Severe Early‐Onset Parkinsonian Syndrome Caused by <scp><i>PLA2G6</i></scp> Heterozygous Variants

Oliveira, Pérola de; Montanaro, Vinícius Viana Abreu; Carvalho, Daniel R.; Martins, Bernardo; Ferreira, Alessandra; Cardoso, Francisco

doi:10.1002/mdc3.13230

Cited by 7 publications

(9 citation statements)

References 10 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%

“…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. 1 In this context, we point out that peak-dose dystonic dyskinesia and spasms affecting the oromandibular region in response to low-dose levodopa are not uncommon in PLA2G6-parkinsonism, with spasms resembling those seen in multiple system atrophy (Video S1, Case S2).…”

supporting

confidence: 86%

“…Their report supports the sensitivity of DAT imaging in detecting "premotor" PD and further implies the existence of striatal compensatory mechanisms in the presymptomatic stage of PD. 2 We observed a similar pattern of early DAT depletion in two asymptomatic members of a family carrying the same G2019S LRRK2 gene mutations, with one subject (case 2) 3 showing intact nigral anatomy with 7 T-MRI but impaired nigrostriatal pathway, as reflected by the [ 123 I]-FP-CIT striatal uptake. 3 After 9 years this patient has still not been diagnosed with clinical PD, confirming a similar long presymptomatic phase during which several disease-induced striatal mechanisms of compensation occur.…”

Section: Data Availability Statementsupporting

confidence: 52%

“…2 We observed a similar pattern of early DAT depletion in two asymptomatic members of a family carrying the same G2019S LRRK2 gene mutations, with one subject (case 2) 3 showing intact nigral anatomy with 7 T-MRI but impaired nigrostriatal pathway, as reflected by the [ 123 I]-FP-CIT striatal uptake. 3 After 9 years this patient has still not been diagnosed with clinical PD, confirming a similar long presymptomatic phase during which several disease-induced striatal mechanisms of compensation occur. 4 The other asymptomatic mutation carrier (case 1), 3 who had loss of the trilayered structure of substantia nigra or nigrosome at MRI and abnormal DAT imaging at baseline, progressed to clinical disease in 2 years, supporting a forthcoming conversion to PD in subjects with imaging evidence of nigral cell loss.…”

Section: Data Availability Statementsupporting

confidence: 52%

“…

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.

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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%

supporting

confidence: 86%

Section: Data Availability Statementsupporting

confidence: 52%

Section: Data Availability Statementsupporting

confidence: 52%

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confidence: 93%

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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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Frequency of Hereditary and GBA1‐Related Parkinsonism in Latin America: A Systematic Review and Meta‐Analysis

Saffie Awad,

Teixeira‐dos‐Santos,

Santos‐Lobato

et al. 2023

Movement Disorders

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BackgroundIdentifying hereditary parkinsonism is valuable for diagnosis, genetic counseling, patient prioritization in trials, and studying the disease for personalized therapies. However, most studies were conducted in Europeans, and limited data exist on admixed populations like those from Latin America.ObjectivesThis study aims to assess the frequency and distribution of genetic parkinsonism in Latin America.MethodsWe conducted a systematic review and meta‐analysis of the frequency of parkinsonian syndromes associated with genetic pathogenic variants in Latin America. We defined hereditary parkinsonism as those caused by the genes outlined by the MDS Nomenclature of Genetic Movement Disorders and heterozygous carriers of GBA1 pathogenic variants. A systematic search was conducted in PubMed, Web of Science, Embase, and LILACS in August 2022. Researchers reviewed titles and abstracts, and disagreements were resolved by a third researcher. After this screening, five researchers reanalyzed the selection criteria and extracted information based on the full paper. The frequency for each parkinsonism‐related gene was determined by the presence of pathogenic/likely pathogenic variants among screened patients. Cochran's Q and I2 tests were used to quantify heterogeneity. Meta‐regression, publication bias tests, and sensitivity analysis regarding study quality were also used for LRRK2‐, PRKN‐, and GBA1‐related papers.ResultsWe included 73 studies involving 3014 screened studies from 16 countries. Among 7668 Latin American patients, pathogenic variants were found in 19 different genes. The frequency of the pathogenic variants in LRRK2 was 1.38% (95% confidence interval [CI]: 0.52–2.57), PRKN was 1.16% (95% CI: 0.08–3.05), and GBA1 was 4.17% (95% CI: 2.57–6.08). For all meta‐analysis, heterogeneity was high and publication bias tests were negative, except for PRKN, which was contradictory. Information on the number of pathogenic variants in the other genes is further presented in the text.ConclusionsThis study provides insights into hereditary and GBA1‐related parkinsonism in Latin America. Lower GBA1 frequencies compared to European/North American cohorts may result from limited access to gene sequencing. Further research is vital for regional prevalence understanding, enabling personalized care and therapies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Levodopa/benserazide/aripiprazole/haloperidol

2021

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Severe Early‐Onset Parkinsonian Syndrome Caused by PLA2G6 Heterozygous Variants

Cited by 7 publications

References 10 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

Frequency of Hereditary and GBA1‐Related Parkinsonism in Latin America: A Systematic Review and Meta‐Analysis

Levodopa/benserazide/aripiprazole/haloperidol

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