Late-onset riboflavin transporter deficiency: a treatable mimic of various motor neuropathy aetiologies

Abstract

ObjectiveRiboflavin transporter deficiencies (RTDs), involving SLC52A3 and SLC52A2 genes, have recently been related to Brown-Vialetto-Van Laere (BVVL) syndrome, a hereditary paediatric condition associating motor neuropathy (MN) and deafness. BVVL/RTD has rarely been reported in adult patients, but is probably underdiagnosed due to poor knowledge and lack of awareness of this form of disease among neurologists. In this study, we aimed to investigate the phenotype and prognosis of RTD patients with late-onset MN.MethodsWe retrospectively collected clinical, biological and electrophysiological data from all French RTD patients with MN onset after 10 years of age (n=6) and extracted data from 19 other similar RTD patients from the literature.ResultsAdult RTD patients with MN had heterogeneous clinical presentations, potentially mimicking amyotrophic lateral sclerosis or distal hereditary motor neuropathy (56%), multinevritis with cranial nerve involvement (16%), Guillain-Barré syndrome (8%) and mixed motor and sensory neuronopathy syndromes (20%, only in SLC52A2 patients). Deafness was often diagnosed before MN (in 44%), but in some patients, onset began only with MN (16%). The pattern of weakness varied widely, and the classic pontobulbar palsy described in BVVL was not constant. Biochemical tests were often normal. The majority of patients improved under riboflavin supplementation (86%).InterpretationWhereas late-onset RTD may mimic different acquired or genetic causes of motor neuropathies, it is a diagnosis not to be missed since high-dose riboflavin per oral supplementation is often highly efficient.

Benefit of high‐dose oral riboflavin therapy in riboflavin transporter deficiency

“…A summary of the articles that reported follow-up data in each of the domains is shown in Table S1. Forty-seven of those patients had RTD2 due to biallelic mutations in SLC52A2, [2][3][4]12,[14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] 46 had RTD3 due to biallelic mutations in SLC52A3 18,20,24,27,31, and one patient had a mutation in both SLC52A2 and SLC52A3. 58 Seventy-six of the 94 patients (80.9%) showed an overall improvement after riboflavin supplementation, and the remaining (19.1%) were stable after riboflavin supplementation.…”

New Insights into the Neurodegeneration Mechanisms Underlying Riboflavin Transporter Deficiency (RTD): Involvement of Energy Dysmetabolism and Cytoskeletal Derangement

“…Empirical studies showed that RF administration gradually improves symptoms, as muscle strength, motor function, respiration, hearing, and vision in some children affected by RTD [ 64 , 65 , 66 ]. This prompted researchers to investigate at the molecular and cellular level possible beneficial effects of RF supplementation to RTD in vivo or in vitro models.…”

Newborn screening of neuromuscular diseases

“…Low-cost treatments such as salbutamol or pyridostigmine can avoid sudden death or disability in the course of a long diagnostic journey. BVVL, a recessive disorder caused by a loss of function mutation in one of the three different intestinal riboflavin transporter genes, can be managed with a high dose of riboflavin [85] , and leads to severe bulbospinal atrophy in absence of treatment. Unfortunately, neither CMS not BVVL can be identified by any sensitive biomarker and are thus not amenable to NBS; identification of such disorders at birth should therefore be carried out through whole exome or targeted sequencing.…”