Auditory neuropathy in Brown–Vialetto–Van Laere syndrome due to riboflavin transporter RFVT2 deficiency

Abstract

ABBREVIATIONS ABR Auditory brainstem reflexes ANSD Auditory neuropathy spectrum disorder BVVL Brown-Vialetto-Van Laere syndrome OAE Otoacoustic emissions AIM Mutations in the genes encoding the riboflavin transporters RFVT2 and RFVT3 have been identified in Brown-Vialetto-Van Laere syndrome, a neurodegenerative disorder characterized by hearing loss and pontobulbar palsy. Treatment with riboflavin has been shown to benefit individuals with the phenotype of RFVT2 deficiency. Understanding the characteristics of hearing loss in riboflavin transporter deficiency would enable early diagnosis and therapy. METHOD We performed hearing assessments in seven children (from four families) with RFVT2 deficiency and reviewed results from previous assessments. Assessments were repeated after 12 months and 24 months of riboflavin therapy and after cochlear implantation in one individual. RESULTS Hearing loss in these individuals was due to auditory neuropathy spectrum disorder (ANSD). Hearing loss was identified between 3 years and 8 years of age and progressed rapidly. Hearing aids were not beneficial. Riboflavin therapy resulted in improvement of hearing thresholds during the first year of treatment in those with recent-onset hearing loss. Cochlear implantation resulted in a significant improvement in speech perception in one individual. INTERPRETATION Riboflavin transporter deficiency should be considered in all children presenting with an auditory neuropathy. Speech perception in children with ANSD due to RFVT2 deficiency may be significantly improved by cochlear implantation. Brown-Vialetto-Van Laere syndrome (BVVL) is a progressive neurodegenerative disorder characterized by hearing loss and pontobulbar palsy. 1 Recently, mutations in SLC52A2 and SLC52A3, encoding the riboflavin transporters RFVT2 and RFVT3 respectively, have been identified in a number of individuals with BVVL. 2,3 The phenotype of individuals with RFVT2 deficiency includes hearing loss and sensory ataxia with an onset in early childhood , followed by progressive upper limb weakness, optic atrophy, bulbar weakness, and respiratory failure. 4 While the clinical phenotype of children with BVVL due to RFVT2 deficiency has been reported in detail, the characteristics of the hearing loss have not been explored, despite it often being a presenting or early feature in affected individuals. Reports of individuals with RFVT2 deficiency and of genetically undifferentiated cohorts of individuals with BVVL classify the hearing impairment as a 'sen-sorineural hearing loss' without a clear description of its characteristics. 1,4 Functional studies have demonstrated that SLC52A2 mutations reduce riboflavin transporter expression and riboflavin uptake. 4,5 Riboflavin is critical for the biosynthe-sis of flavin mononucleotide and flavin adenine dinu-cleotide, important cofactors for carbohydrate, amino-acid, and lipid metabolism. Flavin adenine dinucleotide acts as an electron acceptor in acyl-CoA dehydrogenation reactions in mitochondrial fatty acid b-oxidation and bra...

Reversible posterior column dysfunction in Brown–Vialetto–Von Laere syndrome

“…Clinically, the patient demonstrated a remarkable improvement in sensory ataxia followed by improvement in bulbar function. Sensorineural deafness did not improve, which is in keeping with the pattern noted in the literature . The differential diagnosis of abnormal dorsal column signals and sensory ataxia includes deficiencies of vitamin B 12 , folate, copper, and vitamin E, as well as human immunodeficiency virus, tabes dorsalis, and demyelination.…”

An update on the genetics, clinical presentation, and pathomechanisms of human riboflavin transporter deficiency

“…There have since been a further 10 publications reporting on 23 newly diagnosed RTD2 cases, and 12 reporting on 27 newly diagnosed RTD3 cases . A patient harboring a heterozygous pathogenic mutation in SLC52A3 and heterozygous SLC52A2 variant of unknown significance has been described, which will be considered as a RTD3 case here.…”

The Clinical Journey of Patients with Riboflavin Transporter Deficiency Type 2

“…Previous studies that aimed to understand the characteristics of hearing loss in patients with riboflavin transporter deficiency type 2 identified that hearing loss was due to auditory neuropathy. 30,31 Auditory neuropathy is a rare condition reported in only 8% of children per year who are newly diagnosed with hearing loss. 32 Otoacoustic emissions testing used in most American states as part of their universal hearing screening program will not identify auditory neuropathy.…”

“…Recent work has shown that a cochlear implant can have positive effects on both sound and speech perception in children with riboflavin transporter deficiency. 30,31 It has been reported that children with auditory neuropathy receive greater benefit if they are implanted early before a substantial delay in their language development. 33 In our cohort, we found a potential significant delay in the recognition of auditory neuropathy and for receiving a cochlear implant, which may have resulted in a poorer hearing outcome post-implant.…”