Severe Childhood Neuronopathy that Responds to Riboflavin
Abstract & Commentary
By Sotirios Keros, MD, PhD
Instructor, Department of Pediatrics, Division of Pediatric Neurology, Weill Cornell Medical College
Dr. Keros reports no financial relationships relevant to this field of study.
Synopsis: A new mutation is identified in a riboflavin transporter gene as a cause of Brown-Vialetto-Van Leare syndrome, a sensorimotor neuronopathy, which displays clinical improvement with riboflavin therapy.
Source: Foley AR, et al. Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2. Brain 2014;137:44-56.
Brown-vialetto-van leare syndrome (bvvls), also occasionally referred to as Brown syndrome, is a rare but severe form of autosomal recessive congenital neurodegenerative disorder causing sensorimotor deficits in children. Initially described as "infantile amyotrophic lateral sclerosis of the family type" BVVLS has come to represent a constellation of symptoms that include sensorineural deafness, pontobulbar paralysis, respiratory insufficiency, and various patterns of limb weakness.
Within the past several years, three mutations in a riboflavin transporter gene (SLC52A1, SLC52A2, and SLC52A3) causing riboflavin deficiency have been discovered, with the A2 and A3 versions of the mutations (coding for human transporter proteins RFVT2 and RFVT3, respectively) linked to some patients with BVVLS. In this study, the authors perform a detailed characterization of 18 patients with newly confirmed SLC52A2 mutations, and describe clinical improvement with high-dose riboflavin therapy.
Seventy-eight patients were enrolled from 21 medical centers and fit a phenotype of sensorimotor neuropathies and cranial neuropathies, both with and without respiratory insufficiency. None of the 78 had mutations in SLC52A1 or SLC52A3. Eighteen individuals (13 probands and five family members) of the 78 had various mutations in SLC52A2, which were verified with Sanger sequencing. The age at the time of genetic diagnosis of patients ranged from 2-52 years old. Seven different missense mutations and one premature stop mutation were identified (six mutations were novel, while two were previously reported). Two of five patients had respiratory chain abnormalities (decreased complex I activity and slightly decreased complex IV activity) obtained from muscle samples. Sural nerve biopsies in six patients were consistent with a chronic axonal neuropathy, with fibrosis and degeneration but with no findings of regeneration, inflammation, or demyelination. Brain MRI was normal in all 14 patients tested. A riboflavin transport assay in an in vitro expression system revealed absent or moderately decreased transport in all seven mutations tested.
Clinically, the first abnormalities were noted in this group between 7 months and 5 years of age. The most common presenting symptom was an ataxic gait (in half the patients). Other presenting symptoms were hearing loss (n = 3), vision loss or nystagmus and ptosis (n = 3), and upper extremity weakness and respiratory failure (n = 1 each). All patients eventually developed hearing loss, and 14 of 15 were diagnosed with optic atrophy. Eleven patients had tongue fasciculations, and 13 developed respiratory insufficiency, which led to one death at age 3.5 years. A common feature of almost all patients was a rapidly progressing weakness first affecting the neck extensors, then the distal upper extremities followed by the proximal upper limbs, resulting in subgravity strength. The authors note that lower extremity weakness was mild and that all patients remained ambulatory if given neck and trunk support. Neurophysiologic testing revealed a sensory axonal neuropathy, which preceded an axonal motor neuropathy, with severity greater in the upper extremity in all patients, consistent with the clinical findings.
Sixteen patients began high-dose oral riboflavin therapy. Acylcarnitine profiles were abnormal in 10 of 17 patients tested prior to riboflavin therapy, with correction to normal in 9 of 10 after therapy. Detailed responses to riboflavin are presented for two patients. First, a 22-month-old boy who presented with a 6-month history of nystagmus, 4 months of ataxic gait, and 3 weeks of hand and bulbar weakness leading to respiratory failure and inability to swallow. During 4 weeks of riboflavin he was extubated, was able to feed, and regained upper extremity strength. A second child — whose symptoms began at age 2 with sensory ataxia, upper limb weakness, hearing loss, and vision loss, and progressed to respiratory insufficiency and inability to sit and stand by age 7 — was treated at age 10. After 3 months of riboflavin therapy, there was improvement in audiometry testing, respiratory status, and visual evoked potentials, all of which had previously been consistently declining. An additional 17 months of therapy led to increases in height and weight for the first time in 4 years, and improvements in motor function such that she could sit and stand independently.
This study adds yet another congenital neurologic disorder to the rapidly growing list of diseases that have an identified genetic etiology, with the important fact that this one comes with evidence of an effective, widely available, and safe treatment. SLC52A2 mutations are likely the most common cause of BVVLS. The patients in this report with SLC52A2 mutations had a remarkably similar phenotype, with optic atrophy, a sensorimotor neuropathy (much worse in the upper extremities and neck), hearing loss, and respiratory insufficiency. While somewhat anecdotal pending forthcoming data, it seems that high-dose riboflavin therapy can lead to substantial improvement, and might have the potential to reverse all symptoms if initiated early enough. Although BVVLS is rare, the highly specific phenotype of SLC52A2 will hopefully allow clinicians seeing young children with any of the characteristic symptoms to recognize this disorder and initiate timely empiric riboflavin therapy while waiting for genetic confirmation of the diagnosis.