Recessive null-allele variants in MAG associated with spastic ataxia, nystagmus, neuropathy, and dystonia

Michael Zech; Theresa Brunet; Matej Škorvánek; Astrid Blaschek; Katharina Vill; Britta Hanker; Irina Hüning; Vladimír Haň; Petra Došekova; Zuzana Gdovinová; Bader Alhaddad; Riccardo Berutti; Tim M. Strom; Evžen Růžička; Erik Jan Kamsteeg; Jasper J. van der Smagt; Matias Wagner; Robert Jech; Juliane Winkelmann

doi:10.1016/j.parkreldis.2020.06.027

Recessive null-allele variants in MAG associated with spastic ataxia, nystagmus, neuropathy, and dystonia

Michael Zech^*, Theresa Brunet, Matej Škorvánek, Astrid Blaschek, Katharina Vill, Britta Hanker, Irina Hüning, Vladimír Haň, Petra Došekova, Zuzana Gdovinová, Bader Alhaddad, Riccardo Berutti, Tim M. Strom, Evžen Růžička, Erik Jan Kamsteeg, Jasper J. van der Smagt, Matias Wagner, Robert Jech, Juliane Winkelmann

^*Corresponding author for this work

Institute of Human Genetics

6 Citations (Scopus)

Abstract

Introduction: The gene encoding myelin-associated glycoprotein (MAG) has been implicated in autosomal-recessive spastic paraplegia type 75. To date, only four families with biallelic missense variants in MAG have been reported. The genotypic and phenotypic spectrum of MAG-associated disease awaits further elucidation. Methods: Four unrelated patients with complex neurologic conditions underwent whole-exome sequencing within research or diagnostic settings. Following determination of the underlying genetic defects, in-depth phenotyping and literature review were performed. Results: In all case subjects, we detected ultra-rare homozygous or compound heterozygous variants in MAG. The observed nonsense (c.693C > A [p.Tyr231*], c.980G > A [p.Trp327*], c.1126C > T [p.Gln376*], and 1522C > T [p.Arg508*]) and frameshift (c.517_521dupAGCTG [p.Trp174*]) alleles were predicted to result in premature termination of protein translation. Affected patients presented with variable combinations of psychomotor delay, ataxia, eye movement abnormalities, spasticity, dystonia, and neuropathic symptoms. Cerebellar signs, nystagmus, and pyramidal tract dysfunction emerged as unifying features in the majority of MAG-mutated individuals identified to date. Conclusions: Our study is the first to describe biallelic null variants in MAG, confirming that loss of myelin-associated glycoprotein causes severe infancy-onset disease with central and peripheral nervous system involvement.

Original language	English
Journal	Parkinsonism and Related Disorders
Volume	77
Pages (from-to)	70-75
Number of pages	6
ISSN	1353-8020
DOIs	https://doi.org/10.1016/j.parkreldis.2020.06.027
Publication status	Published - 08.2020

Funding

This study was funded by institutional funding from Technische Universität München, Munich, Germany, Helmholtz Zentrum München, Munich, Germany, and Charles University, Prague, Czech Republic ( PROGRES Q27 ). This study was also funded by the Czech Ministry of Education under grant AZV: NV19-04-00233 and under the frame of EJP RD, the European Joint Programme on Rare Diseases ( EJP RD COFUND-EJP N° 825575 ), as well as the Slovak Grant and Development Agency under contract APVV-18-0547 and the Slovak Research and Grant Agency under contract number VEGA 1/0596/19 to M.S., V.H., P.D. and Z.G. M.Z. was supported by an internal research program at Helmholtz Zentrum München, Munich, Germany (“Physician Scientists for Groundbreaking Projects”). In family C, whole-exome sequencing was performed in the framework of the German project “TRANSLATE NAMSE”, an initiative from the National Action League for People with Rare Diseases (Nationales Aktionsbündnis für Menschen mit Seltenen Erkrankungen, NAMSE) facilitating innovative genetic diagnostics for individuals with suggested rare diseases.

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Research Area: Medical Genetics

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Zech, M., Brunet, T., Škorvánek, M., Blaschek, A., Vill, K., Hanker, B., Hüning, I., Haň, V., Došekova, P., Gdovinová, Z., Alhaddad, B., Berutti, R., Strom, T. M., Růžička, E., Kamsteeg, E. J., van der Smagt, J. J., Wagner, M., Jech, R., & Winkelmann, J. (2020). Recessive null-allele variants in MAG associated with spastic ataxia, nystagmus, neuropathy, and dystonia. Parkinsonism and Related Disorders, 77, 70-75. https://doi.org/10.1016/j.parkreldis.2020.06.027

