A genetic, neuronopathic disorder characterized by bilateral sensorineural deafness and variable, but progressive cranial and spinal motor nerve involvement.
Pontobulbar Palsy with Deafness; Progressive Bulbar Palsy with Perceptive Deafness; Progressive Bulbar Palsy with Sensorineural Deafness.
First described by Charles Brown in 1894 as an inherited, infantile form of amyotrophic lateral sclerosis. This was followed by a report of a hereditary and progressive from of bulbar paralysis by E. Vialetto in 1936 and finally a description of a chronic progressive form of pontobulbar paralysis with deafness by J. Van Laere in 1966.
Unknown, but approximately 100 cases have been reported in the literature with an unaccounted number of affected siblings and relatives. The female to male ratio is in the range of 3 to 5:1 and males seem to be affected more severely.
Most of the familial cases are thought to be autosomal recessively transmitted, however, genetic heterogeneity with autosomal recessive and autosomal dominant transmission as well as a mutant gene carried on the X-chromosome have also been suggested in a few cases. Approximately half of the cases are considered sporadic. In BVVLS 1, the mutations responsible for the disorder affect the SLC52A3 gene which is responsible for the development of riboflavin (vitamin B12) transporter protein which is present on chromosome 20p13. The riboflavin transporter protein member 3 is often called RFVT3. It is use to transport vitamin B12 across membranes and within cells. This gene belongs to a family of gene called Solute Carrier Family 52 Riboflavin Transporter Members. In BVVLS 2, the genetic defect is caused by mutations in the SLC52A2 gene, which is located on chromosome 8q24.3. Both genes encode riboflavin transporter proteins (RFVT 2 by SLC52A2 and RFVT3 by SLC52A3, respectively) that are responsible for the absorption of vitamin B2 into cells. RFVT2 is mainly present in the central nervous system, while RFVT 3 is found in high concentrations in epithelial cells of the small bowel. These mutations result in reduced riboflavin uptake and riboflavin transporter protein expression. Riboflavin is the precursor of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which act as electron acceptors and donors in numerous enzymatic reactions in different subcellular compartments (cytosol, peroxisomes, lysosomes, mitochondria). They are involved in the respiratory chain and in the metabolism of carbohydrates, proteins, and mitochondrial fatty acids. Early onset of weakness in the neck and upper limbs is a common finding in patients with mutations in SLC52A2, whereas in patients with SLC52A3 mutations the onset of weakness is typically more generalized. In addition, patients with SLC52A2 mutations often lack signs of upper motor neuron involvement in the lower limbs, a clinical feature commonly described in patients with SLC52A3 mutations (see also “Clinical aspects”).