Papers by Dian Kesumapramudya
Birth of spinal muscular atrophy unaffected baby from genetically at-risk parents following a pre-implantation genetic screening: A case report
Iranian Journal of Reproductive Medicine, Oct 12, 2022
Background: Spinal muscular atrophy (SMA) is characterized by the homozygous deletion of the surv... more Background: Spinal muscular atrophy (SMA) is characterized by the homozygous deletion of the survival motor neuron-1 gene. Pre-implantation genetic testing for monogenic diseases through in-vitro fertilization program was developed to provide a reliable genetic diagnostic method for SMA. Case presentation: The couple who was confirmed as carriers of SMA visited the Morula IVF Clinic, Jakarta, Indenesia seeking for an in-vitro fertilization expert opinion in relation to the pre-implantation genetic testing for SMA. Utilizing polymerase chain reaction-restriction fragment length polymorphism, we have successfully screened for unaffected embryos that were characterized by a normal presence of the survival motor neuron-1 exon 7-8 and survival motor neuron-2 exon 7-8. The frozen embryo was subsequently transferred and a healthy unaffected female baby was born with undetected deletion of the survival motor neuron-1 gene. Conclusion: This successful embryo pre-implantation screening case could potentially accommodate the demands of genetically at-risk couples who are apprehensive about conceiving a child who might inherit monogenic disorders such as SMA. Key words: In-vitro fertilization, Spinal muscular atrophy, Preimplantation diagnosis.
Hybrid learning method based on feature clustering and scoring for enhanced COVID-19 breath analysis by an electronic nose
Artificial Intelligence in Medicine
Journal of Medical Case Reports
Background Spinal muscular atrophy is a recessively inherited autosomal neuromuscular disorder, w... more Background Spinal muscular atrophy is a recessively inherited autosomal neuromuscular disorder, with characteristic progressive muscle weakness. Most spinal muscular atrophy cases clinically manifest during infancy or childhood, although it may first manifest in adulthood. Although spinal muscular atrophy has come to the era of newborn screening and promising treatments, genetically confirmed spinal muscular atrophy patients are still rare in third world countries, including Indonesia. Case presentations We presented three Indonesian patients with spinal muscular atrophy genetically confirmed during adulthood. The first case was a 40-year-old male who presented with weakness in his lower limbs that started when he was 9 years old. At the age of 16 years, he could no longer walk and started using a wheelchair. He first came to our clinic at the age of 38 years, and was diagnosed with spinal muscular atrophy 2 years later. The second patient was a 58-year-old male who presented with l...
Attention Deficit/Hyperactivity Disorder (ADHD): Age Related Change of Completion Time and Error Rates of Stroop Test
The Kobe journal of medical sciences
Attention Deficit/Hyperactivity Disorder (ADHD) is a common neurobehavioral problem in children t... more Attention Deficit/Hyperactivity Disorder (ADHD) is a common neurobehavioral problem in children throughout the world. The Stroop test has been widely used for the evaluation of ADHD symptoms. However, the age-related change of the Stroop test results has not been fully clarified until now. Sixty-five ADHD and 70 age-matched control children aged 6-13 years were enrolled in this study. ADHD was diagnosed based on DSM-IV criteria. We examined the completion time and error rates of the Congruent Stroop test (CST) and Incongruent Stroop test (IST) in ADHD and control children. No significant difference was observed in the completion time for CST or IST between the ADHD and control children at 6-9 years old. However, ADHD children at 10-13 years old showed significantly delayed completion time for the CST and IST compared with controls of the same age. As for the error rates of the CST and IST, ADHD and control children at 6-9 years old showed no difference. However, error rates of CST a...
