Reply: The p.Ser107Leu in BICD2 is a mutation ‘hot spot’ causing distal spinal muscular atrophy

Sir,

Thank you for the opportunity to reply to the correspondence concerning our recent publication in Brain, ‘Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2’ (Rossor et al., 2015). We read with great interest the letter from Bansagi et al. and thank the authors for providing further evidence that p.Ser107Leu in BICD2 is a mutation ‘hot spot’.

Bansagi et al. (2015) describe two unrelated families with a typical Spinal Muscular Atrophy Lower Extremity Dominant (SMALED) phenotype. In both families, affected individuals presented at birth with either toe deformities or talipes and delayed motor milestones. All affected individuals achieved independent ambulation although motor development was affected with one individual requiring a wheelchair for long distances. In agreement with our paper, sensorimotor conduction studies were normal with pathological signs of denervation only evident on needle EMG and muscle MRI (Rossor et al., 2015). Although not directly stated, Bansagi et al. comment on the selective fatty replacement of gluteus medius, vastus lateralis, rectus femoris, semi-membranosus, lateral and medial gastrocnemius on muscle MRI, indirectly suggesting that the adductors and semi tendinosus muscles were spared. This confirms our observation that thigh muscle MRI may be a useful tool for directing genetic testing in SMALED, and that mutations in BICD2 (and also DYNC1H1 which shares the same muscle MRI pattern) may affect the innervation of a subgroup of muscles during neurodevelopment (Rossor et al., 2015; Scoto et al., 2015). We would agree with Bansagi et al. that scapular winging is a common feature of BICD2 SMALED, although it was present in only 13 of 32 members of our cohort, 10 of whom were from the same large family with the p.Ser107Leu mutation and its absence should not detract from the diagnosis.

Of the 15 reported families with BICD2 SMALED (Neveling et al., 2013; Oates et al., 2013; Peeters et al., 2013; Synofzik et al., 2013; Rossor et al., 2015), including one reported by Bansagi et al., four were de novo mutations emphasizing that mutations in BICD2 may be a common cause of sporadic SMALED. While it is acknowledged that the p.Ser107Leu mutations is likely to arise due to C>T transitions through spontaneous deamination of 5-methylcytosine, it is worth noting that two of the de novo mutations we report were outside of this ‘hot spot’, (p.Ile189Phe and p.Glu774Gly) (Rossor et al., 2015).

Of the 55 reported patients with BICD2 SMALED, four patients have been described with learning difficulties. Although this is a higher figure than one would expect by chance, it remains unclear as to whether mutations in BICD2 also lead to disorders of cortical neuronal migration and learning difficulties in the same way as patients with SMALED due to mutations in DYNC1H1 (Scoto et al., 2015).