PLA2G6 (phospholipase A2 group VI) hereditary late-onset Parkinson disease is a genetic form of parkinsonism (often called PARK14) caused by harmful changes (variants) in the PLA2G6 gene. This gene makes an enzyme called iPLA2β, which helps repair and renew the fatty layers (phospholipids) that build cell membranes and keep mitochondria healthy. When the gene does not work properly, damaged lipids build up, membranes become unstable, and brain cells—especially dopamine-producing neurons—are stressed by inflammation, iron imbalance, and faulty energy handling. Over time, this can lead to Parkinson-like movement problems, sometimes with dystonia, mood or thinking changes, and, in some people, signs of the broader disorder group known as PLA2G6-associated neurodegeneration (PLAN). Although most PLA2G6 parkinsonism starts in youth or early adulthood, late-onset cases have been reported, showing that age at onset can vary widely. PubMed+4NCBI+4PMC+4

Mutations in PLA2G6 can cause a spectrum called PLA2G6-associated neurodegeneration (PLAN). One adult phenotype presents with parkinsonism (slowness, stiffness, tremor) sometimes mixed with dystonia, sometimes with early cognitive/psychiatric features, and may or may not show brain iron changes. It’s usually autosomal recessive, often levodopa-responsive, and can progress faster than typical idiopathic PD in some genotypes. Management is largely symptom-directed PD care with genetics-aware counseling. Journal of Medical Genetics+3NCBI+3Frontiers+3

Another names

• PARK14 (autosomal recessive parkinsonism linked to chromosome 22q13 / PLA2G6)

• PLA2G6-associated dystonia-parkinsonism (a PLAN subtype)

• PLA2G6-associated neurodegeneration (PLAN) — umbrella term that includes several clinical pictures, one of which is dystonia-parkinsonism and, less commonly, late-onset parkinsonism without clear brain iron on MRI. NCBI+2ScienceDirect+2

Types

Doctors use “types” here to describe presentations along a spectrum rather than strict separate diseases, because the same gene can produce different pictures in different people or even the same family.

1. Pure parkinsonism, adult or late onset – Looks like typical Parkinson disease with tremor, slowness, stiffness, balance issues; may have good or mixed levodopa response; brain MRI may or may not show iron. Reported cases include late-onset parkinsonism. BioMed Central+1

2. Dystonia-parkinsonism – Parkinson features plus dystonia (twisting postures or cramps), often beginning in the hands or feet; onset often in teens or early adulthood, but age varies. NCBI+1

3. PLAN with brain iron accumulation – Part of the NBIA family; MRI may show iron in the globus pallidus/substantia nigra with movement problems and sometimes faster thinking changes. ScienceDirect

4. Atypical PLAN presentations – Some people show cerebellar signs (unsteady gait), neuropsychiatric symptoms, or cognitive decline; others show little or no iron on MRI despite PLA2G6 variants. PMC+1

Key idea: the same gene can produce early, adult, or late-onset disease, with or without iron on scans. That is why genetic testing helps confirm the diagnosis. NCBI

Causes

1. Loss of iPLA2β enzyme activity – Damaged membranes are not repaired well; toxic lipids accumulate and harm neurons. PMC

2. Mitochondrial dysfunction – Energy factories fail; neurons become vulnerable to stress. PMC

3. Iron handling abnormalities – Some patients show brain iron accumulation, which accelerates oxidative damage. ScienceDirect

4. Lipid remodeling defects – Shorter/altered phospholipid chains disturb membrane fluidity and synapses. (Shown in model systems.) PNAS

5. Neuroinflammation – Damaged lipids trigger inflammatory cascades that further injure neurons. ScienceDirect

6. Synaptic trafficking problems – Axons and synapses struggle to move and recycle membrane packages. PMC

7. Calcium signaling changes – Certain PLA2G6 mutations disturb Ca²⁺ signaling that neurons need for survival. Nature

8. Dopaminergic neuron vulnerability – Midbrain dopamine cells depend heavily on membrane/mitochondrial health and are first to fail. Frontiers

