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

Abstract

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.

The Genotypic and Phenotypic Spectrum of BICD2 Variants in Spinal Muscular Atrophy

“…At the other end of the spectrum are severe cases with prenatal onset of severe hypotonia and joint contractures, and these patients often die in childhood. 16,19,20 Many of our patient's features were consistent with the severe form of SMALED2. However, until that time, only missense variants had been reported to cause disease.…”

“…At the mild end are cases such as that of a boy with late‐onset disease of mild course whose mother carried the same variant but was asymptomatic and a 70‐year‐old Brazilian man with a 40‐year history of slowly progressive gait difficulty in the setting of a presumably inherited variant. At the other end of the spectrum are severe cases with prenatal onset of severe hypotonia and joint contractures, and these patients often die in childhood …”

Loss of BICD2 in muscle drives motor neuron loss in a developmental form of spinal muscular atrophy

“…BICD2 is a cargo adaptor protein, comprising a N-terminal region that mediates binding to the dimerization domain of DYNC1H1 and a C-terminal cargo binding domain (Hoogenraad et al, 2001). Missense mutations throughout BICD2 have been 5 shown to cause SMALED2 (Storbeck et al, 2017), yet the disease mechanism is unclear. Mutations in the N-terminal domain increase the affinity to the dynein complex (Huynh and Vale, 2017), whereas the p.Glu774Gly mutation in the C-terminal domain has no effect on DYNC1H1 binding, but disrupts the interaction with its cargo Rab6, causing a loss of function phenotype (Peeters et al, 2013).…”

Targeted sequencing with expanded gene profile enables high diagnostic yield in non-5q-spinal muscular atrophies

“…The overlap between neuropathies and myopathies is also shown by myopathic individuals carrying nonsense mutations in NEFL gene, formerly linked to neurogenic disorders (Agrawal et al, 2014). Mutations in BICD2, traditionally resulting in a congenital SMA (Neveling et al, 2013;Oates, et al, 2013;Peeters et al, 2013), were recently linked to myopathic features or arthrogryposis multiplex congenita (AMC) (Ravenscroft et al, 2016;Storbeck et al, 2017;Unger et al, 2016). Moreover, myasthenic syndromes due to SYT2 (Herrmann et al, 2014), SLC5A7 (Barwick et al, 2012;Bauche et al, 2016), and VAMP1 (Salpietro et al, 2017) mutations may also resemble HMNs, and should be included in the differential diagnosis on an individual basis.…”