WDR45 mutations in Rett (-like) syndrome and developmental delay: Case report and an appraisal of the literature

doi:10.1016/j.mcp.2016.01.003

Molecular and Cellular Probes

Volume 30, Issue 1, February 2016, Pages 44-49

https://doi.org/10.1016/j.mcp.2016.01.003 Get rights and content

Highlights

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A novel splice-site mutation in WDR45 was discovered in a pediatric patient with Rett-like syndrome.
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Current knowledge about the mutational and clinical spectrum for WDR45 mutations is reviewed.
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Clinical symptoms ranged from mild cognitive delay to early-onset epileptic encephalopathy.
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Analysis of WDR45 may be considered in patients with Rett-like phenotypes and/or developmental delay regardless of severity.

Abstract

Mutations in the WDR45 gene have been identified as causative for the only X-linked type of neurodegeneration with brain iron accumulation (NBIA), clinically characterized by global developmental delay in childhood, followed by a secondary neurological decline with parkinsonism and/or dementia in adolescence or early adulthood. Recent reports suggest that WDR45 mutations are associated with a broader phenotypic spectrum. We identified a novel splice site mutation (c.440-2 A > G) in a 5-year-old Argentinian patient with Rett-like syndrome, exhibiting developmental delay, microcephaly, seizures and stereotypic hand movements, and discuss this finding, together with a review of the literature. Additional patients with a clinical diagnosis of Rett (-like) syndrome were also found to carry WDR45 mutations before (or without) clinical decline or signs of iron accumulation by magnetic resonance imaging (MRI). This information indicates that WDR45 mutations should be added to the growing list of genetic alterations linked to Rett-like syndrome. Further, clinical symptoms associated with WDR45 mutations ranged from early-onset epileptic encephalopathy in a male patient with a deletion of WDR45 to only mild cognitive delay in a female patient, suggesting that analysis of this gene should be considered more often in patients with developmental delay, regardless of severity. The increasing use of next generation sequencing technologies as well as longitudinal follow-up of patients with an early diagnosis will help to gain additional insight into the phenotypic spectrum associated with WDR45 mutations.

Introduction

Neurodegeneration with brain iron accumulation (NBIA, previously known as Hallervorden-Spatz disease) is a group of neurodegenerative diseases characterized by iron accumulation generally observed in the globus pallidus and substantia nigra, and occasionally in the cortex and cerebellum. The term NBIA was introduced by Hayflick et al. in 2003 for all neurological disorders that lead to progressive extrapyramidal symptoms, intellectual impairment and magnetic resonance imaging (MRI) evidence of abnormal brain iron deposition [1].

To date, mutations in ten genes have been recognised as causative for NBIA subtypes [2]. Most of these subtypes can be diagnosed by MRI, in combination with clinical findings, and can be confirmed by specific mutation analysis. While NBIA1 and NBIA2 and some rarer subtypes have been known for more than a decade, the use of modern next-generation sequencing technologies has led to the discovery of several additional forms in the last years; among them is the only known X-linked NBIA form caused by mutations in the WDR45 gene [3]. While mutations in this gene were originally identified in a very restricted phenotype, recent studies [4], [5], [6] suggest that the phenotypic spectrum may be substantially broader, including Rett- and Rett-like syndrome, epileptic phenotypes and isolated intellectual disability. We present here a 5-year-old Argentinian patient with Rett-like syndrome who carries a novel splice site mutation (c.440-2 A > G) in the WDR45 gene, and appraise and discuss the current knowledge of the mutational and clinical spectra linked to WDR45 mutations.

Section snippets

Case report

The female patient (Fig. 1A) was born to healthy, unrelated Argentinian parents via Caesarean section after a complicated pregnancy with placental haematoma and abruption in the first trimester. She showed delayed motor milestones with head control at eight months and unassisted walking at 24 months of age as well as acquired microcephaly. The patient had two febrile seizures at the age of two years with later electro-encephalograms (EEGs) revealing abnormal background rhythms. At the time of

BPAN: the first X-linked NBIA type

Mutations in the WDR45 gene on the X chromosome were first described as causative for a new NBIA subtype in the years 2012 and 2013 via exome sequencing in two groups of patients with a very distinctive phenotype called “static encephalopathy of childhood with neurodegeneration in adulthood” (SENDA) [8], [9]. The affected individuals universally showed an early-onset global developmental delay that was static until adolescence/early adulthood when a secondary neurological decline was noted

Conclusion and future perspectives

The increasing use of next generation sequencing methods now allows analyses of a group of genes (so-called panel analysis), the whole exome or genome of patients at reduced costs. For heterogeneous diseases, such as NBIA, Rett-like syndrome or intellectual disability, these approaches provide substantial advances compared with classical Sanger sequencing of one (or a few) candidate genes, although interpretation of the results as well as ethical questions remain challenges [23]. From what is

Acknowledgements

We thank A. Surur and M. Albarenque for help with MRI imaging. ALR is Principal Investigator from the Argentina National Research Council (CONICET). Anne Tschentscher was supported by a dissertation grant of the “Heinrich und Alma Vogelsang Stiftung”. The authors do not have any conflicts of interest.

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As shown in Fig. 2, there was the case with thinning of the corpus callosum even when the brain atrophy was mild without expansion of the ventricles. Takano et al. [9,15], Hoffjan et al. [11] and Russo et al. [14] also reported thinning of corpus callosum separately from cerebral atrophy. Therefore, thinning of corpus callosum may be one of the characteristic imaging findings of BPAN.
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Original research articleWDR45 mutations in Rett (-like) syndrome and developmental delay: Case report and an appraisal of the literature

Highlights

Abstract

Introduction

Section snippets

Case report

BPAN: the first X-linked NBIA type

Conclusion and future perspectives

Acknowledgements

Methods

Am. J. Hum. Genet.

Park. Relat. Disord.

J. Neurol. Sci.

Pediatr. Neurol.

Eur. J. Med. Genet.

Unraveling the Hallervorden-Spatz syndrome: pantothenate kinase-associated neurodegeneration is the name

Curr. Opin. Pediatr.

Neurodegeneration with brain iron accumulation: diagnosis and management

J. Mov. Disord.

β -Propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation

Brain

De novo WDR45 mutation in a patient showing clinically Rett syndrome with childhood iron deposition in brain

J. Hum. Genet.

Novel WDR45 mutation and pathognomonic BPAN imaging in a young female with mild cognitive delay

Pediatrics

Early-onset epileptic encephalopathy as the initial clinical presentation of WDR45 deletion in a male patient

Eur. J. Hum. Genet.

Original research article
WDR45 mutations in Rett (-like) syndrome and developmental delay: Case report and an appraisal of the literature