Beta Propeller Protein Associated Neurodegeneration
Summary
- Rare autosomal recessive neurodegenerative disorder caused by mutations in WDR45 gene
- Characterised by progressive cognitive decline, dystonia, and parkinsonism
- Distinctive MRI findings of iron accumulation in the globus pallidus and substantia nigra
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 findings:
- T1-weighted images:
- Hypointensity in globus pallidus and substantia nigra
- T2-weighted images:
- Hypointensity in globus pallidus and substantia nigra with central hyperintensity ("eye-of-the-tiger" sign)
- Susceptibility-weighted imaging (SWI):
- Marked hypointensity in globus pallidus and substantia nigra
- CT findings:
- Hyperdensity in affected basal ganglia structures
- 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 management:
- Levodopa for parkinsonian symptoms
- Anticholinergics for dystonia
- Anticonvulsants for seizures
- Iron chelation therapy:
- Limited evidence for efficacy
- Supportive care:
- Physical therapy
- Occupational therapy
- Speech therapy
- Genetic counselling for affected families
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 |
| Huntington's disease | Caudate atrophy and lack of iron accumulation |
| Wilson's disease | Copper accumulation in basal ganglia, "face of giant panda" sign on T2-weighted MRI |
| Juvenile Parkinson's disease | Dopaminergic deficit on DaTscan, lack of iron accumulation |
| Dystonia musculorum deformans | Lack of iron accumulation, normal MRI findings |