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Glucocerebrosidase and 15-20% of sporadic EOPD. [89-91] Over 100 types of
The glucocerebrosidase (GBA) gene encoding mutations including sequence substitutions, insertions
a lysosomal enzyme called glucocerebrosidase and exonic deletions/duplications (or dosage mutations)
that hydrolyses the beta-glycosidic linkage of in the parkin gene have been described in diverse
glucosylceramide, a ubiquitous sphingolipid present in ethnic groups. [92] While homozygous or compound
the plasma membrane of mammalian cells. Over 200 heterozygous mutations are causative, heterozygous
[75]
mutations have been described in GBA, including point mutations have been suggested to increase the risk for
mutations, deletions and recombination alleles derived PD. [93,94] The predisposing effects of heterozygote were,
from the pseudogene sequence. These mutations usually however, soon questioned by other studies in which
[76]
cause a recessive lysosomal storage disorder - Gaucher they were reported as common in control subjects as
disease (GD), which is characterized by macrophages in PD patients. [95,96] These conflicting observations,
enlarged with deposits of glucosylceramide. as suggested by some studies, may come from the
heterogeneous effects of different types of mutations,
The initial recognition of an association between PD which may have different origins and pathogenic effects.
and GBA mutations came from the clinical observations For example, a haplotype analysis for a European EOPD
of parkinsonian manifestations in genotypically family series demonstrated that exonic rearrangements
heterogeneous patients with GD. [77] Moreover, brain occurred independently whereas point mutations may
samples from autopsy-confirmed PD cases revealed have been transmitted by a common founder. [97] In
significantly higher carrier frequencies (14%) than addition, some studies suggested that dosage mutations
the estimated GBA mutation carrier frequency in are more pathogenic than sequence mutations in the
the general population (0%). [78] The frequency and development of familial PD. [98,99] However, these results
distribution of GBA mutations in PD vary among remain to be confirmed by large-scale studies, and it is
populations. Ashkenazi Jewish PD patients have the unclear whether the dosage mutations are associated
highest carrier frequency with a range 13.7-31.3%, with typical sporadic PD.
compared with 4.5-6.2% in controls. [79,80] It was lower
in nonAshkenazi-Jewish populations, ranging 2.8-12%, PINK1
compared with 0.2-5.3% controls from the same Mutations in the PTEN-induced putative kinase
populations. [81-83] Among all the mutations, L444P and 1 (PINK-1) gene are the second common cause of
N370S turned out to be the most frequently identified autosomal recessive EOPD after parkin. The gene
in PD patients. Although N370S is also common in resides on chromosome 1p35-36 (PARK6) and encodes
European populations, it has not been encountered a protein locating on mitochondria. [100-102] Evidences
among Asians. [84] In contrast, L444P was believed as are gathering that PINK-1 is crucial for the normal
a panethnic mutation associated with PD. [85,86] A most functions of mitochondria and might participate in
recent multi-center study including 5691 patients the detoxification of proteins. [103] Different PINK-1
and 4898 controls from 16 centers revealed that either mutations including missense, nonsense, splice site
mutation was found in 15% of patients and 3% of mutations and entire PINK-1 gene deletion have been
controls among Ashkenazi Jewish subjects, and in 3% identified in both familial [104] and sporadic EOPD
of patients versus 1% of controls among nonAshkenazi cases, [105,106] with a frequency ranging from 1% to 8%.
Jewish subjects. The odds ratio for any GBA mutation However, single heterozygous PINK-1 mutations have
[87]
in patient’s versus controls was 5.43 across centers, also been reported in healthy controls and large-scale
which is the highest effect size conferred by the known case-control studies confirming the association between
risk variants for PD. There is preliminary evidence PINK-1 mutations, and sporadic PD are not available.
that, overall, mutation carriers have an earlier age at
onset (AAO), more atypical clinical manifestations, DJ‑1
more cognitive changes and more likely to have affected The DJ-1 gene (PARK7) encodes a protein belonging to
relatives. [82,88] the DJ-1/Thi/PfpI protein super family. It was initially
described in association with oncogenesis and male
GENETIC VARIANTS IN INCONCLUSIVE OR rat infertility, [107,108] and later found to be associated
NEGATIVE ASSOCIATION WITH PARKINSON’S with autosomal recessive EOPD. [109,110] DJ-1 is proposed
DISEASE to play a role in protecting neurons from oxidative
stress and protecting against mitochondrial damage. [111]
Parkin A few PD-causing mutations have been identified,
The most frequent mutations in early-onset including exon deletions, truncations, homozygous and
PD (EOPD) (AAO ≤ 50 years) patients are those identified heterozygous point mutations, which predominantly
in the parkin gene, which account for up to 50% of result in loss of function. [109,112] However, there is
autosomal recessive juvenile parkinsonism (AR-JP) currently a lack of information about the frequency of

118 Neuroimmunol Neuroinflammation | Volume 1 | Issue 3 | December 2014