PLA2G6 mutations associated with a continuous clinical spectrum from neuroaxonal dystrophy to hereditary spastic paraplegia

Abstract

PLA2G6-associated neurodegeneration (PLAN) and hereditary spastic paraplegia (HSP) are 2 groups of heterogeneous neurodegenerative diseases. In this study, we report PLA2G6 gene mutations in 3 families from Turkey, Morocco, and Romania. Two affected Turkish siblings presenting HSP adds the disease to PLAN phenotypes. They were homozygous for the PLA2G6 missense c.2239C>T, p.Arg747Trp variant and the ages of onset were 9 and 21. Parkinsonism, dystonia or cognitive decline were not the clinical elements in these patients contrary to the cases that has been previously reported with the same variant, however, iron accumulation was evident in their cranial magnetic resonance imaging. The Moroccan patient was homozygous for a novel missense c.1786C>T, p.Leu596Phe variant and the Romanian patient had 2 novel mutations; c.1898C>T, p.Ala633Val and c.1765_1768del, p.Ser589ThrfsTer76. Both of these patients conformed better to childhood onset PLAN with the age of onset at 4 and 7 years, respectively. Interestingly, all identified mutations were affecting the highly conserved patatin-like phospholipase domain of the PLA2G6 protein.

Keywords: PLA2G6-associated neurodegeneration, PLAN; HSP, next-generation sequencing; hereditary spastic paraplegia.

Fig 1

Variations identified in PLA2G6 gene. c.2239C>T, p.R747W variant in Cases 1 and 2 (a), c.1786C>T, p.L596F variation in Case 3 (b) and c.1765_1768delTCTG, p.Ser589Thrfs*76 and c.1898C>T, p.A633V variations in Case 4 (c). Black boxes indicate affected family members that are homozygous for the variation. Electropherograms are shown below. Domain structure of the PLA2G6 gene indicating the position of the mutations (modified from Engel et al. 2010) (d)

Fig 2

MRI findings. Axial gradient-recalled echo image shows bilateral hypointensity in both globi pallidi (arrows) consistent with iron accumulation in Case 1 at age 27. (a). Axial gradient-recalled echo sequence of Case 2 at age 32 depicts hypointensity in both globi pallidi (a′) and substantia nigra (a″) (arrows) consistent with iron accumulation. Sagittal T1-weighted images demonstrate callosal elongation (black arrow) and claval hypertrophy (curved white arrow) (b), marked atrophy of cerebellum on T2-weighted image (b′) of Case 3 at the age of seven. T2-weighted sagittal scan shows vermian atrophy and claval hypertrophy (arrow) (c), T1-weighted axial image demonstrates cerebellar atrophy (c′), and there was no evidence of iron deposition in basal ganglia on T2-weighted axial scan (c″) in Case 4 at age 10.