Long-term efficacy of deep brain stimulation in PLA2G6-related Parkinson’s disease: A case report with literature review

TL;DR

A patient with a rare genetic form of Parkinson's disease showed long-term motor improvement with brain stimulation, but also experienced cognitive decline.

Contribution

Demonstrates long-term motor benefits of DBS in PLA2G6-related Parkinson’s disease and highlights non-motor symptom challenges.

Findings

Deep brain stimulation improved motor function and quality of life for three years in a patient with PLA2G6-related Parkinson’s disease.

The patient experienced cognitive decline, emphasizing the need to monitor non-motor symptoms in this condition.

Abstract

A patient with early-onset PARK14 and novel PLA2G6 variants underwent globus pallidus internus deep brain stimulation, achieving sustained three-year motor and quality-of-life improvements. Although a literature review supports motor benefits, our case’s cognitive decline highlights the need for comprehensive assessment of non-motor symptoms and quality-of-life in this rare disorder.

Full text

PLA2G6-associated neurodegeneration (PLAN) is a rare autosomal recessive neurodegenerative disorder often associated with brain iron accumulation [1]. The clinical spectrum of PLAN includes infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (ANAD) and adult-onset parkinsonism (PARK14). PARK14 typically presents as early-onset Parkinson’s disease (PD), often complicated by dystonia, pyramidal signs, and neuropsychiatric symptoms [2]. While levodopa offers initial benefit, patients frequently develop early and refractory motor complications, necessitating advanced therapies like deep brain stimulation (DBS) [[2], [3], [4], [5]]. Here, we present a case of PARK14 with novel compound heterozygous PLA2G6 variants who underwent globus pallidus internus (GPi) DBS, followed by a literature review to contextualize the role of DBS in this disorder.

A 26-year-old man presented with lower extremity stiffness and an abnormal gait, with a background of depression, generalized anxiety, and frequent panic attacks. His paternal grandmother had a history of PD. At age 27, he developed a left-hand tremor, prompting referral to a movement disorder specialist. Neurological examination revealed resting and postural tremor in both upper limbs, with moderate rigidity and bradykinesia affecting all four limbs. During walking, he exhibited rightward trunk deviation with each left foot strike in a characteristic, reproducible pattern. The deviation disappeared during long-stride or backward walking, consistent with truncal dystonia (Video 1). Brain MRI showed minimal iron deposition not reaching pathological levels and no focal atrophy (Supplementary Fig. 1A). Dopamine transporter imaging demonstrated bilaterally reduced uptake, with specific binding ratios of 3.89/3.94 (right/left) and corresponding Z-scores of –4.04/–4.00 (Supplementary Fig. 1B). However, ^123^I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy was normal, arguing against idiopathic PD (Supplementary Fig. 1C). Cognitive assessments were within the normal range: Mini-Mental State Examination (MMSE) 30 and Montreal Cognitive Assessment (MoCA) 27. He was diagnosed with early-onset PD.

Levodopa (up to 450 mg/day) improved parkinsonism but not dystonia. Trihexyphenidyl was added and titrated to 6 mg/day, resulting in mild dystonia improvement. The addition of zonisamide 50 mg/day further reduced tremor and parkinsonism. Seven months later, he was hospitalized for a suicide attempt. Subsequent genetic testing identified novel compound heterozygous PLA2G6 variants (c.1977C>G (p.N659K) and c.2129G>A (p.R710H)), establishing a diagnosis of PARK14. Both variants were rare in public databases and predicted to be deleterious by multiple in silico tools. Details of allele frequencies and prediction scores are summarized in Supplementary Table 1.

