PLA2G6-associated late-onset parkinsonism in a Sudanese family

Abstract

Introduction: The phospholipase A2 group VI gene (PLA2G6) encodes an enzyme that catalyzes the hydrolytic release of fatty acids from phospholipids. Four neurological disorders with infantile, juvenile, or early adult-onset are associated with PLA2G6 genetic alterations, namely infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (ANAD), dystonia-parkinsonism (DP), and autosomal recessive early-onset parkinsonism (AREP). Few studies in Africa reported PLA2G6-associated disorders and none with parkinsonism of late adult onset.

Material and methods: The patients were clinically assessed following UK Brain Bank diagnostic criteria and International Parkinson and Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Brain MRI without contrast was performed. Genetic testing was done using a custom-made Twist panel, screening 34 known genes, 27 risk factors, and 8 candidate genes associated with parkinsonism. Filtered variants were PCR-amplified and validated using Sanger sequencing and also tested in additional family members to study their segregation.

Result: Two siblings born to consanguineous parents developed parkinsonism at the age of 58 and 60 years, respectively. MRI showed an enlarged right hippocampus in patient 2, but no overt abnormalities indicative of INAD or iron deposits. We found two heterozygous variants in PLA2G6, an in-frame deletion NM_003560:c.2070_2072del (p.Val691del) and a missense variant NM_003560:c.956C>T (p.Thr319Met). Both variants were classified as pathogenic.

Conclusion: This is the first case in which PLA2G6 is associated with late-onset parkinsonism. Functional analysis is needed to confirm the dual effect of both variants on the structure and function of iPLA2β.

Figure 1

Heredogram showing the segregation result of two siblings diagnosed with autosomal recessive late onset Parkinsonism, their mother and two healthy sibling . the first variant (p.Val691del) was considered M1 while the second variant (p.Thr319Met) is considered M2. The red plus indicates a carrier of the variant while the wild type is indicated with (wt). The red arrow indicated the targeted individual for the panel.

Figure 2

T2‐weighted MRI brain scans of patient 1 showing moderate hippocampal expansion on the left side, as indicated with the red arrow. (A) Coronal section. (B) Horizontal section.

Figure 3

Homology modeling of iPLA2‐β showing the effect of the mutant variant (p.Thr319Met)on the structure of the protein, inflicting at least four clash point (indicated with dotted purple lines) with the surrounding amino acid residues. (A) Three‐dimensional structure of the protein iPLA2‐β, with the site of amino acid changed indicated in red arrow. (B) Wild type residue Threonine. (C) Mutant residue Methionine.