Preface

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is an autosomal dominant disorder affecting 1 in about 3,000 people. NF1 is defined as a major monogenic neurocutaneous disorder. The NF1 gene was identified and reported in 1990. Since then, genetic analysis and cellular and molecular biological studies on the pathogenesis and pathophysiology of NF1 have rapidly progressed. The NF1 gene encodes a Ras GTPase-activating protein (Ras-GAP) named neurofibromin. Neurofibromin is a large protein that includes up to 2,818 amino acids and 57 exons. Dysfunction of this gene by germline mutations causes constitutive activation of Ras-mitogen activated protein kinase (MAPK) signaling, which promotes tumorigenesis in central and peripheral neuronal tissues. The classical cutaneous lesions of NF1 include pigmented café-au-lait macules and small axillar or inguinal freckles, and dermal, subcutaneous, and plexiform nodular and diffuse types of neurofibromas.

Germline mutations of the NF1 gene are completely penetrated. Therefore, NF1 gene mutation occurs in a wide variety of cells and tissues. Consequently, in addition to the classical cutaneous lesions described above, NF1 affects multiple organ systems exhibiting neurological and psychiatric disorders, abnormal orthopedic manifestations, and impaired endocrine functions. However, the appearance of organ-specific lesions varies in patients with NF1. The quality of life in patients with NF1 is severely affected by this wide range of symptoms.

This book is organized into three sections covering the fundamental, clinical, and basic aspects of NF1. An introductory chapter in the first section supplements and introduces the text, indicating the point of view to be adopted by the reader.

The second section includes four chapters. The first chapter discusses bone lesions in children with NF1, with a focus on dysplastic patterns of scoliosis in the spinal lesions. The second chapter presents a retrospective and descriptive study on a novel radiological entity in NF1-diffuse neurofibromatous tissue called DNFT, which is distinct from commonly reported neurofibromas. This is the first reported descriptive study of DNFT in NF1. The third chapter reports on the prevalence, association with brain tumors or cortical malformations, types, and management of seizures in adults with NF1. It also discusses a possible association with the defective neurofibromin function on the mechanism of epilepsy. The final chapter in this section describes several endocrine disorders that are characteristic in children or adolescents with NF1. Mechanisms for the greater incidence of short stature in patients with NF1 are discussed, focusing on the dysregulation of intracellular cAMP in the brain due to neurofibromin dysfunction.

The third section includes four chapters. The first chapter in this section describes NF1-induced neuronal (NF1-iN) cells from cultured fibroblasts of patients with NF1 by direct conversion technologies. This technology enables the investigation of NF1 neuronal cells directly instead of using a mouse system. NF1-iN-cells show significantly different aberrant gene expression and quite different morphology from that of human control iN-cells. The chapter authors present their important

findings on rescuing the aberrant gene expression of NF1-iN cells, which could lead to the development of novel therapeutic drugs for neuronal disorders in NF1. The second chapter discusses how the Ras-GAP function of neurofibromin is precisely controlled by an alternative splicing event that occurs in NF1 exon 23a (currently called exon 31 in the NF1 nomenclature), which locates in the GAPrelated domain (GRD) of the NF1 gene. The authors present their investigation on the complex molecular mechanisms of developmental stage-specific and tissue- or organ-specific expression of mouse Nf1 exon 23a. Investigation of the role of the expression of exon23a expression on the learning and memory behaviors using a mutant mouse system is examined. The third chapter discusses the regulation of another splicing event of the NF1 gene, which occurs in exon 51 (former exon 43. Exon 51 is alternatively transcribed to produce either a nuclear localization sequence (NLS) or ΔNLS neurofibromin isoforms. The authors emphasize that neurofibromin accumulates in the nucleus and resides on the spindle throughout cellular mitosis. Therefore, the loss of NLS neurofibromins (ΔNLS) causes defective chromosomal positioning and cell ploidy leading to tumorigenesis. The final chapter in this section reviews a recent understanding of the altered metabolic features of the tumors related to NF1 and their potential implications for the development of novel therapeutic perspectives, especially targeting malignant peripheral nerve sheath tumors (MPNSTs). The authors suggest several potential important molecules for inhibiting the proliferation of malignant NF1 tumors, which could also lead to the development of novel therapeutic drugs.

All chapters in the book include original research performed by the authors. The clinical and basic scientific data presented in the book should contribute to a more accurate diagnosis of NF1 and to the development of novel therapeutic agents for the disease.

I appreciate all the authors who submitted their original investigative works for inclusion in this book. The associate academic editor of the book, Dr. Yuichi Yoshida, provided excellent and meaningful comments when reviewing the submitted chapters. Additionally, Ms. Tomoko Tsujita, my former secretary while I was working at Fukuoka University School of Medicine, greatly assisted me in editing this work. Finally, I am extremely grateful to Author Service Manager Mr. Josip Knapić at IntechOpen for his kind assistance.

> **Dr. Juichiro Nakayama** Emeritus Professor, Fukuoka University, Fukuoka, Japan

> > **Dr. Yuichi Yoshida** Faculty of Medicine, Tottori University, Japan

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