Table 1.

Early-Onset and Late-Onset Adult Parkinson Disease: Monogenic Causes


Gene 1		PD Designation 2MOI% of Adult PDCommentsGeneReview / Reference / OMIM Entry
GBA1 3
(formerly GBA)		PARK-GBAAD3%-7%
(20% in AJ ancestry)
  • Onset age may be <50 yrs.
  • Higher likelihood of cognitive impairment, atypical motor findings & severe progression
  • Associated w/dementia w/Lewy bodies
  • Variable penetrance dependent on age, variant, & ethnicity 4
  • Consider if family history of Gaucher disease.
OMIM 606463
LRRK2 PARK-LRRK2AD1%-2%
(13%-30% in AJ ancestry; 41% in African Berber ancestry)
  • Classic manifestations w/less non-motor involvement
  • Variable penetrance dependent on age, variant, & ethnicity 5
 LRRK2-Related PD
PARK7
(DJ1)		PARK-DJ1ARRare
  • Phenotype similar to PARK-Parkin
  • ID &/or seizures occasionally
  • Risk to heterozygotes unknown
OMIM 606324
PINK1 PARK-PINK1ARRare
(3.7% of early-onset adult PD)
  • Phenotype similar to PARK-Parkin
  • Non-motor manifestations incl psychiatric features more common
  • Heterozygotes may have ↑ PD risk.
 PINK1 Type of Young-Onset PD
PRKN PARK-ParkinAR1%
(4.6%-10.5% of early-onset adult PD)
  • Slow progression
  • Can have lower-limb dystonia, dyskinesias, hyperreflexia
  • Mild non-motor manifestations
  • Heterozygotes may have ↑ PD risk.
 Parkin Type of Early-Onset PD
SNCA PARK-SNCAADRare
  • Onset age may be <50 yrs
  • Cognitive & psychiatric features more likely
OMIM 168601, 605543
VPS13C Not assignedARRareEarly-onset PD w/very rapid progression; truncating variants cause severe disease.Puschmann [2017], Reed et al [2019]
VPS35 PARK-VPS35ADRare
  • Classic PD w/tremor
  • Fewer non-motor manifestations
 VPS35-Related PD

AD = autosomal dominant; AJ = Ashkenazi Jewish; AR = autosomal recessive; ID = intellectual disability; MOI = mode of inheritance; PD = Parkinson disease

See Parkinson disease: Phenotypic Series to view genes associated with this phenotype in OMIM.

1.

Genes are listed in alphabetic order.

2.

Nomenclature based on Marras et al [2016]

3.

There is some disagreement among researchers as to whether GBA1 (formerly GBA) should be classified as a monogenic disorder or, alternatively, a risk factor – due to its low age-related penetrance. However, of note, some GBA1 variants (including the fairly common Leu444Pro variant) have estimated penetrance approaching that of LRRK2 variants [Gan-Or et al 2015, Lee et al 2017].

4.

The estimated penetrance of the c.1226A>G (p.Asn409Ser) GBA1 variant is 6%-14% for all populations. Higher penetrance is reported for severe GBA1 variants [Gan-Or et al 2015].

5.

The estimated penetrance of the c.6055G>A (p.Gly2019Ser) LRRK2 variant is 25%-43% for all populations [Marder et al 2015, Lee et al 2017]. The estimated penetrance for other LRRK2 variants may be higher or lower, possibly related to the location of the variant within the gene [Trinh et al 2014].

From: Parkinson Disease Overview

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