Fragile-X and FXTAS
The Follow up Research of Fragile X Families involves a study of the association between molecular variations in the fragile gene, the physical, behavioral and cognitive features of both children and adults affected with fragile X syndrome particularly in females. Establishing diagnosis was done through screening program in special school, where many individuals with intellectual disabilities get education services. Fragile X site that has been combined with PCR-based molecular method were established by PhD student from University of New South Wales (UNSW), Sydney with minimal equipments and now become routine diagnosis services not only for research but also for patient services. Since then, Fragile X syndrome become predominant research topic in Diponegoro University and become the only research center offers clinical and molecular testing for fragile X syndrome diagnosis in Indonesia. We study index cases, as well as their parents, grandparents and siblings. Screening among the extended family is the most important thing to be done when a new case has been found in order to find other affected cases and/or to identify carriers both male and female. Eventually, genetic counseling has to be done to disclose information regarding their carrier status, the probability having children with FXS, and to give reproductive options. This study is performed in collaboration with the leading Fragile X centers worldwide such as Medical Investigation Neurodevelopmental Disorders (MIND) Institute, UC Davis, California USA, the Department of Human Genetics Radboud University Nijmegen medical Centre (RUNMC), The Netherlands and Laboratory Medicine, National University Hospital, Singapore. Many important publications in this field were published from CEBIOR that contribute important information about fragile X syndrome in Indonesia, even, from Asia.
Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) and Fragile-X associated phenotype research is a FXS research expansion funded by Directorate General of Higher Education Republic Indonesia in 2010 and done in conjunction with MIND Institute, UC Davis, USA. We evaluate the premutation (carriers) males who are 50 years of age and older, and who have a high risk to develop tremor and ataxia associated with their FXS carriers status. We carry out neuropsychological and neuroimaging studies to develop FXTAS diagnosis apart from using standard neurological examination. Psychiatric-like phenotype among premutation females have also been addressed since current research studies were observing significant evident. We found an area near Yogyakarta, the village Semin of Gunung Kidul regency, with many Fragile X cases at the Special School and a very large FXS pedigree. Almost 50% of pupils had Fragile X syndrome. Many of them looked older and we found again the first case of FXTAS. We are going on with our study, looking after those cases up to now.
Subtelomeric Deletions and Duplications (STDs)
Preliminary discoveries of ID individuals with STDs using Multiplex Ligation-dependent Probe Amplification (MLPA) technique require a follow up study. This is considered necessary to study the genotype-phenotype correlation. We investigate molecular aberrations in ID individuals’ parents and siblings. This study is also done in collaboration with Department of Human Genetics Radboud University Nijmegen Medical Centre (RUNMC), The Netherlands and MRC Holland (Dr. Jan Schouten)
Disorder of Sex Development (DSD)
Disorders of Sex Development (DSD) were previously referred to hermaphroditism, intersex, or ambiguous genitalia. The term is defined as congenital conditions in which development of chromosomal, gonadal, or anatomical sex are atypical. Normally, we will be able to decide the sex of a baby by looking at his/her external genitalia. In the chromosome analysis, normal males and females will have XY and XX sex chromosomes respectively. A person with DSD may be born with genital ambiguity, or has a sexual development which does not follow the normal female nor male development. There may be a condition in which their sex chromosomes are different from their gender identity. This will lead to gender confusion, not only in the patients themselves, but also their family, doctors, and their surroundings.
The diagnosis of DSDs impacting the future sexual function and sex identity in individuals and their families requires a targeted and structured approach, involving a multidisciplinary team with effective communication between the disciplines. A guidance protocol on management of DSD is needed for medical community since the implementation and outcome are varies depending on the factors such as the level and type of disorder, their socioeconomic status, their culture and religion, ethical considerations, as well as patient’s and family’s reaction towards DSD. The national general guideline of DSD management should be set and standardized to provide adjustable implementation for the various conditions of the patients and their families. Therefore, DSD management should be employed differently along with the diversity of cultural and demographic background in societies. However, in Indonesia, DSD management has not gained much attention by the Ministry of Health (or government) since infectious tropical diseases are still the priority as the major causes of death.
The formation of Sexual Adjustment Multidisciplinary Team (SAT) since 1989, is the only team available in Indonesia with the members from Dr. Kariadi Hospital and Faculty of Medicine Diponegoro University (FMDU), which consists of specialists from various departments: urology, plastic surgery, gynecology, endocrinology, andrology, anesthesiology, genetics, psychiatry, pathology, psychology, legal medicine, religion and social-medical staffs. The purpose of the Team is to make an accurate diagnosis, and to provide reassurance, support, information, and resources to the patient’s family.
The main goal of DSD management is to reach an optimum quality of life. Understanding this issue by the general medical community in Indonesia, including an extensive research of the patients and identifying the structure of each ethnic and cultural background, is necessary for the management of patients with DSD. In cooperation with two research centers in DSD, Erasmus University Medical Center Rotterdam, The Netherlands (Prof. SLS Drop and Prof. L. Loeijenga) and the Murdoch Children Research Institute (MCRI) (Prof. A. Sinclair and Prof. G Warne), University of Melbourne, Australia, our Center for Biomedical Research (CEBIOR) Faculty of Medicine Diponegoro University is currently undertaking research in this field. The research on DSD is generally divided on two main issues which are a cohort study on severe DSD and a study on isolated hypospadias, with a total over 800 patients included.
Studies on severe DSD have been done on 3 main subjects i.e. genetic causes, variable clinical phenotype and hormonal status; gonadal cancer pathology; and psychological aspects of DSD. Congenital adrenal hyperplasia (CAH) is one of our special interests. A cohort study of CAH includes about 90 families who have been followed for their physical development, therapeutic result monitoring, IQ, and psychological condition. Hormonal analysis both for diagnosis and monitoring using saliva have been used for children to avoid invasive blood collection. Medication such as hydrocortison which is not available in Indonesia has been supplied by Prof. SLS Drop and other charity foundation from Australia. This CAH study has been continued for hormonal and compliance study in collaboration with Dr. Hedi Claahsen-van der Grinten, Ph.D from RUNMC. The availability of hydrocortisone and fludrocortisone has been proposed by our group to Ministry of Health and BPOM (National Agency of Drugs and Food Control of Republic Indonesia/NADFC). It should be produced within this year.
Other special interests are Androgen insensitivity syndrome (AIS) and pathology of germ cell tumour. AIS is known as the most common cause of feminized males found in our DSD population. Novel mutated genes such as WWOX and SF1 genes were also found in our population.
The study of isolated hypospadia has its main purpose to find possible clinical-environmental and genetic factors which play a role in the development of hypospadias. Their clinical and epidemiological data, as well as questionnaires on environmental conditions, have been recorded. For this study we have collaborated with Prof. Andrew Sinclair from the Murdoch Children Research Institute (MCRI), Melbourne, Australia. On going research on gonadal dysgenesis is still being held with Prof. Sinclair and his colleagues.