Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood. The authors have recently reported the identification of SLC52A2, encoding riboflavin transporter RFVT2, as a new causative gene for Brown-Vialetto-Van Laere syndrome. They used both exome and Sanger sequencing to identify SLC52A2 mutations in patients presenting with cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency. Clinical, neurophysiological and biochemical characterization of patients with mutations in SLC52A2 were undertaken, functionally analysed the most prevalent mutations and initiated a regimen of high-dose oral riboflavin. They identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy (manifesting with sensory ataxia, severe weakness of the upper limbs and axial muscles with distinctly preserved strength of the lower limbs), hearing loss, optic atrophy and respiratory insufficiency. They demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression, and report the response to high-dose oral riboflavin therapy in patients with SLC52A2 mutations, including significant and sustained clinical and biochemical improvements in two patients and preliminary clinical response data in 13 patients with associated biochemical improvements in 10 patients. In another study, the authors report the case of a previously healthy child presenting at 6 months of age with mild feeding difficulties and then developing hypotonia, progressive bulbar palsy with respiratory compromise and lower motor neuron signs, causing her to spend 4 months in the Paediatric Intensive Care Unit. Neurophysiological studies demonstrated a motor neuronopathy involving anterior horn cells and cranial nerve nuclei and abnormal brainstem auditory evoked potentials, leading to a diagnosis of Brown-Vialetto-van Laere Syndrome, confirmed by genetic testing (SLC52A3). Magnetic Resonance Imaging showed signal changes in the dorsal column of the spinal cord. She developed a coarse face and abnormal hair pattern. Sustained clinical improvement has been observed during almost 4 years of high-dose riboflavin therapy. These studies suggest that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated soon after the onset of symptoms.