Brain and Development, 2012
Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder that is caus... more Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder that is caused by loss of the survival motor neuron gene, SMN1. SMA treatment strategies have focused on production of the SMN protein from the almost identical gene, SMN2. Valproic acid (VPA) is a histone deacetylase inhibitor that can increase SMN levels in some SMA cells or SMA patients through activation of SMN2 transcription or splicing correction of SMN2 exon 7. It remains to be clarified what concentration of VPA is required and by what mechanisms the SMN production from SMN2 is elicited. We observed that in two fibroblast cell lines from Japanese SMA patients, more than 1 mM of VPA increased SMN2 expression at both the transcript and protein levels. VPA increased not only full-length (FL) transcript level but also exon 7-excluding (D7) transcript level in the cell lines and did not change the ratio of FL/D7, suggesting that SMN2 transcription was mainly activated. We also found that VPA modulated splicing factor expression: VPA increased the expression of splicing factor 2/alternative splicing factor (SF2/ASF) and decreased the expression of heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1). In conclusion, more than 1 mM of VPA activated SMN2 transcription and modulated the expression of splicing factors in our SMA fibroblast cell lines.
BACKGROUND Attention Deficit/Hyperactivity Disorder (ADHD) is a common neurobehavioral problem in... more BACKGROUND Attention Deficit/Hyperactivity Disorder (ADHD) is a common neurobehavioral problem in children throughout the world. The Stroop test has been widely used for the evaluation of ADHD symptoms. However, the age-related change of the Stroop test results has not been fully clarified until now. METHODS Sixty-five ADHD and 70 age-matched control children aged 6-13 years were enrolled in this study. ADHD was diagnosed based on DSM-IV criteria. We examined the completion time and error rates of the Congruent Stroop test (CST) and Incongruent Stroop test (IST) in ADHD and control children. RESULTS No significant difference was observed in the completion time for CST or IST between the ADHD and control children at 6-9 years old. However, ADHD children at 10-13 years old showed significantly delayed completion time for the CST and IST compared with controls of the same age. As for the error rates of the CST and IST, ADHD and control children at 6-9 years old showed no difference. Ho...
BACKGROUND: Attention Deficit/Hyperactivity Disorder (ADHD) is a common neurobehavioral problem i... more BACKGROUND: Attention Deficit/Hyperactivity Disorder (ADHD) is a common neurobehavioral problem in children throughout the world. The Stroop test has been widely used for the evaluation of ADHD symptoms. However, the age-related change of the Stroop test results has not been fully clarified until now. METHODS: Sixty-five ADHD and 70 age-matched control children aged 6-13 years were enrolled in this study. ADHD was diagnosed based on DSM-IV criteria. We examined the completion time and error rates of the Congruent Stroop test (CST) and Incongruent Stroop test (IST) in ADHD and control children. RESULTS: No significant difference was observed in the completion time for CST or IST between the ADHD and control children at 6-9 years old. However, ADHD children at 10-13 years old showed significantly delayed completion time for the CST and IST compared with controls of the same age. As for the error rates of the CST and IST, ADHD and control children at 6-9 years old showed no difference. However, error rates of CST and IST in the ADHD children at 10-13 years were significantly higher than those of control of the same age. CONCLUSIONS: Age may influence the results of Stroop test in ADHD children. For the ages of 10-13 years old, the Stroop test clearly separates ADHD children from control children, suggesting that it may be a useful screening tool for ADHD among preadolescent children.
Journal of Medical Case Reports
Background Spinal muscular atrophy is a genetic disorder characterized by degeneration of lower m... more Background Spinal muscular atrophy is a genetic disorder characterized by degeneration of lower motor neurons, leading to progressive muscular atrophy and even paralysis. Spinal muscular atrophy usually associated with a defect of the survival motor neuron 1 (SMN-1) gene. Classification of spinal muscular atrophy is based on the age of onset and maximum motor function milestone achieved. Although spinal muscular atrophy can be screened for in newborns, and even confirmed earlier genetically, this remains difficult in Third World countries such as Indonesia. Case presentation A 28-year-old Asian woman in the first trimester of her second pregnancy, was referred to the neurology department from the obstetric department. Her milestone history showed she was developmentally delayed and the ability to walk independently was reached at 26 months old. At 8 years old, she started to stumble and lose balance while walking. At this age, spinal muscular atrophy was suspected because of her cli...
