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Riboflavin transporter deficiency (RTD) has been reported in more than 100 genetically diagnosed cases to date.

Onset may occur from early infancy until adulthood, with a more severe presentation at a younger age. The most frequent presenting symptoms are cranial neuropathy, sensory ataxia, muscle weakness and respiratory insufficiency due to diaphragmatic paralysis. The cranial neuropathy leads to sensorineural hearing loss, loss of vision due to optic atrophy, dysarthria, dysphagia, feeding problems, facial weakness and eye movement impairments. Peripheral neuropathy in combination with anterior horn cell dysfunction and atrophy of the sensory tracts in the spinal cord causes muscle weakness with atrophy and (sensory) ataxia. Diaphragmatic paralysis in combination with general muscle weakness may rapidly lead to respiratory insufficiency, especially in infants and young children. Often, feeding through a nasogastric tube or gastrostomy device and artificial ventilation and tracheotomy are required. Sensory ataxia and optic atrophy seem more prevalent in RFVT2 than RFVT3 deficient patients.

Pathogenic biallelic mutations in the genes SLC52A2 and SLC52A3 that encode riboflavin transporter 2 and 3 cause RTD2 and RTD3, respectively. Riboflavin (Vitamin B2) is a water-soluble vitamin that is essential for normal metabolism. The loss of function of the riboflavin transporter results in cellular flavin deficiency in different tissues. As flavins play an important role in mitochondrial function, mitochondrial dysfunction might act as a pathomechanism contributing to neurodegeneration in RTD.

Diagnosis is only possible through mutational analysis of all genes coding for riboflavin transporters. Biochemical tests can show abnormalities such as abnormal (MADD-like) plasma acylcarnitine profiles, abnormal urine organic acids and decreased plasma flavin levels; however, approximately 50% of patients have normal results. Magnetic resonance imaging (MRI) is normal in the large majority of RTD patients. Electrophysiological testing (EMG) can show findings consistent with a sensorimotor axonal neuropathy with signs of anterior horn cell dysfunction, but normal results can also be observed.

Differential diagnosis include neuromuscular diseases, in particular congenital or mitochondrial myopath and rapidly progressive neuropathies.

Prenatal diagnosis is possible if family mutations in the SLC52A2 or SLC52A3 genes are known.

Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.

Riboflavin supplementations is lifesaving and daily administration of a high dose oral riboflavin supplementation should be started immediately upon suspicion of RTD; treatment is lifelong. In cases with early onset, assisted ventilation, tracheostomy, and maintenance of nutrition via gastrostomy may be required. Regular clinical evaluation is required and includes neurological examination as well as evaluation of hearing and vision, respiratory function and skeletal deformities like scoliosis. Depending on the symptoms, physical and speech therapy should be initiated. Cochlear implants have proven highly successful for hearing loss in RTD.

If untreated, RTD is progressive and often fatal, with respiratory insufficiency as the main cause of death. However, severity and rate of progression vary between patients. When treated with high doses of riboflavin, the majority of patients show improvement over time and early treatment may even result in full recovery and normal development. In contrast, patients with irreversible damage may show stabilization but no improvement of symptoms. No deaths have been reported in riboflavin-treated patients.