Clinical features and blood iron metabolism markers in children with beta-propeller protein associated neurodegeneration

https://doi.org/10.1016/j.ejpn.2020.07.010Get rights and content

Highlights

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    First study focusing on potential alterations in blood iron metabolism in BPAN.

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    Elevation of sTfr/log ferrit – possible new biochemical marker of BPAN.

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    Gradually decreasing severity of epilepsy in some BPAN patients.

Abstract

Background

Neurodegeneration with brain iron accumulation constitutes a group of rare progressive movement disorders sharing intellectual disability and neuroimaging findings as common denominators. Beta-propeller protein-associated neurodegeneration (BPAN) represents approximately 7% of the cases, and its first signs are typically epilepsy and developmental delay. We aimed to describe in detail the phenotype of BPAN with a special focus on iron metabolism.

Material and methods

We present a cohort of paediatric patients with pathogenic variants of WD-Repeat Domain 45 gene (WDR45). The diagnosis was established by targeted panel sequencing of genes associated with epileptic encephalopathies (n = 9) or by Sanger sequencing of WDR45 (n = 1). Data on clinical characteristics, molecular-genetic findings and other performed investigations were gathered from all participating centres. Markers of iron metabolism were analysed in 6 patients.

Results

Ten children (3 males, 7 females, median age 8.4 years) from five centres (Prague, Berlin, Vogtareuth, Tubingen and Cologne) were enrolled in the study. All patients manifested first symptoms (e.g. epilepsy, developmental delay) between 2 and 31 months (median 16 months). Seven patients were seizure-free (6 on antiepileptic medication, one drug-free) at the time of data collection. Neurological findings were non-specific with deep tendon hyperreflexia (n = 4) and orofacial dystonia (n = 3) being the most common. Soluble transferrin receptor/log ferritin ratio was elevated in 5/6 examined subjects; other parameters of iron metabolism were normal.

Conclusion

Severity of epilepsy often gradually decreases in BPAN patients. Elevation of soluble transferrin receptor/log ferritin ratio could be another biochemical marker of the disease and should be explored by further studies.

Introduction

Neurodegeneration with brain iron accumulation (NBIA) constitutes a group of rare progressive movement disorders typically accompanied by intellectual disability and abnormal iron deposition in basal ganglia. The estimated prevalence rate of NBIA is 2/1 000 000 [1]. The heterogeneous group includes conditions of variable clinical course, genetic background as well as neuroimaging findings. Beta-propeller protein-associated neurodegeneration (BPAN) represents approximately 7% of NBIA cases [[2], [3], [4]]. It is caused by mutation of WD-Repeat Domain 45 gene (WDR45) located on Xp11.23 encoding WD repeat domain phosphoinositide-interacting protein 4 involved in autophagy [5,6]. Patients with BPAN present with stable global developmental delay during childhood ranging from mild to severe intellectual disability. Further cognitive deterioration occurs in adolescence or early adulthood, followed by parkinsonism and progressive dystonia in early adulthood [7,8]. Currently, no specific treatment for BPAN is available. Administration of L-DOPA may ameliorate the symptoms of parkinsonism, however its use is limited by early development of dyskinesias [3]. The majority of reported cases resulted from de novo WDR45 pathogenic variants in female patients; however, familiar occurrence and male patients were also described [9,10]. Similarly to other NBIA, we can observe specific changes on brain MRI caused by abnormal iron accumulation. In BPAN these features comprise of T2 hypointensity in the substantia nigra and globus pallidus and T1 hyperintensity of the substantia nigra with a central hypointensity. Although less prominent than in older individuals, this finding was reported in children as young as five years of age [3,4,11,12] and even earlier on specialized SWI (susceptibility-weighted) sequences [13]. Despite known pathophysiological mechanism of abnormal iron accumulation in brain, to our knowledge, no studies have analysed potential alterations in blood iron metabolism. In our study, we aimed to describe the clinical picture of BPAN patients, with a special focus on abnormalities in blood iron metabolism.

Section snippets

Participants and data collection

We included paediatric patients with heterozygous or hemizygous pathogenic variants in WDR45 detected by molecular genetic testing. Subjects with previously known pathogenic variant in WDR45 were recruited from five different centres (Motol University Hospital, Prague; Schön Klinik, Vogtareuth; Kliniken der Stadt Köln – Children Hospital, Köln; DRK Kliniken Berlin-Westend, Berlin; University Children's Hospital, Tübingen) in the period 11/2016–1/2018. Molecular genetic examination was performed

Demographic characteristics, psychomotor development and physical characteristics

Seven females and three males were included in the study. Age of subjects ranged from 11 months to 16.3 years (median 8.4 years) at the time of data collection, (for details see Table 1). Seven out of ten patients presented with global developmental delay during the first year of life. The remaining three patients had either normal motor development with a speech delay (n = 1) or unremarkable initial development with a subsequent gradual deceleration (n = 2). Developmental regression (loss of

Discussion

We present a retrospective study that summarizes clinical and molecular genetic findings of ten children with BPAN and confirmed pathogenic variants in WDR45. To our knowledge, this is one of the largest cohorts of paediatric patients with WDR45-associated BPAN. We have identified a possible new biochemical marker associated with BPAN - the increase of the sTfr/logFerrit. Also, we described a novel pathogenic variant of WDR45.

All of our patients had developmental delay ranging from mild to

Conclusion

BPAN is a rare neurodegenerative disease with distinct clinical course and typical findings of abnormal iron accumulation on brain MRI. In children it manifests with developmental delay, epilepsy or both. The severity of epilepsy tends to decrease in time; in later age a significant proportion of patients achieve seizure freedom and in some, the anticonvulsive therapy can be successfully withdrawn. Brain MRI is initially normal or only with non-specific changes such as delayed myelination.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This study was supported by the project for conceptual development of research organization 00064203 and by MH CR AZV NU20-04-00279. We would like to thank our patients and their parents for the participation and consent for the analyses.

References (33)

  • Y.A. Zarate et al.

    Lessons from a pair of siblings with BPAN

    Eur. J. Hum. Genet.

    (2016)
  • M. Nakashima et al.

    WDR45 mutations in three male patients with West syndrome

    J. Hum. Genet.

    (2016)
  • L. Villard et al.

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

    Eur. J. Hum. Genet.

    (2015)
  • Yuta Ichinose et al.

    Characteristic MRI findings in beta-propeller protein-associated neurodegeneration (BPAN)

    Neurol. Clin. Pract.

    (2014)
  • K. Takano 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.

    (2016)
  • D. Staněk et al.

    Detection Rate of Causal Variants in Severe Childhood Epilepsy Is Highest in Patients with Seizure Onset within the First Four Weeks of Life

    (2018)
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