Within 23 months of treatment, he developed severe, debilitating dyskinesias, leading to feeding difficulties, weight loss, and another hospitalization. OFF periods occupied 25 % of his day. Due to these refractory motor complications and his psychiatric history, bilateral GPi DBS was chosen over the subthalamic nucleus (STN) to minimize cognitive and psychiatric risks. Directional leads and a pulse generator (Vercise Cartesia and Vercise Genus DBS system, Boston Scientific, MA, USA) were implanted. Stimulation was initiated bilaterally: Case+, contacts 2/3/4- (33 %), 60 μs, 130 Hz, 1.3 mA. Dyskinesia and truncal dystonia were nearly completely controlled, and OFF periods were reduced (Video 1). OFF time was further reduced by increasing levodopa to 600 mg/day and adding opicapone 25 mg (equivalent to 50 mg capsule) and rasagiline 1 mg. Given dystonia improvement following DBS and the potential for cognitive side effects, trihexyphenidyl was discontinued.

At 3 years postoperatively, stimulation settings were 3.5 mA, 60 μs, and 130 Hz bilaterally. Motor function (Movement Disorders Society-Unified Parkinson’s Disease Rating Scale, MDS-UPDRS III) remained stable, motor complications (MDS-UPDRS IV) improved, and his quality of life (PDQ-39) was markedly enhanced (Table 1). However, his cognition declined (MMSE 26, MoCA 20), likely reflecting disease progression.Table 1DBS outcomes.Baseline3 yearsMDS-UPDRS part III (Medication-on state) a2620 Tremor subscore b11 Rigidity subscore b61 Bradykinesia subscore b1615 Gait and postural stability subscore b21MDS-UPDRS part III (Medication-off state)34NA Tremor subscore b1NA Rigidity subscore b8NA Bradykinesia subscore b21NA Gait and postural stability subscore b3NAMDS-UPDRS part IV126Dyskinesia score c70PDQ-39 summary index5324PDQ-39 mobility score9560PDQ-39 ADL score3833PDQ-39 emotional well-being score7554PDQ-39 stigma score560PDQ-39 social support score420PDQ-39 cognition score4438PDQ-39 communication score170PDQ-39 bodily discomfort score588SCOPA AUT97LEDD d8501100MMSE e3026MoCA e2721Abbreviations: LEDD, Levodopa equivalent daily dose; MDS-UPDRS, Movement Disorder Society Unified Parkinson’s Disease Rating Scale; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; NA, not assessed; PDQ-39, Parkinson’s Disease Questionnaire-39; SCOPA AUT, Scales for Outcomes in Parkinson’s disease-autonomic dysfunction.aThe evaluation during the medication-on state was conducted approximately one hour after levodopa administration. Motor function at 3 years was assessed in the medication-on/stimulation-on state.bMotor subscores were defined as follows: rigidity (MDS-UPDRS item 3.3); tremor (items 3.15–3.18); bradykinesia (items 3.2, 3.4–3.8, and 3.14); and gait/postural stability (items 3.9–3.13).cDyskinesia scores were derived from MDS-UPDRS items 4.1 and 4.2.dDaily oral medications were levodopa 450 mg, trihexyphenidyl 6 mg, and zonisamide 50 mg preoperatively, and levodopa 600 mg, opicapone 25 mg, rasagiline 1 mg, and zonisamide 50 mg postoperatively.eCognitive assessments were performed in the medication-on state at baseline, and in the medication-on/stimulation-on state at 3 years.

