Beta-propeller protein-associated neurodegeneration (BPAN)

Neurodegenerative diseases
Metabolic diseases

General description

Beta-propeller protein-associated neurodegeneration (BPAN) represents the most common form of neurodegeneration with brain iron accumulation (NBIA), characterized by a distinctive biphasic clinical course involving static encephalopathy in childhood followed by progressive neurodegeneration in adolescence and adulthood.

BPAN is caused by pathogenic variants in the WDR45 gene located on chromosome Xp11, which encodes a β-propeller scaffold protein known as WIPI4 (WD repeat domain, phosphoinositide interacting protein 4). The WDR45 protein plays a crucial role in the early stages of autophagy, especially ferritinophagy, a specialized form of autophagy responsible for degrading ferritin, the iron storage protein.

Clinical manifestations

BPAN exhibits a characteristic biphasic clinical course that distinguishes it from other neurodegenerative disorders. The disease typically manifests in early childhood with global developmental delay, intellectual disability, and epilepsy, followed by a period of relative stability before the onset of progressive neurodegeneration in adolescence or early adulthood.

The early childhood phase is characterized by static encephalopathy with global developmental delay, speech impairment, intellectual disability, and seizure. The second phase of the disease typically begins in mid-adolescence or early adulthood and is characterized by progressive neurological deterioration. The onset of this phase is usually heralded by the development of movement disorders, particularly dystonia and parkinsonism.

Referenes

  1. Papandreou, Apostolos, et al. "Expanding the spectrum of early neuroradiologic findings in β propeller protein-associated neurodegeneration." American Journal of Neuroradiology 43.12 (2022): 1810-1814.

Iron deposition

Anatomical regions
  • Globus pallidus
  • Substantia nigra
  • Cerebral peduncle
Bilateral
T1WI
Hyperintensity
T2WI
Hypointensity
FLAIR
Hypointensity

When parkinsonism appears in BPAN, T2WI reveals hypointensity in the globus pallidi, substantia nigra, and cerebral peduncles, reflecting iron deposition. T1WI shows hyperintensities in the corresponding regions.

Atrophy

Anatomical regions
  • Cerebrum
  • Cerebellum
  • Corpus callosum
Bilateral
Morphology
Atrophy

Atrophy is observed in the bilateral cerebral and cerebellar hemispheres, in addition to the corpus callosum.