Article
Biochemistry & Molecular Biology
Giovanni Bisello, Katarzyna Kusmierska, Marcel M. Verbeek, Jolanta Sykut-Cegielska, Michel A. A. P. Willemsen, Ron A. Wevers, Krystyna Szymanska, Jaroslaw Poznanski, Jakub Drozak, Katarzyna Wertheim-Tysarowska, Agnieszka Magdalena Rygiel, Mariarita Bertoldi
Summary: Aromatic amino acid decarboxylase (AADC) deficiency is a rare monogenic disease that causes intellectual disability, movement disorders, and autonomic dysfunction. In this study, a novel mutation of AADC was identified, which resulted in a significant decrease in enzymatic activity. The defect was found to be due to the mispositioning of the catalytically competent intermediate. These findings provide insights into the pathogenesis of AADC deficiency and a potential target for precision therapy.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Editorial Material
Medicine, Research & Experimental
Paul Wuh-Liang Hwu, Karl Kiening, Irina Anselm, David R. Compton, Takeshi Nakajima, Thomas Opladen, Phillip L. Pearl, Agathe Roubertie, Thomas Roujeau, Shin-ichi Muramatsu
Summary: This commentary provides an overview of the putamen as an established target site for gene therapy in treating AADC deficiency and Parkinson's disease, showcasing the rationale behind targeting this brain structure based on its neuroanatomy and function in motor control. The efficacy and safety of intraputaminal gene therapy in restoring dopamine synthesis by using low doses of adeno-associated viral vector serotype 2 to deliver the hAADC gene are well tolerated, leading to sustained improvements in motor and nonmotor symptoms of AADC deficiency and improved uptake and conversion of exogenous L-DOPA into dopamine in Parkinson's patients.
EMBO MOLECULAR MEDICINE
(2021)
Article
Gastroenterology & Hepatology
Yuta Sugiyama, Yumiko Mori, Misaki Nara, Yusuke Kotani, Emiko Nagai, Hiroki Kawada, Mayu Kitamura, Rika Hirano, Hiromi Shimokawa, Akira Nakagawa, Hiromichi Minami, Aina Gotoh, Mikiyasu Sakanaka, Noriho Iida, Takashi Koyanagi, Takane Katayama, Shigefumi Okamoto, Shin Kurihara
Summary: Gut microbiota can produce aromatic amines, which are different from dietary sources. The production of these aromatic amines is related to the activity of aadc in gut bacteria and may have an impact on diseases such as osteoporosis and irritable bowel syndrome. Human AADC inhibitors can inhibit the production of aromatic amines in gut bacteria.
Review
Microbiology
Sara Goncalves, Daniela Nunes-Costa, Sandra Morais Cardoso, Nuno Empadinhas, John David Marugg
Summary: Serotonin is a vital compound found in animals, plants, and bacteria. It plays critical roles in regulating body functions and its depletion is associated with neurological disorders in humans. Investigating the biosynthetic pathways of serotonin in bacteria, which may serve as a potential source of serotonin, could lead to important discoveries and the development of new therapeutic strategies.
FRONTIERS IN MICROBIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Riccardo Montioli, Carla Borri Voltattorni
Summary: AADC deficiency is a rare autosomal recessive neurometabolic disorder caused by mutations in the DDC gene, resulting in decreased enzyme activity and affecting the synthesis of dopamine and serotonin. Clinical, genetic, and biochemical studies have contributed significantly to the understanding and diagnosis of AADC deficiency, providing insights into the molecular mechanisms of the disorder.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Endocrinology & Metabolism
Alberto Burlina, Antonella Giuliani, Giulia Polo, Daniela Gueraldi, Vincenza Gragnaniello, Chiara Cazzorla, Thomas Opladen, Georg Hoffmann, Nenad Blau, Alessandro P. Burlina
Summary: The study introduces a rapid new method to identify AADC deficiency using reagents and equipment widely used in neonatal screening programs. The analysis of 3-OMD concentrations in healthy newborns and patients receiving L-Dopa treatment demonstrated the effectiveness of the method, laying the foundation for potential deployment in expanded neonatal screening to enable early diagnosis for effective treatment.
MOLECULAR GENETICS AND METABOLISM
(2021)
Review
Biotechnology & Applied Microbiology
Yingying Wang, Yan Chen, Alei Zhang, Kequan Chen, Pingkai Ouyang
Summary: Serotonin, a monoamine neurotransmitter, plays a crucial role in the modulation of the nervous system. Impairments in its synthesis and homeostasis are linked to various disorders, including depression, Parkinson's disease, and anxiety. Current methods of obtaining serotonin are time-consuming, low yield, and rely on unstable raw material supply. However, with the advancements in synthetic biology, microbial synthesis of serotonin has gained attention for its advantages in terms of production cycle, continuity, and environmental friendliness. Despite this, the yield of serotonin is still insufficient for industrialization, prompting the need for strategies to increase its production.
APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
(2023)
Article
Genetics & Heredity
Susanna Rizzi, Carlotta Spagnoli, Melissa Bellini, Carlo Alberto Cesaroni, Elisabetta Spezia, Patrizia Bergonzini, Elisa Caramaschi, Luca Soliani, Emanuela Claudia Turco, Benedetta Piccolo, Laura Demuth, Duccio Maria Cordelli, Giacomo Biasucci, Daniele Frattini, Carlo Fusco
Summary: AADCd is a rare metabolic disorder characterized by early-onset hypotonia, severe developmental delay, movement disorders, and dysautonomia. This multicentric study aims to identify the prevalence of AADCd in a population with neurodevelopmental disorders by detecting 3-OMD in dried blood spots. It is important to investigate patients with defined clinical characteristics and start treatment early to improve outcomes.
Article
Neurosciences
Anouke van Rumund, Lukas Pavelka, Rianne A. J. Esselink, Ben P. M. Geurtz, Ron A. Wevers, Brit Mollenhauer, Rejko Krueger, Bastiaan R. Bloem, Marcel M. Verbeek
Summary: The study found that Parkinson's disease patients using peripheral decarboxylase inhibitors had elevated serum AADC enzyme activity, which may lead to the need for increased levodopa dosage to maintain therapeutic effects.
NPJ PARKINSONS DISEASE
(2021)
Article
Dentistry, Oral Surgery & Medicine
Joanna Smardz, Helena Martynowicz, Anna Wojakowska, Joanna Wezgowiec, Cyprian Olchowy, Dariusz Danel, Grzegorz Mazur, Mieszko Wieckiewicz
Summary: This exploratory research aimed to evaluate the levels of TPH1 and DDC in individuals with sleep bruxism compared to those without. The study found no significant differences in enzyme levels between the two groups, but a significant negative correlation between tonic SB episodes and DDC levels was observed.
CLINICAL ORAL INVESTIGATIONS
(2022)
Article
Endocrinology & Metabolism
Agathe Roubertie, Thomas Opladen, Heiko Brennenstuhl, Oya Kuseyri Huebschmann, Lisa Flint, Michel A. Willemsen, Vincenzo Leuzzi, Angels Garcia Cazorla, Manju A. Kurian, Marie Celine Francois-Heude, Paul Hwu, Bruria Ben Zeev, Karl Kiening, Thomas Roujeau, Roser Pons, Toni S. Pearson
Summary: The autosomal recessive defect of aromatic L-amino acid decarboxylase (AADC) leads to a severe neurological disorder with combined deficiency of dopamine, serotonin and catecholamines. Gene therapy, specifically using Eladocagene exuparvovec, has been approved for the treatment of AADC deficiency, providing a new era of causal therapy. The International Working Group on Neurotransmitter related Disorders has developed guidelines for the management, preparation, and follow-up of AADC deficiency patients undergoing gene therapy.
JOURNAL OF INHERITED METABOLIC DISEASE
(2023)
Article
Clinical Neurology
Giada Rossignoli, Karolin Kramer, Eleonora Lugara, Haya Alrashidi, Simon Pope, Carmen De la Fuente Barrigon, Katy Barwick, Giovanni Bisello, Joanne Ng, John Counsell, Gabriele Lignani, Simon J. R. Heales, Mariarita Bertoldi, Serena Barral, Manju A. Kurian
Summary: AADC deficiency is a complex inherited neurological disorder characterized by cognitive and motor delay, which can be modeled using patient-derived neuronal models. Therapeutic approaches such as gene therapy and L-DOPA treatment have shown promise in improving neuronal developmental defects and dopamine metabolism deficiency in this condition.
Article
Endocrinology & Metabolism
Carmen Longo, Riccardo Montioli, Giovanni Bisello, Luana Palazzi, Mario Mastrangelo, Heiko Brennenstuhl, Patrizia Polverino de Laureto, Thomas Opladen, Vincenzo Leuzzi, Mariarita Bertoldi
Summary: Compound heterozygosis in aromatic amino acid decarboxylase (AADC) deficiency is a complex condition that results in severe neurological impairment. This study identified and characterized two new heterodimers in AADC deficiency patients, revealing differences in activity and stability. Understanding the functional properties of these heterodimers can provide insights into the pathophysiological mechanisms of AADC deficiency.
