Pediatric Genetics and Endocrinology

Dau-Ming Niu

Chia-Feng Yang

Yehn-Jang Chen

Team Achievements

1. The treatment and research of Fabry disease are unparalleled globally, receiving the Gold Award for National Biotechnology and Medical Quality from the Ministry of Science and Technology, certifying it as the world's leading treatment.
2. The treatment efficacy for drug-type phenylketonuria is ranked first in the world.
3. Established the world's most efficient Pompe disease diagnosis and treatment system, with the world's best treatment results.
4. Established the leading Asia-Pacific newborn screening diagnosis and treatment center, responsible for two-thirds of abnormal screening referrals in the country.
5. First to discover that the incidence of homocystinuria and pigmentary retinopathy in a certain indigenous area is the highest in the world.
6. First to discover that the incidence of Fabry disease in Taiwan is the highest in the world, with the world's largest sample bank of Fabry disease. The treatment and research achievements of Fabry disease have been recognized by domestic and foreign experts and scholars.
7. Established the first rare disease patient association in Taiwan, "Society of Care and Friendship for Congenital and Metabolic Diseases," actively tracking and caring for rare disease patients, and advocating for the rights of rare disease patients.

Establishment of the leading newborn screening, diagnosis, and treatment center in the Asia-Pacific region.

Our center is the largest abnormal referral center for newborn screening in Taiwan, responsible for the diagnosis of two-thirds of abnormal cases detected by newborn screening nationwide. We have a "Genetic Counseling Center Laboratory," which is a gene testing laboratory certified by the Department of Health, responsible for genetic testing for referral and external examination. Currently, we can perform genetic testing for 48 inherited diseases. Our center is also continuously developing testing and treatment methods for other newborn screening items, establishing the leading newborn screening diagnosis and treatment center in the Asia-Pacific region.

 

Our center has been devoted to the diagnosis, testing, and research of rare diseases for many years, and our past efforts have yielded fruitful results:

(1) The treatment efficacy for phenylketonuria (PKU) is world-leading.

The treatment team at Taipei Veterans General Hospital pioneered the use of monitoring prolactin levels in the blood, instead of the nerve conduction substance monitoring method used by other medical centers, which requires regular lumbar puncture. In addition, higher doses of nerve conduction drugs were administered to the affected children in the neonatal period, resulting in better clinical outcomes. Currently, the average IQ of PKU patients treated at Taipei Veterans General Hospital is 97, which is world-leading and significantly higher than the average IQ of PKU patients treated by other medical teams (70+ at the time for both domestic and foreign well-known medical centers). This research result has been published in the top-tier neurology journal Archives of Neurology and has received recognition from international experts and scholars. Professor Hoffmann, the world's leading expert on PKU nerve conduction from Heidelberg University Children's Hospital in Germany, even came to Taiwan specifically to observe the research results and praised the efforts. Dr. Niu was also invited by Professor Fukuyama, the chief editor of the renowned international journal Brain & Development, to write a related review article.

expert comment:

(2) The world's most efficient diagnostic and treatment system for Pompe disease, with the best treatment outcomes in the world

Our team has developed a highly efficient diagnostic method for newborn-onset Pompe disease that meets four rapid diagnostic criteria for infantile Pompe disease, enabling patients to receive treatment: 1. GAA enzyme activity in newborn screening blood spots is less than <0.50 umol/L/hr; 2. Hypotonia; 3. Serum creatine kinase (CK) levels are greater than 250 U/L; and 4. Left ventricular mass index (LVMI) is greater than 80 g/m2.7.

Newborns with positive screening for Pompe disease who are transferred to our hospital can receive accurate diagnosis and treatment within 6 hours. Therefore, the average time from birth to treatment for patients identified through our screening system can be shortened to within 10 days, which is the fastest in the world. In comparison, the average time to start treatment at the second-fastest center in the world is 22 days. Although the difference is only 10 days, there is a significant impact on the prognosis of patients.

