Clinical Manifestations of Parkinson Disease

Parkinson disease (PD), a neurodegenerative disorder, is characterized by slowed movement (bradykinesia), resting tremor, muscle rigidity, and often postural instability, particularly in later stages of the disease [Bloem et al 2021]. The first clinical manifestations are typically unilateral and may include other abnormal movements such as postural or action tremor as well as limb dystonia. Common associated non-motor findings include insomnia, depression, anxiety, rapid eye movement (REM) sleep behavior disorder, fatigue, constipation, and hyposmia. As part of a prodromal phase, non-motor findings may predate the clinical diagnosis of PD by years [Bloem et al 2021]. With disease progression, bilateral manifestations, balance disturbances with falls, and other complications such as levodopa-induced dyskinesias and motor fluctuations develop [Bloem et al 2021]. Dementia and/or psychosis occur in 30%-40% of affected individuals.

The clinical diagnosis of PD is based on the clinical findings of bradykinesia plus rest tremor and/or rigidity. An important supportive diagnostic feature is a beneficial response to dopaminergic therapy. Dementia is not an exclusion criterion for diagnosis. Operational clinical research criteria for PD have been defined in the Queen Square Brain Bank and the International Parkinson and Movement Disorder Society (MDS) criteria [Gibb & Lees 1989, Postuma et al 2015].

In instances of diagnostic uncertainty, especially in the early stages of PD, neuroimaging such as dopamine transporter single-photon emission computed tomography (DAT-SPECT) or fluorodopa positron emission tomography (PET) can be used to make a more definitive diagnosis of dopaminergic deficit [Bega et al 2021]. While these studies can help to support the presence of dopaminergic dysfunction, they cannot distinguish between PD and other degenerative disorders that include parkinsonism such as Parkinson-plus syndromes (see Differential Diagnosis). DAT-SPECT is most commonly used to distinguish PD from essential tremor; normal DAT-SPECT results can also be used to verify that a symptomatic individual has a typically non-degenerative form of parkinsonism, such as drug-induced parkinsonism or GTP cyclohydrolase 1-deficient dopa-responsive dystonia. Laboratory tests such as copper studies or imaging studies such as brain MRI may be useful in excluding alternative diagnoses such as Wilson disease, infarction, tumor, or normal-pressure hydrocephalus.

Typical PD is associated with brain alpha-synuclein deposition and Lewy body formation at autopsy; however, a clinically similar phenotype can occur without Lewy body formation. This is particularly common in some monogenic forms of PD (e.g., LRRK2- and PRKN-related PD) [Poulopoulos et al 2012, Doherty et al 2013, Kalia et al 2015, Morris et al 2024]. The pathologic diversity of PD, particularly monogenic PD, has been highlighted by the use of alpha-synuclein seed amplification assays (alpha-syn-SAA), demonstrating that around 30% of individuals with LRRK2-related PD have a negative alpha-syn-SAA [Siderowf et al 2023].

The onset of PD is most commonly around age 68 years but can vary considerably. The following are generally accepted descriptions regarding age of onset [Mehanna et al 2022]:

• Juvenile-onset PD: age <21 years
• Early-onset PD: age 21-50 years
• Late-onset PD: age ≥50 years

Complex parkinsonism may occur in some forms of early-onset and juvenile-onset parkinsonism and may be indicated by additional features such as intellectual disability (which may predate the onset of parkinsonism), early dementia, seizures, spasticity, eye movement abnormalities, severe dystonia, poor or incomplete response to levodopa, and in some individuals brain iron accumulation on brain MRI, overlapping with neurodegeneration with brain iron accumulation (NBIA) disorders. Complex early-onset or juvenile-onset parkinsonism may be caused by biallelic pathogenic variants in ATP13A2, DAGLB, DNAJC6, FBXO7, PLA2G6, PTPA, PTRHD1, SYNJ1, and VPS13C [Lunati et al 2018, Riboldi et al 2022].

Adult-Onset Monogenic PD

Table 1 lists the genes associated with early-onset monogenic PD (age 21-50 years) and late-onset monogenic PD (age ≥50 years). Table 1 uses the recommended designations by the International Parkinson and Movement Disorder Society Task Force for Nomenclature of Genetic Movement Disorders, in which the phenotype prefix, PARK, is followed by the italicized gene symbol (e.g., PARK-LRRK2) [Marras et al 2016, Lange et al 2022].

GBA1 (OMIM 168600). GBA1 pathogenic variants have variable penetrance dependent on age, genotype, and ethnicity, as well modifier variants and environmental factors [Iwaki et al 2019, Lüth et al 2020]. Disagreement exists as to whether PARK-GBA1 should be classified as a monogenic disorder or a risk factor due to its low age-related penetrance, particularly in population cohorts [Ji et al 2020]. However, some Gaucher disease-causing GBA1 variants (e.g., p.Leu483Pro) have an estimated penetrance of PD approaching that of LRRK2 pathogenic variants [Gan-Or et al 2015, Lee et al 2017]. The estimated penetrance of a heterozygous GBA1 pathogenic variant causing PD is 10%-15% by age 80 years in Gaucher disease cohorts and 20%-30% in PD cohorts [Balestrino et al 2020]. Population-based estimates of penetrance are much lower (e.g., 1.1%-5.4% by age 75 years) [Straniero et al 2020].