@article{31c5dacfb9804d68980f404d75cf8830,

title = "Recessive null-allele variants in MAG associated with spastic ataxia, nystagmus, neuropathy, and dystonia",

abstract = "Introduction: The gene encoding myelin-associated glycoprotein (MAG) has been implicated in autosomal-recessive spastic paraplegia type 75. To date, only four families with biallelic missense variants in MAG have been reported. The genotypic and phenotypic spectrum of MAG-associated disease awaits further elucidation. Methods: Four unrelated patients with complex neurologic conditions underwent whole-exome sequencing within research or diagnostic settings. Following determination of the underlying genetic defects, in-depth phenotyping and literature review were performed. Results: In all case subjects, we detected ultra-rare homozygous or compound heterozygous variants in MAG. The observed nonsense (c.693C > A [p.Tyr231*], c.980G > A [p.Trp327*], c.1126C > T [p.Gln376*], and 1522C > T [p.Arg508*]) and frameshift (c.517\_521dupAGCTG [p.Trp174*]) alleles were predicted to result in premature termination of protein translation. Affected patients presented with variable combinations of psychomotor delay, ataxia, eye movement abnormalities, spasticity, dystonia, and neuropathic symptoms. Cerebellar signs, nystagmus, and pyramidal tract dysfunction emerged as unifying features in the majority of MAG-mutated individuals identified to date. Conclusions: Our study is the first to describe biallelic null variants in MAG, confirming that loss of myelin-associated glycoprotein causes severe infancy-onset disease with central and peripheral nervous system involvement.",

author = "Michael Zech and Theresa Brunet and Matej {\v S}korv{\'a}nek and Astrid Blaschek and Katharina Vill and Britta Hanker and Irina H{\"u}ning and Vladim{\'i}r Ha{\v n} and Petra Do{\v s}ekova and Zuzana Gdovinov{\'a} and Bader Alhaddad and Riccardo Berutti and Strom, \{Tim M.\} and Ev{\v z}en Rů{\v z}i{\v c}ka and Kamsteeg, \{Erik Jan\} and \{van der Smagt\}, \{Jasper J.\} and Matias Wagner and Robert Jech and Juliane Winkelmann",

note = "Funding Information: This study was funded by institutional funding from Technische Universit{\"a}t M{\"u}nchen, Munich, Germany, Helmholtz Zentrum M{\"u}nchen, Munich, Germany, and Charles University, Prague, Czech Republic ( PROGRES Q27 ). This study was also funded by the Czech Ministry of Education under grant AZV: NV19-04-00233 and under the frame of EJP RD, the European Joint Programme on Rare Diseases ( EJP RD COFUND-EJP N° 825575 ), as well as the Slovak Grant and Development Agency under contract APVV-18-0547 and the Slovak Research and Grant Agency under contract number VEGA 1/0596/19 to M.S., V.H., P.D. and Z.G. M.Z. was supported by an internal research program at Helmholtz Zentrum M{\"u}nchen, Munich, Germany (“Physician Scientists for Groundbreaking Projects”). In family C, whole-exome sequencing was performed in the framework of the German project “TRANSLATE NAMSE”, an initiative from the National Action League for People with Rare Diseases (Nationales Aktionsb{\"u}ndnis f{\"u}r Menschen mit Seltenen Erkrankungen, NAMSE) facilitating innovative genetic diagnostics for individuals with suggested rare diseases. Publisher Copyright: {\textcopyright} 2020 Elsevier Ltd Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2020",

month = aug,

doi = "10.1016/j.parkreldis.2020.06.027",

language = "English",

volume = "77",

pages = "70--75",

journal = "Parkinsonism and Related Disorders",

issn = "1353-8020",

publisher = "Elsevier Ltd",

}

Zech, M, Brunet, T, Škorvánek, M, Blaschek, A, Vill, K, Hanker, B , Hüning, I, Haň, V, Došekova, P, Gdovinová, Z, Alhaddad, B, Berutti, R, Strom, TM, Růžička, E, Kamsteeg, EJ, van der Smagt, JJ, Wagner, M, Jech, R & Winkelmann, J 2020, 'Recessive null-allele variants in MAG associated with spastic ataxia, nystagmus, neuropathy, and dystonia', Parkinsonism and Related Disorders, vol. 77, pp. 70-75. https://doi.org/10.1016/j.parkreldis.2020.06.027

TY - JOUR

T1 - Recessive null-allele variants in MAG associated with spastic ataxia, nystagmus, neuropathy, and dystonia

AU - Zech, Michael

AU - Brunet, Theresa

AU - Škorvánek, Matej

AU - Blaschek, Astrid

AU - Vill, Katharina

AU - Hanker, Britta

AU - Hüning, Irina

AU - Haň, Vladimír

AU - Došekova, Petra

AU - Gdovinová, Zuzana

AU - Alhaddad, Bader

AU - Berutti, Riccardo

AU - Strom, Tim M.

