The pathogenesis of Parkinson's disease is closely related to genetic factors. This article has systematically reviewed the research progress of molecular genetic mechanism on Parkinson's disease by focusing on the role of six high-penetrance pathogenic genes (SNCA, LRRK2, PRKN, PINK1, PARK7, and VPS35) and some risk genes (such as GBA1). These genetic variants eventually converge in three core pathogenic biological pathways, including lysosomal-autophagy pathway disorder, mitochondrial quality control disorder and α-synuclein metabolic abnormality. In-depth understanding of these molecular mechanisms is of great significance for the development of targeted therapy and realization of precision medicine for this disease.
Humans ; Parkinson Disease/metabolism* ; alpha-Synuclein/genetics* ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics* ; Genetic Predisposition to Disease ; Protein Kinases/genetics* ; Animals ; Glucosylceramidase/genetics* ; Ubiquitin-Protein Ligases/genetics*

Abstract Background: Optimal mucosal visibility during esophagogastroduodenoscopy (EGD) is critical for diagnostic accuracy but is often impaired by the presence of mucus and bubbles. This study aimed to compare the efficacy and safety of four premedication regimens for mucosal visualization during sedated EGD. Methods: A double-blind randomized controlled trial was conducted at the Endoscopy Unit of Dr. Zainoel Abidin General Hospital, Banda Aceh, Indonesia, from January to December 2024. Patients scheduled for elective diagnostic EGD were randomly assigned to: Group 1 (simethicone 40 mg at 30 minutes before the procedure), Group 2 (simethicone 40 mg + 100 mL 5% sodium bicarbonate at 2 hours), Group 3 (simethicone 40 mg + N-acetylcysteine 600 mg in 100 mL water at 2 hours), or Group 4 (all three agents at 2 hours). Primary outcomes were mucosal visibility (6-site, 3-point scoring system with lower scores indicating superior mucosal visibility); procedural metrics (irrigation volume and duration); and safety (the lowest recorded SpO₂%). Data were analyzed using ANOVA or Kruskal–Wallis for continuous variables, and Chi-square or Fisher’s exact test for categorical variables, with post hoc testing as applicable. Results: A total of 168 patients were randomized into four groups (n=42 each). Groups 3 and 4 showed superior mucosal visibility compared to Groups 1 and 2 (p=0.004), with no significant difference between Groups 3 and 4. Irrigation volume differed significantly (p=0.018), lowest in Group 4. Group 3 had the shortest procedure time (3.1 ± 1.2 minutes), significantly more efficient than Groups 1 and 2, but similar to Group 4. Oxygen saturation was slightly lower in Group 3 (p<0.005), though all groups remained within safe clinical limits. Conclusions: Simethicone and N-acetylcysteine given two hours before endoscopy effectively enhanced mucosal visibility and procedural efficiency without compromising safety, offering a practical alternative to more complex regimens.
esophagogastroduodenoscopy ; mucosa visibility ; premedication ; simethicone ; N-acetylcysteine

