Neurodegenerative Disease Parkinson’s Disease
that even a single PINK-1 mutation conveys a risk of PD,56,60,61 couple of studies reported conflicting evidence.58,62
but a Imaging and
psychophysical studies support the hypothesis that PINK-1 heterozygotes compensate for mild dopamine deficiency even when no motor signs of PD are apparent.63,64
PARK7 – DJ-1 The association between DJ-1 mutations and EOPD was discovered in 2003 in two European families: a Dutch family and an Italian family.65 Mutations in DJ-1 are less common than PRKN or PINK-1,66 rare in Asian patients with PD.67
to parkinsonism. Magnetic resonance imaging (MRI) findings suggest iron accumulation; however, autopsy data are not available.88
Glucocerebrosidase While GBA mutations are among the most frequently recognised genetic mutations in EOPD, a PARK assignment was never made for this gene. Case series have reported early-onset parkinsonism in Gaucher disease patients who, by definition, carry two GBA mutations.89
and are very When 89 American EOPD cases were
genotyped for DJ-1 mutations, a single heterozyogote was identified.68 DJ-1-associated EOPD is described as being similar to PRKN65
and
indistinguishable from idiopathic EOPD. One study reported normal olfaction in DJ-1 carriers similar to PRKN carriers, but the number of mutation carriers was small.69
PARK8 – Leucine-rich Repeat Kinase 2 The association between leucine-rich repeat kinase 2 (LRRK2) mutations and PD was discovered in 2004.70
In contrast to the other PARK genes,
the frequency of LRRK2 mutations is similar in EOPD and late-onset PD.71,72
2877510G→A), is found in up to 1% of sporadic and 4% of familial PD cases worldwide.72
18.3% of Ashkenazi Jewish74,75
Additional mutations, including the I2020T in Japanese patients76 R1441C, Y1699C in Caucasians,77
have been described. The presentation of LRRK2-related PD is heterogeneous,78–80 but it is
usually associated with good response to treatment with levodopa and dopamine agonists, and may be complicated by dyskinesia.72
Thirty-four
LRRK2 G2019S carriers were compared with 891 non-carriers in a study of EOPD cases. Disease characteristics between the groups were similar, except that LRRK2 carriers were less likely to suffer from tremor and were more likely to manifest the postural instability gait difficulty motor phenotype (PIGD).81
There were no other clinical differences
between carriers and non-carriers, including other manifestations of PIGD (e.g. worse motor performance and cognitive impairment).81
Gan-Or and others also found that carriers of G2019S mutations were more likely to present with gait impairment compared with gluco- cerebrosidase (GBA) mutation carriers.82
restricted to EOPD cases) reported impaired olfaction.83 The most frequently reported LRRK2 mutation, G2019S (nt.
However, up to 39% of Northern African Arab73 individuals with PD carry the mutation. and the
and
Among PD patients, GBA mutations have been associated with earlier age at onset.91
One study suggested that carriers of severe GBA mutations (e.g. L444P) may have a higher risk for PD than carriers of milder mutations (e.g. N370S).92
Even a single
mutation in GBA may increase the risk for PD. Case–control studies have shown that carrying a single GBA mutation (heterozygous) is more common among PD patients than among healthy controls.90 8.3% of Ashkenazi Jews and up to 1% of non-Jews carry a mutation.90
As many as
Most studies assessing the GBA
mutation carriers did not distinguish between EOPD and late-onset PD. In 699 EOPD cases, including 37 GBA carriers, mutation carriers were more likely to self-report cognitive impairment than non-carriers. However, no difference on cognitive screening with the Mini-Mental State Exam (MMSE) was noted.93
Therefore, it is possible that EOPD GBA carriers are more likely to develop cognitive impairment.
Summary
In summary, EOPD is a complex disorder likely caused by an interaction between genetic and environmental factors. The overall genetic contribution to EOPD has received limited analysis. Mellick and others looked at 74 EOPD participants and found a mutation frequency of 7%.96 Macedo and others looked at 187 EOPD participants in The Netherlands and reported a mutation frequency of 4%.29
More recently, a study from
Studies of LRRK2 carriers (not There were
variable findings on pathology, but most cases demonstrated Lewy body pathology.77,84,85
In summary, while not restricted to early-onset illness, the LRRK2 mutation is among the most common genetic mutation that can be identified in EOPD cases with and without a family history of PD.72
PARK9 – ATP13A2 Mutations in ATP13A2 were identified in 2006 in consanguineous Jordanian families with Kufor Rakeb syndrome.86
13 movement disorder centres in the US reported a mutation frequency of 16%. There are several reasons for the higher rate of mutation carriers in this latter study. They included genotyping of common GBA mutations, L444P and N370S, which were not analysed in the other studies, and they used participants from diverse ethnicities including Ashkenazi Jews and Hispanic patients, in whom mutation frequency is higher (G2019S LRRK2 in Ashkenazi Jews and PRKN in Hispanics). While much has been discovered during the past decade, most risk factors for EOPD remain unknown. n
Roy N Alcalay is an Assistant Professor in the Division of Movement Disorders in the Department of Neurology at Columbia University Medical Center in New York, where he recently completed a post- doctoral fellowship. His primary research interests are the genetic risk factors for Parkinson’s disease and cognitive impairment.
In contrast to the rest
of the genetic forms of EOPD, carriers of ATP13A2 have a distinct phenotype, different from non-carriers.
The Kufor Rakeb syndrome is associated with juvenile, atypical parkinsonism, usually rapidly progressive with only transient response to levodopa treatment.87
The syndrome is inherited in an autosomal recessive fashion and presents with dementia and spasticity in addition 32 EUROPEAN NEUROLOGICAL REVIEW
Cheryl Waters is the Albert B and Judith L Glickman Professor in the Division of Movement Disorders in the Department of Neurology at Columbia University Medical Center. She has been involved in research on the genetics of Parkinson’s disease and the treatment of this disorder and has been an investigator in numerous studies involving a variety of new medical and surgical treatments.
Two independent autopsy studies suggest that GBA carriers are more likely to have cortical Lewy bodies associated with dementia with Lewy bodies.94,95
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