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Riboflavin transporter deficiency
Riboflavin transporter deficiency (RTD) is a progressive motor neuron disorder characterized by respiratory insufficiency, sensorineural deafness and progressive ponto-bulbar palsy.
80 cases have been reported in the literature to date.
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. 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.
Amyotrophic lateral sclerosis, Joubert syndrome, Madras motor neuron disease and Nathalie syndrome (see these terms) share many symptoms with RTD. Glutaric acidemia type 2 (see this term) may resemble early-onset RTD, however laboratory analyses revealing dicarboxylic glutaric, and ethylmalonic aciduria and suberylglycine with very low carnitine levels in plasma exclude RTD.
Inheritance is autosomal recessive.
Management and treatment
Symptomatic treatment must be addressed promptly in early onset cases: assisted ventilation, tracheostomy when necessary, and maintenance of nutrition via gastrostomy may be required. As some symptoms may be irreversible, daily administration of riboflavin (10 mg/kg per day in 3 doses) should be started prior to definitive diagnosis. Regular clinical evaluation during the course of treatment must be accompanied by neurological examination and testing of cranial nerves, hearing tests, electrocardiograms and ultrasound studies of the diaphragm.
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.