Introduction: Accurate diagnosis of thyrotoxicosis, a condition resulting from excessive thyroid hormone activity, is essential for appropriate management. However, access to diagnostic tools such as thyrotropin receptor antibody (TRAb) assays and thyroid ultrasonography remains limited in resource-constrained settings, highlighting the need for cost-effective alternatives. Recent studies suggest that the free triiodothyronine to free thyroxine (FT3/FT4) ratio may serve as a potential biomarker for differentiating the causes of thyrotoxicosis. Methodology: This cross-sectional study evaluated the FT3/FT4 ratio in newly diagnosed thyrotoxicosis patients aged ≥18 years recruited from Hospital Tengku Ampuan Rahimah, Hospital Banting, Klinik Kesihatan Pelabuhan Klang, and Klinik Kesihatan Pandamaran between February and December 2025. All participants underwent thyroid function testing (FT3, FT4, and TSH) and autoantibody assessment (TRAb and anti-thyroid peroxidase [anti-TPO]). Diagnostic performance of the FT3/FT4 ratio for Graves’ disease was assessed using receiver operating characteristic (ROC) curve analysis. Results: Fifty-eight patients were included, of whom 58.6% were diagnosed with Graves’ disease. Patients with Graves’ disease had significantly higher FT3 levels (median 16.8 pmol/L; IQR 10.9–25.7) compared to those with non-Graves’ thyrotoxicosis (median 8.3 pmol/L; IQR 5.3–13.5; p <0.001), with similar trends observed for FT4 levels (p <0.001). However, the FT3/ FT4 ratio did not differ significantly between groups (p >0.05), with an overall ROC AUC of 0.572, indicating poor discriminatory ability. Subgroup analysis based on FT4 levels improved performance; at FT4 <30 pmol/L, the FT3/FT4 ratio demonstrated 75.0% sensitivity, 91.7% specificity, and 87.5% diagnostic accuracy at a cutoff of 0.3445 (AUC = 0.813; 95% CI: 0.570–1.000; p = 0.069). No significant association was observed between the FT3/FT4 ratio and TRAb or anti-TPO. Conclusion The FT3/FT4 ratio has limited overall diagnostic utility but may provide adjunctive value in selected biochemical contexts, particularly in settings with limited access to immunological testing.
Diagnosis, Differential ; Thyroxine ; Triiodothyronine ; Thyrotoxicosis ; Cross-Sectional Studies

Introduction: Dopaminomas or dopamine-secreting pheochromocytomas are rare neuroendocrine tumors that frequently lack the classic paroxysmal symptoms of catecholamine excess (headache, sweating, palpitation). Diagnosing these tumors is exceptionally challenging when biochemical markers— specifically markedly elevated urinary dopamine—are interpreted in patients receiving exogenous Levodopa (L-DOPA) therapy, as the intake obscures clinical significance. Case: A 76-year-old male with ischemic heart disease, stage 4 chronic kidney disease, and new-onset hypertension was admitted for acute cholecystitis. Imaging studies incidentally revealed bilateral adrenal masses and demonstrated lipid-rich characteristics upon further evaluation with computed tomography (CT) adrenal washout. Biochemical evaluation revealed extreme elevations in 24-hour urinary dopamine (47,534 nmol/24 hours; normal <3,237) and 3-methoxytyramine (18.93 µmol/24 hours; normal <2.60), whereas downstream urinary noradrenaline (5.0 nmol/24 hours; normal 71.5–505.3), adrenaline (4.0 nmol/24 hours; normal 9.2–122.3), normetanephrine (0.22 µmol/24 hours; normal 0.88–2.88), and metanephrine (0.25 µmol/24 hours; normal 0.33–1.53) levels were all significantly below their respective reference ranges. The diagnosis was complicated by the patient’s concurrent use of L-DOPA/Benserazide for flupentixol-induced parkinsonism. L-DOPA is a direct precursor to dopamine; its administration can cause massive, false-positive elevations in urinary dopamine, mimicking a dopaminoma’s biochemical signature. However, the unique combination of profoundly high dopamine alongside suppressed downstream catecholamines and metanephrines suggested a true dopaminesecreting tumor—potentially secondary to dopamine beta-hydroxylase (DBH) deficiency—rather than drug interference. Conclusion This case illustrates the profound difficulty in diagnosing dopaminoma when exogenous L-DOPA therapy creates a near-identical biochemical profile. The diagnostic dilemma is further amplified by vague symptomatology, multiple comorbidities, and non-suggestive imaging. However, the finding of isolated dopamine hypersecretion with suppressed metanephrines serves as a critical clinical clue. This pattern points toward an intratumoral biosynthetic defect rather than drug interference. Clinicians must maintain a high index of suspicion and perform meticulous biochemical fractionation to identify these rare, dopamineisolated secreting tumors.
Dopamine ; Levodopa

