Case reportNovel features in a patient homozygous for the L347P mutation in the PINK1 gene
Introduction
The PARK6 locus was mapped first in a Sicilian family with an autosomal recessive form of Parkinsonism. Mutations in the PTEN induced putative kinase 1 (PINK1) gene were subsequently identified as the cause of this form of Parkinsonism [1]. Causative mutations in PINK1 have now been identified in Japanese, Israeli, Filipino, Italian, Irish, American and Taiwanese families, indicating that mutations in PINK1 are distributed world-wide [2], [3], [4]. To date, the majority of patients with homozygous or compound heterozygous mutations in the PINK1 gene have been described as having typical Parkinsonism, but atypical features such as hyperreflexia, psychiatric disturbances, marked orthostatic hypotension, dystonia at onset, and dementia have also been observed. This suggests that the clinical phenotype may be more complex than is seen in typical PD.
The present study was undertaken to determine the prevalence of known PINK1 mutations in several patient groups in a clinic-based population. Although only one patient was found to carry a homozygous PINK1 mutation, this case is of particular interest because a detailed description of the phenotype of this particular mutation (p.L347P) has not been previously reported. Furthermore, this is the first such case with a confirmed PINK1 mutation to undergo fluoro-L-dopa positron emission tomography (F-Dopa PET). The clinical findings in this patient suggest it may be possible to differentiate mutations in the PINK1 gene from other genetic forms of Parkinsonism based on clinical features. Finally, our patient originated from the Philippines, which is of particular interest as the two patients previously reported with this mutation are also of Filipino origin, raising the possibility of a founder effect.
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Patients and methods
We screened 299 patients from the outpatient clinic at the Parkinson's Institute from three different cohorts; (i) 21 patients with the diagnosis of Parkinsonism before age 40 years (13 men, eight women, current age range 27–62 years), (ii) 38 subjects with a positive family history (iii) 228 patients with typical, late-onset Parkinson's disease (PD) (157 men, 71 women, current age range 50–94 years). One hundred and sixty-two control samples were obtained from spouses/significant others of
Results
One patient was homozygous for the p.L347P mutation in the PINK1 gene (Fig. 1). No other mutations were detected in 460 patients and controls. We excluded a larger deletion of exon 5 on the corresponding allele by quantitative gene dosage. We performed sequence analysis for DSC-3 of the DYT3 multiple transcript system because of the Filipino background of our patient, but did not detect the characteristic sequence change found in patients with a DYT3/Lubag phenotype.
Case report
A 36 year-old Filipino woman first noticed a resting tremor of her left leg and mild gait difficulties soon after giving birth to her second daughter at age 30. When first seen at our Institute (by JT) at age 34, the shaking had spread to her arms, and she reported a dramatic diurnal variation of her symptoms, such that on awakening she was virtually symptom free through mid-morning. By mid-day she would typically become fully symptomatic. There was no family history of Parkinsonism.
Discussion
While only one PINK1 mutation (p.L374P) was identified in this study, this case proved to be interesting and potentially important for several reasons. First, although sleep benefit has been described in other patients with PINK1 mutations, the diurnal variation in our patient was dramatic early in her illness, as she was virtually asymptomatic for the first few hours each morning, before becoming fully symptomatic by mid-day. In our experience, this degree of diurnal variation is exceptional
Acknowledgments
We are indebted to the families and patients of this study for their participation. Without their interest, this study would not have been possible. We thank Venus Ilagan, Tracy L. Stewart, Grace S. Liang, and Neng C. Huang for their help ascertaining patients. This study was supported by the Draper Family fund.
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PINK1 p.Leu347Pro mutations in Malays: Prevalence and illustrative cases
2020, Parkinsonism and Related DisordersCitation Excerpt :To our knowledge, the occurrence of this sign has not specifically been assessed in monogenic PD. If confirmed in other cases, brain MRI - which is much more widely available compared to functional dopaminergic scans, especially in under-resourced settings [1] - could prove helpful in diagnosing PD, and differentiating AR-EOPD from other conditions such as dopa-responsive dystonia, which is sometimes clinically challenging and results in long diagnostic delays [2,5]. Our patients' MRIs additionally demonstrated hyperintensities involving the corticospinal tracts and, in the case of Patient 1, hypothalamus as well, which was previously unreported in PARK-PINK1; these changes could possibly suggest that the p. Leu347Pro mutation is a more aggressive variant.
Nonmotor Signs in Genetic Forms of Parkinson's Disease
2017, International Review of NeurobiologyGenetics of Parkinson's Disease: Genotype–Phenotype Correlations
2017, International Review of NeurobiologyCitation Excerpt :This contrasts with other studies which have found that such features may be occasionally present in PINK1 patients, although no comparison with noncarriers was performed (Bonifati et al., 2005; Doostzadeh, Tetrud, Allen-Auerbach, Langston, & Schüle, 2007). Regarding other nonmotor features, it is interesting to note that patients with PINK1 mutations manifest quite significant hyposmia (Doostzadeh et al., 2007; Eggers et al., 2010; Ferraris et al., 2009); some may also show autonomic dysfunction (Albanese et al., 2005; Quattrone et al., 2008), although the number of studied patients is small. RBD does not appear to occur, even in advanced cases (Tuin et al., 2008).
PINK1 (PARK6) and Parkinson's Disease
2010, Blue Books of NeurologyCitation Excerpt :Response to treatment is good or excellent in most cases, and remains sustained for many years, although drug-related dyskinesias and fluctuations of symptoms often occur early. Atypical features at onset, such as dystonia and diurnal fluctuations, seem to be rarer in PINK1-related than in parkin-related ARP, being reported in less than one third of PINK1 biallelic mutation carriers, mostly with very early onset.5,20,23 Leutenegger and colleagues20 reported a large inbred family from Sudan with eight patients homozygous for the A217D mutation, presenting with juvenile-onset parkinsonism (range 9 to 17 years old) with diurnal fluctuations and sleep benefit, which in some cases resembled levodopa-responsive dystonia.20
Recurrent Biallelic p.L347P PINK1 Variant in Polynesians with Parkinsonism and Isolated Dopa-Responsive Dystonia
2022, Movement Disorders Clinical Practice