**Meet the editor**

Kenji Ikehara is a professor and director in Nara Study Center of the Open University of Japan. He is also a fellow of International Institute for Advanced Studies (IIAS) of Japan and an Emeritus Professor of Nara Women's University. He graduated from Department of Industrial Chemistry, Faculty of Engineering, Kyoto University in 1968 and received his B. Eng (1968), and

successively M. Eng. (1970) and D. Eng. (1976) degrees from Kyoto University. He engaged in studies on Sporulation Initiation of Bacillus subtilis and on the origins and evolutional processes of microbial genes, the genetic code, and proteins during around 30 years in Nara Women's University. Consequently, he has proposed GC-NSF(a) hypothesis on the origin of Genes, GNC-SNS hypothesis on the genetic code, protein 0th-order structure hypothesis on proteins and [GADV]-protein world hypothesis on the origin of life.

Contents

**Preface IX** 

Kenji Ikehara

**Part 1 Background of Genetic Disorder 1** 

Chapter 2 **Inbreeding and Genetic Disorder 21** 

Kannan Thirumulu Ponnuraj

**Multifactorial Diseases 81** 

Chapter 7 **Genomic Study in** β**-Thalassemia 149** 

Paulino Goméz-Puertas and Juan Pié

Chapter 8 **HMG–CoA Lyase Deficiency 169** 

Chapter 6 **Thalassemia Syndrome 101**  Tangvarasittichai Surapon

**Part 2 Unifactorial or Unigenetic Disorder 99** 

Chapter 1 **Origin of the Genetic Code and Genetic Disorder 3** 

Gonzalo Alvarez, Celsa Quinteiro and Francisco C. Ceballos

Chapter 3 **Cytogenetic Techniques in Diagnosing Genetic Disorders 45** 

Chapter 4 **Functional Interpretation of Omics Data by Profiling Genes and Diseases Using MeSH–Controlled Vocabulary 65**  Takeru Nakazato, Hidemasa Bono and Toshihisa Takagi

Chapter 5 **Targeted Metabolomics for Clinical Biomarker Discovery in** 

Saovaros Svasti, Orapan Sripichai, Manit Nuinoon, Pranee Winichagoon and Suthat Fucharoen

Beatriz Puisac, María Arnedo, Mª Concepción Gil-Rodríguez, Esperanza Teresa, Angeles Pié, Gloria Bueno, Feliciano J. Ramos,

Ulrika Lundin, Robert Modre-Osprian and Klaus M. Weinberger

## Contents

#### **Preface XIII**

	- **Part 2 Unifactorial or Unigenetic Disorder 99**

X Contents


Contents VII

Chapter 20 **Prader–Willi Syndrome, from Molecular Testing and Clinical** 

Chapter 21 **Turner Syndrome and Sex Chromosomal Mosaicism 431** Eduardo Pásaro Méndez and Rosa Mª Fernández García

Chapter 22 **Microstomia: A Rare but Serious Oral Manifestation of** 

**Study to Diagnostic Protocols 409** 

Maria Puiu and Natalia Cucu

**Inherited Disorders 449**

Aydin Gulses

Chapter 10 **Alström Syndrome 205**  Cristina Maria Mihai, Jan D. Marshall and Ramona Mihaela Stoicescu

	- **Part 3 Multifactorial or Polygenic Disorder 319**

Chapter 20 **Prader–Willi Syndrome, from Molecular Testing and Clinical Study to Diagnostic Protocols 409**  Maria Puiu and Natalia Cucu

VI Contents

Chapter 9 **Mitochondrial HMG–CoA Synthase Deficiency 189** María Arnedo, Mónica Ramos, Beatriz Puisac, Mª Concepción Gil-Rodríguez, Esperanza Teresa, Ángeles Pié, Gloria Bueno, Feliciano J. Ramos,

