Phenotypic extremes of BICD2-opathies: from lethal, congenital muscular atrophy with arthrogryposis to asymptomatic with subclinical features

• Published in: European journal of human genetics : EJHG 2017-09, Vol.25 (9), p.1040-1048
• Main Authors: Storbeck, Markus, Horsberg Eriksen, Beate, Unger, Andreas, Hölker, Irmgard, Aukrust, Ingvild, Martínez-Carrera, Lilian A, Linke, Wolfgang A, Ferbert, Andreas, Heller, Raoul, Vorgerd, Matthias, Houge, Gunnar, Wirth, Brunhilde
• Format: Article
• Language: English
• Subjects: Adult; Arthrogryposis; Arthrogryposis - diagnosis; Arthrogryposis - genetics; Asymptomatic Diseases; Benign; Children; Congenital diseases; Degeneration; Disease; Etiology; Female; Fetuses; Humans; Infant; Lethality; Male; Mechanical ventilation; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Muscle, Skeletal - metabolism; Muscles; Muscular Atrophy, Spinal - diagnosis; Muscular Atrophy, Spinal - genetics; Mutation, Missense; Neuromuscular diseases; Pedigree; Phenotype; Spinal muscular atrophy; Syndrome
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2017.98

Heterozygous variants in BICD cargo adapter 2 (BICD2) cause autosomal dominant spinal muscular atrophy, lower extremity-predominant 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.581A>G, 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.