MOLECULAR GENETICS AND METABOLISM
(2021)
Review
Neurosciences
Tingyan Wu, Weili Cai, Xi Chen
Summary: Neurotransmission signaling is a conserved system with important regulatory events. The role of excitatory and inhibitory neurotransmitter systems in brain function is well established. Recent research has shown that epigenetic regulation plays a crucial role in controlling the expression of neurotransmitter-related genes and its dysregulation is associated with neurological disorders. This article explores the epigenetic regulation of dopamine, GABA, glutamate, and serotonin genes, and discusses how targeting these mechanisms can lead to improved treatments for neurological disorders.
NEUROBIOLOGY OF DISEASE
(2023)
Article
Clinical Neurology
Hongmei Wang, Jiahong Li, Ji Zhou, Lifang Dai, Changhong Ding, Mo Li, Weixing Feng, Fang Fang, Xiaotun Ren, Xiaohui Wang
Summary: This article reports a Chinese patient with AADC deficiency who was initially misdiagnosed with epilepsy. The accurate diagnosis of AADCD was established through analysis of neurotransmitters in cerebrospinal fluid (CSF) and two novel missense mutations in the DDC gene were identified.
FRONTIERS IN NEUROLOGY
(2022)
Letter
Pediatrics
Rai-Hseng Hsu, Ni-Chung Lee, Ming-Tai Lin, Ting-An Yen, Yin-Hsiu Chien, Wuh-Liang Hwu
PEDIATRICS AND NEONATOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Huang-Yi Li, Ni-Chung Lee, Yu-Ting Chiu, Yu-Wen Chang, Chu-Chung Lin, Cheng-Li Chou, Yin-Hsiu Chien, Wuh-Liang Hwu, Wei-Chieh Cheng
Summary: In order to discover small molecules as stabilizers for acid alpha-glucosidase (GAA) in Pompe disease cells, a unique chemical space of 16 stereoisomers was screened, leading to the identification of stabilizers 17 and 18. Further modifications and evaluation using protein thermal shift study resulted in the identification of pyrrolidine 21 as a potent stabilizer for rh-GAA, improving enzymatic activity in a cell-based Pompe model. Pyrrolidine 21 has the potential to enhance the efficacy of enzyme replacement therapy (ERT) in cells and in vivo.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Genetics & Heredity
Yu-Kang Hsu, Yin-Hsiu Chien, Steven Shinn-Forng Peng, Wuh-Liang Hwu, Wang-Tso Lee, Ni-Chung Lee, Eric Po-Yu Huang, Wen-Chin Weng
Summary: The study aimed to investigate the CNS progression in patients with infantile-onset Pompe disease (IOPD) and its clinical impact and predictors. The findings showed that CNS involvement in IOPD expanded from white matter to gray matter, and the MRI scores were positively correlated with age and negatively correlated with IQ scores. Neuroaxonal injury and decreased IQ scores may be associated with the progression of CNS involvement in IOPD. Neurofilament light chain could serve as a biomarker for CNS involvement in IOPD.
GENETICS IN MEDICINE
(2023)
Letter
Immunology
Yu-Chia Chen, Shiann-Tarng Jou, Ni-Chung Lee, Bor-Luen Chiang, Hsin-Hui Yu
JOURNAL OF CLINICAL IMMUNOLOGY
(2023)
Editorial Material
Pediatrics
Wuh-Liang Hwu
PEDIATRICS AND NEONATOLOGY
(2023)
Letter
Pediatrics
Jeng-Hung Wu, Yu-Jui Wang, Jau-Yu Liau, Ni-Chung Lee, En-Ting Wu
PEDIATRICS AND NEONATOLOGY
(2023)
Review
Pediatrics
Yin-Hsiu Chien, Wuh-Liang Hwu
Summary: Newborn screening has been developed to identify newborns with severe but treatable conditions. Taiwan's system has been optimized to enable multiplex screening and increased conditions to be screened. However, challenges include knowledge gaps, long-term clinical evidence for new therapies, management of phenotypic variations, and cost-effectiveness of extended screening programs.
PEDIATRICS AND NEONATOLOGY
(2023)
Letter
Pediatrics
Hui-An Chen, Nai-Qi Chen, Rai-Hseng Hsu, Wuh-Liang Hwu
PEDIATRICS AND NEONATOLOGY
(2023)
Article
Genetics & Heredity
Rai-Hseng Hsu, Hui-An Chen, Yin-Hsiu Chien, Wuh-Liang Hwu, Ju-Li Lin, Hui-Ling Weng, Yi-Ting Lin, Yu-Ching Lin, Ni-Chung Lee
Summary: This study found that taking extended release cornstarch (Glycosade) at bedtime can increase blood glucose levels and improve sleep quality in patients with GSDIa. It also reduces the levels of alanine aminotransferase and aspartate aminotransferase, leading to an improvement in quality of life.
