Homozygous PLA2G6 (PARK 14) gene mutation associated neuropsychiatric phenotypes from southern India

Sakhardande, Kasturi Atmaram; Reddi, Venkata Senthil Kumar; Mishra, Saumya; Navin, Karthick; Ramu, Aashraya; Arunachal, Gautham; Mangalore, Sandhya; Yadav, Ravi; Jain, Sanjeev

doi:10.1016/j.parkreldis.2021.07.026

Cited by 5 publications

(7 citation statements)

References 4 publications

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“…Most PLA2G6-parkinsonism cases reported after our systematic review 2 confirm that psychiatric issues often occur early in the disease course and even precede extrapyramidal manifestations, which may be initially misinterpreted as secondary to antipsychotic treatment. 2,3,[5][6][7] Interestingly, Li et al 6 described a Chinese female harboring compound heterozygous variants in PLA2G6 and presenting with neuropsychiatric symptoms soon after pregnancy, therefore, strengthening our suggestion that onset or rapid deterioration of clinical manifestations in PLA2G6-parkinsonism might be triggered by dramatic hormonal fluctuations, as previously spotlighted in five cases. 2 Regardless of the extent of levodopa responsiveness, most cases recently reported developed early dyskinesia, 3,6,7 which are often prominent in the lower face, as also demonstrated by Ravat et al's video.…”

supporting

confidence: 86%

“…1 In addition, it should be mentioned that a functional relation has been demonstrated between increased dopamine turnover and lower DAT transporter. 5 It is therefore not surprising that presynaptic compensatory changes include a reduction in the membrane DAT binding, which is also evident in early-disease stages and serves to optimize dopamine utilization by surviving nerve terminals. 6 In this regard, both our findings and the findings by Sambin and colleagues 1 highlight the very early activation of striatal regulatory changes in premotor PD.…”

Section: Data Availability Statementmentioning

confidence: 99%

“…8 Our deep phenotyping approach revealed several diagnostic clues to PLA2G6-parkinsonism, for which some mutant alleles show geographical clustering and disease-modifying treatments are under investigation. 2,5 Further evidence might establish whether early DBS can affect the natural course of PLA2G6-parkinsonism.…”

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confidence: 99%

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Reply to: Juvenile PLA2G6‐parkinsonism due to Indian ‘Asian’ p.R741Q mutation, and response to STN DBS

et al. 2022

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We are grateful for Ravat et al.'s interest in our article on PLA2G6-parkinsonism. 1,2,3 They reported an additional case showing some clinicoradiological diagnostic hints we highlighted, including young onset of levodopa-responsive parkinsonism, occurrence of truncal dystonia and cerebellar signs, early development of levodopa-induced dyskinesia, and presence of cerebellar atrophy as well as possible lack of iron deposition on brain MRI. 2 Their case 1 reinforces our observation that NM_003560.4(PLA2G6):c.2222G > A (p. Arg741Gln) is the most frequent variant in Indian cases of PLA2G6-parkinsonism. 2 It also adds to the hitherto scant evidence that deep brain stimulation (DBS) may be effective for managing symptoms and early complications of dopaminergic treatment in this disorder. 1,2 Further cases of PLA2G6-parkinsonism are in keeping with the main findings of our work and confirm the core phenotype depicted therein, 2-7 including another patient we identified (Table 1, Case S1). This is a 35-year-old female born to consanguineous Pakistani parents after uncomplicated pregnancy and birth. She experienced occasional falls during childhood and required crutches because of lower-limb spasticity since her teenage years. Despite a mild learning difficulty, she completed her secondary education at a normal school. At age 16, she had a psychotic FIG. 1. Sagittal T1 (A) and axial T2 (B) magnetic resonance (MR) images show mild cerebellar atrophy. 99mTc-TRODAT SPECT scan (C) reveals bilateral, asymmetric reduction of tracer uptake, more prominent on the left side, with putaminal uptake more reduced than the caudate bilaterally, consistent with the pattern seen in Parkinson's disease. [Color figure can be viewed at wileyonlinelibrary.com]

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supporting

confidence: 86%

Section: Data Availability Statementmentioning

confidence: 99%

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Reply to: Juvenile PLA2G6‐parkinsonism due to Indian ‘Asian’ p.R741Q mutation, and response to STN DBS

et al. 2022

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“…This variant has been previously reported from Saudi Arabia, Pakistan, and India with possible geographical clustering. 4,5 Patient demonstrated significant improvement in bradykinesia and dystonia with levodopa/carbidopa (100/25 mg thrice a day; Video S2). He was also started on immunomodulatory therapy in the form of corticosteroids and azathioprine for posterior uveitis in the right eye.…”

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confidence: 99%

Unusual Presentation of PLA2G6‐Related Neurodegeneration with Retinal Vasculitis

Mehta

Takkar

Singh

et al. 2021

Movement Disord Clin Pract

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“…p.R741Q variants in two individuals (P1, P2) with AREP[Sakhardande et al, 2021], and a p.R741W variant in an individual (P3) with INAD. These variants lie in the region succeeding the calmodulin-binding domain.…”

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confidence: 99%

Missense variants inPLA2G6contribute to a spectrum of clinical syndromes and provide pharmacogenomic correlates

Janardhanan

Anbhazagan

Viswanath

et al. 2023

Preprint

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Background: Risk alleles in a gene for a genetic disorder can often cause a spectrum of syndromes. The number of copies, deleteriousness and position in the sequence could influence phenotype manifestation. Methods: Whole exome sequencing in 310 individuals from 100 families with severe mental illness revealed 851 instances of variants in the PLA2G6 gene. We assessed the population frequency and deleteriousness of the nonsynonymous variants using in-silico prediction methods. Molecular docking analyses with antipsychotics was performed to investigate possible pharmacogenomic implications of the PLA2G6 mutations identified. Results: We found six nonsynonymous variants predicted to be deleterious by VarSome. The frequency of non-synonymous variants was found to vary across populations. The preliminary molecular docking analysis suggests that chlorpromazine and risperidone are predicted to bind at three drug-binding sites however, risperidone has a greater binding affinity to PLA2G6. The occurrence of variants close to these drug-binding sites suggests a possible mechanism for the mediation of parkinsonian side effects on drug intake in patients harboring these variants. Conclusion: Variants in the PLA2G6, a gene previously known to be associated with Parkinsons disease may thus contribute to the risk of psychiatric phenotypes, as observed in these 9 individuals from 6 families with severe mental illness.

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Homozygous PLA2G6 (PARK 14) gene mutation associated neuropsychiatric phenotypes from southern India

Cited by 5 publications

References 4 publications

Reply to: Juvenile PLA2G6‐parkinsonism due to Indian ‘Asian’ p.R741Q mutation, and response to STN DBS

Reply to: Juvenile PLA2G6‐parkinsonism due to Indian ‘Asian’ p.R741Q mutation, and response to STN DBS

Unusual Presentation of PLA2G6‐Related Neurodegeneration with Retinal Vasculitis

Missense variants inPLA2G6contribute to a spectrum of clinical syndromes and provide pharmacogenomic correlates

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