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Journal Review: Neuronopathy

Posted in Journal Reviews on 13th Mar 2014

Riboflavin and the Axon

Reviewer: Dr Natalie Lakomska, Honorary Neurophysiology Registrar, The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK

The “old yellow pigment” which was first isolated from cow’s milk in 1879, by an English chemist Alexander Wynter Blyth has shown to be a successful therapeutic intervention for patients for whom no disease modifying therapy had previously been available. Discovered in 1925 by a Nobel prize winner, Professor Otto Warburg, it is now known as Riboflavin or vitamin B2, due to its ribityl side chain and Latin “flavus” for yellow. It has recently shown to lead to symptomatic improvement when supplemented in high dosage in a childhood form of Motor Neuron Disease (MND).

First described in 1894, Brown–Vialetto–Van Laere syndrome (BVVL) is a neurodegenerative disorder where children and young adults develop progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency.

Without treatment this progressive neurodegenerative condition leads to early demise.

Riboflavin penetrates the blood-brain barrier and is taken up by the riboflavin transporter into neurons and astrocytes. The active forms flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) are cofactors for a number of redox enzymes and play key roles in the transfer of electrons in biological oxidation–reduction cycles.

The exact mechanism of transport was only recently discovered (van Herwaarden et al., 2007; Yonezawa et al.,2008; Yamamoto et al. 2009).

A multicentre study based at UCL Institute of Neurology and the Institute of Child Health, also including teams in Australia, France, Lebanon and the United States, characterised patients with causative gene mutations (SLC52A2) encoding the riboflavin transporter RFVT2. RFVT2 transporter mutations were shown to lead to reduced riboflavin uptake and reduced riboflavin transporter protein expression. A core phenotype was identified (respiratory insufficiency, optic atrophy, hearing loss, sensory ataxia, upper limb and axial muscle weakness with preserved lower limb strength) in a group of 18 patients with compound heterozygous or homozygous mutations in SLC52A2.

Biochemically high-dose riboflavin therapy (up to 50mg/kg/day in paediatric and 1500mg/day in adult patients) produced a biochemical normalisation of acylcarnitine profile and an increase in the active forms riboflavin: flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN). Clinically a reversal of continual functional decline was achieved with improvement in audiometric testing, pulmonary function tests, and visual evoked potentials.

Patients in this SLC52A2-specific cohort gained improvement in hand function, walking, oral intake, were able to come off respiratory support. This is a breakthrough in finding a treatable cause for a type of motor neuron disease, lighting a candle of hope for adult MND.

Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2. Foley A, Menzes M, Pandraud A et al. Brain 2014: 137; 44-56.

ACNR: Published online 13/3/14