The Kobe journal of medical sciences, 2015
BACKGROUND Spinal muscular atrophy (SMA) is a common neuromuscular disorder caused by mutations i... more BACKGROUND Spinal muscular atrophy (SMA) is a common neuromuscular disorder caused by mutations in SMN1. More than 95% of SMA patients carry homozygous SMN1 deletions. Thus, the SMN1 deletion test should be performed initially as part of the diagnostic process. However, SMN2, a highly homologous gene, hampers detection of SMN1 deletion. To differentiate between SMN1 and SMN2, many analysis methods have been developed yet they are not all available worldwide. AIM To establish a simple but accurate SMN1-deletion detection system that can be used worldwide. METHODS Fifty DNA samples (29 SMA patients and 21 controls) from dried blood spots (DBS) on filter paper were assayed. All participants had previously been screened for SMA by PCR-restriction fragment length polymorphism (PCR-RFLP) using DNA extracted from freshly collected blood. DNA was extracted from DBS that had been stored at room temperature (20-25℃) for between 1 and 8 years. Competitive oligonucleotide priming-PCR (COP-PCR) ...
Neurology International, 2020
Attention deficit hyperactivity disorder (ADHD) is one of the most common neurobehavioural in the... more Attention deficit hyperactivity disorder (ADHD) is one of the most common neurobehavioural in the children. Genetic factor is known one of the factors which contributed in ADHD development. VNTR polymorphism in 3’UTR exon 15 of DAT1 gene and exon 3 of DRD4 gene are reported to be associated in ADHD. In this study we examine the association of ADHD with VNTR polymorphism of DAT1 and DRD4 gene in Indonesian children. Sixty-five ADHD children and 70 normal children (6-13 years of age), were included in the study, we matched by age and gender. ADHD was diagnosed by DSM-IV. We performed a casecontrol study to found the association between ADHD and VNTR polymorphism of DAT1 and DRD4 genes. The 10-repeat allele of DAT1 and 2-repeat allele of DRD4 were higher in Indonesian children. Although the frequency of these allele was higher, but it was similar both in ADHD and control groups. Neither DAT1 nor DRD4 gene showed showed significant difference in genotype distribution and frequency allel...
School reopening: Evidence-based recommendations during COVID-19 pandemic in Indonesia
Since the first Coronavirus Disease 2019 (COVID-19) case was reported, it has run amok and caused... more Since the first Coronavirus Disease 2019 (COVID-19) case was reported, it has run amok and caused global changes. It has affected human lives in almost every aspect, including education. In response to COVID-19, governments and policy-makers decided to shift the educational activities into online learning and institute school closure. As of March 2020, many countries worldwide have implemented school closure, including Indonesia. Large scale social distancing and stay-at-home policies have begun to negatively impact society’s physical and mental health. As people start to adapt to the first wave of the COVID-19 pandemic, policy-makers and the government need to consider how to reopen the schools and its system to keep students and staff safe. School reopening is an important step toward loosening the lockdown. Schools play a crucial role in preserving children's well-being. The objective of this review was to give a recommendation to facilitate school reopening. Research article...
Dried Blood Spot Screening System for Spinal Muscular Atrophy with Allele-Specific Polymerase Chain Reaction and Melting Peak Analysis
Genetic Testing and Molecular Biomarkers
Background and Aim: Spinal muscular atrophy (SMA) is a lower motor neuron disease with autosomal ... more Background and Aim: Spinal muscular atrophy (SMA) is a lower motor neuron disease with autosomal recessive inheritance caused by homozygous SMN1 deletions. Although SMA has been considered as incurable, newly developed drugs improve life prognoses and motor functions of patients. To maximize the efficacy of the drugs, SMA patients should be treated before symptoms become apparent. Thus, newborn screening for SMA is strongly recommended. In this study, we aim to establish a new simple screening system based on DNA melting peak analysis. Materials and Methods: A total of 124 dried blood spot (DBS) on FTA® ELUTE cards (51 SMN1-deleted patients with SMA, 20 carriers, and 53 controls) were punched and subjected to direct amplification of SMN1 and CFTR (reference gene). Melting peak analyses were performed to detect SMN1 deletions from DBS samples. Results: A combination of allele-specific polymerase chain reaction (PCR) and melting peak analyses clearly distinguished the DBS samples with and without SMN1. Compared with the results of fresh blood samples, our new system yielded 100% sensitivity and specificity. The advantages of our system include (1) biosafe collection, transfer, and storage for DBS samples, (2) obviating the need for DNA extraction from DBS preventing contamination, (3) preclusion of fluorescent probes leading to low PCR cost, and (4) fast and high-throughput screening for SMN1 deletions. Conclusion: We demonstrate that our system would be applicable to a real-world newborn screening program for SMA, because our new technology is efficient for use in routine clinical laboratories that do not have highly advanced PCR instruments.