9. Autophagy/mitophagy impairment – Damaged mitochondria are not cleared efficiently; toxic by-products build up. BioMed Central

10. Genetic background (modifier genes) – Other genes can shift age at onset and symptom mix. (Shown by phenotype variability across families.) BioMed Central+1

11. Specific variant effects – Certain changes (e.g., p.D331Y) are linked to adult-onset pure parkinsonism; others drive earlier, broader disease. BioMed Central

12. Heterozygous effects (possible) – Some reports propose risk from single-allele variants in typical PD, though causality is debated. Nature+1

13. Oxidative stress from polyunsaturated lipid damage – Oxidized phospholipids accumulate and injure membranes and proteins. PMC

14. Abnormal lysophospholipid signaling – Broken lipid pieces act as bioactive signals that can disturb neurons. PMC

15. Cerebellar involvement – In some patients, cerebellar atrophy contributes to gait and coordination problems. Frontiers

16. Protein aggregation pathways – Stress from lipid/mitochondrial injury may favor alpha-synuclein pathology typical of PD. (Mechanistic reviews.) ScienceDirect

17. Age-related decline of iPLA2β – Natural drop-off with aging may help explain late-onset cases when combined with variants. BioMed Central

18. Membrane–organelle contact defects – Faulty contact sites between organelles disrupt calcium and lipid exchange. PMC

19. Impaired axonal transport – Membrane traffic slowdown starves synapses of needed components. PMC

20. Environmental and physiological stressors – Illness, head trauma, or metabolic stress may unmask symptoms earlier in vulnerable neurons (inference consistent with variable penetrance reported). BioMed Central

Symptoms

1. Slowness of movement (bradykinesia) – Daily tasks feel slow and effortful; small steps, reduced arm swing. NCBI

2. Stiffness (rigidity) – Muscles feel tight; turning in bed or getting up can be hard. NCBI

3. Resting tremor – Shaking in a hand at rest that eases with movement; not present in everyone. NCBI

4. Balance problems – Unsteady stance, falls, trouble with quick turns or narrow spaces. NCBI

5. Dystonia – Painful twisting or cramps in a foot or hand, sometimes triggered by walking or writing. Tremor and Other Hyperkinetic Movements

6. Gait changes – Shuffling steps, freezing in doorways, difficulty starting or stopping. BioMed Central

7. Speech and swallowing changes – Soft voice, slurred words, choking on thin liquids in some patients. NCBI

8. Mood symptoms – Anxiety, depression, irritability can appear early or along the way. NCBI

9. Thinking changes – Slowed thinking or executive difficulties; some may progress to more noticeable cognitive problems. NCBI+1

10. Sleep problems – Acting out dreams (REM sleep behavior disorder), insomnia, daytime sleepiness. NCBI

11. Autonomic symptoms – Constipation, lightheadedness on standing, urinary urgency. NCBI

12. Olfaction loss – Reduced sense of smell is common in PD-like disorders. NCBI

13. Cerebellar signs in some – Poor coordination or wide-based gait when the cerebellum is involved. Frontiers

14. Variable levodopa response – Some improve well; others have limited or mixed benefit. BioMed Central

15. Fluctuations and dyskinesia – With time on levodopa, extra involuntary movements or “wearing-off” can appear, similar to other PD forms. Tremor and Other Hyperkinetic Movements

Diagnostic tests

A) Physical exam (at the bedside)

1. Unified Parkinson’s Disease Rating Scale (UPDRS) motor exam – The neurologist times movements, rates tremor/rigidity, and checks gait/posture to grade severity and track change. This is the core bedside assessment for parkinsonism. NCBI

2. Pull test for postural stability – A quick backward tug tests balance reflexes; repeated loss of balance supports parkinsonism severity. NCBI

3. Gait analysis – Observation of stride length, freezing, turning, and arm swing helps distinguish parkinsonism from other causes of unsteady walking. NCBI