Comparing the prognosis of Pompe disease treatment among different countries, our team has achieved the world's best treatment outcomes for Pompe disease patients. This achievement has been published in the prestigious pediatric journal, the Journal of Pediatrics.

Very Early ERT Linked With Better Outcomes in Infantile-Onset Pompe Disease

Very early enzyme replacement therapy (ERT) is associated with better outcomes in patients with Infantile-onset Pompe disease (PD), according to a new study.

This finding was based on a rapid diagnostic and treatment strategy adopted at Taipei Veterans General Hospital in Taiwan. The study results were published in the Journal of Medical Genetics.

The researchers conducted a long-term follow-up study in which they analyzed the outcomes of very early ERT in patients with Infantile-onset PD.

Read more about the diagnosis of Pompe disease

Between January 1, 2010, and February 28, 2021, the researchers screened a total of 1,228,539 infants. Of these, 33 were confirmed to have Infantile-onset PD, and 26 were regularly treated and monitored at the same hospital. The average age of the patients when they started ERT was 9.75 days.

The patients were followed up for an average of 6.18 years. The researchers found that all patients had normal heart sizes, motor milestones, and cognitive function. Their lung function was near normal or normal. 

“Compared with patients in other studies, our patients had better outcomes in all aspects,” the researchers wrote. They also concluded that starting ERT before irreversible muscle damage has occurred is very important, underscoring the meaningfulness of newborn screening for PD.

PD is a rare genetic disease characterized by a deficiency or absence of the lysosomal acid alpha-glucosidase enzyme, whose role is to cleave glycogen to form glucose. There are 2 types of PD based on the age of onset and the presence of cardiomyopathy. Infantile-onset PD is the most severe form affecting babies, ages 0 to 12 months, while Late-onset PD is usually less severe with symptoms appearing after age 1. There is usually no cardiac involvement in Late-onset PD.

Reference
Yang C, Liao TE, Chu Y, et al. Long-term outcomes of very early treated infantile onset Pompe disease with short-term steroid premedication: experiences from a nationwide newborn screening programme. J Med Genet. Published online September 22, 2022. doi:10.1136/jmg-2022-108675

(3) First discovery of the highest incidence of hyperhomocysteinemia and retinitis pigmentosa in a certain indigenous tribe in the world

Our team was the first to discover that the incidence of hyperhomocysteinemia in a certain indigenous tribe is about 1/200, which is the highest in the world compared to other ethnic groups with an incidence of 1/200,000. The carrier rate in this tribe is about 1/7.8. Our further research found that the residents of this tribe generally lack folic acid. Under this condition, carriers will have a much higher concentration of homocysteine in their bodies than normal people, which can increase the incidence of cardiovascular diseases such as heart disease, atherosclerosis, and stroke. Supplementing with folic acid can effectively reduce the concentration of homocysteine in carriers' bodies to reduce the risk of cardiovascular diseases. Due to the lack of local medical resources and the high carrier and incidence rates of rare diseases, we also regularly go to the area to conduct health education activities to improve the local residents' understanding of rare diseases and promote correct medical treatment, care, and eugenics concepts. Our team also first discovered that the incidence of retinitis pigmentosa (RP) in this tribe is the highest in the world (1/100). Through our cooperation with Academia Sinica, we found that this retinitis pigmentosa is caused by a gene mutation related to glycosylation, which is a completely unpublished gene related to retinitis pigmentosa. This discovery leads the pathogenesis of retinitis pigmentosa to a new field and provides new research and treatment directions for such patients.

