Rolandic epilepsy (RE) is a common epileptic syndrome, which child neurologists often see. However, many problems concerning RE remains unsolved despite previous extensive studies. This paper discusses the current status of knowledge and our own observation especially on neurophysiological aspects of RE, such as the morphology of rolandic discharge (RD), effectiveness of clonazepam on RD, rhythmic slow activity, extreme somatosensory evoked potentials, and generator of RD. RD is characteristic of RE, and sometimes appearsto be enigmatic to child neurologists. RE is a representative epileptic syndrome in childhood, and should be investigated further to address its underlying mechanism.
The Nobel Prize was created in 1901, according to the will of Alfred Nobel who left tremendous estate by inventing of dynamite. In the fields of natural science, prizes are given to distinguished scientists in three categories, namely physics, chemistry, and physiology or medicine. During the past 100 years, the Nobel Prize have become undoubtedly the most prestigious international prize. Nobel laureates are always the most respected scientists in the world. There have been 478 recipients in the three categories, 177 of them belonging to physiology or medicine. In March 2002, an international forum commemorating the centennial of the Nobel Prize was held in Tokyo and Kyoto under the auspices of the Science Council of Japan, focusing upon creativity. Guest speakers including prize winners, officers of the Nobel Foundation, and members of the Nobel Committee participated actively. In particular, Japanese laureates, including Drs. Ezaki, Tonegawa, Shirakawa and Noyori met together at the Symposium, and discussed what is creativity and how it is nurtured? At about the same time the Centennial Exhibition of the Nobel Prize was held in the National Science Museum in Tokyo. From these two commemorative events, informative messages were extracted and given to young colleagues of the Japanese Society of Child Neurology.
Despite a wealth of recent information about the molecular basis of Duchenne muscular dystrophy (DMD), there is no effective treatment for this condition because the mechanism how dystrophin deficiency produces the muscle fiber degradation is unknown. Much effort has been made to develop a new treatment for DMD on clinical and molecular bases. This symposium consist of reports on recent advance of the gene, molecular and clinical therapies for DMD. It also discusses recent topics of therapeutic trial for glycogen storage diseases, featuring recombinant human acid alpha-glucosidase GAA enzyme therapy for fatal glycogen storage disease type II.
Duchenne muscular dystrophy (DMD) is an X-linked, lethal muscle disorder caused by mutations in the dystrophin gene. Although an adeno-associated virus (AAV) vector-mediated gene transfer provides an attractive approach to the treatment of DMD, limitation in insertion size up to 4.9 kb excludes incorporation of a full-length dystrophin cDNA (14 kb) into an AAV vector. We previously generated micro-dystrophin transgenic dystrophindeficient mdx mice. In 4.9 kb rod-truncated micro-dystrophin CS 1 transgenic mdx mice, dystrophic phenotypes were ameliorated almost completely (Biochem Biophys Res Common 2002; 293: 1265-72). We therefore constructed an AAV vector expressing micro-dystrophin CS 1 driven by a skeletal muscle-specific MCK promoter, as the expression of the LacZ gene driven by the MCK promoter is longer in an AAV vector than in the CMV promoter in the skeletal muscle (Gene Ther 2002; 9: 1576-88). We injected the AAV-MCK A CS1 intothe anterior tibial (TA) muscles of 5-week-old mdx mice, which exhibit active cycles of muscle degeneration/regeneration. At 8 weeks after the AAV vector injection, a large percentage of fibers were dystrophin-positive (10 to 50%). Even 24 weeks after injection, 15 to 75% of myofibers expressed micro-dystrophin. Dystrophin-positive fibers often had centrally located nuclei in the mice, however, the ratio was significantly reduced compared with that of dystrophin-negative fibers. We also measured tetanic force of AAV-MCK A CS1-treated and non-treated mdx TA to evaluate functional amelioration. Non-treated mdx TA muscles showed marked reduction of specific tetanic force, while AAV-injected muscles showed moderate improvement. In conclusion, our study demonstrated that introduction of A CS 1 micro-dystrophin with an AAV vector successfully protected mdx muscles from progressive dystrophic degeneration.
This article reviews the clinical application of gentamicin treatment for nonsense mutations. Since gentamicin is applied only for Duchenne muscular dystrophy caused by a nonsense mutation, genetic diagnosis of DMD is reviewed, Of the two reports describing gentamicin treatment of DMD, one concluded it to be effective, and the other to be ineffective.
As there is no cure in Duchenne muscular dystrophy (DMD), we must pay attention to the management of its cardiopulmonary complications. In 1984, DMD patients died at the mean age of 18.2 years in my hospital. From autopsy findings, the cause of death was respiratory failure in 75% of them, and left-sided heart failure 12.5%. First, we had to know the relationship between cardiac and respiratory systems. Based on the findings of right-sided heart catheterization, patients with respiratory failure were classified into Forrester's subset 1' normal left ventricular function. These results showed that these patients require treatment with a respirator, but not with digitalis and/or diuretics. Since 1984, we tried cuirass ventilation, which prolonged their lives by about 3 years. Since 1991, NIPPV was introduced in Japan, and prolonged their lives by about 5.5 years. Nowadays TIPPV with tracheostomy is not the first choice of treatment, but we do not hesitate to select this treatment any more. As for left-sided heart failure, brain natriuretic paptide (BNP) is now considered a useful parameter of left ventricular function. Japanese clinical researcher proposed treatment based on values of BNP in left-sided heart failure. In 1980s, the mean interval from the onset of heart failure to death was only 16 months. Recently we feel that better resultshave already been accomplished. In 2002 Kawai reported that average age at death in Japan was 26.8 years old. Moreefforts must be made until cure of this disease is found.
Muscle glycogen storage diseases (GSDs) are disorders of inborn error of metabolism, in which gene therapy restoring the deficient enzymes may ultimately cure the diseases. However, considering the pathophysiological basis of GSDs other treatments such as substrate supplementation, activation of the residual enzyme and enzyme replacement, are also important. Therapeutic trials in progress include the combined use of vitamin B6 and cornstarch for GSD type V, enzyme replacement therapy using rh-alpha-glucosidase for GSD type II, and ketogenic diet for GSD type IX.