Paulino Gómez-Puertas and Juan Pié

Cristina Maria Mihai, Jan D. Marshall and Ramona Mihaela Stoicescu

**A Pulmonary Genetic Disorder 227** Michael Sjoding and D. Kyle Hogarth

Jonay Poveda Nuñez, Alberto Ortiz,

Chapter 14 **Fabry Cardiomyopathy: A Global View 277** 

Daniela Quaglino, Federica Boraldi, Giulia Annovi and Ivonne Ronchetti

**Part 3 Multifactorial or Polygenic Disorder 319**

Manuel J. Santos and Alfonso González

**Later After Treatment 333**

Chapter 18 **Genetic Basis of Inherited Bone Marrow Failure Syndromes 357** 

Chapter 15 **The Multifaceted Complexity of Genetic Diseases:** 

Yoshinari Uehara, Bo Zhang and Keijiro Saku

Chapter 13 **Fabry Disease: A Metabolic Proteinuric Nephropathy 255** 

Ana Belen Sanz and Maria Dolores Sanchez Niño

Rocio Toro Cebada, Alipio Magnas and Jose Luis Zamorano

**A Lesson from Pseudoxanthoma Elasticum 289**

**Genetic Disorders Reveal the Mechanisms 321**

Chapter 17 **Repair of Impaired Host Peroxisomal Properties Cropped Up Due to Visceral Leishmaniasis May Lead to Overcome Peroxisome Related Genetic Disorder Which May Develop** 

Chapter 19 **Bernard Soulier Syndrome: A Genetic Bleeding Disorder 393**  Basma Hadjkacem, Jalel Gargouri and Ali Gargouri

Salil C. Datta, Shreedhara Gupta and Bikramjit Raychaudhury

Chapter 10 **Alström Syndrome 205**

Chapter 12 **Tangier Disease 239**

Chapter 16 **Peroxisomal Biogenesis:** 

Yigal Dror

Chapter 11 **Alpha One Antitrypsin Deficiency:** 


Preface

were saved.

years old, respectively.

All life on the Earth, including the human race, originated from one common ancestor (comonote) which appeared on the primitive earth about 3.8~4.0 billion years ago after chemical evolutions from simple inorganic to complex organic compounds. The first life successively evolved from simple to complex organisms, such as prokaryotes, mono-cellular eukaryotes, multi-cellular micro-organisms, plants, animals and human beings. Human beings appeared on this planet between 25 and 7 million years ago and have suffered from many kinds of disease for a long time, many of which might lead to death, such as lethal viruses like smallpox and influenza and infectious bacteria like as cholera and tuberculosis. However, human beings have acquired intelligence so as to understand scientifically many concerns in various kinds of fields, including the medical sciences. Thus, human beings actually acquired the knowledge of viruses and micro-organisms to fight against diseases. Many people have seriously hoped to live as long as possible and even to get eternal life with the acquisition of intelligence. It is well-known in Asian countries that Shi Huángdì (BC259-BC210), who was an emperor

in ancient China, tried to get eternal life and took various kinds of chemicals.

Human beings were protected from infection by viruses - such as the smallpox virus by the intravenous injection of vaccines into their bodies. Owing to the medical technology of vaccines - which were first discovered by Jenner in 1796 - many lives

Furthermore, penicillin - one of the antibiotics - was first discovered by Fleming in 1881. Subsequently, many kinds of antibiotics - such as streptomycin and kanamycin were discovered. Consequently, many people were also released from diseases caused by infectious bacteria and many lives were saved, since many patients were even

In these ways, the development of medical technologies and medicines has protected human beings from many kinds of diseases caused by the infection of viruses and bacteria, resulting in extending the life span of human beings. Currently, many Japanese people can live until between 90 and 100 years old. For example, the average life spans of females and males living in Japan had reached 86.4 and 79.6 years old by 2009, respectively, while the comparative figures in 1950 were about only 62 and 58

cured of infectious diseases which lead to death through taking the antibiotics.

## Preface

All life on the Earth, including the human race, originated from one common ancestor (comonote) which appeared on the primitive earth about 3.8~4.0 billion years ago after chemical evolutions from simple inorganic to complex organic compounds. The first life successively evolved from simple to complex organisms, such as prokaryotes, mono-cellular eukaryotes, multi-cellular micro-organisms, plants, animals and human beings. Human beings appeared on this planet between 25 and 7 million years ago and have suffered from many kinds of disease for a long time, many of which might lead to death, such as lethal viruses like smallpox and influenza and infectious bacteria like as cholera and tuberculosis. However, human beings have acquired intelligence so as to understand scientifically many concerns in various kinds of fields, including the medical sciences. Thus, human beings actually acquired the knowledge of viruses and micro-organisms to fight against diseases. Many people have seriously hoped to live as long as possible and even to get eternal life with the acquisition of intelligence. It is well-known in Asian countries that Shi Huángdì (BC259-BC210), who was an emperor in ancient China, tried to get eternal life and took various kinds of chemicals.

Human beings were protected from infection by viruses - such as the smallpox virus by the intravenous injection of vaccines into their bodies. Owing to the medical technology of vaccines - which were first discovered by Jenner in 1796 - many lives were saved.

