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Prevalence and Phenotypic Spectrum of PINK1 Mutations in Parkinson’s Disease
found also in homozygous or compound heterozygous states in Table 1: Frequency of Bi-allelic and Single
parkinsonian patients. In particular, L347P was identified
in homozygosity in three Philipino patients and in heterozygosity in
three out of 50 Philipino controls, likely due to a founder effect in this
Reference n 2 Muts (%) 1 Mut (%) Country Selection AAO
Conversely, four of the five non-missense variants
10 92 15.2 1.1 Tunisia FP 53 (9-87)
240 2.5 0.0 SP 63 (25–85)
(including two non-sense, one splice-site mutation, one single
9, 15 90 8.9 0.0 Mainly ARP NA
nucleotide deletion and one 3bp insertion) were also found in
homozygosity or compound heterozygosity in autosomal recessive
21 47 4.3 0.0 Mainly ARP 53 (10–85)
families. Prediction of pathogenicity using dedicated software
190 0.5 1.1 Eastern Asia SP 37 (7–81)
identified only about half of heterozygous missense mutations as
11 177 4.0 0.6 Mainly ARP NA (<60)
possibly or probably pathogenic, while the remaining half were Europe
predicted to be benign.
Therefore, it is likely that at least a subset of 13 116 3.4 3.4 Mainly Italy EOP 36 (18–45)
these heterozygous rare variants do not substantially affect the
24 80 2.5 1.3 Singapore EOP 44 (<55)
protein’s structure or function, although in some cases bioinformatic
6 58 1.7 0.0 Italy EOP NA (<50)
predictions have been contradicted by
18 127 1.6 0.8 Taiwan EOP 33 (5–40)
in vitro functional results
demonstrating a severe functional impairment of
23 65 1.5 3.1 Italy EOP 43 (25–51)
20 72 1.4 4.2 Korea EOP 39 (13–50)
expressing a mutation predicted as benign.
7 289 0.7 2.1 North Mix 51 (14–83)
1, 16, 17 1,130 0.5 1.8 Italy Mix 50 (17–85)
Bi-allelic mutations in the PINK1 gene represent the second cause of
25 92 0.0 3.3 South Tyrol, EOP 39 (26–45)
ARP after Parkin, and ~70 probands have been described so far. The
reported frequency of bi-allelic mutations varied from 0 to 15% in 33 131 0.0 2.3 Norway Mix 50 (31–75)
distinct studies, a variability that likely depends on the different 26 73 0.0 1.4 Taiwan EOP 48 (24–55)
inclusion criteria adopted by each molecular screening (i.e. early
22 768 0.0 1.2 England Mix NA
onset only, autosomal recessive only, etc.) and different ethnicity of
29 74 0.0 1.4 Australia EOP 42 (26–50)
the tested populations (see
32 290 0.0 0.3 Ireland Mix 70%
Table 1). About two-thirds of probands
carrying bi-allelic mutations had a family history compatible with
30 66 0.0 0.0 Portugal FP 45 (20–60)
recessive inheritance (multiple affected cases in the same
31 175 0.0 0.0 Norway, LOP 61 (45–79)
generation and/or parental consanguinity), while 19 (27%) were
sporadic. Indeed, the highest mutation rates were found in selected
27 55 0.0 0.0 Korea EOP <50
cohorts of familial PD cases, including highly inbred families or
*In all PINK1 mutation screens including at least 50 patients published by 30 September
families with likely autosomal recessive inheritance, mainly from 2008. n = number of probands; 2 muts = homozygotes or compound heterozygotes;
Tunisia and Japan (15.2 and 8.9%, respectively).
1 mut = heterozygotes; ARP = autosomal recessive parkinsonism; EOP = early-onset
parkinsonism; LOP = late-onset parkinsonism; FP = familial parkinsonism; SP = sporadic
cases (<40–50 years of age) unselected for family history, the parkinsonism; Mix = cohorts including both familial and sporadic cases, irrespective of
frequency of bi-allelic mutations ranged between 0 and
age at onset; AAO = age at onset.
while these were usually not found in late-onset PD
In our large cohort of late-onset cases (602 probands low Unified Parkinson’s Disease Rating Scale (UPDRS) III motor scores
with age at onset ≥50 years), only one sporadic patient was and preserved functional and working abilities after many years of
compound heterozygous for two PINK1 missense mutations.
disease. Response to dopaminergic treatment is good or excellent in
most cases, and tends to persist for many years, although drug-
The prevalence of heterozygous rare variants, in mixed patient related dyskinesias and fluctuations of symptoms often occur early.
cohorts including sporadic and familial cases of all onset ages, ranged Only one PINK1 homozygous patient has been described who
between 0.3 and 4.2% in different studies (see Table 1).
These underwent surgery for bilateral subthalamic nucleus deep brain
variants were rarely detected in large screenings of ARP stimulation (DBS). In this patient, a 60-year-old woman with onset of
and in fact the vast majority of heterozygous disease at 31 years of age, DBS produced a substantial benefit, with
carriers were reported to be sporadic. ~45% reduction of the UPDRSIII off score, which persisted over time.
Age at Onset, Progression and Treatment The mean age at onset of PINK1 heterozygotes is 49.0 years (SD: 12.3;
Similarly to other genes causative of ARP, PINK1 causes parkinsonism range 13–73), about 15 years older than that of PINK1 bi-allelic carriers,
that usually differs from idiopathic PD only for the earlier onset (<50 and about 60% of cases had onset in the fifth or sixth decade of life.
years of age ), better and sustained response to levodopa and slower
disease progression. The disease usually becomes clinically manifest Clinical Features
in the third or fourth decade (about 65% of cases for whom age at With the already mentioned exceptions of earlier age at onset (<50
onset is available), with a mean age at onset of 32.4 years (standard years), slower disease progression and better response to levodopa,
deviation [SD] 11.8). However, patients have been reported with onset ARP due to PINK1 bi-allelic mutations is overall similar to idiopathic
in the first to second decades as well as the seventh decade of life PD. On average, patients appear to have a more frequent onset in a
(range: nine to 67 years).
Despite these occasional reports, lower limb and higher occurrence of akinetic–rigid presentation, gait
patients with onset above 50 years of age are rare and nearly impairment, urinary urgency and early drug-induced dyskinesias.
invariably found among relatives of early-onset probands.
Atypical features at onset, such as dystonia and diurnal fluctuations,
Progression is generally slow, and many patients maintain relatively have been reported in fewer than one-quarter of PINK1 bi-allelic
EUROPEAN NEUROLOGICAL REVIEW 41