4. Facial expression and speech exam – Masked face, soft speech, and reduced blink rate are common PD-like features; their presence supports the clinical picture. NCBI

5. Cranial nerve and eye movement check – Looks for atypical features (e.g., severe vertical gaze palsy) that would suggest a different diagnosis; typical eye movements favor PLA2G6 parkinsonism over PSP. NCBI

B) Manual/functional tests (simple office tools or timed tasks)

6. Finger tapping / hand opening-closing – Timed repetitive tasks reveal bradykinesia and asymmetry; simple, repeatable, and sensitive to change with medication. NCBI

7. Heel tapping / toe tapping – Lower-limb version of rapid alternating movements to grade leg bradykinesia that affects walking. NCBI

8. Timed Up and Go (TUG) – Time to stand, walk 3 meters, turn, and sit; slower times reflect mobility and fall risk in parkinsonism. NCBI

9. Smell identification test – Standardized “scratch-and-sniff” cards quantify smell loss, a supportive PD-like feature. NCBI

10. MoCA or similar cognitive screen – Brief test of attention, executive function, and memory; helps capture thinking changes sometimes seen in PLAN-related parkinsonism. NCBI

C) Laboratory and pathological tests

11. Genetic testing for PLA2G6 – Sequencing (and deletion/duplication analysis) confirms the diagnosis; panels for early-onset or familial parkinsonism often include PLA2G6. Family testing clarifies inheritance. NCBI+1

12. Ruling out Wilson disease – Serum ceruloplasmin and copper studies when onset is early or features are unusual, to avoid missing a treatable mimic. NCBI

13. Thyroid and B12 levels – Hypothyroidism or B12 deficiency can worsen gait and cognition; checking helps remove confounders. NCBI

14. CSF or skin alpha-synuclein seeding assays (where available) – Research and early clinical assays can support a synucleinopathy diagnosis when imaging is unclear. (Supportive to PD biology; availability varies.) ScienceDirect

15. Ferritin/iron studies (contextual) – Blood iron markers do not diagnose NBIA, but combined with MRI findings and genetics they help a comprehensive work-up for iron disorders. ScienceDirect

D) Electrodiagnostic / physiologic tests

16. Polysomnography (sleep study) – Confirms REM sleep behavior disorder (acting out dreams), which supports a PD-like process and guides safety counseling. NCBI

17. Surface EMG/accelerometry for tremor – Quantifies tremor frequency and pattern, helping separate rest tremor from essential or dystonic tremor. NCBI

18. Autonomic function testing (e.g., tilt table, QSART) – Documents neurogenic orthostatic hypotension or sweating changes that often accompany parkinsonism. NCBI

E) Imaging tests

19. Brain MRI (with susceptibility-weighted imaging/QSM) – Looks for iron in globus pallidus/substantia nigra (NBIA pattern) and for cerebellar or cortical atrophy; in adult PLA2G6 parkinsonism, MRI may be normal or lack visible iron. ScienceDirect+1

20. Dopamine transporter imaging (¹²³I-ioflupane SPECT, “DaTscan”) – Shows reduced dopamine terminals in the striatum; supports a degenerative parkinsonian process even when MRI is unrevealing. NCBI

Non-pharmacological treatments (therapies & other supports)

1. Individualized physiotherapy program – Task-specific gait/balance, cueing, dual-task training; improves walking and reduces falls in PD. Refer to a PD-experienced PT. PubMed

2. Aerobic exercise – Regular moderate-to-vigorous walking/cycling improves motor function and fatigue; build gradually. PubMed

3. Resistance/strength training – Helps bradykinesia and functional capacity when combined with balance training. PubMed

4. Tai Chi – Randomized trials show better balance and fewer falls; benefits persist long-term with practice. New England Journal of Medicine+2PubMed+2

5. Speech therapy (LSVT LOUD) – Intensive voice treatment improves loudness and communication versus usual care. PubMed+2BMJ+2