Furthermore, penicillin - one of the antibiotics - was first discovered by Fleming in 1881. Subsequently, many kinds of antibiotics - such as streptomycin and kanamycin were discovered. Consequently, many people were also released from diseases caused by infectious bacteria and many lives were saved, since many patients were even cured of infectious diseases which lead to death through taking the antibiotics.

In these ways, the development of medical technologies and medicines has protected human beings from many kinds of diseases caused by the infection of viruses and bacteria, resulting in extending the life span of human beings. Currently, many Japanese people can live until between 90 and 100 years old. For example, the average life spans of females and males living in Japan had reached 86.4 and 79.6 years old by 2009, respectively, while the comparative figures in 1950 were about only 62 and 58 years old, respectively.

#### X Preface

It is reported that the highest cause of Japanese deaths is malignant tumour or cancer. Cancers induced by genetic defects leading to deviation from the normal control of cell division can be regarded as a kind of genetic disorder. The genetic defects may occur in all organs, such as the kidney, the spleen, the stomach, the lung and the intestine etc. In addition, it is quite difficult to cure these cancers by the usual treatments such as administration of medicines (except for removal of malignant tumours by surgical operations) because at the present time it is impossible to site-specifically replace the substituted bases to the original/normal bases. This is the reason why cancers are at the top of the Japanese death causes although human beings are released from many kinds of infectious diseases.

Preface XI

**Kenji Ikehara**

Japan

The Open University of Japan, Nara Study Centre, International Institute for Advanced Studies of Japan

must recognise themselves as being a carrier of a genetic disorder as well as their impending death. However, I believe that it is important for the patient to know whether he or she is a carrier or non-carrier of even a genetic disorder resulting in death in the future, because the patient can do their best against the disease during their remaining life based on the state of knowledge regarding the genetic disorder.

Certainly, it is quite difficult or almost impossible to cure a genetic disorder fundamentally at the present time. However, our knowledge of genetic functions has rapidly accumulated since the double-stranded structure of DNA was discovered by Watson and Crick in 1956. Therefore, nowadays it is possible to understand the reasons why genetic disorders are caused. It is probable that the knowledge of genetic disorders described in this book will lead to the discovery of an epoch of new medical treatment and relieve human beings from the genetic disorders of the future, because human beings had overcome many difficulties already (such as infectious diseases through the discovery of new medical treatment using vaccines for protection against infection form viruses and of special medicines known as antibiotics for curing diseases caused by the infection of micro-organisms). As such, I have a presentiment that a new age is now dawning with respect to the overcoming of genetic disorders. The dawn may set in suddenly upon a big discovery for a new medical treatment which will be achieved by one genius in the future - because such kinds of big discoveries have always been carried out suddenly by geniuses, such as Jenner and Fleming. I hope that the descriptions in this book will contribute to such a discovery,

of a new medical treatment for genetic disorders.

Many genetic disorders are caused by base substitutions on double-stranded DNA, as with cancers. Although the mutated bases must be replaced with the original/normal bases in order to completely cure the disorders, it is quite difficult to achieve this purpose at the present time, again, as with the case of cancers as described above. Thus, genetic disorders remain diseases which are difficult to cure. In addition, mutations causing genetic disorders may occur in any cells carrying genetic elements or DNA and at anytime. Therefore, the organisms living on earth have been exposed to danger-generating base substitutions without exception, and genetic disorders may be induced in any organs because human beings are multi-cellular organisms.

There are two big problems with genetic disorders. One is that it is quite difficult to cure them, as described above. However, in addition to the knowledge about such mechanisms as DNA replication, transcription and the translation of genetic information, human beings have rapidly accumulated knowledge about the base substitutions or mutations occurring on chromosomal DNA which cause various genetic diseases, ever since Watson and Crick discovered the double-stranded structure of DNA in 1956. This knowledge is always significant because it may helpful in devising another medical treatment to cure genetic disorders. Surely, there exist several examples that the knowledge retrieved symptoms or succeeded even to save of patients suffered by genetic disorders. For example, many of the genetic disorders caused by abnormalities of metabolic enzymes could be relieved by going on a diet, which restricts the excess accumulation of the metabolite as a substrate of the enzyme and/or supplies a decreased metabolite as a product of the enzyme. In the case of a genetic disorder causing an excess accumulation of metabolites, it may be also useful to employ the intravenous administration of medicine, which can reduce the formation of toxic metabolites.

