Laura A. Adang, Amy Pizzino, Alka Malhotra, Holly Dubbs, Catherine Williams, Omar Sherbini, Anna-Kaisa Anttonen, Gaetan Lesca, Tarja Linnankivi, Chloé Laurencin, Matthieu Milh, Charles Perrine, Christian P. Schaaf, Anne-Lise Poulat, Dorothee Ville, Tanner Hagelstrom, Denise L. Perry, Ryan J. Taft, Amy Goldstein, Arastoo Vossough, Ingo Helbig, Adeline Vanderver. Phenotypic and imaging spectrum associated with WDR45. Pediatric Neurology, in press.
Mutations in the X-linked gene WDR45 cause neurodegeneration with brain iron accumulation type 5 (NBIA5). Global developmental delay is seen at an early age with a slow progression to dystonia, parkinsonism, and dementia due to progressive iron accumulation in the brain.
We present 17 new cases and reviewed 106 reported cases of NBIA5. Detailed information related to developmental history and key time to event measures was collected.
Within this cohort, there were 19 males. Most individuals were molecularly diagnosed by whole exome testing. Overall 10 novel variants were identified across 11 subjects. All individuals were affected by developmental delay, most prominently in verbal skills. Most individuals experienced a decline in motor and cognitive skills. While most individuals were affected by seizures, the spectrum ranged from provoked seizures to intractable epilepsy. The imaging findings varied as well, often evolving over time. The classic iron accumulation in the globus pallidus and substantia nigra was noted half of our cohort and was associated with an older age of image acquisition, while myelination abnormalities were associated with a younger age.
WDR45 is a progressive and evolving disorder, which is often delayed in diagnosis. Developmental delay and seizures predominate early childhood, followed by a progressive decline of neurologic function. There is variable expressivity in the clinical phenotypes of individuals with WDR45 mutations, suggesting that this gene should be considered in the diagnostic evaluation of children with myelination abnormalities, iron deposition, developmental delay, and epilepsy depending on the age at evaluation.