Introduction: Arginine vasopressin deficiency (AVP-D) is characterized by impaired antidiuretic hormone secretion, leading to polyuria and a significant dehydration risk. The British Islamic Medical Association classifies AVP-D as a “very high risk” condition, advising against Ramadan fasting. However, many patients fast due to religious convictions, creating a gap between clinical guidelines and patient practice. This study evaluates the clinical outcomes and safety of fasting in this population. Methodology: A single-centre retrospective cohort study was conducted at Hospital Putrajaya. We included adults with permanent AVP-D on desmopressin therapy for more than 1 year who fasted during Ramadan 2025. Data were extracted from electronic medical records and patient consultations. Primary outcomes included hospitalization rates, dehydration symptoms, and desmopressin dose adjustments. Results: Of the 43 patients (mean age 42.4 ± 15.28 years; 53.5% female), 27 successfully fasted for a mean of 27.6 ± 6.56 days. Pre-Ramadan counseling was documented in only 55.8% of cases. While 25.9% of participants experienced dehydration symptoms (thirst, dizziness), and 22.2% broke their fast for safety reasons, there were no hospitalizations. None of the patients required additional desmopressin dose adjustments. Most patients (66.7%) maintained twicedaily desmopressin dosing (Sahur and Iftar). Anterior pituitary deficiencies were present in 70.3% of the cohort. Conclusion Despite being classified as very high risk, many AVP-D patients safely complete Ramadan fasting without severe adverse events. However, the high rate of dehydration symptoms and the significant gap in pre-Ramadan counseling (44.2% un-counseled) highlight the need for structured clinical reviews 4–6 weeks prior to Ramadan to optimize hydration and dosing
Humans ; Diabetes Insipidus, Neurogenic ; Retrospective Studies ; Arginine ; Fasting

Introduction: Arginine vasopressin deficiency (AVP‑D), previously termed central diabetes insipidus, is a rare paediatric endocrine disorder that may present as an early manifestation of diverse hypothalamic–pituitary conditions. Identifying the underlying etiology is crucial for guiding management and surveillance; however, in some children, the cause remains unresolved, leading to primarily symptomatic treatment. In Malaysia, published literature on paediatric AVP‑D has been limited to isolated case reports, with no cohort‑level data available. This study aims to describe the clinical features, etiological spectrum, and treatment patterns of paediatric AVP-D in a single-centre Malaysian cohort, emphasizing diagnostic yield, unresolved causes, and the central role of neuroimaging. Methodology: A retrospective review was conducted of children diagnosed with AVP-D. Data collected included age at symptom onset, age at presentation, clinical features, etiological classification, neuroimaging findings, comorbidities, treatment modalities, and follow-up outcomes. Descriptive statistics were used for analysis. Results: Twelve children were included, with a median age of 9.8 years; two-thirds were male. Children were referred at a median age of 3.4 years, with presentation ranging from the neonatal period to 10.4 years. Diagnostic delay was minimal overall, although 25% experienced delays exceeding 1 year. The water deprivation test was performed in 33.3% of patients. Magnetic resonance imaging (MRI) was completed in all children and served as the principal determinant of etiology. Structural abnormalities were identified in 50% of the cohort, including semilobar holoprosencephaly (33.3%), Arnold– Chiari I malformation (8.3%), and pituitary stalk interruption syndrome (8.3%). The posterior pituitary bright spot was absent in most patients, and 50% required repeat MRI to clarify evolving neurohypophyseal features. Tumor-related AVP-D accounted for 8.3%, while one-third had no definitive etiology despite imaging. Initial therapy included desmopressin (58.3%), hydrochlorothiazide (25%), and diluted sublingual desmopressin (8.3%), with most requiring dose escalation. Growth impairment occurred in 66.7% of patients, and delayed puberty in 16.7%. Conclusion MRI played a central role in defining etiology, with half of the cohort demonstrating congenital structural abnormalities. Persistent unresolved cases highlight the diagnostic challenges of AVP-D and underscore the importance of early MRI and longitudinal endocrine follow-up.
Child ; Cohort Studies ; Diabetes Insipidus, Neurogenic ; Arginine

