Background/Objectives: Background: Early-onset Alzheimer’s disease (EOAD) is primarily inherited in an autosomal dominant pattern, with mutations in the APP, PSEN1, and PSEN2 genes being central contributors. Diagnosing Alzheimer’s poses challenges due to the coexistence of various co-pathologies, and treatment options remain limited for most patients, apart from familial cases linked to specific genetic mutations. While significant research on Alzheimer’s genetics has been conducted in both Asian and Caucasian populations, the specific mutations and their clinical impacts in EOAD are still inadequately explored. This review aims to provide a detailed analysis of commonly reported genetic mutations and associated clinical features in EOAD patients from Asian and Western populations. Methods: Following the PRISMA-ScR guidelines, a systematic database search was conducted for studies published between 2016 and 2023. After screening 491 records, 36 studies from Asian cohorts and 40 from Western cohorts met the inclusion criteria. Results: The analysis revealed 127 unique mutations in the Asian population and 190 in the Western population. About 16.7% of Asian and 21.9% of Western studies covered both familial and sporadic AD, with consistent patterns across groups. Some mutations were shared between the populations and displayed similar clinical features, while others were population-specific. Conclusions: These findings underscore the considerable variability in EOAD mutations and phenotypes, emphasizing the importance of genetic testing in younger patients to enhance diagnostic accuracy and guide treatment strategies effectively.

Background/Objectives: Aromatic L-amino acid decarboxylase deficiency (AADC-D; OMIM #608643) is a rare autosomal recessive neurometabolic disorder caused by pathogenic variants in the DDC gene, leading to impaired of monoamine neurotransmitter biosynthesis. AADC, a pyridoxal-5′-phosphate (PLP)-dependent enzyme, catalyzes the conversion of L-dopa and 5-hydroxytryptophan (5-HTP) to dopamine and serotonin, respectively. Early diagnosis remains challenging due to the limited specificity of current biochemical approaches. This study aimed to evaluate plasma AADC enzyme activity using these physiological substrates by High-Performance Liquid Chromatography (HPLC)-based method and assess its potential utility in the biochemical diagnosis of AADC deficiency. Methods: Plasma AADC activity was quantified using physiological substrates (L-dopa and 5-HTP) by HPLC with electrochemical and fluorescence detection. Sanger sequencing of the DDC gene was performed in two suspected patients to identify pathogenic variants. Results: Two genetically confirmed AADC-D patients demonstrated reduced enzyme activity. Using L-dopa as substrate, enzyme activity in patients was 12.4 and 26.1 pmol/min/mL, both below the published reference interval (36–129 pmol/min/mL). Using 5-HTP as substrate, enzyme activity was 1.5 and 5.1 pmol/min/mL; Patient 1 showed activity below the reference interval (2.0–7.1 pmol/min/mL), while Patient 2 demonstrated activity within the lower range of reported values. Reduced enzyme activity was consistent with the clinical features and molecular findings with identification of pathogenic variants in the DDC gene (c.175G>A and c.714+4A>T). Conclusions: Plasma AADC activity measurement demonstrates potential as a functional biochemical biomarker that augments molecular genetic testing in the biochemical evaluation of AADC deficiency. Further studies involving larger patient cohorts are required to further evaluate its diagnostic performance and broader clinical applicability.

Background/Objectives: Early detection of mitochondrial disorders remains challenging due to phenotypic heterogeneity and limited access to definitive molecular diagnostics. Circulating biomarkers such as growth differentiation factor-15 (GDF-15) and fibroblast growth factor-21 (FGF-21) have emerged as potential adjunct indicators. This study evaluated the screening and stratification utility of GDF-15 and FGF-21 in individuals assessed for suspected mitochondrial disease. Methods: Archived biological specimens collected between 2016 and 2017 were analysed from 221 individuals stratified into clinically high-risk, screen-positive non-high-risk, post-mortem unexplained death and healthy controls groups. Plasma and fibroblast lysate concentrations of GDF-15 and FGF-21 were quantified using enzyme-linked immunosorbent assays. Biomarker performance was assessed using receiver operating characteristic (ROC) analysis, comparative group analysis and correlation testing across clinically defined referral groups. Results: Both biomarkers were significantly elevated in clinically high-risk and screen-positive individuals compared with controls. GDF-15 demonstrated better discriminatory performance than FGF-21, with an area under the curve (AUC) of 0.7187 ± 0.0556 versus 0.6301 ± 0.0603. At a threshold of 300 pg/mL, GDF-15 demonstrated high sensitivity with moderate specificity for differentiation between clinically defined high-risk individuals and controls. Correlation analysis showed weak associations between GDF-15 and lactate and ammonia, while FGF-21 correlated modestly with glucose and alkaline phosphatase. A moderate positive correlation was observed between GDF-15 and FGF-21 across the overall cohort. Conclusions: GDF-15 and, to a lesser extent, FGF-21 may support early screening and stratification of individuals evaluated for suspected mitochondrial disease and assist in prioritising cases for further diagnostic evaluation.