Fast and noninvasive electronic nose for sniffing out COVID-19 based on exhaled breath-print recognition
Despite its high accuracy to detect the severe acute respiratory syndrome coronavirus 2 (SARS-CoV... more Despite its high accuracy to detect the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the reverse transcription-quantitative polymerase chain reaction (RT-qPCR) approach possesses several limitations (e.g., the lengthy invasive procedure, the reagent availability, and the requirement of specialized laboratory, equipment, and trained staffs). We developed and employed a low-cost, noninvasive method to rapidly sniff out the coronavirus disease 2019 (COVID-19) based on a portable electronic nose (GeNose C19) integrating metal oxide semiconductor gas sensor array, optimized feature extraction, and machine learning models. This approach was evaluated in profiling tests involving a total number of 615 breath samples (i.e., 333 positive and 282 negative COVID-19 confirmed by RT-qPCR) obtained from 83 patients in two hospitals located in the Special Region of Yogyakarta, Indonesia. Four different machine learning algorithms (i.e., linear discriminant analysis (LDA), support ...
Paediatrica Indonesiana
Background Symptomatic congenital cytomegalovirus (CMV) infection has an impact mainly on neurolo... more Background Symptomatic congenital cytomegalovirus (CMV) infection has an impact mainly on neurological sequelae, including sensorineural deafness. Because of the long-term impact, early treatment of CMV infection is mandatory. However, predictive factors for hearing function improvement in CMV infection therapy remain unexamined. Objective To evaluate potential predictive factors for hearing improvement in pediatric CMV infection therapy. Methods All medical record data of patients aged 0-6 years with CMV infection who completed a 6-week course of ganciclovir therapy or a combination of a 4-week course of ganciclovir and a 2-week course valganciclovir from January 2013 to December 2017 were collected. Age at onset of therapy, gender, gestational age, nutritional status, multi-organ involvement, and neurological symptoms were studied as potential predictive factors of hearing improvement in CMV therapy. The effectiveness of CMV infection therapy on improving hearing function was meas...
International Journal of Neonatal Screening
Spinal muscular atrophy (SMA) is a common neuromuscular disease with autosomal recessive inherita... more Spinal muscular atrophy (SMA) is a common neuromuscular disease with autosomal recessive inheritance. The disease gene, SMN1, is homozygously deleted in 95% of SMA patients. Although SMA has been an incurable disease, treatment in infancy with newly developed drugs has dramatically improved the disease severity. Thus, there is a strong rationale for newborn and carrier screening for SMA, although implementing SMA carrier screening in the general population is controversial. We previously developed a simple, accurate newborn SMA screening system to detect homozygous SMN1 deletions using dried blood spots (DBS) on filter paper. Here, we modified our previous system to detect the heterozygous deletions of SMN1, which indicates SMA carrier status. The system involves a calibrator-normalized relative quantification method using quantitative nested PCR technology. Our system clearly separated the DBS samples with one SMN1 copy (carrier status with a heterozygous deletion of SMN1) from the...
