WDR45 mutations may cause a MECP2 mutation-negative Rett syndrome phenotype

Leonora Kulikovskaja; Adrijan Sarajlija; Dusanka Savic-Pavicevic; Valerija Dobricic; Christine Klein; Ana Westenberger

doi:10.1212/NXG.0000000000000227

WDR45 mutations may cause a MECP2 mutation-negative Rett syndrome phenotype

Leonora Kulikovskaja, Adrijan Sarajlija, Dusanka Savic-Pavicevic, Valerija Dobricic, Christine Klein^*, Ana Westenberger

^*Corresponding author for this work

15 Citations (Scopus)

Abstract

Mutations in the autophagy-related WD domain repeat 45 (WDR45) gene cause beta-propeller protein-associated neurodegeneration (BPAN), a distinct form of neurodegeneration with brain iron accumulation (NBIA).1,2 Clinical and imaging features comprise childhood-onset global developmental delay with further regression in early adulthood, progressive dystonia, parkinsonism, stereotypies, and iron deposition in the basal ganglia. Female and the few existing male patients show similar phenotypes, probably because of somatic mosaicism in males and skewed X-chromosome inactivation (XCI) in females, as WDR45 is located on Xp11.23. To date, about 60 cases have been reported, many of whom had a different initial clinical diagnosis.3 Hyperkinetic movements and stereotypies overlap with Rett syndrome features, another X-linked disorder most commonly caused by MECP2 mutations. Indeed, for 7% of the reported cases of BPAN, the initial diagnosis was Rett syndrome,3 prompting us to perform the first mutational screen of the WDR45 gene in a large cohort of MECP2 mutation-negative Rett syndrome patients.

...

Original language	English
Article number	e227
Journal	Neurology: Genetics
Volume	4
Issue number	2
ISSN	2376-7839
DOIs	https://doi.org/10.1212/NXG.0000000000000227
Publication status	Published - 01.04.2018

Funding

The Article Processing Charge was funded by Land Schleswig-Holstein within the funding programme Open Access Publikationsfonds. The project was funded by the Hermann and Lilly Schilling Foundation (to Christine Klein). The authors acknowledge financial support by Land Schleswig-Holstein within the funding programme Open Access Publikationsfonds for the open access publication process. Christine Klein is an associate editor of Annals of Neurology. She serves as a medical advisor of Centogene and Biogen. She is the recipient of a career development award from the Hermann and Lilly Schilling Foundation. She is funded by the Deutsche Forschungsgemeinschaft, the European Union, and the Possehl Foundation and received institutional support from the University of Lübeck for genetics research. Ana Westenberger is funded by the Deutsche Forschungsgemeinschaft. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being
SDG 10 Reduced Inequalities

Research Areas and Centers

Research Area: Medical Genetics

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10.1212/NXG.0000000000000227

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title = "WDR45 mutations may cause a MECP2 mutation-negative Rett syndrome phenotype",

abstract = "Mutations in the autophagy-related WD domain repeat 45 (WDR45) gene cause beta-propeller protein-associated neurodegeneration (BPAN), a distinct form of neurodegeneration with brain iron accumulation (NBIA).1,2 Clinical and imaging features comprise childhood-onset global developmental delay with further regression in early adulthood, progressive dystonia, parkinsonism, stereotypies, and iron deposition in the basal ganglia. Female and the few existing male patients show similar phenotypes, probably because of somatic mosaicism in males and skewed X-chromosome inactivation (XCI) in females, as WDR45 is located on Xp11.23. To date, about 60 cases have been reported, many of whom had a different initial clinical diagnosis.3 Hyperkinetic movements and stereotypies overlap with Rett syndrome features, another X-linked disorder most commonly caused by MECP2 mutations. Indeed, for 7\% of the reported cases of BPAN, the initial diagnosis was Rett syndrome,3 prompting us to perform the first mutational screen of the WDR45 gene in a large cohort of MECP2 mutation-negative Rett syndrome patients. ...",

author = "Leonora Kulikovskaja and Adrijan Sarajlija and Dusanka Savic-Pavicevic and Valerija Dobricic and Christine Klein and Ana Westenberger",

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T1 - WDR45 mutations may cause a MECP2 mutation-negative Rett syndrome phenotype

AU - Kulikovskaja, Leonora

AU - Sarajlija, Adrijan

AU - Savic-Pavicevic, Dusanka

AU - Dobricic, Valerija

AU - Klein, Christine

AU - Westenberger, Ana

PY - 2018/4/1

Y1 - 2018/4/1

N2 - Mutations in the autophagy-related WD domain repeat 45 (WDR45) gene cause beta-propeller protein-associated neurodegeneration (BPAN), a distinct form of neurodegeneration with brain iron accumulation (NBIA).1,2 Clinical and imaging features comprise childhood-onset global developmental delay with further regression in early adulthood, progressive dystonia, parkinsonism, stereotypies, and iron deposition in the basal ganglia. Female and the few existing male patients show similar phenotypes, probably because of somatic mosaicism in males and skewed X-chromosome inactivation (XCI) in females, as WDR45 is located on Xp11.23. To date, about 60 cases have been reported, many of whom had a different initial clinical diagnosis.3 Hyperkinetic movements and stereotypies overlap with Rett syndrome features, another X-linked disorder most commonly caused by MECP2 mutations. Indeed, for 7% of the reported cases of BPAN, the initial diagnosis was Rett syndrome,3 prompting us to perform the first mutational screen of the WDR45 gene in a large cohort of MECP2 mutation-negative Rett syndrome patients. ...

AB - Mutations in the autophagy-related WD domain repeat 45 (WDR45) gene cause beta-propeller protein-associated neurodegeneration (BPAN), a distinct form of neurodegeneration with brain iron accumulation (NBIA).1,2 Clinical and imaging features comprise childhood-onset global developmental delay with further regression in early adulthood, progressive dystonia, parkinsonism, stereotypies, and iron deposition in the basal ganglia. Female and the few existing male patients show similar phenotypes, probably because of somatic mosaicism in males and skewed X-chromosome inactivation (XCI) in females, as WDR45 is located on Xp11.23. To date, about 60 cases have been reported, many of whom had a different initial clinical diagnosis.3 Hyperkinetic movements and stereotypies overlap with Rett syndrome features, another X-linked disorder most commonly caused by MECP2 mutations. Indeed, for 7% of the reported cases of BPAN, the initial diagnosis was Rett syndrome,3 prompting us to perform the first mutational screen of the WDR45 gene in a large cohort of MECP2 mutation-negative Rett syndrome patients. ...

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DO - 10.1212/NXG.0000000000000227

M3 - Short survey

AN - SCOPUS:85048727177

SN - 2376-7839

VL - 4

JO - Neurology: Genetics

JF - Neurology: Genetics

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ER -

WDR45 mutations may cause a MECP2 mutation-negative Rett syndrome phenotype

Abstract

Funding

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