(4) First to discover that Taiwan has the highest incidence rate of Fabry disease in the world, and owns the largest Fabry disease sample repository in the world

In 2009, our center was the first to discover that the incidence rate of cardiac Fabry disease (IVS4+919G>A mutation) in Taiwanese males was as high as 1/1600, and in females as high as 1/800. This was published in Circulation: Cardiovascular Genetics. We also further confirmed that Taiwanese individuals carrying this gene mutation, after the age of 40, had a 67% incidence rate of hypertrophic cardiomyopathy in males and 35% in females. This study demonstrates that Fabry disease is a very important health issue for Taiwanese people. Therefore, our center has collaborated with multiple hospitals in Taiwan to establish a nationwide Fabry disease referral and consultation system to assist with the diagnosis of Fabry disease throughout the country. We have currently identified over 2200 cases of individuals with Fabry disease gene mutations, making it the largest sample repository in the world.

(5) Research findings published in the top-ranking cardiology journal, the Journal of the American College of Cardiology (JACC).

Our research team has discovered that patients with cardiac Fabry disease may have severe and irreversible heart damage even in the absence of obvious heart symptoms. Using advanced cardiac magnetic resonance imaging techniques, we found that a significant proportion of patients with cardiac Fabry disease had developed significant cardiac fibrosis without cardiac enlargement or any obvious clinical symptoms. This continuous silent deterioration is similar to the common B-type hepatitis in Taiwan, where most patients have no obvious symptoms before developing cirrhosis, leading to irreversible damage if the optimal treatment opportunity is missed.

Currently, early detection of cardiac Fabry disease in newborns and their families can be achieved through newborn screening. Through comprehensive monitoring by medical teams, early treatment strategies and medication timing can be formulated to prevent irreversible heart damage.

This research was published in 2016 in the top-ranking cardiology journal, the Journal of the American College of Cardiology (JACC), and also won first place in the 106th Taipei Veterans General Hospital Physician Academic Paper Award.

Dr. Niu Dau-ming's research and treatment of Fabry disease are leading the world, attracting the attention of scholars worldwide. Dr. Niu is often invited to share his treatment experience and present the latest research findings at conferences on Fabry disease or lysosomal-related diseases in various countries.

(6) Revolutionary research results of our center in Fabry disease research

Our team conducted immunostaining studies on myocardial slices of Fabry disease patients and found that despite not seeing any obvious pathology through tissue staining and electron microscopy, there was a significant accumulation of GB3 within lysosomes in cardiac cells. In early stages, GB3 accumulation was limited to lysosomes, but as the disease progressed, it spread beyond lysosomes. Our study suggests that GB3 immunostaining can serve as an early detection method for Fabry disease patients. This test allows for early detection and treatment before irreversible damage occurs. These findings were published in Genetics in Medicine this year, and after presenting this research at the 2017 Global Fabry Disease Conference in New Orleans, our director, Dr. Niu Dau-ming, received high praise from conference chairman Mehdi Namdar, who called it a "revolutionary discovery."

(7) Owning the world's most comprehensive Fabry disease research and treatment center

With the assistance of the hospital, our center established the first "Rare Disease Treatment Center" in the Asia-Pacific region in the Department of Pediatrics on the 9th floor of Zhongzheng Building in the year 2011. We have also formed a medical service team to provide a safe and high-quality medical environment centered around rare disease patients.

We provide treatment services for Fabry disease patients that are open at night and on weekends and holidays to accommodate patients who have difficulty seeking medical attention during regular business hours. We adhere to the service philosophy of "treating patients as if they were family" and strive to provide the highest quality service to our patients. Our center was awarded the Gold Award for the SNQ National Quality Award by the Bureau of Health Promotion in 2020.

(8) Invited to serve as a member of the steering committee for the world's most important Fabry disease observational clinical trial research program (FOS)

FOS is currently the most important long-term tracking program for Fabry disease patients in the world. By registering data from clinical doctors, it collects current status, clinical diagnosis, and evaluation data of clinical efficacy after treatment of Fabry disease patients across international and medical centers. Due to our center's achievements in Fabry disease, Director Niu Daoming was also selected as the only steering committee member in Asia for this international project, guiding various committees under it to conduct comprehensive tracking research on Fabry disease. Currently, we are the medical center with the highest number of cases received by a single institution in various countries around the world, so this project is highly valued by our center.

