Original Article| Volume 109, P56-62, August 2020

Phenotypic and Imaging Spectrum Associated With WDR45



      Mutations in the X-linked gene WDR45 cause neurodegeneration with brain iron accumulation type 5. Global developmental delay occurs at an early age with 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 neurodegeneration with brain iron accumulation type 5. 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. Although 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 in half of our cohort and was associated with older age of image acquisition, whereas myelination abnormalities were associated with younger age.


      WDR45 mutations lead to a progressive and evolving disorder whose diagnosis is often delayed. Developmental delay and seizures predominate in early childhood, followed by a progressive decline of neurological 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.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Pediatric Neurology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Hayflick S.J.
        • Kurian M.A.
        • Hogarth P.
        Neurodegeneration with brain iron accumulation.
        Handbook Clin Neurol. 2018; 147: 293-305
        • Wan H.
        • Wang Q.
        • Chen X.
        • et al.
        WDR45 contributes to neurodegeneration through regulation of ER homeostasis and neuronal death.
        Autophagy. 2020; 16: 531-547
        • Stanga D.
        • Zhao Q.
        • Milev M.P.
        • Saint-Dic D.
        • Jimenez-Mallebrera C.
        • Sacher M.
        TRAPPC11 functions in autophagy by recruiting ATG2B-WIPI4/WDR45 to preautophagosomal membranes.
        Traffic. 2019; 20: 325-345
        • Haack T.B.
        • Hogarth P.
        • Kruer M.C.
        • et al.
        Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA.
        Am J Hum Genet. 2012; 91: 1144-1149
        • Haack T.B.
        • Hogarth P.
        • Gregory A.
        • Prokisch H.
        • Hayflick S.J.
        BPAN: the only X-linked dominant NBIA disorder.
        Int Rev Neurobiol. 2013; 110: 85-90
        • Hayflick S.J.
        • Kruer M.C.
        • Gregory A.
        • et al.
        beta-Propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation.
        Brain. 2013; 136: 1708-1717
        • Long M.
        • Abdeen N.
        • Geraghty M.T.
        • Hogarth P.
        • Hayflick S.
        • Venkateswaran S.
        Novel WDR45 mutation and pathognomonic BPAN imaging in a young female with mild cognitive delay.
        Pediatrics. 2015; 136: e714-e717
        • Saitsu H.
        • Nishimura T.
        • Muramatsu K.
        • et al.
        De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood.
        Nat Genet. 2013; 45 (449e1): 445-449
        • Abidi A.
        • Mignon-Ravix C.
        • Cacciagli P.
        • Girard N.
        • Milh M.
        • Villard L.
        Early-onset epileptic encephalopathy as the initial clinical presentation of WDR45 deletion in a male patient.
        Eur J Hum Genet. 2016; 24: 615-618
        • Vanderver A.
        • Simons C.
        • Helman G.
        • et al.
        Whole exome sequencing in patients with white matter abnormalities.
        Ann Neurol. 2016; 79: 1031-1037
        • Frankenburg W.K.
        • Dodds J.
        • Archer P.
        • Shapiro H.
        • Bresnick B.
        The Denver II: A Major Revision and Restandardization of the Denver Developmental Screening Test.
        Denver Developmental Materials, Denver, CO1990
        • Jeong S.U.
        • Kim G.C.
        • Jeong H.J.
        • et al.
        The validity of the Bayley-III and DDST-II in preterm infants with neurodevelopmental impairment: a pilot study.
        Ann Rehabil Med. 2017; 41: 851-857
        • Carvill G.L.
        • Liu A.
        • Mandelstam S.
        • et al.
        Severe infantile onset developmental and epileptic encephalopathy caused by mutations in autophagy gene WDR45.
        Epilepsia. 2018; 59: e5-e13
        • Burger B.J.
        • Rose S.
        • Bennuri S.C.
        • et al.
        Autistic siblings with novel mutations in two different genes: insight for genetic workups of autistic siblings and connection to mitochondrial dysfunction.
        Front Pediatr. 2017; 5: 219
        • Nakashima M.
        • Takano K.
        • Tsuyusaki Y.
        • et al.
        WDR45 mutations in three male patients with west syndrome.
        J Hum Genet. 2016; 61: 653-661
        • Morikawa M.
        • Takano K.
        • Motobayashi M.
        • et al.
        Clinical features of a female with WDR45 mutation complicated by infantile spasms: a case report and literature review.
        Brain Dev. 2017; 39: 804-807
        • Takano K.
        • Shiba N.
        • Wakui K.
        • et al.
        Elevation of neuron specific enolase and brain iron deposition on susceptibility-weighted imaging as diagnostic clues for beta-propeller protein-associated neurodegeneration in early childhood: additional case report and review of the literature.
        Am J Med Genet A. 2016; 170a: 322-328
        • Khalifa M.
        • Naffaa L.
        Exome sequencing reveals a novel WDR45 frameshift mutation and inherited POLR3A heterozygous variants in a female with a complex phenotype and mixed brain MRI findings.
        Eur J Med Genet. 2015; 58: 381-386
        • Rathore G.S.
        • Schaaf C.P.
        • Stocco A.J.
        Novel mutation of the WDR45 gene causing beta-propeller protein-associated neurodegeneration.
        Mov Disord. 2014; 29: 574-575