Riboflavin transporter deficiency, Pontobulbar palsy and neurosensory deafness, Progressive bulbar palsy with sensorineural deafness, Brown-Vialetto-van Laere syndrome (BVVLS), Fazio-Londe syndrome
Incidence
Inheritance is autosomal recessive. Very rare condition, believed to be less than 1 in 1,000,000. Approximately 100 cases reported.
Clinical Characteristics
RTD onset may occur from infancy through adolescence. Childhood and adolescent presentation with bulbar palsy and muscle weakness is often preceded by sensorineural deafness; some patients are reported to remain free of additional symptoms after the onset of deafness for weeks, others for a decade. Patients presenting at a young age (before age 4) often present with respiratory compromise due to diaphragmatic paralysis and demonstrate a very rapid progression. Bulbar palsy manifests with facial weakness, ptosis and reduced horizontal eye movements, dysphagia and slurred speech. Motor neuron limb signs may be displayed as adducted shoulders sloping asymmetrically with winging scapula, ankle contractures and abnormally sharp deep tendon reflexes. Gait alteration may also be observed. Retinitis pigmentosa and macular hyperpigmentation have been reported in some cases. Autonomic dysfunction (reported in 7% of late-onset cases), tremor (8%) and epilepsy (4%) have been reported.
Mutations in SLC52A2 (8q24.3) and SLC52A3 (20p13, previously known as C20orf54) have been linked to RTD. These two genes, along with SLC52A1, encode putative riboflavin transporter proteins; their role in the nervous system has yet to be elucidated. Individuals with mutations in the SLC52A2 gene are now considered to have “Riboflavin Transporter Deficiency, Type 2†or RTD Type 2 for short, whereas those with mutations in the SLC52A3 gene have RTD Type 3. Neuronal loss in the motor nuclei of the cranial nerves, situated at the level of the spinal bulb and degeneration of the anterior horn cells of the spinal cord is described in childhood onset cases.
Mutational analysis of all three riboflavin transporter genes may be performed. Abnormalities in plasma flavin levels and abnormalities in the acylcarnitine profile have been observed in some but not in all patients, protein levels of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) may be reduced.
Progression is highly variable, life expectancy in untreated patients presenting before age 4 is less than 1 year with 85% mortality, untreated patients presenting during childhood (4-10 years) and adolescence (11-17 years) fare better (53% and 19% mortality respectively) and have a life-expectancy of over 10 years post-onset. The disorder becomes generalized leading to hypotonia, amyotrophy and progressive paralysis; respiratory insufficiency is the cause of death. Riboflavin treatment has yielded significant clinical improvement in all but one patient treated to date. Long-term studies are ongoing.