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 - http://www.scopus.com/inward/record.url?scp=85087294875&partnerID=8YFLogxK
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 -