(9) Impressive research achievements were awarded the Outstanding Research Award by the Ministry of Science and Technology in 2018.

Under the leadership of Director Niu Dau-ming, the medical research team has made remarkable achievements in the field of inherited metabolic disorders after many years of effort. They have developed world-renowned results and characteristics, which have been recognized by experts and scholars from various countries. In addition, they were awarded the Outstanding Research Award by the Ministry of Science and Technology in 2018.

(10)Representing Taipei Veterans General Hospital, won the Rare Disease Prevention and Treatment Contribution Award in 2019.

Director Niu Dau-ming and his team have long been devoted to the research and prevention of rare diseases, and their achievements over the years have created many "firsts" in the medical history of rare diseases in Taiwan. The National Health Agency has been promoting rare disease prevention and treatment for twenty years since the promulgation of the Rare Disease Prevention and Control Act. To recognize the units that have made significant contributions to rare disease prevention and treatment over the past two decades, Director Niu Dau-ming, representing Taipei Veterans General Hospital, stood out among 13 recommended units and won the first place in the Rare Disease Prevention and Treatment Contribution Award for medical units. The award was presented by Director-General Wang Ying-wei of the National Health Agency, and received by Vice Superintendent Huang Hsin-chang and Director Niu Dau-ming on behalf of Taipei Veterans General Hospital.

(11) The 18th Outstanding Alumni of National Yang-Ming University.

The Rare Disease and Genetic Disorders team of the Department of Pediatrics at National Yang-Ming University has achieved remarkable academic success in the field of genetic diseases, which has been recognized by domestic and international experts and scholars over the years. In 2020, the team was recommended and elected as outstanding alumni in the academic category of the 18th National Yang-Ming University Alumni Awards.

(12) The treatment and research of Fabry disease are unparalleled worldwide and were honored with the Gold National Quality Label Award, known as the "Oscar" of Taiwan's biotechnology and medical industry, in 2020.

(13) Establish an internationally top-notch genetic disease research and testing center

Building on 20 years of genetic research, establish an internationally top-notch genetic disease research and testing center. The current main focuses include:

     (a) Using next-generation sequencing to establish a precision medicine-focused research and service team

In 2018, the laboratory of this center passed the certification extension of the gene testing laboratory of the National Health Department. It is currently planning to complete the international TAF ISO15189 medical laboratory certification application by mid-2021, providing the hospital with high-quality gene sequencing services. By integrating the genetic medicine fields of various departments within the hospital, this center has established a precision medicine-focused research and service team and developed clinical services and medical innovation research within the hospital.

• Successfully developed Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS) testing services and established a rapid diagnosis platform.

In 2017, our center completed the establishment of relevant equipment and technology in the development of next-generation sequencing (NGS) technology, and trained personnel for operation and analysis to provide high-quality services. In response to the needs of various departments in the hospital, such as the Department of Ophthalmology, Neurology Center, Psychiatry Center, Department of Otolaryngology, Pediatrics, and Cardiology, in genetic diagnosis and research, we developed gene diagnostic panels to meet their specific needs. Currently, our center has completed gene diagnostic panels for all inherited diseases and provides them for use in various departments. As of now, the total number of NGS samples processed by our center has exceeded 2,000.

n 2019, our center successfully developed Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS) testing services, and conducted an industry-academia collaboration with a bioinformatics company to develop a rapid diagnosis platform for WES and WGS. Currently, we continue to optimize the rapid diagnosis platform. We hope that in the future, with a simple and fast operation and interpretation interface, we can promote the use of the platform to all physicians in the hospital and assist them in genetic diagnosis and interpretation.