GBA1 should be considered if there is a family history of Gaucher disease, although this seems to be rare in certain populations (e.g., Asian, African). Some GBA1 pathogenic variants are more common in individuals of Ashkenazi Jewish ancestry. Identification of a GBA1 pathogenic variant may be important for determining risk of Gaucher disease in offspring, and drug trial eligibility but may not fully account for an autosomal dominant family history of PD or the occurrence of early-onset disease that may be due to other high-penetrance variants.

Juvenile-Onset Monogenic PD

Pathogenic variants in several genes have been associated with juvenile-onset monogenic PD (i.e., onset age generally <21 years but can vary) (see Table 2). Inheritance of juvenile-onset monogenic PD is usually autosomal recessive; the clinical presentation often includes additional manifestations such as dystonia, spasticity, gaze palsy, intellectual disability, early dementia, and seizures [Lunati et al 2018, Riboldi et al 2022]. Many individuals have been reported from underrepresented populations [Lim et al 2024].

Other suspected genes involved in monogenic PD. Evidence that pathogenic variants in other genes may be associated with monogenic PD is less well supported [Blauwendraat et al 2020]. Genes reported to be associated with monogenic PD with conflicting evidence include DNAJC13, EIF4G1, GIGYF2, HTRA2, LRP10, TMEM230, and UQCRC1 [Lin et al 2020, Brücke et al 2025]. Pathogenic variants in CHCHD2 have largely been reported in East Asian populations.

Additional studies are needed to confirm and clarify the role of pathogenic variants in these genes in PD causation. While these genes may appear on PD multigene testing panels, it is suggested that they not be included in diagnostic testing because of their currently uncertain role (see Evaluation Strategies).

Mode of Inheritance

Monogenic Parkinson disease (PD) is inherited in an autosomal dominant (LRRK2, RAB32 [p.Ser71Arg], SNCA, and VPS35), autosomal recessive (ATP13A2, DNAJC6, FBXO7, PARK7 [DJ1], PINK1, PLA2G6, PRKN, SYNJ1, and VPS13C), or X-linked (RAB39B) manner.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Almost all individuals diagnosed with autosomal dominant PD inherited a monogenic PD-related pathogenic variant from a parent, who may or not be affected.
• In very rare instances, an individual diagnosed with autosomal dominant PD has the disorder as the result of a de novo pathogenic variant.
• If the proband appears to be the only affected family member (i.e., a simplex case), predictive molecular genetic testing may be considered for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, variable expression, or (especially in PARK-LRRK2) reduced penetrance. Therefore, de novo occurrence of a monogenic PD-related pathogenic variant cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant.
• 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 gonadal (or somatic and gonadal) 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 (gonadal) cells only.

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 is known to have the autosomal dominant PD-related pathogenic variant identified in the proband, the risk to each sib of inheriting the pathogenic variant is 50%.
• While all sibs who inherit a familial pathogenic variant will be at increased risk for PD, not all heterozygous sibs will manifest the disease. Reduced, age-related penetrance is well recognized, particularly in PARK-LRRK2.
• PARK-SNCA is associated with higher penetrance, although this varies with type of pathogenic variant [Koros et al 2017].
• If the monogenic PD-related pathogenic variant identified 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 possibility of parental gonadal mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the monogenic PD-related pathogenic variant identified in the proband but are clinically unaffected, sibs are still presumed to be at increased risk for PD because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.

Offspring of a proband

• Each child of an individual with an autosomal dominant PD-related pathogenic variant has a 50% chance of inheriting the pathogenic variant.
• The probability that offspring who inherit a pathogenic variant will manifest PD increases with advancing age.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an individual with autosomal recessive PD are presumed to be heterozygous for a monogenic PD-related pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a monogenic PD-related 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 PD is not yet determined.
  • Individuals who are heterozygous for a pathogenic variant in PARK7, PINK1, or PRKN (genes typically associated with autosomal recessive adult-onset PD) probably do not have a significantly increased risk of PD.
  • No increased risk of PD has been shown in recent large studies of individuals with single heterozygous PRKN pathogenic variants [Yu et al 2021, Zhu et al 2022].

Sibs of a proband

• If both parents are known to be heterozygous for a monogenic PD-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
• The risk to heterozygotes of developing PD is not yet determined.
  • Individuals who are heterozygous for a pathogenic variant in PARK7, PINK1, or PRKN (genes typically associated with autosomal recessive adult-onset PD) probably do not have a significantly increased risk of PD.
  • No increased risk of PD has been shown in recent large studies of individuals with single heterozygous PRKN pathogenic variants [Yu et al 2021, Zhu et al 2022].