MOLECULAR GENETICS & GENOMIC MEDICINE
(2023)
Article
Genetics & Heredity
Rai-Hseng Hsu, Chen-Hao Lee, Yin-Hsiu Chien, Shuan-Pei Lin, Miao-Zi Hung, Nai-Chi Chen, Yi-Lin Lin, Wuh-Liang Hwu, Ni-Chung Lee
Summary: This study evaluated a referral system to increase the yield of whole-exome sequencing (WES) for congenital anomalies (CAs). The study found that pathogenic variants in 14 genes were discovered in 16 patients with CA, resulting in a positive diagnostic rate of 40%. However, more than half of the CA patients still do not have a genetic diagnosis by current technologies.
MOLECULAR GENETICS & GENOMIC MEDICINE
(2023)
Article
Clinical Neurology
Sung -Pin Fan, Yih-Chih Kuo, Ni-Chung Lee, Yin-Hsiu Chien, Wuh-Liang Hwu, Yu-Hsuan Huang, Han- Lin, Tai -Chung Tseng, Tung -Hung Su, Shiou-Ru Tzeng, Chien -Ting Hsu, Huey -Ling Chen, Chin-Hsien Lin, Yen-Hsuan Ni
Summary: In this retrospective analysis, the clinical characteristics and long-term outcomes of a large cohort of WD patients were determined. Differences were observed between the neuro-psychiatric group and the hepatic group in terms of presentation, neuroimaging, genetic information, and prognosis. The findings suggest that the clinical characteristics and prognosis of WD are influenced by ethnic differences.
JOURNAL OF MOVEMENT DISORDERS
(2023)
Article
Endocrinology & Metabolism
Pin-Wen Chen, Wuh-Liang Hwu, Ni-Chung Lee, Yin-Hsiu Chien
Summary: This study demonstrates that the detection of L-dopa metabolite 3-OMD can be easily integrated into existing newborn screening programs to facilitate early diagnosis and effective treatment of AADC deficiency. Among 157,371 newborns screened, 8 newborns were found to have elevated 3-OMD concentration, and 6 of them were confirmed to carry two pathogenic DDC variants. The results suggest that this screening method can be an important tool for identifying and treating AADC deficiency.
MOLECULAR GENETICS AND METABOLISM
(2023)
Article
Clinical Neurology
Pin-Shiuan Chen, Ni-Chung Lee, Chieh-Ju Sung, Ya-Wen Liu, Wen-Chin Weng, Pi-Chuan Fan, Wang-Tso Lee, Yin-Hsiu Chien, Chao-Szu Wu, Yueh-Feng Sung, Ming-Chen Tsai, Yi-Chung Lee, Hsueh-Wen Hsueh, Sabrina Mai-Yi Fan, Meng-Chen Wu, Hsun Li, Huan-Yun Chen, Han- Lin, Chih-Hsin Ou-Yang, Wuh-Liang Hwuh, Chin-Hsien Lin
Summary: This study describes the clinical characteristics and functional findings in a cohort of patients with NDUFAF5 mutations, and reveals significant heterogeneity and divergent prognosis based on age at onset. This research is important for understanding the association between NDUFAF5 mutations and Leigh syndrome.
MOVEMENT DISORDERS
(2023)
Article
Genetics & Heredity
Meng-Ju Melody Tsai, Miao-Zi Hung, Yi-Lin Lin, Ni-Chung Lee, Yin-Hsiu Chien, Wuh-Liang Hwu
Summary: Using whole-genome sequencing data, this study identified 3826 variants in 71 genes responsible for autosomal recessive LSDs in a Taiwanese population. By curating these variants, the study estimated the incidence rate of LSDs in Taiwan to be between 13 per 100,000 and 94 per 100,000, providing important information for screening and treatment methods.
NPJ GENOMIC MEDICINE
(2023)
Article
Neurosciences
Nihal A. Salem, Lawrence Manzano, Michael W. Keist, Olga Ponomareva, Amanda J. Roberts, Marisa Roberto, R. Dayne Mayfield
Summary: This study identified cell-type specific gene expression changes associated with alcohol dependence in the medial prefrontal cortex of mice. The results revealed dysregulated gene co-expression networks and differentially expressed genes in multiple cell types, highlighting the involvement of inhibitory neurons and astrocytes in alcohol dependence. Novel targets for studying molecular mechanisms contributing to alcohol dependence were also identified.
NEUROBIOLOGY OF DISEASE
(2024)
Article
Neurosciences
Laura E. Hawley, Megan Stringer, Abigail J. Deal, Andrew Folz, Charles R. Goodlett, Randall J. Roper
Summary: This study found that the overexpression of DYRK1A protein in Down syndrome mice varies with age, sex, and brain region, and reducing the copy number of Dyrk1a can decrease the expression of DYRK1A. These sex-specific patterns of DYRK1A overexpression may provide mechanistic targets for therapeutic intervention in Down syndrome.
NEUROBIOLOGY OF DISEASE
(2024)