AU - Růžička, Evžen

AU - Kamsteeg, Erik Jan

AU - van der Smagt, Jasper J.

AU - Wagner, Matias

AU - Jech, Robert

AU - Winkelmann, Juliane

N1 - Funding Information: This study was funded by institutional funding from Technische Universität München, Munich, Germany, Helmholtz Zentrum München, Munich, Germany, and Charles University, Prague, Czech Republic ( PROGRES Q27 ). This study was also funded by the Czech Ministry of Education under grant AZV: NV19-04-00233 and under the frame of EJP RD, the European Joint Programme on Rare Diseases ( EJP RD COFUND-EJP N° 825575 ), as well as the Slovak Grant and Development Agency under contract APVV-18-0547 and the Slovak Research and Grant Agency under contract number VEGA 1/0596/19 to M.S., V.H., P.D. and Z.G. M.Z. was supported by an internal research program at Helmholtz Zentrum München, Munich, Germany (“Physician Scientists for Groundbreaking Projects”). In family C, whole-exome sequencing was performed in the framework of the German project “TRANSLATE NAMSE”, an initiative from the National Action League for People with Rare Diseases (Nationales Aktionsbündnis für Menschen mit Seltenen Erkrankungen, NAMSE) facilitating innovative genetic diagnostics for individuals with suggested rare diseases. Publisher Copyright: © 2020 Elsevier Ltd Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/8

Y1 - 2020/8

N2 - Introduction: The gene encoding myelin-associated glycoprotein (MAG) has been implicated in autosomal-recessive spastic paraplegia type 75. To date, only four families with biallelic missense variants in MAG have been reported. The genotypic and phenotypic spectrum of MAG-associated disease awaits further elucidation. Methods: Four unrelated patients with complex neurologic conditions underwent whole-exome sequencing within research or diagnostic settings. Following determination of the underlying genetic defects, in-depth phenotyping and literature review were performed. Results: In all case subjects, we detected ultra-rare homozygous or compound heterozygous variants in MAG. The observed nonsense (c.693C > A [p.Tyr231*], c.980G > A [p.Trp327*], c.1126C > T [p.Gln376*], and 1522C > T [p.Arg508*]) and frameshift (c.517_521dupAGCTG [p.Trp174*]) alleles were predicted to result in premature termination of protein translation. Affected patients presented with variable combinations of psychomotor delay, ataxia, eye movement abnormalities, spasticity, dystonia, and neuropathic symptoms. Cerebellar signs, nystagmus, and pyramidal tract dysfunction emerged as unifying features in the majority of MAG-mutated individuals identified to date. Conclusions: Our study is the first to describe biallelic null variants in MAG, confirming that loss of myelin-associated glycoprotein causes severe infancy-onset disease with central and peripheral nervous system involvement.

AB - Introduction: The gene encoding myelin-associated glycoprotein (MAG) has been implicated in autosomal-recessive spastic paraplegia type 75. To date, only four families with biallelic missense variants in MAG have been reported. The genotypic and phenotypic spectrum of MAG-associated disease awaits further elucidation. Methods: Four unrelated patients with complex neurologic conditions underwent whole-exome sequencing within research or diagnostic settings. Following determination of the underlying genetic defects, in-depth phenotyping and literature review were performed. Results: In all case subjects, we detected ultra-rare homozygous or compound heterozygous variants in MAG. The observed nonsense (c.693C > A [p.Tyr231*], c.980G > A [p.Trp327*], c.1126C > T [p.Gln376*], and 1522C > T [p.Arg508*]) and frameshift (c.517_521dupAGCTG [p.Trp174*]) alleles were predicted to result in premature termination of protein translation. Affected patients presented with variable combinations of psychomotor delay, ataxia, eye movement abnormalities, spasticity, dystonia, and neuropathic symptoms. Cerebellar signs, nystagmus, and pyramidal tract dysfunction emerged as unifying features in the majority of MAG-mutated individuals identified to date. Conclusions: Our study is the first to describe biallelic null variants in MAG, confirming that loss of myelin-associated glycoprotein causes severe infancy-onset disease with central and peripheral nervous system involvement.

UR - https://www.scopus.com/pages/publications/85087294875

U2 - 10.1016/j.parkreldis.2020.06.027

DO - 10.1016/j.parkreldis.2020.06.027

M3 - Journal articles

C2 - 32629324

AN - SCOPUS:85087294875

SN - 1353-8020

VL - 77

SP - 70

EP - 75

JO - Parkinsonism and Related Disorders

JF - Parkinsonism and Related Disorders

ER -

Recessive null-allele variants in MAG associated with spastic ataxia, nystagmus, neuropathy, and dystonia

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