To contextualize our findings, we conducted a literature review (PubMed, 2000–2025) and identified 10 previously reported PLAN patients treated with DBS: nine with the PARK14 phenotype and one with ANAD [[2], [3], [4], [5], [6], [7], [8], [9]]. Methodological details are provided in the Supplementary Material. The clinical features of these 10 cases, together with the present case, are summarized in Table 2. The patients were geographically diverse and varied in genotypes and clinical phenotypes, reflecting the heterogeneity of PLAN. PARK14 patients typically developed parkinsonism in early adulthood (17 to 39 years, median: 28 years), often accompanied by dystonia, pyramidal signs, cerebellar features, or myoclonus. Non-motor symptoms such as depression, anxiety, and cognitive impairment were frequently reported. Brain MRI was unremarkable in half of the cases, while others showed mild cerebellar atrophy or iron accumulation. Consistent with previous reports linking missense variants to milder phenotypes, most patients carried homozygous or compound heterozygous missense mutations [1].Table 2. Clinical characteristics and DBS outcomes of our case and previously-reported cases.CaseOur caseCase 1Case 2Case 3Case 4Case 5Case 6Case 7Case 8Case 9Case 10AuthorsTsuboi et al. 2025Chen et al. 2023Chen et al. 2023Onder et al. 2023Ravat et al. 2022Magrinelli et al. 2021Yamashita et al. 2017Wirth et al. 2017Choi et al. 2016Choi et al. 2016Cif et al. 2014Sex/current age (y)M/32F/38F/34M/27M/20F/43M/53M/25M/39M/41F/15CountryJapanChinaChinaTurkeyIndiaUnited KingdomJapanFranceSouth KoreaSouth KoreaFranceParental consanguinityNoNANAYesNoNoYesNoNANAYesFamily historyPD (Paternal grandmother)UnremarkableUnremarkableUnremarkableUnremarkableUnremarkableSister affectedNABrother affected (case 9)Brother affected (case 8)NAAge at onset (y)273330241727392329353Symptoms at onsetDystoniaBradykinesiaBradykinesia, stiffnessBradykinesia, walking difficultyBradykinesia, stiffness, resting tremorDystoniaNABradykinesia and hypertoniaNANASocial and communication difficultiesMotor featuresParkinsonism, wearing off, dyskinesia, dystoniaParkinsonism, wearing off, dyskinesia, postural instabilityParkinsonism, wearing off, dyskinesia, dystonia, ataxic gait, postural instabilityParkinsonism,wearing off, dystonia, pyramidal signsParkinsonism,wearing off, dyskinesia, ataxic gaitParkinsonism, dyskinesia, dystonia, pyramidal signs, cerebellar signs, myoclonus, postural instabilityParkinsonism, wearing off, dyskinesia, dystonia, apraxia of eye-opening, hyperreflexia, postural instabilityParkinsonism, dystonia, wearing off, dyskinesiaParkinsonism, wearing off, dyskinesiaParkinsonism, wearing off, dyskinesiaGeneralized dystonia, spasticity, myoclonus, cerebellar signs, tremor, oculogyric crisis, ocular dysmetriaNonmotor featuresDepression, anxiety, sleep disturbance, panic disorder, pain, urinary frequency, hyperhidrosisCognitive impairment, depression, anxiety, fatigue, pain, Sleep disturbance, hyperhidrosis, constipation, urinary symptomsSleep disturbance, RBD, decreased appetite, anxiety, depressionConstipation,RBD, cognitive impairment, optic atrophyCognitive impairmentCognitive impairment, anxiety, depressionIncontinence, urinary urgency, hallucination, psychosis, olfactory disorder, restless LegDepression, anxiety, aggressiveness, apathy, ICB, DDS, hallucination, delusionsNANADevelopmental cognitive impairment, atypical absence seizureBrain MRIUnremarkableMild cerebellar atrophyNo iron depositionMild cerebellar atrophyNo iron depositionIron accumulation in basal gangliaMild cerebellar atrophyMild cerebellar atrophyNo iron depositionUnremarkableUnremarkableUnremarkableUnremarkableSubtle cerebellar atrophyiron accumulation in globus pallidus and substantia nigraResponse to LevodopaGoodGoodGoodGoodGoodGoodNAGoodGoodGoodNADisease duration before DBS3 years5 years4 years3 years4 years11 yearsNA2 yearsNANA12 yearsDuration of medication treatment before DBS2 yearsNANANA1 year1 yearNANAa few yearsa few yearsNADBS targetGPiSTNSTNSTNSTNGPiSTNSTNSTNSTNGPiResponse to DBSMarked improvement in truncal dystonia and dyskinesia with reduced off time. Clinical assessments were summarized in Table 1Improved motor scores (off-state MDS-UPDRS III, 71 to 35), dyskinesia (MDS-UPDRS IV 4.1–4.2, 2 to 0), non-motor symptoms (MDS-UPDRS I, 17 to 10) at 2-year follow-upImproved motor scores (off-state MDS-UPDRS III, 56 to 27), dyskinesia (MDS-UPDRS IV 4.1–4.2, 3 to 2), non-motor symptoms (MDS-UPDRS I, 17 to 8) at 4-month follow-upAlmost independent ADL performance with improved motor scores (off-state MDS-UPDRS III, 80 to 35; on-state, 30 to 25) at 8-month follow-upExcellent dyskinesia relief (>90 %) and OFF-period reduction with improved motor scores (off-state UPDRS III, 61 to 16) at 3-month follow-upTruncal dystonia improvement with complete dyskinesia cessation, enabling increased levodopa dosageNAMarked improvement in motor and non-motor symptoms at 1-year follow-upExcellent outcome in motor fluctuationsExcellent outcome in motor fluctuationsNo recurrence of status dystonicus, near-complete resolution of oculogyric crises, and significant upper-limb tremor reduction with improved object handling at 9-month follow-upMutations in PLA2G6 genesCompound heterozygous mutations: c.1977C > G (p.N659K); c.2129G > A (p.R710H)Compound heterozygous mutations: c.1937C > A (p.P646H); c.1A > G (p.M1V)Compound heterozygous mutations: c.991G > T (p.D331Y); c.1934_1938del (p.R645Qfs*?)Homozygous mutation: c.1894C > T (p.R632W)Homozygous mutation: c.2222G > A (p.R741Q)Compound heterozygous mutations: c.956C > T (p.T319M); c.1061 T > C (p.L345P)homozygous mutation c.1495G > A (p.A499T)Compound heterozygous mutations: c.109C > T (p.R37X); c.2321G > T (p.S774I)Compound heterozygous mutations: c.359G > A (p.W120*); c.1742G > A (p.R581Q)Compound heterozygous mutations: c.359G > A (p.W120*); c.1742G > A (p.R581Q)Homozygous mutation: c.1640A > G (p.E547G)Abbreviations: DBS, deep brain stimulation; GPi, globus pallidus internus; MDS UPDRS, Movement Disorder Society Unified Parkinson’s Disease Rating Scale; NA, not available; PD, Parkinson's disease; RBD, REM sleep behavior disorder; STN, subthalamic nucleus.

