Invitae Riboflavin Transporter Deficiency Neuronopathy Panel


Test description

The Invitae Riboflavin Transporter Deficiency Neuronopathy Panel analyzes two genes associated with riboflavin transporter deficiency, which is also known as Brown-Vialetto-Van Laere syndrome and Fazio-Londe disease. These genes were curated based on the available evidence to date to provide a comprehensive test for this condition.

Individuals with clinical signs and symptoms of riboflavin transporter deficiency may benefit from diagnostic genetic testing to confirm the diagnosis, guide clinical treatment and inform recurrence risk within a family.

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Primary panel (2 genes)


Alternative tests to consider

Riboflavin transporter deficiency may also have nonspecific or overlapping features with other neurological disorders, in which case clinicians may consider Invitae’s Comprehensive Neuropathy panel, which includes genes associated with Charcot-Marie-Tooth disease, distal hereditary motor neuropathy, hereditary sensory and autonomic neuropathy and hereditary spastic paraplegia.

Riboflavin transporter deficiency neuronopathy is a neurodegenerative disorder characterized by progressive axonal sensorimotor neuropathy. Clinical features of this disorder include bulbar palsy (facial weakness, drooping eyelids, difficulty speaking and swallowing), weakness and distal muscle atrophy in the limbs (typically more severe in the upper than lower limbs), respiratory distress due to diaphragmatic weakness, and gait ataxia. Sensorineural hearing loss occurs in many individuals and may be the presenting symptom. Historically, the clinical subtype of riboflavin transporter deficiency neuronopathy that includes hearing loss has been called Brown-Vialetto-Van Laere syndrome, and the clinical subtype that does not include hearing loss has been called Fazio-Londe disease. Onset of symptoms typically occurs in early childhood;however, genetically confirmed early-adult onset cases have been reported. Since the discovery of the underlying molecular defect in this disorder, high-dose riboflavin supplementation has been reported to be an effective treatment.

SLC52A2 and SLC52A3 are the only known causes of riboflavin transporter deficiency neuronopathy. However, due to the rareness of this disorder, the clinical sensitivity of this panel has not been confirmed.

Riboflavin transporter deficiency neuronopathy is inherited in an autosomal recessive manner.

In families with genetically confirmed riboflavin transporter deficiency neuronopathy penetrance is high, but the number of families reported in the literature is low due to the rareness of this disorder.

Riboflavin transporter deficiency neuronopathy is a rare disorder and has a prevalence of less than 1 in 1,000,000.

The clinical presentation of riboflavin transporter deficiency neuronopathy is variable, and may be difficult to distinguish clinically from other neurological disorders. Genetic testing may confirm a suspected diagnosis or rule out other disorders with similar symptoms. A genetic diagnosis may also help guide treatment and inform recurrence risk.

  1. Bosch, AM, et al. Brown-Vialetto-Van Laere and Fazio Londe syndrome is associated with a riboflavin transporter defect mimicking mild MADD: a new inborn error of metabolism with potential treatment. J. Inherit. Metab. Dis. 2011; 34(1):159-64. PMID: 21110228
  2. Bosch, AM, et al. The Brown-Vialetto-Van Laere and Fazio Londe syndrome revisited: natural history, genetics, treatment and future perspectives. Orphanet J Rare Dis. 2012; 7:83. PMID: 23107375
  3. Dipti, S, et al. Brown-Vialetto-Van Laere syndrome; variability in age at onset and disease progression highlighting the phenotypic overlap with Fazio-Londe disease. Brain Dev. 2005; 27(6):443-6. PMID: 16122634
  4. Foley, AR, et al. Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2. Brain. 2014; 137(Pt 1):44-56. PMID: 24253200
  5. Green, P, et al. Brown-Vialetto-Van Laere syndrome, a ponto-bulbar palsy with deafness, is caused by mutations in c20orf54. Am. J. Hum. Genet. 2010; 86(3):485-9. PMID: 20206331
  6. Johnson, JO, et al. Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease. Brain. 2012; 135(Pt 9):2875-82. PMID: 22740598
  7. Manole, A, Houlden, H. Riboflavin Transporter Deficiency Neuronopathy. 2015 Jun 11. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 26072523
  8. Srour, M, et al. Mutations in riboflavin transporter present with severe sensory loss and deafness in childhood. Muscle Nerve. 2014; 50(5):775-9. PMID: 24616084

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
SLC52A2 NM_024531.4
SLC52A3 NM_033409.3