Brown-Vialetto-Van Laere Syndrome: Clinical and Neuropathologic Findings with Immunohistochemistry for C20orf54 in Three Affected Patients

Abstract

Brown-Vialetto-Van Laere syndrome (BVVLS) is a rare degenerative neurological disorder characterized by pontobulbar palsy and sensorineural deafness. Since its initial description in 1894, fewer than 100 cases have been reported, and published neuropathological analyses of these cases are extremely rare. Recently, individuals with BVVLS have been found to carry mutations in the C20orf54 gene, which encodes the human homolog for a rat riboflavin transporter. We present the case of a male who presented at the age of 5 years with sensorineural deafness, as well as those of 2 infant sisters who presented at 11 and 13 months of age with weakness and ataxia, respectively. All cases were genetically confirmed. We include the 1st immunohistochemical characterization of C20orf54 expression in BVVLS and controls. Results showed punctate axonal staining in the control cases that was dramatically reduced in the 3 BVVLS cases compared to the 5 controls. This decreased staining was seen even in the neocortex, which was unaffected in the BVVLS cases by routine histology. While the implications of these results are far from definitive, and although the evaluation of more cases is needed, immunohistochemistry for the C20orf54 protein may eventually be useful, in the right clinical scenario, as a screening test when selecting cases for sequencing of the C20orf54 gene to diagnose BVVLS at autopsy.

Clinical presentation and outcome of riboflavin transporter deficiency: mini review after five years of experience

“…These patients had a confirmed sensorimotor axonal neuropathy and no weakness in the lower limbs or cerebellar signs, therefore a disturbed proprioception due to a progressive sensory neuropathy or neuronopathy seemed the cause of this gait disorder. In 5/33 patients with RFVT3 deficiency gait or truncal ataxia was described, without information on the presence or absence of a neuropathy (Green et al 2010; Malafronte et al 2013). Cerebellar signs were reported in one RFVT3 deficient patient described by Green et al…”

“…A total of 31 patients was not treated with riboflavin supplementation and these patients all demonstrated a gradual deterioration (Green et al 2010; Johnson et al 2010; Dezfouli et al 2012; Johnson et al 2012; Ciccolella et al 2012; Malafronte et al 2013; Ciccolella et al 2013; Bandettini Di Poggio et al 2014; Srour et al 2014). Fifteen patients (RFVT2: 6; RFVT3: 9) were reported to have died at the time of publication.…”

Clinical and genetic diversity of SMN1-negative proximal spinal muscular atrophies

“…Patients with Brown-Vialetto-Van Laere syndrome type 1 have decreased plasma levels of riboflavin and its coenzyme forms ( Bosch et al , 2011 ). Furthermore, immunohistochemical characterization of SLC52A3 expression in patients with Brown-Vialetto-Van Laere syndrome type 1 shows a dramatically reduced punctate axonal staining ( Malafronte et al , 2013 ). Oral supplementation of riboflavin provides a life-saving treatment for young patients ( Bosch et al , 2011 , 2012 ; Anand et al , 2012 ; Ciccolella et al , 2012 ; Koy et al , 2012 ; Spagnoli et al , 2014 ).…”

Brown-Vialetto-Van Laere syndrome: a novel diagnosis to a common presentation

“…Similar mutation was reported by Malafronte et al in one of his cases, who reported neuropathological and immunohistochemistry findings of three individuals with BVVLS. This was a 12-year-old boy diagnosed with BVVLS who had presented with sensorineural hearing loss at the age of 5 years 5. Green et al also published the characteristics of seven families with BVVLS.…”