OBJECTIVE: To explore the genetic etiology of two fetuses with Mosaic variegated aneuploidy syndrome (MVA) in a pedigree. METHODS: A 30-year-old pregnant woman, who presented at the Center for Medical Genetics and Prenatal Diagnosis of Shandong Maternal and Child Health Care Hospital on November 16, 2023, was enrolled. Clinical data of the pedigree were collected, and peripheral blood samples from the parents and amniotic fluid samples from the two fetuses were obtained for genomic DNA extraction. Whole exome sequencing (WES) was performed on both fetuses, followed by Sanger sequencing for familial validation and pathogenicity analysis of candidate variants. Chromosomal karyotyping of the parents was conducted to quantify the proportion of premature chromatid separation (PCS). This study was approved by the Medical Ethics Committee of Shandong Maternal and Child Health Care Hospital (Ethics No. 2024-034). RESULTS: Both fetuses exhibited structural brain anomalies and developmental delays during the second trimester. Amniocyte karyotyping revealed low-level mosaic aneuploidy involving multiple chromosomes, while chromosomal microarray analysis (CMA) showed no abnormalities. Pregnancy termination was performed for fetus 1. WES identified compound heterozygous variants in BUB1B, i.e., c.2363_2364del (p.S788Cfs*29) and ss804270619: G>A, in both fetuses. Sanger sequencing confirmed paternal inheritance of c.2363_2364del and maternal inheritance of ss804270619:G>A. According to the American College of Medical Genetics and Genomics (ACMG) and Clinical Genome Resource (ClinGen) Standards and Guidelines for the Interpretation of Sequence Variants, the c.2363_2364del variant was classified as likely pathogenic (PVS1 + PM2_Supporting). Parental karyotyping demonstrated PCS traits, with a higher proportion of abnormal metaphases in the father. CONCLUSION The compound heterozygous variants c.2363_2364del (p.S788Cfs*29) and ss804270619: G>A in BUB1B may constitute the genetic etiology of the two MVA fetuses in this pedigree.
Humans ; Female ; Pregnancy ; Adult ; Mosaicism ; Protein Serine-Threonine Kinases/genetics* ; Chromosome Disorders/diagnosis* ; Pedigree ; Heterozygote ; Prenatal Diagnosis ; Aneuploidy ; Male ; Fetus ; Karyotyping

Gastrointestinal polyposis syndromes are primarily characterized by multiple polyps in the gastrointestinal tract, with their pathogenic mechanisms largely related to genetic factors and involving multiple signaling pathways. Adenomatous polyposis syndromes are mainly associated with APC gene variants, while some cases may arise from MUTYH gene variants. Peutz-Jeghers syndrome is primarily linked to STK11 gene variants. Juvenile polyposis syndrome is mainly associated with variants in the SMAD4 and BMPR1A genes. PTEN hamartoma tumor syndrome is predominantly caused by PTEN gene variants. Hereditary mixed polyposis syndrome is primarily related to variants of the GREM1 and BMPR1A genes. This article systematically summarizes the advances in genetic research on Gastrointestinal polyposis syndromes to enhance clinicians' understanding of these diseases and improve their diagnostic and therapeutic approaches.
Humans ; Adenomatous Polyposis Coli/genetics* ; Smad4 Protein/genetics* ; Peutz-Jeghers Syndrome/genetics* ; PTEN Phosphohydrolase/genetics* ; Bone Morphogenetic Protein Receptors, Type I/genetics* ; Intestinal Polyposis/congenital* ; Intercellular Signaling Peptides and Proteins/genetics* ; Adenomatous Polyposis Coli Protein/genetics* ; Protein Serine-Threonine Kinases/genetics* ; AMP-Activated Protein Kinase Kinases ; Neoplastic Syndromes, Hereditary

