Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2.

Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood. We recently reported the identification of SLC52A2, encoding riboflavin transporter RFVT2, as a new causative gene for Brown-Vialetto-Van Laere syndrome. We used both exome and Sanger sequencing to identify SLC52A2 mutations in patients presenting with cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency. We undertook clinical, neurophysiological and biochemical characterization of patients with mutations in SLC52A2, functionally analysed the most prevalent mutations and initiated a regimen of high-dose oral riboflavin. We identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy (manifesting with sensory ataxia, severe weakness of the upper limbs and axial muscles with distinctly preserved strength of the lower limbs), hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression, and we report the response to high-dose oral riboflavin therapy in patients with SLC52A2 mutations, including significant and sustained clinical and biochemical improvements in two patients and preliminary clinical response data in 13 patients with associated biochemical improvements in 10 patients. The clinical and biochemical responses of this SLC52A2-specific cohort suggest that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated soon after the onset of symptoms

Disruption of Slc52a3 gene causes neonatal lethality with riboflavin deficiency in mice.

Homeostasis of riboflavin should be maintained by transporters. Previous in vitro studies have elucidated basic information about riboflavin transporter RFVT3 encoded by SLC52A3 gene. However, the contribution of RFVT3 to the maintenance of riboflavin homeostasis and the significance in vivo remain unclear. Here, we investigated the physiological role of RFVT3 using Slc52a3 knockout (Slc52a3−/−) mice. Most Slc52a3−/− mice died with hyperlipidemia and hypoglycemia within 48 hr after birth. The plasma and tissue riboflavin concentrations in Slc52a3−/− mice at postnatal day 0 were dramatically lower than those in wild-type (WT) littermates. Slc52a3−/− fetuses showed a lower capacity of placental riboflavin transport compared with WT fetuses. Riboflavin supplement during pregnancy and after birth reduced neonatal death and metabolic disorders. To our knowledge, this is the first report to indicate that Rfvt3 contributes to placental riboflavin transport, and that disruption of Slc52a3 gene caused neonatal mortality with hyperlipidemia and hypoglycemia owing to riboflavin deficiency

Skin Temperature Changes of Receivers Laogong on the Left Hand in Remote Action Experiment(II)

Two persons who have a 40-year history as a pair practicing a martial art which front-detects a partner\u27s attack sign performed remote action experiment a total of 4 times over 2 years. In all runs, the two subjects were in two different rooms, and the sender emitted a qi of attack only once during an 80-second trial under double blinded and randomized conditions. In this report, the temperature data of the second experimental series were analyzed and tested. The difference between the average temperature changes during a period of 2 seconds before the 1 second of sending was statistically significant at 5% or less. The time of change was the same as in part I which analyzed the first experimental series. Then, the differences between three large peaks which occurred around -41 (p=3.7%) sec (peak I), 0 sec (13.4) (peak II), +36 sec (1.3) (peak III) in the frequency histogram which Yamamoto 8) reported were also analyzed and tested. PeakII showed a statistically significant value of 1% or less between the difference of the average temperature change near the sending time, however there was no significance near peaks I and III

Skin Temperature Changes of Receivers Laogong on the Left Hand in Remote Action Experiment(II)

ECG analysis was done for a qi-receiver during Toh-ate (remote action; an ancient Japanese martial art) with double blind. Two practitioners were isolated in two rooms under the condition of cutting normal information transfer. One practitioner (sender) sent qi randomly once par trial of 80 seconds and the other (receiver) tried to perceive the qi; at the time he perceived it, he pushed a switch. Their sending times, receiving times and physiological data were recorded during the experiments. The receiver\u27s ECG R-R intervals were measured, and their fluctuations before and after the sending times were analyzed. As a result, in a group of trials without the receiver\u27s switch signals, the coefficient of variation of R-R intervals for 10 seconds after the sending times was larger by a statistically significant amount (1%) than before them.第１３回生命情報科学シンポジウ