Clinical, Neuroimaging, and Molecular Characterization of a Juvenile PLAN-like Phenotype in Two Siblings Carrying p.Arg645Gln and an Unresolved Exon 4–7 Copy-Number Gain: A Case Report

Abstract

PLA2G6-associated neurodegeneration (PLAN) is an autosomal recessive neurodegenerative spectrum encompassing infantile, juvenile/atypical and adult-onset phenotypes. Juvenile PLAN may initially resemble autism spectrum disorder or nonspecific developmental regression, delaying diagnosis. We describe a 14-year-old boy and his 9-year-old sister, both with initially normal early development, followed by progressive gait impairment, speech and cognitive regression, epilepsy or paroxysmal events, contractures and loss of independent ambulation. Brain MRI in both siblings demonstrated marked symmetric cerebellar atrophy, susceptibility-weighted hypointensity of the globus pallidus and substantia nigra compatible with iron accumulation and bilateral optic nerve thinning. Electroneurography showed selective motor axonal involvement. Molecular testing identified the same two heterozygous PLA2G6 findings in both children: c.1934G>A (p.Arg645Gln), classified as likely pathogenic by the diagnostic laboratory, and a copy-number gain encompassing exons 4–7. Parental testing was unavailable; therefore, the phase of the findings could not be established, and it remains unknown whether they are in trans or in cis. The shared phenotype is highly suggestive of juvenile PLAN. However, unresolved phase and incomplete structural characterization of the copy-number gain preclude confirmation of biallelic PLA2G6 involvement and definitive molecular attribution. These related cases provide a descriptive account of a juvenile PLAN-like phenotype, without independently attributing the phenotype to p.Arg645Gln, establishing variant pathogenicity or a specific genotype–phenotype correlation.