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that regulates translation of mRNAs with highly be directed at disease risk, disease progression, or both.
structured 5’-sequences. The most popular mutations, A mutation or genetic variant can be considered a risk
p.Ala502Val and p.Arg1205His mutation were found biomarker for PD if it is associated with the disease. The
to be with PD in some population. However, later discovery of mutations that cause monogenetic forms
replication studies in multiple ethnicities failed to of PD has allowed clinical investigators to determine
confirm EIF4G1 mutations as a cause or a susceptible the cause of the disease and to predict the risk for
factor for familial or sporadic PD. [133,140,141] developing the disease. However, at least two factors
have to be simultaneously considered before defining
BST1 such mutations as biomarkers: the penetrance of the
Recently, GWAS in PD have provided association mutations and the variability of AAO of PD caused
evidence at 16 loci, including a region encompassing by the mutations. Mutations that confer high risk of
a gene encoding bone marrow stromal cell antigen developing a disease usually display a high penetrance
1 (BST1) on 4p15. [142] Interestingly, all PD-associated (> 80%), and the variability of AAOs of patients
single-nucleotide polymorphisms (SNPs) on the carrying such mutations is usually low. In autosomal
BST1 locus lie within linkage disequilibrium blocks dominant form of PD, the most affirmatively causative
containing only the BST1 gene. [142] However, by direct mutations are those within the SNCA and LRRK2
sequencing of the entire coding region of BST1, we did genes. Point mutations, duplications, and triplications
not reveal a variant associated with PD. [143] of SNCA cause PD with high penetrance. However, the
AAO of each mutation type in this gene is associated
CONCERNS ON THE TRANSLATION OF GENETIC with a fairly high variability among cases (ranging
INFORMATION INTO CLINICAL APPLICATIONS from mid- 30s to late 80s), making it difficult to use
these mutations to predict the onset and course. On the
Molecular diagnosis of Parkinson’s disease: possibilities other hand, although the causative role of the LRRK2
and concerns G2019S mutation is not in question, and the AAO is less
As mutations in several genes are able to cause variable (usually at 60s), it is clear that the penetrance
monogenic forms of PD, molecular diagnosis using of this gene is only 30-40%. Therefore, carrying this
these mutations for familial PD is possible. However, mutation does not unequivocally predict development
cautions must take before extensive applications of of PD during a lifetime. [145] The situation for the risk
these mutations to genetic counseling, because most of variants associated with the onset and progression of
our knowledge about the genetic basis of PD remains sporadic PD are even more complicated and puzzling
preliminary. According to the latest European Federation as it may involve multiple independent and interactive
of Neurological Societies guidelines on the molecular factors. Thus, the value of a genetic biomarker in
diagnosis of PD, [144] for mutations that are detected predicting an individual’s risk of developing the disease
in rare familial forms of PD, such as point mutation is questionable at the current stage.
or multiplication of SNCA in familial PD, molecular
diagnosis should be considered only for clearly familial Can genetic variations help in molecular classification of
cases. Even for the LRRK2 genes in which mutations Parkinsonian disorders?
are much more prevalent in Europeans, molecular Parkinsonian disorders are a group of clinically and
testing is only recommended for cases with dominant pathogenically diverse disorders. For diagnostic and
inheritance of parkinsonian syndromes, and testing therapeutic purposes, it has long been expected to
for the G2019S mutation is only recommended for classify this clinical complex further. Currently, the
familial and sporadic patients in the Ashkenazi Jews classification of these disorders is mainly based on
or North African Arabs. Similarly, testing for mutations pathological findings. According to autopsy findings,
in recessive PD-genes (parkin, PINK-1, DJ-1) is only the histological characteristics in the patients’
recommended for families suggestive of recessive brain have been classified as α-synucleinopathies
inheritance (affected sib pairs) or sporadic patients and non-α-synucleinopathies, the latter including
with very early onset (< 35 years). For most of the other tauopathies, TDP-43 proteinopathies and nonspecific
mutations, using of them for genetic testing should wait degeneration in the pars compacta of the substantia
until their causative role in the disease is convincingly nigra (SNPc). [146] However, this classification is made
established. postpartum and, therefore, less useful for preclinical
and clinical diagnosis. Interestingly, studies have
Use of genetic variation as predictive biomarkers for demonstrated that similar pathologies might result
Parkinson’s disease: is it possible now? from the influence of mutations in genes that are part
A biomarker is a substance used as an indicator of of the same pathways. [11,147] For example, PD cases
normal biologic and pathogenic processes, or responses with mutations in SNCA, LRRK2 and GBA genes
to a therapeutic intervention. Biomarkers for PD may usually display a common α-synuclein pathology,

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