6. Swallowing therapy (SLT with EMST, compensatory strategies) – Reduces aspiration risk and supports nutrition. NICE

7. Occupational therapy – Energy conservation, home safety, ADL adaptations, cognitive strategies. NICE

8. Parkinson nurse specialist follow-up – Regular review for meds, education, and community support. NICE

9. Falls prevention program – Balance training + home hazard reduction + vitamin D as appropriate. NICE

10. Orthostatic hypotension (OH) non-drug plan – Salt/water repletion, compression garments, head-up sleeping, small frequent meals. PMC+1

11. Constipation toolkit – Fluids, fiber (including psyllium), physical activity; escalate to laxatives if needed. PMC+1

12. Sleep hygiene – Consistent schedule, light exposure, treat RBD/insomnia with clinician guidance. General PD care standards apply. NICE

13. Anxiety/depression support (CBT/psychotherapy) – Part of multidisciplinary PD care; improves quality of life. NICE

14. Cognitive strategies & planning – Routine setting, reminders, carer education; consider cholinesterase inhibitors if dementia (clinician-led). NICE

15. Cueing strategies for freezing – Visual stripes, metronome beats, or auditory cues to unlock gait. PubMed

16. Bone health – Weight-bearing exercise; vitamin D where indicated to reduce fracture risk with falls. NICE

17. Driving & work assessment – Safety evaluation and adaptations when motor/cognitive changes emerge. NICE

18. Carer training & respite – Education reduces complications and improves outcomes. NICE

19. Community programs (dance, boxing, cycling classes) – Improve fitness, balance, and engagement. PubMed

20. Nutrition counseling – Protein redistribution can smooth levodopa response; avoid overall protein restriction without supervision. NICE

Drug treatments

1. Carbidopa/Levodopa (immediate-release) – First-line for motor symptoms; titrated to effect many times/day. FDA Access Data

2. Carbidopa/Levodopa extended/controlled-release – Smoother plasma levels to reduce OFF time. FDA Access Data

3. Levodopa intestinal gel (DUOPA/CLES) – PEG-J pump infuses over 16 h; reduces OFF time in advanced PD. Label caps levodopa ~2000 mg/day. FDA Access Data+1

4. Levodopa inhalation powder (INBRIJA) – On-demand rescue for sudden OFF episodes, used with an inhaler. FDA Access Data

5. Carbidopa/levodopa/entacapone combo – A COMT inhibitor added to levodopa to prolong effect. FDA Access Data

6. Entacapone (COMTAN) – Add-on for wearing-off; monitor dyskinesia and GI effects. FDA Access Data

7. Opicapone (ONGENTYS) – Once-daily COMT inhibitor to reduce OFF time. FDA Access Data

8. Tolcapone (TASMAR) – Potent COMT inhibitor; liver toxicity risk requires strict monitoring—used rarely. FDA Access Data

9. Pramipexole (MIRAPEX) – Dopamine agonist for early/adjunct therapy; watch impulse-control, sleepiness. FDA Access Data

10. Ropinirole (REQUIP/XL) – Dopamine agonist; label details titration and adverse effects. FDA Access Data+1

11. Rotigotine transdermal (NEUPRO) – Once-daily patch covering 24 h symptoms; skin reactions possible. FDA Access Data

12. Apomorphine injection (APOKYN) – Rapid rescue for OFF; requires antiemetic planning and supervision. FDA Access Data+1

13. Apomorphine sublingual film (KYNMOBI) – Needle-free rescue for OFF; initiated under supervision. FDA Access Data

14. Rasagiline (AZILECT) – MAO-B inhibitor for mild symptoms or as adjunct; watch drug interactions. FDA Access Data

15. Safinamide (XADAGO) – Adjunct to levodopa for OFF time reduction; reversible MAO-B inhibition. FDA Access Data

16. Selegiline (ELDEPRYL/ZELAPAR) – MAO-B inhibitor; mild symptomatic effect in early disease. FDA Access Data

17. Amantadine ER (GOCOVRI) – Best for levodopa-induced dyskinesia; hallucinations and livedo reticularis possible. FDA Access Data

