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Riboflavin Transporter Deficiency Neuronopathy.

Authors

Manole A1, Houlden H2.

Source

GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.
2015 Jun 11.

Author information

1
MRC Centre for Neuromuscular Diseases, Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom
2
Department of Molecular Neurosciences and MRC Centre for Neuromuscular Diseases, Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom

Excerpt

CLINICAL DESCRIPTION:

Riboflavin transporter deficiency neuronopathy is characterized by motor neuronopathy (manifest as proximal and distal limb weakness, often with severe distal wasting and breathing problems due to paralysis of the diaphragm), sensory neuronopathy (manifest as gait ataxia), and cranial neuronopathy (manifest as optic atrophy, sensorineural deafness, and bulbar palsy). Onset is usually in infancy or in childhood before age eight years; however, on occasion individuals with genetically confirmed disease present in the third decade. When untreated, most infants with riboflavin transporter deficiency rapidly become ventilator dependent and die in the first years of life. In the majority of affected individuals the initial finding is sensorineural deafness, which is usually progressive and severe. The time between the onset of deafness and the development of other manifestations varies but is usually one to two years. In some individuals an intercurrent event, usually an injury or infection, appears to precipitate the initial manifestations or worsen existing findings.

DIAGNOSIS/TESTING:

The diagnosis of riboflavin transporter deficiency neuronopathy is based on clinical, neurophysiologic, neuroimaging, and laboratory findings as well as the identification of biallelic pathogenic variants in either SLC52A2 or SLC52A3 on molecular genetic testing.

MANAGEMENT:

Treatment of manifestations: High-dose oral supplementation of riboflavin between 10 mg and 50 mg/kg/day improves symptoms and signs on clinical examination, improves objective testing (vital capacity, brain stem evoked potentials, nerve conduction studies), and normalizes acylcarnitine levels. The optimal dose is as yet unknown. Because oral riboflavin supplementation is effective (and possibly life saving), it should begin as soon as a riboflavin transporter deficiency neuronopathy is suspected and continued lifelong unless the diagnosis is excluded by molecular genetic testing. Supportive care includes: respiratory support; physiotherapy to avoid contractures; occupational therapy to support activities of daily living; orthotics for limb and trunk bracing; speech and language therapy to avoid choking and respiratory problems; wheel chair as needed; low vision aids as needed; routine management of scoliosis to avoid long-term respiratory problems; and routine management of depression. Surveillance: At three months and six months after initiation of riboflavin supplementation: follow-up physical and neurologic examinations, and measurement of blood riboflavin/FAD/FMN and acylcarnitine analysis. Thereafter, follow up should be biannual in older individuals and more frequent in younger children. Agents/circumstances to avoid: Dietary restriction of riboflavin. Evaluation of relatives at risk: When the SLC52A2 or SLC52A3 pathogenic variants in the family are known, it is appropriate to perform molecular genetic testing on the older and younger sibs of an affected individual to identify as early as possible those who would benefit from early treatment with riboflavin supplementation and monitoring for potential complications of the disorder. Pregnancy management: Females who have riboflavin transporter neuronopathy or are heterozygous for a pathogenic variant in SLC52A2 or SLC52A3 should have riboflavin supplements before and during pregnancy and when breast feeding to avoid inducing riboflavin deficiency in the baby.

GENETIC COUNSELING:

Riboflavin transporter deficiency neuronopathy is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic heterozygote (carrier), and a 25% chance of being unaffected and not a carrier. Heterozygote (carrier) testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the SLC52A2 or SLC52A3 pathogenic variants in the family are known.

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