• Using next-generation sequencing (NGS) technology, we participate in national and international precision medicine initiatives:

In the field of next-generation sequencing (NGS) research, our center was invited to participate in the national precision medicine initiative, "Asia-Pacific Biomedical Silicon Valley Precision Medicine Flagship Project." We provided whole-genome sequencing services for patients with undiagnosed rare genetic diseases in our hospital, in order to identify novel and unknown pathogenic mutations. In May 2018, our application for the Ministry of Science and Technology's Precision Medicine Key Project, "Three-Year Project Plan for Precision Medicine in Women and Children's Health," was approved, and we established a nationwide integrated precision medicine model for hearing loss. At the end of 2020, we signed a memorandum of understanding (MOU) with the National Health Research Institutes and Japan's largest pharmaceutical company, Takeda Pharmaceutical Company, to conduct research on precision medicine for Fabry disease.

• We have established a next-generation sequencing-based newborn screening test and a diagnosis team.

With the advancements in next-generation sequencing technology and the development of artificial intelligence, we anticipate that the future of newborn screening will enter the era of next-generation sequencing screening. Our center has established a next-generation sequencing technology platform, which provides a basis for genetic diagnosis and functional genomics research within the hospital. We have already established a newborn screening panel for genetic diseases, drug metabolism, and physical traits that can prevent, treat, or take action against 2384 diseases and 70 drugs/metabolites. This has received attention from domestic technology companies, and we will sign contracts for industry-academic cooperation to promote this newborn screening, which will benefit more newborns. We have also collaborated with physicians from the pediatric cardiology, neurology, gastroenterology, and renal immunology departments to form a newborn screening diagnostic team. As a result, our center will become the world's first newborn screening research and diagnostic center based on next-generation sequencing.

• Establish a genetic research database platform in our institute, as well as an artificial intelligence analysis system for next-generation sequencing data.

Integrating next-generation sequencing technology and big data, we are establishing a genetic variation database for congenital genetic diseases and other diseases related to gene mutations. This will be an important asset for academic research in our institute and will provide relevant data for our colleagues to conduct related research. Through the development of genetic disease gene detection kits and whole-genome sequencing technology, we are gradually establishing a genetic variation map for various departments' genetic diseases. In the future, this database will provide important reference materials for other research projects in our institute. We are currently collaborating with the National Health Research Institutes and the Taiwan AI Development Foundation to jointly establish an artificial intelligence analysis system for next-generation sequencing data.

  (b) Develop innovative treatment technologies for rare diseases.

• Pioneering the development of a mouse model with genetic mutations commonly found in the Taiwanese population for use in research on the treatment of various next-generation drugs.

We have successfully pioneered the development of the world's first mouse model for Fabry disease with the most common mutation. Using cutting-edge gene editing technology, we have developed preclinical trials for gene therapy. Our research team has previously successfully developed CRISPR/Cas9 gene editing therapy for cardiac variant Fabry disease, which is commonly found in Taiwanese patients. By cutting out mutated DNA sequences in patient cells, we were able to not only correct abnormal RNA splicing of the GLA gene but also restore normal expression and activity of GLA enzyme protein, as well as clear Gb3 from lysosomes in cells, achieving the therapeutic goal. We are now able to use our self-made disease animal models for preclinical trials.

• Collaborate with internationally renowned medical technology companies to conduct clinical trials on a new generation of gene therapy technology for rare diseases.

Our team is actively developing gene therapy technology for Fabry disease, and has achieved very good results in preclinical trials on Fabry disease mouse models, far superior to reports published worldwide. In 2019, we presented our results at the 6th Update on Fabry Disease conference held in Prague, where the conference chairman, Fabry disease expert Professor David G. Warnock, praised our results as the best treatment outcome seen to date. The internationally renowned gene therapy company 4DMT will also sign a contract with us to jointly conduct human trials for Fabry disease gene therapy. Harvard University Professor Luk Vandenberghe has also contacted us to begin further gene therapy research.

