As mentioned, autosomal dominant variants in the BSCL2 gene are a common cause of distal hereditary motor neuropathy with intrinsic hand muscle-predominant involvement (dHMN- V). In several cases, spasticity may be associated to this dHMN (Silver syndrome or SPG17) and in some patients a mild-to-moderate sensory involvement may also found comprising a clinical diagnosis of axonal Charcot-Marie-Tooth (CMT-2). Patients frequently present with pes cavus and osteotendinous reflexes are generally preserved or augmented. It is important to note that up to 20-25% of patients may be asymptomatic with or without mild distal atrophy upon clinical examination. Finally, onset of symptoms is equally heterogenous, ranging from the first to the seventh decade.
Nerve conduction studies are pathological in the majority of cases, showing a predominant axonal motor neuronopathy, with some rarer cases of sensory involvement. Interestingly, whole body muscle-MRI shows a similar profile of muscle fat replacement (even if they present a different clinical phenotype), with predominant soleus, tibialis anterior and thenar eminence involvement.
The families that have been described show a broad phenotypic variability, even within the same family. However, the disease, with rare exceptions, is slowly progressive, and most patients remain autonomous for activities of daily living even after several decades of disease progression. Individuals carrying the p.Ser90Leu variant have been found to exhibit a more severe phenotype, some becoming wheelchair-bound. Moderate respiratory insufficiency can be present rarely.
BSCL2