18. Amantadine IR (SYMMETREL) – Older formulation; can help tremor/dyskinesia with careful monitoring. FDA Access Data+1

19. Istradefylline (NOURIANZ) – A2A antagonist adjunct that reduces OFF time; insomnia/hallucination possible. FDA Access Data+1

20. Carbidopa/levodopa micro-/pump formulations (e.g., VYALEV) – Continuous subcutaneous levodopa delivery; newest label notes 24-h infusion schedules. FDA Access Data

Key genotype note: Many PLA2G6 patients are levodopa-responsive, but patterns vary by variant (e.g., D331Y often looks like levodopa-responsive early PD; other genotypes may show dystonia-parkinsonism with faster decline). Start with standard PD algorithms and adjust to phenotype. BioMed Central

Dietary molecular supplements

1. Vitamin D – Frequently recommended in PD care for bone/fall risk; dose per national bone-health guidance. NICE

2. Psyllium/soluble fiber – Improves constipation and bowel regularity. Typical adult doses are used; increase fluids. PMC+1

3. Protein redistribution (strategy, not a pill) – Shift most daily protein to evening to improve daytime levodopa effect; do not reduce total protein without a dietitian. NICE+2michaeljfox.org+2

4. Hydration & electrolytes – Supports constipation and OH; small frequent fluids, clinician-guided salt where appropriate. PMC

5. Caffeine (caution) – May help alertness; can worsen tremor/OH and sleep—individualize. PMC

6. Pro-kinetic nutrition pattern – Low-glycemic small meals to blunt post-prandial hypotension. Practical Neurology

7. General high-fiber diet – Vegetables, whole grains to ease constipation and support gut health in PD. e-jmd.org

8. Omega-3 intake (dietary focus) – Cardiometabolic benefits; PD-specific motor benefits uncertain. Use food-first approach. NICE

9. Avoid “neuroprotective” supplement claims – NICE advises against vitamin E or unproven OTC neuroprotection; discuss any supplement with clinicians. NICE

10. Creatine: don’t use for PD – Specifically not recommended by NICE. NICE

Immunity-booster / regenerative / stem-cell drugs

(There are no FDA-approved regenerative or stem-cell drugs for PD as of today; use is clinical-trial only. I won’t give dosing for experimental agents.)

1. Cell replacement (iPSC/hES-derived dopaminergic neurons) – Early Phase I/II trials show safety signals and graft survival with potential motor gains; access only via trials. Nature+2Nature+2
2. Allogeneic vs autologous cell therapy – Meta-analyses and reviews suggest feasibility but emphasize heterogeneity and surgical complexity. BioMed Central+1
3. Neural stem cells – Remain investigational with technical hurdles across the peri-operative pathway. PMC
4. Immune-targeted therapies (anti-α-syn vaccines/antibodies) – Ongoing trials; so far no disease-modifying approval. PMC
5. Industry landscape – Multiple programs are active; some proceed to Phase III, others are restructured—illustrating uncertainty. Reuters+1

Bottom line – Consider trials at centers of excellence; avoid clinics selling “stem cells” outside regulated studies. PMC

Surgical/procedural options

1. Deep Brain Stimulation (DBS: STN or GPi) – Proven for medication-refractory motor fluctuations/dyskinesia; best in levodopa-responsive patients without severe cognitive/psychiatric disease. American Academy of Neurology+1
2. DBS programming & advances (adaptive DBS) – Technique/targets evolve; adaptive systems are investigational but promising for reducing side-effects. American Academy of Neurology+1
3. Continuous levodopa intestinal gel (DUOPA/CLES) – Device-assisted therapy for advanced OFF time when DBS is unsuitable or as adjunct. FDA Access Data+1
4. MR-guided Focused Ultrasound (FUS) thalamotomy/pallidotomy – Incisionless lesioning for tremor or motor complications in selected patients; US approvals have expanded (including staged bilateral options). FDA Access Data+1
5. Multidisciplinary selection – NICE and AAN emphasize careful candidate screening and informed consent for all device-aided therapies. NICE+1

