PLA2G6-associated neurodegeneration: New insights into brain abnormalities and disease progression

Parkinsonism Relat Disord. 2019 Apr:61:179-186. doi: 10.1016/j.parkreldis.2018.10.013. Epub 2018 Oct 13.


Introduction: PLA2G6-associated neurodegeneration (PLAN) comprises a continuum of three phenotypes with overlapping clinical and radiologic features.

Methods: Observational clinical study in a cohort of infantile and childhood onset PLAN patients and genetic analysis of the PLA2G6 gene. We analysed chronological evolution in terms of age at onset and disease course through a 66-item questionnaire. We performed qualitative and quantitative assessment of MRI abnormalities and searched for clinical and radiological phenotype and genotype correlations.

Results: Sixteen PLAN patients (mean age: 10.2 years, range 3-33) were evaluated, with a median onset (years) of signs/symptoms as follows: neurological regression (1.5), oculomotor abnormalities (1.5), hypotonia (1.8), gait loss (2.2), pyramidal signs (3.0), axonal neuropathy (3.0), dysphagia (4.0), optic atrophy (4.0), psychiatric symptoms (4.0), seizures (5.9), joint contractures (6.0), dystonia (8.0), bladder dysfunction (13.0) and parkinsonism (15.0). MRI assessment identified cerebellar atrophy (19/19), brain iron deposition (10/19), clava hypertrophy (8/19) and T2/FLAIR hyperintensity of the cerebellar cortex (6/19). The mid-sagittal vermis relative diameter (MVRD) correlated with age at onset of clinical variants, meaning that the earlier the onset, the more severe the cerebellar atrophy. All patients harboured missense, nonsense and frameshift mutations in PLA2G6, including four novel variants.

Conclusions: Cerebellar atrophy was a universal radiological sign in infantile and childhood onset PLAN, and correlated with the severity of the phenotype. Iron accumulation within the globus pallidum and substantia nigra was also a common and strikingly uniform feature regardless of the phenotype.

Keywords: Childhood PLAN; Infantile PLAN; Infantile neuroaxonal dystrophy; Magnetic resonance imaging (MRI); Neurodegeneration with brain iron accumulation (NBIA); PLA2G6-associated neurodegeneration (PLAN); PLA2G6-gene; atypical neuroaxonal dystrophy.

Publication types

  • Multicenter Study
  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Atrophy / pathology
  • Cerebellum / diagnostic imaging
  • Cerebellum / pathology*
  • Child
  • Child, Preschool
  • Cross-Sectional Studies
  • Globus Pallidus / diagnostic imaging
  • Globus Pallidus / metabolism*
  • Group VI Phospholipases A2 / genetics
  • Humans
  • Magnetic Resonance Imaging
  • Neuroaxonal Dystrophies / diagnostic imaging
  • Neuroaxonal Dystrophies / pathology*
  • Neuroaxonal Dystrophies / physiopathology*
  • Phenotype
  • Severity of Illness Index
  • Substantia Nigra / diagnostic imaging
  • Substantia Nigra / metabolism*
  • Young Adult


  • Group VI Phospholipases A2
  • PLA2G6 protein, human