Universität zu Köln

Storbeck, Markus, Eriksen, Beate Horsberg, Unger, Andreas, Hoelker, Irmgard, Aukrust, Ingvild, Martinez-Carrera, Lilian A., Linke, Wolfgang A., Ferbert, Andreas, Heller, Raoul, Vorgerd, Matthias, Houge, Gunnar and Wirth, Brunhilde ORCID: 0000-0003-4051-5191 (2017). Phenotypic extremes of BICD2-opathies: from lethal, congenital muscular atrophy with arthrogryposis to asymptomatic with subclinical features. Eur. J. Hum. Genet., 25 (9). S. 1040 - 1049. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5438

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Abstract

Heterozygous variants in BICD cargo adapter 2 (BICD2) cause autosomal dominant spinal muscular atrophy, lower extremitypredominant 2 (SMALED2). The disease is usually characterized by a benign or slowly progressive, congenital or early onset muscle weakness and atrophy that mainly affects the lower extremities, although some affected individuals show involvement of the arms and the shoulder girdle. Here we report unusual extremes of BICD2-related diseases: A severe form of congenital muscular atrophy with arthrogryposis multiplex, respiratory insufficiency and lethality within four months. This was caused by three BICD2 variants, (c.581A4G, p.(Gln194Arg)), (c.1626C>G, p.(Cys542Trp)) and (c.2080C>T, p.(Arg694Cys)), two of which were proven to be de novo. Affected individuals showed reduced fetal movement, weak muscle tone and sparse or no spontaneous activity after birth. Despite assisted ventilation, the condition led to early death. At the other extreme, we identified an asymptomatic woman with a known BICD2 variant (c.2108C>T, p.(Thr703Met)). Radiological examination showed fatty degeneration of selected thigh and calf muscles without clinical consequences. Instead, her son carrying the same variant is affected by a mild childhood onset disease with myopathic and neurogenic features. Mechanisms leading to variable expressivity and onset of BICD2-related disease may include alterations in molecular interactions of BICD2 and suggest the presence of genetic modifiers that may act in a protective fashion to ameliorate or abrogate disease. Our data define an additional severe disease type caused by BICD2 and emphasize a possibly variable etiology of BICD2-opathies with regard to primary muscle and neuronal involvement.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Storbeck, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Eriksen, Beate Horsberg UNSPECIFIED UNSPECIFIED UNSPECIFIED Unger, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoelker, Irmgard UNSPECIFIED UNSPECIFIED UNSPECIFIED Aukrust, Ingvild UNSPECIFIED UNSPECIFIED UNSPECIFIED Martinez-Carrera, Lilian A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Linke, Wolfgang A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ferbert, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Heller, Raoul UNSPECIFIED UNSPECIFIED UNSPECIFIED Vorgerd, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Houge, Gunnar UNSPECIFIED UNSPECIFIED UNSPECIFIED Wirth, Brunhilde UNSPECIFIED orcid.org/0000-0003-4051-5191 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-221198
DOI:	10.1038/ejhg.2017.98
Journal or Publication Title:	Eur. J. Hum. Genet.
Volume:	25
Number:	9
Page Range:	S. 1040 - 1049
Date:	2017
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-5438
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MULTIPLEX CONGENITA; IMPAIRED ENDOCYTOSIS; BICD2 MUTATIONS; MOTOR ADAPTER; DYNACTIN Multiple languages Biochemistry & Molecular Biology; Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/22119