Dalam penyakit kepincangan metabolisme terwaris (inborn errors of metabolism – IEM), terdapat tujuh jenis penyakit berpunca daripada kekurangan enzim yang terlibat dalam metabolisme homosisteina. Paras homosisteina jumlah adalah berbeza mengikut jenis penyakit akibat kekurangan enzim ini. Maka, terdapat keperluan bagi mewujudkan suatu julat rujukan untuk membezakan antara populasi normal dengan populasi berpenyakit. Kajian ini menerangkan penemuan kami berkenaan julat rujukan bagi homosisteina jumlah di kalangan kanak-kanak di Malaysia. Sebanyak 3 ml darah telah diambil daripada 86 individu normal (52 orang kanak-kanak lelaki dan 34 orang kanak-kanak perempuan) dan seterusnya diproses serta dianalisis menggunakan kaedah Kromatografi Cecair Berprestasi Tinggi jenis fasa penukar ion (HPLC-IEC). Hasil kajian mendapati min homosisteina jumlah bagi keseluruhan populasi rujukan ialah sebanyak 8.1 ± 3.89 µM (95% selang keyakinan 7.3-8.9 µM). Julat rujukan yang diwujudkan untuk populasi rujukan adalah sebanyak 2.5 – 16.2 µM dengan had pemutus terendah (lower cut-off) dan had pemutus teratas (upper cut-off) masing-masing adalah 1.0 µM dan 21.0 µM. Julat yang berjaya diwujudkan ini didapati agak tinggi berbanding dengan penyelidik luar. Penemuan ini dapat mengurangkan jumlah kadar positif palsu semasa proses diagnosis penyakit dilakukan. Secara kesimpulannya, kami telah berjaya mewujudkan suatu julat rujukan bagi homosisteina jumlah untuk populasi kanak-kanak di Malaysia. DOI : http://dx.doi.org/10.17576/JSKM-2021-1902-03

Background: Mucopolysaccharidoses type II (MPS II) is an X-linked lysosomal storage disease (LSD). It is due to mutation in IDS gene encoding iduronate-2-sulphatase (IDS) involved in the catabolism of dermatan sulphate and heparan sulphate. Currently, the treatments for MPS II patients are enzyme replacement therapy (ERT) and bone marrow transplantation (BMT). However, ERT is not effectively reducing the central nervous system manifestation and finding the suitable donor maybe quite challenging in BMT. Over the past decades, pharmacological chaperone has been an alternative approach for management of MPS II patient. Here, we described the in vitro profiling of small molecules in group of chondroitin/dermatan (CD) sulphate disaccharide, heparin oligosaccharides, unsaturated heparin disaccharides and 6-O-desulphated heparin oligosaccharide, using recombinant human iduronate-2-sulphatase (rhIDS). Twenty-one small molecule compounds with several concentrations were each screened by inhibition and thermal stability assays. Results: Our study revealed that condroitin dermatan trisulphate (CD3S), heparin tetrasaccharide (H4Sac), heparin octasaccharide (H8Sac) and heparin octadecasaccharide (H18Sac) showed high inhibition constant, Ki and low inhibition concentration, IC50 in comparison to others. In the thermal stability study, only rhIDS incubated with CD3S was found to preserve enzyme activity (20%) after incubated at 67oC. Conclusion: Overall, our experiments discovered that CD3S was able to bind, inhibit and chaperone rhIDS. These features suggest a potential pharmacological chaperone for MPS II.

Retinoblastoma is the most common intraocular malignancy in childhood, typically presenting before five years of age. Early detection is essential in impro