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Indication for molecular testing by multiplex ligation-dependent probe amplification in parkinsonism
E Mutez1,2, M Swiderski2, D Devos1,2,3
1Univ. Lille, Inserm, CHU Lille, U1172 - LilNCog (JPARC) - Lille Neurosciences & Cognition, Lille, France.
Background And Purpose:
The monogenic forms of Parkinson's disease represent <10% of familial cases and a still lower frequency of sporadic cases. However, guidelines to orient genetic testing are lacking. The aim was to establish the interest of multiplex ligation-dependent probe amplification (MLPA) as a primary screening test and to propose clinical criteria to guide genetic diagnostic tests for patients with suspected Mendelian Parkinson's disease.
Methods:
In all, 567 patients with parkinsonism from 547 unrelated families were recruited and two MLPAs were performed for each. All pathogenic G2019S variants in the LRRK2 gene were confirmed by Sanger sequencing and the PRKN gene was screened for a second mutation in the cases of one heterozygous structural variant in the PRKN gene.
Results:
The performance of MLPA was 51/567 (9%) for the entire cohort and included 27 (4.8%) LRRK2 G2019S mutations, 19 (3.4%) PRKN mutations and five (0.9%) SNCA locus duplications. The variables significantly associated with a positive test in the total cohort were North African ancestry (p < 0.0001), female sex (p = 0.004) and younger age at onset (p < 0.0008).
Conclusions:
Retrospective analysis allowed us to refine our indication criteria: (i) North African ancestry, (ii) an age at onset <40 years or (iii) a familial history of parkinsonism with at least one affected first-degree relative. Our study highlights the interest of MLPA testing for other parkinsonism cases with a family history, especially for patients with dementia with Lewy bodies or a multiple-system-atrophy-like phenotype.
Insights
Multiplex ligation-dependent probe amplification (MLPA) effectively screens for genetic Parkinson's disease, identifying mutations in LRRK2, PRKN, and SNCA genes. Refined criteria like North African ancestry and early onset improve diagnostic yield for Mendelian Parkinson's disease.
Area of Science:
- Neurogenetics
- Molecular Diagnostics
Background:
- Monogenic Parkinson's disease (PD) accounts for a small percentage of familial and sporadic cases.
- Lack of clear guidelines complicates genetic testing for suspected Mendelian PD.
Purpose of the Study:
- To evaluate multiplex ligation-dependent probe amplification (MLPA) as a primary screening tool for genetic PD.
- To establish clinical criteria for guiding genetic diagnostic tests in Mendelian PD.
Main Methods:
- 567 patients with parkinsonism underwent MLPA analysis.
- LRRK2 G2019S variants were confirmed by Sanger sequencing; PRKN mutations were further investigated.
Main Results:
- MLPA identified pathogenic variants in 9% of the cohort, including LRRK2 (4.8%), PRKN (3.4%), and SNCA duplications (0.9%).
- Positive genetic tests were associated with North African ancestry, female sex, and younger age at onset.
Conclusions:
- MLPA is a valuable screening test for Mendelian Parkinson's disease.
- Clinical criteria including North African ancestry, age at onset <40 years, or family history improve diagnostic targeting.
- MLPA is also beneficial for parkinsonism with family history, dementia with Lewy bodies, or multiple-system-atrophy-like phenotypes.
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