Clinical, radiological and genetic characterization of PLA2G6-associated neurodegeneration

Abstract

Objective: To characterize the spectrum of clinical, genetic and neuroimaging findings in PLA2G6-associated neurodegeneration (PLAN). Methods: Cross-sectional multi-center study. PLAN patients were examined following a standardized protocol. Sanger and MLPA methods were used to screen point mutations and large deletions/duplications. Two pediatric neuroradiologists performed qualitative assessment of the size, shape and signal intensity of different brain structures on MRI. The relative diameter of the midsagittal vermis (MSV) and the clava size were calculated using a T1-midsagittal section. Results: Sixteen patients from 13 families (mean 10.7 years, range 3–33; 5 males) were identified with missense, nonsense and frameshift mutations in PLA2G6, five of them being novel. Uniparental disomy was identified in twin sisters. Median age at onset (years) of signs/symptoms were: neurological regression (1.5) (n = 15), oculomotor abnormalities (1.5) (n = 6), hypotonia (2) (n = 9), spasticity (3) (n = 13), dysphagia (4) (n = 11), neuropathy (4) (n = 8), seizures (5.9) (n = 8), optic atrophy (6.5) (n = 6), dystonia (9) (n = 9) and parkinsonism (14.5) (n = 4). Qualitative assessment of eighteen MRIs showed cerebellar atrophy (18), pallidum and sustantia nigra hypointensity (8), clava hypertrophy (7), thin corpus callosum (6), hyperintensity of the cerebellar cortex (4) and dentate (4), and cerebral atrophy (3). Age at gait loss correlated with age at onset of neuropathy (r = 0.88) and with the MSV (r = 0.749). Moreover, patients with neuropathy had lower MSV (p = 0.005). Clava size did not correlate with cerebellar atrophy or other clinical variables. Patients with iron deposition had a longer disease duration at the time of MRI (10.3 ± 6.4 versus 2.2 ± 2.8 years, p = 0.02). Conclusion: Our study demonstrated that gait loss in PLA2G6-patients was closely linked to cerebellar atrophy and neuropathy. Dystonia and parkinsonism, together with iron deposition, where later signs of nigrostriatal degeneration. We expand the spectrum of PLA2G6 mutations and identify uniparental disomy as a relevant mechanism, highlighting the importance of parental carrier testing to predict the recurrence risk for families.