Genetic Insights into Early-onset Parkinson’s Disease
Table 1: Genes and Chromosomal Loci Associated with Early-onset Parkinson’s Disease Name
PARK1 PARK2 PARK3 PARK4
PARK5 PARK6 PARK7
PARK8 PARK9
PARK10 PARK11 PARK12 PARK13 PARK14
Locus 4q21.3
6q25.2–q27 2p13 4q 4p14
1p35–p36 1P36
12p11.2–q13.1 1p36
Unknown 2q36–q37 Xq21–q25 2p12
22q.13.1 Glucocerebrosidase 1q21 POLG1 15q25 α-synuclein
Ubiquitin C-terminal hydrolase L1 PTEN-induced kinase-1 (PINK-1) DJ-1
Leucine-rich repeat kinase 2 (LRRK2)
ATP13A2
GIGYF2? (controversial) Unknown
HtrA serine peptidase 2 (HRTA2)?
Phospholipase A2, group VI (PLA2G5)
Glucocerebrosidase (GBA) DNA polymerase gamma 1 younger age at onset rather than with PRKN mutation status.19 Many of
the phenotypic features of PRKN carriers may be explained by the early age at onset rather than by the genetic mutation status.19
Given the early
age at onset of PRKN carriers, many ultimately require surgical intervention in the form of deep brain stimulation (DBS). Data suggest that mutation carriers benefit from DBS, but the clinical response is not superior to that of non-carriers.20
The likelihood that EOPD patients will carry a PRKN mutation is higher in Hispanic people,18
ethnicities.16 Many mutations have been identified in the PRKN gene, and include point mutation and CNV.18
There is an ongoing academic
controversy as to whether PRKN mutations are a risk factor for ‘Parkinson’s disease’ or whether they are the cause of a similar disease that can be named ‘Parkin disease’.21
Autopsies provide conflicting data.
Only six carriers of two PRKN mutations – homozygotes or compound heterozygotes – have been described. Two had Lewy bodies and four did not.22
Furthermore, impaired olfaction, which is frequently seen in EOPD and idiopathic PD, is not present in most PRKN patients.23
Another uncertainty with regard to PRKN mutations is the role of heterozygote mutations.8,19,24–36
While a While traditionally considered an
autosomal recessive disease, even the earliest reports of PRKN mutations reported carriers of a single mutation.17
comprehensive study showed a similar frequency of heterozygous point mutations in PD cases and controls,35
positron-emission
tomography (PET) studies show reduced fluorodopa uptake in nigrostriatal terminals in the caudate and posterior putamen of both symptomatic and asymptomatic PRKN heterozygotes compared with controls. This was similar to the reduction found in sporadic PD.37–39 Regardless of the risk conveyed by a single PRKN mutation, carriers of a single PRKN mutation often develop EOPD with a later age at onset than carriers of two mutations.18
EUROPEAN NEUROLOGICAL REVIEW
Mutation frequency has been estimated to be very low (ranging from 0 to 8%, including heterozygous carriers) in samples of EOPD cases from different ethnicities, including Caucasian,48–50 Korean55
Indian,51 and Japanese patients.56
As with PRKN, the role of heterozygous carrier status as a risk factor for EOPD is controversial.57–59
Taiwanese,52–54 but mutations have been described in multiple PARK3
The PARK3 locus was mapped to chromosome 2p13; however, the associated gene has not yet been identified and disease onset is described as late-onset PD.40
PARK4 – see PARK1
PARK5 – Ubiquitin C-terminal Hydrolase L1 Mutations in ubiquitin C-terminal hydrolase L1 (UCHL1) were described in a German family.41
Ubiquitous; common in Ashkenazi Jews
N370S, L444P, 84gg and others Gene α-synuclein Parkin Where Found
Families in Germany, Italy, US, Greece, Spain, Korea
Ubiquitous; more common in juvenile onset
Four families from southern Denmark and Germany
American and European families Germany
Ubiquitous; however, very rare Families in The Netherlands, Italy, Uruguay
Ubiquitous; most common in North African Arab and Ashkenazi Jews Jordan
Families in the US X-linked L166P, M26I, A104T
G2019S, R1441C, I2020T and Y1699C
Pathogenic Mutations A53T, A30P
Over 70 mutations found; deletions are common Unknown
Duplications and triplications of α-synuclein
Of the two siblings described, one was 49 years of age and the other 51 years of age at disease onset. The disease course of both was indistinguishable from idiopathic PD.41
PARK6 – PTEN-induced Kinase-1 PINK-1 was initially described in three consanguineous families from Italy in 2001.42,43
Like PRKN, carriers of two mutations, either
homozygotes or compound heterozygotes, develop EOPD. PINK-1- related EOPD is very similar to PRKN-related EOPD: carriers often report positive family history and the disease course has been described as slowly progressive, with early onset of drug-induced dyskinesias.43,44 PRKN carriers, PINK-1 carriers may benefit from DBS;20
Like however, in
contrast to PRKN, PINK-1-related EOPD may be associated with psychiatric symptoms including affective and delusional disorders.45 Furthermore, PINK-1-related EOPD is associated with impaired olfaction46
and, in one report, with Lewy body pathology at autopsy.47
Most family studies support the hypothesis 31
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