Parkinson's disease (PD) is a multifactorial disease, and its pathogenesis may be related to factors, such as oxidative stress, mitochondrial dysfunction, and abnormal protein expression. However, from 10 to 15% of PD patients have a genetic predisposition (Zhu et al., 2019). Early-onset PD (EOPD) refers to an earlier age onset (50 or younger) of this disease. EOPD is related mainly to more than 20 gene variants such as ATP13A2, PLA2G6, and PRKN (Zhao et al., 2020). A disease caused by mutation of PLA2G6 is highly genetically and clinically heterogeneous. The clinical manifestations of PLA2G6-related EOPD include mental disorders and/or cognitive decline, non-motor symptoms such as dystonia, and motor symptoms such as resting tremor, muscle rigidity, and bradykinesia (Chan et al., 2008). Although the incidence of EOPD caused by a PLA2G6 mutation is not high, it has a very high disability and mortality rate, and the average age of onset is 22 years (Oliveira et al., 2021). These disease characteristics bring a heavy burden to patients and families with no curative treatment currently available. Therefore, PLA2G6-related EOPD needs more extensive in-depth research. Here, we report a case of EOPD associated with a heterozygous mutation of PLA2G6.

As mentioned earlier, the patient, whose case has been described in this paper, was a young male. The disease course lasted for more than 2 years, with an onset of unstable walking and bradykinesia, and gradually increasing resting tremor. The symptoms progressed rapidly. Brain MRI showed mild atrophic changes in the whole brain. The treatment with Madopar was effective. The genetic test results showed two mutation sites of PLA2G6, including c.991G > T and c.1427 + 1G > A. On the basis of the present findings and the existing evidence base, this is the first reported EOPD case with mutations in these two sites. The overall prognosis of this disease is poor and with a very high disability and mortality rate. Thus, early identification and treatment are of critical significance to patient prognosis.

Abnormalities in the PLA2G6 gene are often manifested in various neurodegenerative diseases (Ji et al., 2019), such as infantile neuroaxonal dystrophy (INAD), atypical infantile neuroaxonal dystrophy (ANAD), dystonia parkinsonism (DP), and autosomal recessive EOPD (Cheng et al., 2019). The mechanism of action may be associated with the D331Y and T572I mutations in the PLA2G6 domain, leading to the reduction of the formation of dopamine neurons and the manifestation of the neuromotor symptom phenotype (Yeh et al., 2021). Several studies have also suggested that potential enzyme activity, DNA methylation, synergistic genetics, and environmental factors may be involved in PLA2G6 gene-related neurological diseases (Guo et al., 2018), which, therefore, have diverse phenotypes. Among these diseases, EOPD related to the PLA2G6 gene is more common in young people. The PLA2G6 gene has been characterized as a locus for parkinsonism with early onset and associated neurological features, particularly dystonia. Many identified mutations have been detected in PLA2G6 gene-related EOPD (Table 1). However, no other compound with a heterozygous mutation of the PLA2G6 gene with c.991G > T and c.1427 + 1G > A has been reported. The c.991G > T site of the PLA2G6 gene is a missense mutation, which may lead to the loss of function of the expressed protein and various motor symptoms (Cheng et al., 2022). In the ClinVar database, the pathogenicity of this variant is classified as pathogenic, and the corresponding disease is EOPD (Shen et al., 2019). Another variant site, c.1427 + 1G > A, is reported to be related to the INAD phenotype (Wan et al., 2022), but the reports of the EOPD phenotype have been scarce. Previous investigations showed that the clinical symptoms of EOPD patients caused by only c.991G > T mutation were relatively mild with typical PD symptoms, no dystonia, and relatively slow disease progression (more than 10 years). In addition, most MRI showed no abnormal signs of cerebral iron deposition (Lu et al., 2012; Xie et al., 2015).

The c.991G > T of a PLA2G6 mutant is associated with approximately 30% of the residual protein activity (Shi et al., 2011), which may explain why EOPD patients with only c.991G > T mutation have generally mild disease symptoms and relatively slow disease progression. Although c.991G > T mutation was also present in this case, the condition of the patient was severe, with rapid disease progression. Two years later, the disease had developed into stage 5 according to the Hoehn-Yahr Scale (off-stage), and the case needed special care with his diet and daily life activities. Thus, the disease seriously affected the patients' quality of life, which is inconsistent with findings concerning patients with a single c.991G > T mutation. The patient also differed from other EOPD patients with PLA2G6 compound heterozygous mutations in terms of cognitive decline and response to madopar. Unlike most patients with PLA2G6 gene-related EOPD, which is associated with cognitive dysfunction, the patient did not experience cognitive decline. In addition, although the patient began to use madopar at the early stage of the disease, the disorder was not well controlled and progressed rapidly and gradually worsened. During the 2 years of disease course, the bradykinesia symptoms gradually progressed along with the appearance of freezing symptoms, such as inability to move and turn over voluntarily. Most patients have a good response to madopar 5–10 years before onset, which was in contrast to the response of this patient, whose side effects appeared early. The reported here results suggests that these characteristics are associated with the presence of a compound heterozygous mutation of the PLA2G6 gene with c.991G > T and c.1427 + 1G > A. Several studies have indicated that the rapid progression of the disease in EOPD patients may be related to the fluctuation of the hormone levels in the body (Magrinelli et al., 2022). However, this case had no obvious history of hormone fluctuations. Thus, it was considered that the severe disease with rapid progression was related to the combination of a c.991G > T mutation and a c.1427 + 1G > A mutation. The identification and research of this case laid the foundation for further understanding of PLA2G6 gene-related neurodegenerative diseases.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

LG, JG, SL, and YL carried out the studies and participated in collecting data. LG and CW performed the statistical analysis and participated in its design. CS, QL, YW, MW, and LH participated in acquisition and draft the manuscript. All authors read and approved the final manuscript.