OBJECTIVE: To analyze the clinical characteristics and genotypic changes of six children with RARS2 gene variants. METHODS: The clinical data of 6 children with RARS2 gene variants diagnosed at the Third Affiliated Hospital of Zhengzhou University from January 2017 to August 2024 were collected. Genetic variants were detected using trio-whole exome sequencing. Genomic DNA was extracted from samples and subjected to high-throughput sequencing. Variants were detected and analyzed using relevant databases and software. Pathogenic variants were validated by Sanger sequencing. The protein structure encoded by a previously unreported variant was predicted using a SWISS-MODEL online server. This study was approved by the Medical Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Ethics No.: 2024-373-01). RESULTS: Among the six children, four were males and two were females, with the most recent follow-up age ranging from 1-year-and-1-month to 7 years old. The age of onset was under 1 year in all cases. All six children exhibited seizures, including infantile spasms in three, spasms and tonic spasms in one, and focal seizures in two. One child became seizure-free for 4 ~ 5 years following Valproic acid combined with topiramate and adrenocorticotropic hormone (ACTH) pulse therapy, but subsequently experienced a relapse. Another child has remained seizure-free for nearly one year with oral sodium valproate, levetiracetam, and a "cocktail" therapy. Seizures were not controlled in the remaining four children. Pontocerebellar hypoplasia was observed on neuroimaging in two children. All six patients exhibited severe psychomotor retardation. A total of 10 RARS2 gene variants were identified, three of which were previously unreported. CONCLUSION The predominant clinical features of Pontocerebellar hypoplasia associated with RARS2 gene variants include infantile onset, severe psychomotor retardation or regression, drug-resistant epilepsy, and feeding difficulties. The characteristic neuroimaging finding is pontocerebellar hypoplasia. However, its appearance may vary widely with time. The majority of affected children have a poor prognosis.
Humans ; Male ; Female ; Child, Preschool ; Infant ; Child ; Olivopontocerebellar Atrophies/genetics* ; Arginine-tRNA Ligase/genetics* ; Mutation ; Cerebellar Diseases

OBJECTIVE: To explore the genetic etiology for a child presenting with motor retardation, language delay, intellectual disability, and dysmorphic features. METHODS: A child presented at Linyi People's Hospital in June 2022 was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples were obtained from the child and her parents. Following extraction of genomic DNA, whole-exome sequencing (WES) was carried out. Candidate variant was validated by Sanger sequencing. Amniotic fluid samples were obtained from the mother's subsequent pregnancies for prenatal diagnosis. This study has been reviewed and approved by the Medical Ethics Committee of Linyi People's Hospital (Ethics No.: 2019-134). RESULTS: The proband was a 2-year-old girl showing developmental delays in motor, language, and intellectual domains, strabismus, hypertelorism, hearing impairment, obesity, and brachymesophalangy of the fifth finger. Magnetic resonance imaging revealed abnormalities of the white matter. Chromosomal microarray analysis (CMA) identified a 15q26.3 duplication (chr15:101562020_102060896 × 3) inherited from her mother. WES has uncovered a heterozygous c.1931A>G (p.Tyr644Cys) variant in the FBXO11 gene. Sanger sequencing confirmed the variant to be de novo in origin. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as likely pathogenic. Prenatal diagnosis revealed that the fetuses from the mother's second and third pregnancies did not harbor the same variant. CONCLUSION The c.1931A>G (p.Tyr644Cys) variant of the FBXO11 gene probably underlay the abnormal phenotype in the child. Based on its genotype and phenotype, the proband was diagnosed with Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities.
Humans ; Female ; Intellectual Disability/genetics* ; Child, Preschool ; F-Box Proteins/genetics* ; Protein-Arginine N-Methyltransferases/genetics* ; Exome Sequencing