Offspring of a proband. The offspring of an individual with autosomal recessive PD are obligate heterozygotes for a pathogenic variant.

X-Linked Inheritance – Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disorder nor will he be hemizygous for the RAB39B pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the RAB39B pathogenic variant cannot be detected in her leukocyte DNA, she most likely has gonadal mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a de novo RAB39B pathogenic variant (in which case the mother is not a heterozygote), or the mother may have somatic/gonadal mosaicism.
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.

Parents of a female proband

• A female proband may have inherited the RAB39B pathogenic variant from either her mother or her father, or the pathogenic variant may be de novo.
• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a de novo pathogenic variant from those with an inherited pathogenic variant. Molecular genetic testing of the mother (and possibly the father, or subsequently the father) can determine if the pathogenic variant was inherited.

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

• If the mother of the proband has a RAB39B pathogenic variant, the chance of the mother transmitting it in each pregnancy is 50%.
  • Males who inherit the pathogenic variant will be affected;
  • Females who inherit the pathogenic variant will be heterozygotes and their risk of developing PD is unknown.
• If the proband represents a simplex case and if the RAB39B pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal gonadal mosaicism.

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

• If the mother of the proband has a RAB39B pathogenic variant, the chance of the mother transmitting it in each pregnancy is 50% (see Sibs of a male proband).
• If the father of the proband has a RAB39B pathogenic variant, he will transmit it to all his daughters and none of his sons.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the RAB39B pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is greater than that of the general population because of the possibility of parental gonadal mosaicism.

Offspring of a proband

• Hemizygous males transmit the RAB39B pathogenic variant to all of their daughters and none of their sons.
• Women with a RAB39B pathogenic variant have a 50% chance of transmitting the pathogenic variant to each child.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the RAB39B pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Predictive testing for LRRK2-, RAB32- (p.Ser71Arg), SNCA-, or VPS35-related adult-onset autosomal dominant PD (i.e., testing of asymptomatic, at-risk individuals)

• Predictive testing for relatives at risk for LRRK2-, RAB32- (p.Ser71Arg), SNCA-, and VPS35-related adult-onset autosomal dominant PD is possible once the monogenic PD-related pathogenic variant has been identified in an affected family member. However, the likelihood that an asymptomatic individual found to be heterozygous for a monogenic PD-related pathogenic variant will develop manifestations of the disorder (and at what age) may be difficult to predict and information on penetrance for the gene/variant should be considered.
• 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 with a positive test result) 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 in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years) for typically adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality should be discussed in the context of formal genetic counseling. The autonomy of the minor is a primary concern and consideration should be given to delay of predictive genetic testing until the at-risk individual is capable of informed decision making.

Note: In a family with an established diagnosis of monogenic PD, it is appropriate to consider testing of symptomatic individuals regardless of age.

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 of having monogenic PD-related pathogenic variant(s).

Prenatal Testing and Preimplantation Genetic Testing

Once the monogenic PD-related pathogenic variant(s) 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 and preimplantation genetic testing. While most health care professionals would consider decisions regarding prenatal and preimplantation genetic testing to be the choice of the parents, discussion of these issues is appropriate.

Author Notes

The Global Parkinson's Genetics Program investigates the genetic basis of Parkinson disease (PD) in collaboration with many global investigators and cohorts. Interested clinicians and investigators may contact gro.2pg@trohoc, and a list of collaborating cohorts and investigators is available at www.gp2.org.

Acknowledgments

Dr Morris acknowledges support from Parkinson's UK, Cure Parkinson's Trust, Progressive Supranuclear Palsy Association, CBD Solutions, Medical Research Council – Rare Disease Research Platform (MR/Y008219/1), Janet Owens Bequest, and Michael J Fox Foundation for the investigations of the genetic basis of familial and early-onset PD and related disorders.

Author History

Janice Farlow, BS, BA; Indiana University School of Medicine (2014-2025)
Tatiana Foroud, PhD; Indiana University School of Medicine (2004-2025)
Shen-Yang Lim, MD, FRACP (2025-present)
Huw Morris, PhD, FRCP (2025-present)
Nathan D Pankratz, PhD; University of Minnesota (2004-2025)
Lola Cook Shukla, MS; Indiana University School of Medicine (2019-2025)
Jeanine Schulze, MS; Indiana University School of Medicine (2019-2025)
Joanne Wojcieszek, MD; Indiana University School of Medicine (2004-2025)

Revision History

• 15 May 2025 (sw) Comprehensive update posted live
• 25 July 2019 (bp) Comprehensive update posted live
• 27 February 2014 (me) Comprehensive update posted live
• 16 October 2006 (me) Comprehensive update posted live
• 25 May 2004 (me) Overview posted live
• 12 November 2003 (tmf) Original submission

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