Expanding The Genotypic And Phenotypic Spectrum Of Beta-Propeller Potein-Associated Neurodegeneration

Beta-propeller-associated neurodegeneration (BPAN) is a very rare early-onset neurodevelopmental-neurodegenerative disorder due to X-linked dominant mutations of the WDR45 gene (1, 2). One hundred and twenty-eight BPAN patients were described so far (3). BPAN, also known as neurodegeneration with brain iron accumulation 5 (NBIA5) or "static encephalopathy of childhood with neurodegeneration in adulthood" (SENDA), is characterized by global early psychomotor delay and epilepsy, followed, in young adulthood, by progressive dystonia, parkinsonism, and cognitive deterioration (4). Brain MRI of affected subjects shows iron accumulation in the globus pallidus and substantia nigra. The pathognomonic MRI finding is the T1-weighted mesencephalic hyperintense signal surrounding the substantia nigra. Cerebral and cerebellar atrophy are also frequently observed (5). Most affected subjects are female. The rare finding of WDR45 mutations in males was initially attributed to the poor viability of hemizygotes. However, recent reports suggest that males carrying a hemizygous WDR45 mutation can present a different phenotype predominated by epileptic encephalopathy (6). To our knowledge, ninety-seven WDR45 mutations have been reported in literature to date. The spectrum of variant types comprises 35 frameshift variants, 21 nonsense variants, 19 splice-site variants, 15 missense variants, 3 in-frame deletions, and 3 large deletions. Most of the identified mutations occurred de novo, with very few exceptions (3).