Sarah Camargos, Rita Guerreiro, Jose Bras and Luis Sergio Mageste. Late-onset and acute presentation of Brown-Vialetto-Van Laere syndrome in a Brazilian family. Neurol Genet. 2018 Feb 1. http://ng.neurology.org/content/4/1/e215?etoc=
Riboflavin transporter deficiency (formerly known as Brown-Vialetto-Van Laere [BVVL] or Fazio-Londe syndrome) is a neurodegenerative disorder characterized by progressive bulbar palsy with sensorineural deafness or bulbar hereditary neuropathy. It is caused by mutations in the riboflavin transporter genes SLC52A2 (RFVT2) or SLC52A3 (RFVT3). It is a rare syndrome with approximately 70 cases reported worldwide, with molecular diagnoses of RFVT2 or RFVT3.1,4 We have previously described the first Brazilian family with a clinical diagnosis of BVVL.
In this report, we extend the clinical spectrum associated with this family and describe a new mutation related to the metabolism of riboflavin.
The proband was a previously healthy woman aged 34 years, who presented with hearing and vision loss in the last 6 months. She was disturbed by facial pain, numbness in the left hemiface, difficulty moving her tongue, dysphagia, weight loss, and bilateral foot drop.
Examination demonstrated bilateral optic atrophy, normal ocular movements, bilateral facial paresis, atrophic tongue, and flaccid dysarthria. Reflexes were brisk except for ankle reflexes that were absent. Plantar responses were indifferent. All sensory modalities were normal. Strength was globally diminished with important distal impairment and foot drop. As dysphagia and dyspnea progressed, a feeding tube was placed and noninvasive ventilation support was initiated. At that time, she was quadriplegic and could not walk.
Electroneuromyography demonstrated cervical and acute lumbar denervation, with chronic neurogenic changes. Audiologic evaluation demonstrated neurosensorial loss.
The patient was the eldest sibling of a consanguineous marriage. She had 3 maternal aunts, also sisters from a consanguineous marriage, with a probable diagnosis of BVVL syndrome.
The patient was started on empiric treatment with riboflavin (1,800 mg per day), and within 6 months of therapy, she could walk with a cane; the feeding tube and noninvasive ventilation were withdrawn. Electroneuromyography was performed after B2 treatment and demonstrated low CMAP amplitudes and persistence of recent denervation.
By analyzing the variability identified by WES in genes previously known to cause riboflavin transporter deficiency, we identified a novel homozygous insertion in SLC52A3….
The mutation was confirmed to be present in homozygosity in the index and was found in heterozygosity in both parents using Sanger sequencing. In addition, WGG revealed a large (1.5 Mb) homozygous region encompassing the SLC52A3 locus (chromosome 20: 643,919–2,146,580 Mb) that was not present in either parent. Consequently, we tested the phenotypically affected aunt, and she presented the mutation in homozygosity…
Here, we report a Brazilian patient with late-onset and uncharacteristic acute and severe presentation, demonstrating some phenotypic heterogeneity within a family. The mutation, a homozygous insertion of 60 bp in SCL52A3, has not been previously described as the cause of riboflavin transporter deficiency. So far, response to riboflavin therapy was documented in 11 patients harboring mutations in RFVT3. Of them, 9 patients demonstrated some response and 2 remained stable. Some authors argue that response tends to be better and more rapid when earlier treatment is started. Riboflavin dose reposition is unknown, and treatment, although generally efficient, is empirical. In addition, there is still no evidence to reassure that treatment would prevent the occurrence of symptoms indefinitely. Despite all this, clinicians might be aware of this potentially treatable condition and initiate riboflavin supplementation as soon as diagnosis is suspected.