 Another one is a problem accompanied by the recent development of genetic analysis for the diagnosis of genetic disorders, because it has made it possible to judge whether a patient is a carrier or non-carrier of an incurable genetic disease, which may lead to death after several years. A patient who has been able to confirm by their diagnosis as a non-carrier of a genetic disorder can live in peace. However, a patient, who has been proven to be a carrier of a genetic disorder must live with continual uneasiness with regard to confronting their coming death during their remaining life, since the patient must recognise themselves as being a carrier of a genetic disorder as well as their impending death. However, I believe that it is important for the patient to know whether he or she is a carrier or non-carrier of even a genetic disorder resulting in death in the future, because the patient can do their best against the disease during their remaining life based on the state of knowledge regarding the genetic disorder.

X Preface

kinds of infectious diseases.

formation of toxic metabolites.

It is reported that the highest cause of Japanese deaths is malignant tumour or cancer. Cancers induced by genetic defects leading to deviation from the normal control of cell division can be regarded as a kind of genetic disorder. The genetic defects may occur in all organs, such as the kidney, the spleen, the stomach, the lung and the intestine etc. In addition, it is quite difficult to cure these cancers by the usual treatments such as administration of medicines (except for removal of malignant tumours by surgical operations) because at the present time it is impossible to site-specifically replace the substituted bases to the original/normal bases. This is the reason why cancers are at the top of the Japanese death causes although human beings are released from many

Many genetic disorders are caused by base substitutions on double-stranded DNA, as with cancers. Although the mutated bases must be replaced with the original/normal bases in order to completely cure the disorders, it is quite difficult to achieve this purpose at the present time, again, as with the case of cancers as described above. Thus, genetic disorders remain diseases which are difficult to cure. In addition, mutations causing genetic disorders may occur in any cells carrying genetic elements or DNA and at anytime. Therefore, the organisms living on earth have been exposed to danger-generating base substitutions without exception, and genetic disorders may

be induced in any organs because human beings are multi-cellular organisms.

There are two big problems with genetic disorders. One is that it is quite difficult to cure them, as described above. However, in addition to the knowledge about such mechanisms as DNA replication, transcription and the translation of genetic information, human beings have rapidly accumulated knowledge about the base substitutions or mutations occurring on chromosomal DNA which cause various genetic diseases, ever since Watson and Crick discovered the double-stranded structure of DNA in 1956. This knowledge is always significant because it may helpful in devising another medical treatment to cure genetic disorders. Surely, there exist several examples that the knowledge retrieved symptoms or succeeded even to save of patients suffered by genetic disorders. For example, many of the genetic disorders caused by abnormalities of metabolic enzymes could be relieved by going on a diet, which restricts the excess accumulation of the metabolite as a substrate of the enzyme and/or supplies a decreased metabolite as a product of the enzyme. In the case of a genetic disorder causing an excess accumulation of metabolites, it may be also useful to employ the intravenous administration of medicine, which can reduce the

 Another one is a problem accompanied by the recent development of genetic analysis for the diagnosis of genetic disorders, because it has made it possible to judge whether a patient is a carrier or non-carrier of an incurable genetic disease, which may lead to death after several years. A patient who has been able to confirm by their diagnosis as a non-carrier of a genetic disorder can live in peace. However, a patient, who has been proven to be a carrier of a genetic disorder must live with continual uneasiness with regard to confronting their coming death during their remaining life, since the patient Certainly, it is quite difficult or almost impossible to cure a genetic disorder fundamentally at the present time. However, our knowledge of genetic functions has rapidly accumulated since the double-stranded structure of DNA was discovered by Watson and Crick in 1956. Therefore, nowadays it is possible to understand the reasons why genetic disorders are caused. It is probable that the knowledge of genetic disorders described in this book will lead to the discovery of an epoch of new medical treatment and relieve human beings from the genetic disorders of the future, because human beings had overcome many difficulties already (such as infectious diseases through the discovery of new medical treatment using vaccines for protection against infection form viruses and of special medicines known as antibiotics for curing diseases caused by the infection of micro-organisms). As such, I have a presentiment that a new age is now dawning with respect to the overcoming of genetic disorders. The dawn may set in suddenly upon a big discovery for a new medical treatment which will be achieved by one genius in the future - because such kinds of big discoveries have always been carried out suddenly by geniuses, such as Jenner and Fleming. I hope that the descriptions in this book will contribute to such a discovery, of a new medical treatment for genetic disorders.

**Kenji Ikehara** The Open University of Japan, Nara Study Centre, International Institute for Advanced Studies of Japan Japan

**Part 1** 

**Background of Genetic Disorder** 
