsible for mitochondrial quality control and removal of dysfunctional mitochondria [Narendra et al 2012, Rakovic et al 2013, Rakovic et al 2019]. Parkin also triggers mitochondrial-induced inflammation through activation of the STING pathway [Sliter et al 2018].

Mechanism of disease causation. It is postulated that the vast majority of PRKN pathogenic variants result in loss of function of normal E3 ubiquitin ligase activity by loss (truncating variants) or inactivation (missense variants) of the protein.

Pathogenic variants may result in the accumulation of its substrates no longer appropriately targeted for degradation; however, this has not been confirmed.

PRKN-specific laboratory technical considerations. Gene-targeted deletion/duplication testing should be considered due to the high rate of exon rearrangements (deletions and duplications of whole exons accounting for about half of PRKN variants; see Table 1).

Published Guidelines / Consensus Statements

• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 5-25-21.
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2018. Accessed 5-25-21.

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Author History

Alexis Brice, MD; Hôpital de la Pitié-Salpêtrière (2001-2013)
Norbert Brüggemann, MD (2013-present)
Alexandra Dürr, MD, PhD; Hôpital de la Pitié-Salpêtrière (2001-2013)
Christine Klein, MD (2013-present)
Christoph Lücking, MD; Ludwig-Maximilians University (2001-2013)

Revision History

• 23 April 2020 (bp) Comprehensive update posted live
• 4 April 2013 (me) Comprehensive update posted live
• 1 October 2007 (me) Comprehensive update posted live
• 6 November 2006 (cd) Revision: prenatal diagnosis available
• 8 July 2005 (me) Comprehensive update posted live
• 14 November 2003 (ab) Revisions
• 3 October 2003 (cd) Revision: change in test availability
• 6 June 2003 (ca) Comprehensive update posted live
• 17 April 2001 (me) Review posted live
• November 2000 (ab) Original submission