Riboflavin transporter deficiency neuronopathy - SLC52A2 or SLC52A3 genes
Riboflavin transporter deficiency neuropathy is a process that affects neurons. Affected people often have sensorineural hearing loss and signs of damage to other auditory nerves. In addition to the nerves in the inner ear, this disease affects the nerves found in the brain stem, specifically in the pontobulbar region. Damage to these nerves causes pontobulbar palsy. Nerves in the pontobulbar region contribute to the control of various voluntary muscular activities, including breathing, speech, and movement of the limbs. As a consequence of pontobulbar palsy, affected individuals may manifest respiratory problems, difficulty speaking, as well as muscle weakness in the face, neck, shoulders, and extremities. Affected individuals may also have spasticity and exaggerated reflexes.
The age of onset of riboflavin transporter deficiency neuropathy can range from infancy to adulthood. When the disease manifests itself in childhood, the first symptoms often include breathing problems due to nerve damage, which can be potentially fatal. When the disease begins in children or young adults, sensorineural hearing loss usually occurs first, followed by signs of pontobulbar palsy. If left untreated, the signs and symptoms of riboflavin transporter deficiency neuropathy get worse over time. Severe respiratory problems and respiratory infections are the most common cause of death in people with this disease. Without treatment, affected children typically survive less than a year. However, people who develop the disease after 4 years of age usually survive for more than 10 years.
Riboflavin transporter deficiency neuropathy encompasses two entities that were previously considered distinct: Brown-Vialetto-Van Laere syndrome (BVVLS) and Fazio-Londe disease. Both entities have similar signs and symptoms, but Fazio-Londe disease does not include sensorineural hearing loss. Because these two diseases share a genetic cause and have overlapping characteristics, it has been proposed that they are forms of the same disease.
This process may be due to mutations in the SLC52A2 gene (solute carrier family 52 member 2), located on the long arm of chromosome 8 (8q24.3) or in the SLC52A3 gene (solute carrier family 52 member 3), located in the short arm of chromosome 20 (20p13). These genes encode riboflavin transporters 2 (RFVT2) and 3 (RFVT3), respectively. Both proteins carry riboflavin (also called vitamin B2) across the cell membrane. The RFVT3 protein is found in especially high concentrations in cells of the small intestine and is important for the absorption of riboflavin during digestion so that the vitamin can be metabolized in the body. The RFVT2 protein is found in cells of the brain and spinal cord and is important to ensure that these tissues have enough riboflavin for proper function. In the cells of the body, riboflavin is the main component of flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) molecules. FAD and FMN are involved in many different chemical reactions and are necessary for a variety of cellular processes. An important function of these molecules is in the production of cellular energy. FAD and FMN are also involved in the breakdown of carbohydrates, fats, and proteins.
At least 11 mutations in the SLC52A2 gene and more than 24 mutations in the SLC52A3 gene have been described in people with riboflavin transporter deficiency neuropathy. Mutations in the SLC52A2 or SLC52A3 gene inhibit protein synthesis or result in an abnormal riboflavin transporter protein with impaired ability to transport riboflavin. Consequently, there is a decrease in the amount of riboflavin available in the body. It is not clear how these changes lead to the disease´s characteristic nerve problems.
Riboflavin transporter deficiency neuropathy generally follows an autosomal recessive pattern of inheritance, meaning that both copies of the gene in every cell must have the mutations for the alteration to be expressed. The parents of an individual with an autosomal recessive disease have one copy of the mutated gene, but they usually do not show signs and symptoms of the disease.
Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with Riboflavin transporter deficiency neuronopathy, by means of the complete PCR amplification of the exons of the SLC52A2 and/or SLC52A3 genes, respectively, and their subsequent sequencing.
Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).