title: Pathophysiology of motor dysfunction in a childhood motor neuron disease caused by mutations in the riboflavin transporter.
abstract: OBJECTIVE
  Brown-Vialetto-Van Laere (BVVL) syndrome is a progressive motor and sensory neuronopathy secondary to mutations in SLC52A2 encoding the riboflavin transporter type 2 (RFVT2). The phenotype is characterized by early childhood onset hearing loss and sensory ataxia followed by progressive upper limb weakness, optic atrophy, bulbar weakness and respiratory failure. To gain further insight into disease pathophysiology and response to riboflavin supplementation, the present study investigated whether axonal ion channel or membrane abnormalities were a feature of BVVL.
  
  
  METHODS
  Axonal excitability studies and clinical assessments were prospectively undertaken on six patients with BVVL secondary to riboflavin transporter deficiency type 2 (age range 10-21 years) at baseline and after 12 months of riboflavin (1000 mg daily) therapy.
  
  
  RESULTS
  At baseline, depolarizing and hyperpolarizing threshold electrotonus was 'fanned out' and superexcitability was increased, while the resting current-threshold gradient and refractoriness were significantly reduced in BVVL patients when compared to controls. Mathematical modeling suggested that functional alterations of myelin underlay these findings with an increase in myelin permeability. Riboflavin therapy resulted in partial normalization of the axonal excitability findings, paralleled by maintenance of muscle strength.
  
  
  CONCLUSIONS
  The present study established that abnormalities in myelin permeability at the paranode was a feature of BVVL and were partially normalized with riboflavin therapy.
  
  
  CONCLUSIONS
  This study reveals a novel pathophysiological process for motor nerve dysfunction in BVVL. It also indicates that nerve excitability studies may be further developed in larger cohorts as a potential biomarker to identify treatment response for BVVL patients.
authors.affiliation: Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, Australia; Discipline of Paediatrics and Child Health, The Children's Hospital at Westmead Clinical School, The University of Sydney, Sydney, Australia; Department of Neurology, The Children's Hospital at Westmead, Sydney, Australia.
authors.forename: Manoj P
authors.initials: MP
authors.lastname: Menezes
authors.affiliation: Discipline of Paediatrics, School of Women's and Children's Health, UNSW Medicine, The University of New South Wales, Sydney, Australia; Neurosciences Research Australia, Sydney, Australia; Department of Neurology, Sydney Children's Hospital, Sydney, Australia. Electronic address: m.farrar@unsw.edu.au.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Farrar
authors.affiliation: Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, Australia; Department of Neurology, The Children's Hospital at Westmead, Sydney, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Webster
authors.affiliation: Department of Neurology, The Children's Hospital at Westmead, Sydney, Australia.
authors.forename: Jayne
authors.initials: J
authors.lastname: Antony
authors.affiliation: Department of Audiology, The Children's Hospital at Westmead, Sydney, Australia.
authors.forename: Katherine
authors.initials: K
authors.lastname: O'Brien
authors.affiliation: Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, Australia; Discipline of Paediatrics and Child Health, The Children's Hospital at Westmead Clinical School, The University of Sydney, Sydney, Australia; Department of Neurology, The Children's Hospital at Westmead, Sydney, Australia.
authors.forename: Robert
authors.initials: R
authors.lastname: Ouvrier
authors.affiliation: Neurosciences Research Australia, Sydney, Australia; Sydney Medical School, Brain & Mind Research Institute, University of Sydney, Sydney, Australia.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Kiernan
authors.affiliation: Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, Australia; Paediatric Gait Analysis Service of New South Wales, Sydney Children's Hospitals Network, Sydney, Australia; Sydney Arthritis and Musculoskeletal Research Network, The University of Sydney, Sydney, Australia.
authors.forename: Joshua
authors.initials: J
authors.lastname: Burns
authors.affiliation: Department of Neurology, Westmead Hospital and Western Clinical School, University of Sydney, Sydney, Australia.
authors.forename: Steve
authors.initials: S
authors.lastname: Vucic
mesh_terms: D000293:Adolescent; D010244:Bulbar Palsy, Progressive / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D005260:Female; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics*; D016472:Motor Neuron Disease / Q000175:diagnosis / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D011446:Prospective Studies; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D055815:Young Adult
chemical_list: D026901:Membrane Transport Proteins; D043562:Receptors, G-Protein-Coupled; C540350:SLC52A2 protein, human; C548553:SLC52A3 protein, human
keywords: Brown–Vialetto–Van Laere (BVVL); Nerve excitability; RFVT2; Riboflavin