Phenotypic and Imaging Spectrum Associated With WDR45

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Developmental delay; Epileptic encephalopathy; Hypomyelination; WDR45.

Figure 1.

Presentation and diagnosis of WDR45. (A) Each line represents the interval in years between clinical onset and diagnosis (n=54, including n=6 males). (B) The age at clinical presentation was compared by sex (line= median value; n=77 females, n=14 males; Mann Whitney test, 2-tailed p value <0.001). (C) Distribution of variants found in the cohort of individuals with WDR45-related disease.

Figure 2.

Key time to event measures and milestones in WDR45-related disease. (A) In the WDR45 population, important events included the presence of seizures, refractory epilepsy, loss of independent ambulation (IA) and loss of assisted ambulation (AA). Other events, such as feeding tube placement, were not consistently found in the medical records or literature. The dark blue bars represent event attained, light blue is not attained, while white bars represent unknown (UK). (B) Age at first seizure was compared across sex cohorts and was not significantly different (n=63 females; n=14 males; Mann Whitney test, two-tailed p value p=0.0590). (C) Developmental skill acquisition plots (“developmental heat maps”) were created to visualize the difference in development between females (left) and males (right). The designation of ‘10’ represents less than 10% of the population has acquired a milestone by the age indicated on the x-axis, while the designation of ‘90’ represents that up to 90% of the population has acquired the skill by the given age. The color-coded heat map indicates the percentage of the population who has attained the milestone at a given age, as shown on the x-axis. milestone acquisition by genotype. (D) Age at developmental skill acquisition was presented with Kaplan-Meier curves as compared across females (blue, solid line) and males (black, dotted line). P-values were calculated using the logrank test comparing sexes (p values included in figure).

Figure 3.

The spectrum of imaging findings in individuals affected by changes in WDR45. A. Imaging from three individuals demonstrating low volume, including of the corpus callosum (* left panel) and supra- and infra-tentorial regions middle panel). B. In some individuals, iron deposition was absent in the initial set of images, but later was evident (second row). Evidence of iron deposition was found in a subset of individuals in the Substantia Nigra (SN) and/or Globus Pallidus (GP) using T2, GRE, and SWI modalities. C. In a subset of individuals, myelination was delayed (left and middle panels) and low in volume (right panel).

Figure 4.

The characteristics identified by MRI correlate with age at imaging acquisition. Age at acquisition was available for 149 MRIs. The Mann Whitney test was used to compare the age of image acquisition by the presence of key radiographic features (2 tailed p <0.0001 for abnormal myelination and iron deposition).