In addition to Fabry disease, due to our outstanding achievements in gene therapy for rare diseases, our center has established animal models for rare diseases and analysis technology, as well as the ability to conduct clinical trials for rare diseases. Domestic and foreign experts, scholars, and companies have actively contacted us for cooperation. For example, we have successfully developed effective novel gene carriers with a well-known foreign gene therapy company. Together, we will develop new gene therapy technologies for important rare diseases in Taiwan, including Pompe disease, Gaucher disease, and others, and we expect to conduct clinical trials at our hospital. We hope to solve the treatment bottleneck for important rare diseases within five to ten years, and become one of the main collaborative medical centers for international rare disease therapy technology development.

(14) Collaborating with Microsoft on the Development of Artificial Intelligence Applications for Rare Disease Diagnosis

Artificial intelligence (AI) is rapidly advancing, and when combined with medical big data and databases, it can help with quick and accurate clinical prediction, diagnosis, and decision-making. To accelerate the diagnosis of rare diseases, Microsoft and the European Rare Disease Organisation (EURORDIS) have formed an alliance to develop AI-based tools for rare disease diagnosis to assist clinical physicians. Our center was invited to participate in the Global Commission to End the Diagnostic Odyssey for Children with a Rare Disease meeting, and Director Dao-Ming Ni was appointed as the only medical professional on the steering committee for the Asia-Pacific region to jointly research and develop solutions to address the current challenges in rare disease diagnosis.

(15) In support of the government's Southbound Policy, we have established cooperative relationships with various Southeast Asian countries.

In 2013, our center began building a partnership with Hai Phong University of Medicine and Pharmacy in Vietnam. We signed a Memorandum of Understanding (MOU) with the university's president, Prof. Pham Van Thuc, to provide advice and share our experience in newborn screening, and to assist Vietnam in establishing newborn screening for lysosomal storage disorders and mass spectrometry. In 2018, the President of the University of the Philippines, Dr. Padilla, also signed an MOU with Taipei Veterans General Hospital, further assisting the Philippines in developing gene diagnostic technology related to lysosomal storage disorders and promoting academic exchange between Taiwan and the Philippines.

Currently, in addition to maintaining a good cooperative relationship with the University of Medicine and Pharmacy at Ho Chi Minh City in Vietnam, our center also collaborates with Director Dung Chi Vu at Hanoi Children's Hospital to assist the hospital in molecular diagnosis and treatment of glycogen storage disease, fatty acid oxidation defects, urea cycle disorders, and some rare diseases. We also work with Dr. Hoang Thi Thanh Huyen at the National Hospital of Obstetrics and Gynecology in Hanoi to assist in molecular testing for Down syndrome and establish newborn screening methods in Vietnam. In addition to Vietnam and the Philippines, we also collaborate with the Kuala Lumpur Central Hospital and the University of Kuala Lumpur in Malaysia on a next-generation sequencing cooperative project. We continue to establish cooperative relationships with well-known universities and hospitals in Southeast Asia to promote Taiwan's high-quality medical services worldwide.

(16)Establishing the first rare disease patient association in Taiwan, actively tracking and caring for rare disease patients, and advocating for their rights:

In 1998, our center assisted in the establishment of the first rare disease patient association in Taiwan, the "Rare Disease Taiwan Association". Through the establishment of the association, we provide assistance and care for patients and their families in all aspects of medical and health education, social resources, and psychological support. We also regularly hold health education activities to promote mutual support and encouragement among patients, giving them the courage to face the challenges of their illnesses and helping children overcome the disease on the long road to treatment. Through these activities, we also strive to raise awareness of rare diseases among the public and government healthcare units, advocating for more social resources to assist patients and their families.

Specialized service: Abnormalities in genetic screening for infants and young children, congenital genetic diseases, chromosomal abnormalities, developmental delays, short stature, obesity, diabetes, abnormal genital development, thyroid enlargement.