Sari Pediatri
Latar belakang. Infeksi Cytomegalovirus (CMV) merupakan penyebab tersering infeksi kongenital ana... more Latar belakang. Infeksi Cytomegalovirus (CMV) merupakan penyebab tersering infeksi kongenital anak di negara berkembang. Infeksi ini dapat menyebabkan tuli sensorineural (SNHL) dan gangguan perkembangan. Di RSUP dr Sardjito, pasien dengan infeksi CMV aktif bergejala akan menjalani terapi 6 minggu Ganciclovir atau 2 minggu terapi Ganciclovir dilanjutkan 4 minggu terapi Valganciclovir. Namun, luaran terapi tersebut belum diteliti lebih lanjut.Tujuan. Melihat luaran terapi ganciclovir dan atau valganciclovir pada pasien infeksi Cytomegalovirus di Instalasi Kesehatan Anak RSUP Dr Sardjito.Metode. Penelitian ini menggunakan metode kohort retrospektif dari data rekam medis pasien dengan diagnosis infeksi CMV aktif di Instalasi Kesehatan Anak RSUP dr Sardjito periode Januari 2014 sampai dengan April 2018. Variabel luaran (BERA dan Denver II) dibandingkan antara pre dan post terapi ganciclovir. Analisis statistik data dasar menggunakan analsisi deskriptif. Untuk variable luaran menggunakan ...
BMC Research Notes
Objective Duchenne/Becker muscular dystrophy (DMD/BMD) is the most common genetic neuromuscular d... more Objective Duchenne/Becker muscular dystrophy (DMD/BMD) is the most common genetic neuromuscular disease in children, resulting from a defect in the DMD gene located on Xp21.2. The new emerging treatment using exon skipping strategy is tailored to specific mutations, thus molecular diagnostics are particularly important. This study aimed to detect the DMD gene deletion in Indonesian DMD/BMD patients and analyze the potential amenability by exon skipping therapy. Results Thirty-four male patients were enrolled in this study, 23 of them (67.6%) underwent muscle biopsy and showed the absence or partially expressed dystrophin protein in immunohistochemistry staining. All patients had very high serum CK levels (10.529 ± 9.97 IU/L). Multiplex PCR revealed the DMD gene deletions in 15 (44.1%) cases. Seventy-eight percent of deletions were clustered in the hot-spot region of exon 43 to 52. Furthermore, seven (20.5%) patients were potentially amenable to exon skipping treatment. Therefore, mu...
Biochemistry and Biophysics Reports, 2015
Corrigendum to: ''Salbutamol inhibits ubiquitin-mediated survival motor neuron protein degradatio... more Corrigendum to: ''Salbutamol inhibits ubiquitin-mediated survival motor neuron protein degradation in spinal muscular atrophy cells'' [Biochem. Biophys. Rep. 4 (2015) 351-356]
Biochemistry and Biophysics Reports, 2015
Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder that is curr... more Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder that is currently incurable. SMA is caused by decreased levels of the survival motor neuron protein (SMN), as a result of loss or mutation of SMN1. Although the SMN1 homolog SMN2 also produces some SMN protein, it does not fully compensate for the loss or dysfunction of SMN1. Salbutamol, a β2-adrenergic receptor agonist and well-known bronchodilator used in asthma patients, has recently been shown to ameliorate symptoms in SMA patients. However, the precise mechanism of salbutamol action is unclear. We treated SMA fibroblast cells lacking SMN1 and HeLa cells with salbutamol and analyzed SMN2 mRNA and SMN protein levels in SMA fibroblasts, and changes in SMN protein ubiquitination in HeLa cells. Salbutamol increased SMN protein levels in a dose-dependent manner in SMA fibroblast cells lacking SMN1, though no significant changes in SMN2 mRNA levels were observed. Notably, the salbutamol-induced increase in SMN was blocked by a protein kinase A (PKA) inhibitor and deubiquitinase inhibitor, respectively. Coimmunoprecipitation assay using HeLa cells showed that ubiquitinated SMN levels decreased in the presence of salbutamol, suggesting that salbutamol inhibited ubiquitination. The results of this study suggest that salbutamol may increase SMN protein levels in SMA by inhibiting ubiquitin-mediated SMN degradation via activating β2-adrenergic receptor-PKA pathways.
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Papers by Dian Kesumapramudya