Skip to content

Beta Propeller Protein Associated Neurodegeneration

Summary

  • A subtype of neurodegeneration with brain iron accumulation (NBIA), caused by WDR45 mutations
  • X-linked dominant, usually from de novo mutations, presenting with childhood developmental delay then adult-onset dystonia-parkinsonism and dementia
  • The hallmark is T1 hyperintensity of the substantia nigra with a central band of hypointensity ("halo"), plus iron in the substantia nigra and globus pallidus1

Pathophysiology

  • Caused by mutations in WDR45 gene on X chromosome (Xp11.23)
  • WDR45 encodes for WIPI4, a protein involved in autophagy
  • Impaired autophagy leads to accumulation of iron and cellular debris
  • Neurodegeneration primarily affects basal ganglia and substantia nigra

Demographics

  • Rare disorder with estimated prevalence of <1/1,000,000
  • Typically presents in childhood or adolescence
  • Female predominance due to X-linked dominant inheritance pattern
  • Males with germline mutations usually do not survive

Diagnosis

  • Clinical features:
    • Progressive cognitive decline
    • Dystonia
    • Parkinsonism
    • Seizures
    • Sleep disorders
  • Genetic testing:
    • Identification of pathogenic variants in WDR45 gene
  • Biochemical markers:
    • Elevated serum ferritin levels
    • Normal ceruloplasmin and copper levels

Imaging

  • MRI:
    • Characteristic T1 hyperintensity of the substantia nigra (± cerebral peduncles) with a central hypointense band
    • Iron-related T2/SWI hypointensity in the substantia nigra and globus pallidus
    • Progressive cerebral and cerebellar atrophy

panels-1

  • A 25-year-old patient presented with possible seizures and parkinsonism.
  • MRI showed pronounced iron deposition in the globi pallidi and substantia nigra.
  • The substantia nigra T1-hyperintensity was typical for the diagnosis of BPAN.

Treatment

  • Symptomatic only (levodopa, anticholinergics, anticonvulsants); iron chelation is of unproven benefit

Differential diagnosis

Differential Diagnosis Distinguishing Feature
Pantothenate Kinase-Associated Neurodegeneration (PKAN) T2 hypointensity in globus pallidus with central hyperintensity ("eye of the tiger" sign)
Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN) Linear hypointensity in substantia nigra on T2-weighted images
PLA2G6-Associated Neurodegeneration (PLAN) Cerebellar atrophy and iron accumulation in globus pallidus and substantia nigra
Kufor-Rakeb syndrome Generalized brain atrophy and occasional iron accumulation in basal ganglia
Aceruloplasminemia Widespread iron accumulation in basal ganglia, thalamus, and cerebral cortex
Neuroferritinopathy Cystic degeneration of basal ganglia with iron accumulation
Wilson's disease Putamen/midbrain T2 change ("face of the giant panda"), without the T1 substantia nigra hyperintensity of BPAN

  1. Wilson et al. Consensus clinical management guideline for beta-propeller protein-associated neurodegeneration. 2021. Developmental medicine and child neurology - Open in new tab. ↩