Spinal muscular atrophies (SMA) are a genetically and clinically heterogeneous group of disorders predominantly of the anterior horn. While the large majority of recessive SMA cases can be explained by mutations in SMN1, the genetic basis of dominant SMA has remained largely elusive. Although mutations have been identified in >12 genes, mutations are found only in less than 30% of dominant SMA cases.1 Recently, BICD2 has been identified to cause dominant SMA.1–⇓3 Here, we provide additional evidence that BICD2 is a cause of dominant SMA and report detailed clinical, electrophysiological and MRI data from a three-generation family with cosegregation of a novel BICD2 mutation. These findings extend current notions of BICD2, demonstrating that it can present with adult-onset combined proximal and distal lower extremity SMA. Our clinical observations not only extend the phenotype of BICD2-related disease, but might also provide novel insights in the pathophysiology of the disease.

The 44-year-old German female index patient (III-2, figure 1A) presented with a 3-year history of a mild symmetric proximal (Medical Research Council (MRC) grade 4) and distal (MRC grade 3) paresis of lower extremities. While able to ambulate independently, she was unable to walk on heels and had difficulties walking on toes and climbing >10 stairs. There was areflexia of lower limbs, high-arched feet (figure 1C) and complete atrophy of the quadriceps muscle (figure 1D) without genu recurvatum. She recalled minor problems in jumping during sports at school, however had not sought medical advice so far. Repeated clinical examinations and motor evoked potentials (MEPs) revealed no evidence for clinical or subclinical upper motor neuron damage. MRI showed bilateral lipomatous atrophy of the vastus lateralis, intermedius and rectus femoris muscle with hallmark preservation3 of hip adductors and semitendinosus muscle (figure 1D). Further clinical and electrophysiological findings are provided in the online supplementary table. Her 70-year-old father (II-3, figure 1A) showed similar clinical and electrophysiological findings (see online supplementary table), however with a later onset. He reported a 5-year history of mild proximal (MRC grade 4) and distal (MRC grade 3) paresis of lower limbs with an inability to walk on heels, impairments in walking on toes and mild difficulties in climbing stairs, but no limitations in walking distance and no need for walking aids. He recalled minor difficulties walking downhill from the age 30 years, however had not sought medical review for this. Somatosensory evoked potentials (SSEP) of the tibial nerve could not be evoked (see online supplementary table). The 13-year-old daughter of the index patient (IV-1, figure 1A) showed a qualitatively similar pattern of clinical and electrophysiological findings (see online supplementary table), with first impairments starting in early school age. Based on the main phenotype of a slowly progressive dominant SMA, BICD2 sequencing was performed, revealing a novel c.2239C>T, p.Arg747Cys missense mutation. This highly conserved (PhyloP 5.49; figure 1B) variant was predicted to be disease causing by in silico predictions (PolyPhen-2), cosegregated with disease in all the three generations (figure 1B) and was not found in the 1000 Genomes database, the 6500 exomes of the National Heart, Lung, and Blood Institute (NHLBI) Exome Variant Server or National Center for Biotechnology Information (NCBI) short genetic variations database (dbSNP).

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Figure 1

Genetic, clinical and MRI findings in the BICD2 family. (A) The pedigree shows dominantly inherited disease in at least four generations with segregation of the p.Arg747Cys BICD2 variant in all three generations where DNA was available (black arrows). (B) Sequence chromatograms of a control and all three affected individuals (top), position of the novel p.Arg747Cys variant in the three coiled-coil domains of BICD2 (middle) and multispecies alignment of the highly conserved exchanged amino acid. (C) High-arched foot in the index patient, as also observed in the other affected family members. (D) MRI (T1-weighted) in the index patient shows bilateral lipomatous atrophy of the vastus lateralis, intermedius and rectus femoris muscle (white arrows) with preservation and slight compensatory hypertrophy of the medial adductors (stars) and semitendinosus muscle (hash key).

Our results further consolidate recent reports of BICD2 as a novel cause of dominant SMA by demonstrating cosegregation of a rare and highly conserved BICD2 variant with disease in three generations. This confirms BICD2 as an important differential diagnosis in spinal muscular atrophy with lower extremity predominance and autosomal-dominant inheritance which can be caused by mutations either in DYNC1H1 4 or in BICD2. MEP results demonstrate that upper motor neuron damage—reported for some BICD2 patients3—can be absent even on a subclinical level. This corroborates the notion that at least in some BICD2 patients presenting with SMA motor neuron damage is indeed limited to the anterior horn.

Additional damage of the upper motor neuron might depend on the BICD2 region of the respective variant. While all variants reported so far for the BICD2 coiled-coil domain 3 (Rab6-binding region) present with SMA as the main phenotype (p.Glu774Gly2; p.Thr703Met,1 p.Arg747Cys (reported here)), variants in the coiled-coil domains 1 and 2 (dynein-binding regions and kinesin-binding regions, respectively) can also include upper motor neuron damage.3 Future studies investigating larger BICD2 cohorts are needed to confirm this possible genotype–phenotype correlation. Future studies should also explore whether the abnormal SSEP findings observed in one of the family members (II-3) indicate a potential dorsal column dysfunction that is associated with BICD2 mutations in at least some of the patients (especially with longer disease duration like in II-3) or whether this is just a coincidental finding.

Our findings extend and revise some of the current notions of BICD2-SMA. We show that BICD2-SMA might lead to impairments in daily living only very late in life (first restrictions at age 65 years in II-3). This clinical observation of late-onset disease courses points to an important insight into pathophysiology: BICD2-dependent dynein–dynactin transport pathways seem to be important not only in the development and maturation,1 but also in the survival of motor neurons. This late-life degeneration of motor neurons may determine the course of disease in at least some BICD2 patients. It demonstrates that BICD2 should be considered in the differential diagnosis even in elderly patients presenting with late-onset SMA. Moreover, it suggests that the term ‘congenital’ SMA, which we1 and others3 have used so far for BICD2-SMA, might not match with its clinical course and should thus be revised.

Our results show that also distal functions of the lower extremity are frequently involved (see online supplementary table), with distal paresis even exceeding proximal paresis in some patients (II-3; III-2). By qualifying BICD2-SMA as a combined proximal and distal SMA, this observation supports and further extends recent clinical descriptions of other BICD2-SMA patients.1 ,3 Taken together, these findings revise the notion of ‘proximal SMA’ which was recently suggested by some authors2 as the main phenotype of BICD2-SMA.