The review revealed that DBS was typically performed within five years of symptom onset, in response to the atypically rapid emergence of motor complications in PARK14 compared to common PD phenotypes. Eight patients received STN DBS and two received GPi DBS, including the present case. Favorable motor outcomes were reported across both targets, with improvements noted in OFF-period parkinsonism, dyskinesia, dystonia, and functional independence. Notably, dystonia, a prominent feature in our patient, responded well to GPi DBS [2]. However, the existing literature has limitations; few studies used quantitative motor scales like the MDS-UPDRS, and systematic reporting on non-motor symptoms and patient-reported outcomes was scarce. Follow-up durations ranged from 3 months to 3 years, with our case representing the longest postoperative follow-up to date.

Our case contributes significantly to this small body of evidence by providing the longest postoperative follow-up to date, with systematic documentation of motor, non-motor, and quality-of-life outcomes. The sustained improvement in motor complications and quality of life over three years confirms the long-term efficacy of GPi DBS for PARK14. Concurrently, the observed cognitive decline underscores that DBS, while effective for motor symptoms, does not alter the underlying neurodegenerative course. Furthermore, the patient's history of a suicide attempt emphasizes the critical need for comprehensive neuropsychiatric assessment, and in such cases, GPi may be the preferred DBS target [10].

In conclusion, this case report and literature review indicate that DBS is a highly effective therapy for managing the complex motor symptoms of PARK14, potentially improving patient quality of life. As attention shifts towards patient-centered care, future research must incorporate long-term follow-up and comprehensive outcome measures to refine therapeutic strategies for this rare and complex disorder.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.