Prevention

1. Exercise most days (balance + cardio + strength). PubMed

2. Home fall-proofing (lighting, rugs, rails). NICE

3. Vitamin D as indicated for bone health. NICE

4. Constipation prevention (fluids, fiber, movement). PMC

5. OH prevention (slow position changes, compression, head-up sleep). PMC

6. Medication review to avoid agents worsening motor/cognitive symptoms. NICE

7. Protein–levodopa timing plan to reduce OFF. michaeljfox.org

8. Vaccinations & infection prevention (illness can worsen PD symptoms). Standard adult immunization per local guidance. NICE

9. Sleep routine to stabilize motor and cognitive function. NICE

10. Carer education & respite to prevent crises. NICE

What to eat & what to avoid

1. Eat: Plenty of vegetables, whole grains, legumes, fruit; adequate protein but shift larger protein portions to evening if you have levodopa fluctuations; fluids through the day; low-glycemic small meals if you get post-meal light-headedness. michaeljfox.org+2NICE+2
2. Avoid/limit: Taking levodopa with high-protein meals, large high-glycemic loads that worsen post-prandial drops, and new supplements without checking interactions. michaeljfox.org+1

When to see a doctor (or urgent care)

1. New or worsening OFF periods, freezing, falls, hallucinations, confusion, severe constipation, choking/cough with meals, or black/tarry stools (GI bleeding). Medication changes or pump/DBS issues need prompt review. Multidisciplinary review is standard in PD guidelines. NICE

FAQs

1. Is PLA2G6 parkinsonism different from regular PD?
   Often earlier onset and may include dystonia/cognition features; some genotypes have classic levodopa response. NCBI+1

2. Will I always show brain iron on MRI?
   Not necessarily; adult-onset PLA2G6 can lack basal-ganglia iron. BioMed Central

3. Does levodopa work?
   Often yes, especially in D331Y; responses vary by mutation and stage. BioMed Central

4. Can exercise slow progression?
   It improves function and falls; disease-modifying effect is under study. PubMed

5. What if I freeze when walking?
   Use cueing (laser lines, metronome beats) and PT strategies. PubMed

6. What helps speech?
   LSVT LOUD has strong evidence for voice and communication. PubMed

7. How do I handle OFF episodes at home?
   Your team may add a rescue like INBRIJA or apomorphine after training. FDA Access Data+1

8. When to think about DBS or pumps?
   If fluctuations/dyskinesia remain troublesome despite optimized meds—and you respond to levodopa. American Academy of Neurology

9. Are stem cells available?
   Only in trials; no approved regenerative therapy yet. Nature+1

10. Can diet help my meds work better?
    Yes: separate levodopa from large protein; consider protein-redistribution with a dietitian. michaeljfox.org

11. What about supplements like vitamin E or creatine?
    Not recommended for neuroprotection in PD. NICE

12. Constipation won’t quit—what next?
    Fluids, fiber/psyllium, activity first; escalate with your clinician. PMC

13. I get light-headed after meals.
    Frequent, smaller, low-glycemic meals + OH measures can help. Practical Neurology

14. Who should coordinate my care?
    Ideally a movement-disorder team with a PD nurse, PT/OT/SLT, and dietitian. NICE

15. Is antipsychotic use safe if I hallucinate?
    Specialist use of quetiapine/clozapine at low doses may be considered; others can worsen motor symptoms. NICE

Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, geological location, weather and previous medical  history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. Regular check-ups and awareness can help to manage and prevent complications associated with these diseases conditions. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. We always try to ensure that the content is regularly updated to reflect the latest medical research and treatment options. Thank you for giving your valuable time to read the article.

The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members

Last Updated: October 12, 2025.

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