Journal of Inherited Metabolic Disease最新文献

{"title":"“East meets West”: SSIEM 2023 Annual Symposium at Jerusalem","authors":"Yair Anikster","doi":"10.1002/jimd.12797","DOIUrl":"https://doi.org/10.1002/jimd.12797","url":null,"abstract":"<p>The 2023 Annual Symposium of the Society for the Study of Inborn Errors of Metabolism (SSIEM) was held in Jerusalem from August 29 to September 1, under the theme “East Meets West.” This gathering was a significant effort to bring together specialists from both Eastern and Western medical traditions, all united by a common goal: to enhance patient care globally by sharing knowledge, experiences, and practices in the field of inborn errors of metabolism (IEM). The symposium hosted more than 1500 participants from 64 different countries, offering a platform where experts could discuss and compare the challenges and innovations faced in different regions, whether they are in the East or the West. By transcending geographical boundaries, this event sought to create a more unified and effective approach to treating IEMs, ensuring that advances in one part of the world could benefit patients everywhere.</p><p>The plenary sessions at SSIEM 2023 reflected this commitment to global collaboration. In the session titled “Where East Meets West – Differential Expression of the Same Disease in Different Regions of the World,” participants explored how the manifestation of certain IEMs varies significantly across regions. Discussions included the higher prevalence of Neuronopathic Gaucher Disease in Eastern populations as opposed to the non-neuronopathic phenotype in the West,<span><sup>1</sup></span> the distinct phenotypes of dihydrolipoamide dehydrogenase deficiency in two Israeli populations,<span><sup>2</sup></span> and Citrin deficiency, which is common in the East but rare in the West.<span><sup>3</sup></span> Citrin deficiency in the far east was also the topic of the SSIEM annual Garrod lecture. These case studies highlighted the importance of understanding regional genetic variations to improve diagnosis and treatment strategies.</p><p>Another session, “The State of the Mitochondria – Old Players, New Roles,” focused on mitochondrial diseases, revealing how new disorders involving inborn errors of vitamins B<sub>3</sub> and B<sub>5</sub><span><sup>4</sup></span> are reshaping our understanding of mitochondrial function. The session underscored the critical role mitochondria play in various IEMs and how emerging research is uncovering new therapeutic targets.</p><p>In “Learning from the Neighbors,” the emphasis was on cross-disciplinary learning within the medical community. The session brought to light how pediatricians can learn from adult IEM cases,<span><sup>5</sup></span> the vital role laboratory scientists play in advancing clinical care, and the integration of big data and machine learning in clinical decision-making. This exchange of knowledge among different medical disciplines is crucial for refining the art of metabolomics and enhancing patient outcomes.</p><p>The session on “The Complexity of Brain Traffic: New Insights from Neurometabolism” provided new perspectives on neurometabolic disorders. Discussions included inborn errors of cel","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"47 5","pages":"839-840"},"PeriodicalIF":4.2,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12797","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of early treatment with intravenous idursulfase and intrathecal idursulfase‐IT on cognitive function in siblings with neuronopathic mucopolysaccharidosis II","authors":"Joseph Muenzer, Barbara K. Burton, Paul Harmatz, Luis González Gutiérrez‐Solana, Matilde Ruiz‐Garcia, Simon A. Jones, Nathalie Guffon, Michal Inbar‐Feigenberg, Drago Bratkovic, Stewart Rust, Michael Hale, Yuna Wu, Karen S. Yee, David A. H. Whiteman, David Alexanderian","doi":"10.1002/jimd.12790","DOIUrl":"https://doi.org/10.1002/jimd.12790","url":null,"abstract":"Mucopolysaccharidosis II (MPS II; Hunter syndrome; OMIM 309900) is a rare, X‐linked, heterogeneous lysosomal storage disease. Approximately two‐thirds of patients develop cognitive impairment, which is difficult to assess in clinical trials, partly owing to the variable nature of cognitive impairment. Analyzing data from siblings can help to minimize this heterogeneity. We report analyses of cognitive function from siblings with MPS II enrolled in clinical trials: a natural history study (NCT01822184), a randomized, open‐label, phase 2/3 study of intravenous (IV) idursulfase with or without intrathecal idursulfase (idursulfase‐IT; NCT02055118), and its extension (NCT2412787). Cognitive function was assessed using Differential Abilities Scales, Second Edition General Conceptual Ability (DAS‐II GCA) scores; Bayley Scales of Infant and Toddler Development, Third Edition; and Vineland Adaptive Behavior Scales, Second Edition Adaptive Behavior Composite (VABS‐II ABC). Seven sets of siblings (six pairs and one set of three) were included. All patients received IV idursulfase and 10 received subsequent idursulfase‐IT. Younger siblings initiated IV idursulfase at an earlier age than their older sibling(s) in six of the sets; the younger sibling started treatment before 1 year of age in three sets. Monthly idursulfase‐IT was generally associated with a stabilization of cognitive function: DAS‐II GCA and VABS‐II ABC scores were higher at age‐matched assessments in the majority of those who either received idursulfase‐IT earlier than their sibling or who received idursulfase‐IT versus no idursulfase‐IT. These data suggest that early initiation of intrathecal enzyme replacement therapy may stabilize or slow cognitive decline in some patients with neuronopathic MPS II.","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"39 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142189610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term safety of sapropterin in paediatric and adult individuals with phenylalanine hydroxylase deficiency: Final results of the Kuvan® Adult Maternal Paediatric European Registry multinational observational study","authors":"François Feillet,&nbsp;Jean-Baptiste Arnoux,&nbsp;María Bueno Delgado,&nbsp;Alberto Burlina,&nbsp;Brigitte Chabrol,&nbsp;Ece Kucuksayrac,&nbsp;Florian B. Lagler,&nbsp;Ania C. Muntau,&nbsp;David Olsson,&nbsp;Sabrina Paci,&nbsp;Frank Rutsch,&nbsp;Francjan J. van Spronsen,&nbsp;the KAMPER investigators","doi":"10.1002/jimd.12796","DOIUrl":"10.1002/jimd.12796","url":null,"abstract":"<p>Phenylketonuria is a rare inherited disorder that disrupts the metabolism of phenylalanine (Phe) to tyrosine by phenylalanine hydroxylase (PAH). Sapropterin dihydrochloride (Kuvan®) is approved for use in Europe to reduce blood Phe levels and improve Phe tolerance in sapropterin-responsive individuals. KAMPER (NCT01016392) is an observational, multinational registry assessing long-term safety and efficacy of sapropterin. Five hundred and seventy-six participants with PAH deficiency were enrolled from nine European countries (69 sites; December 2009–May 2016). Participants were aged &lt;4 years (<i>n</i> = 11), 4 to &lt;12 years (<i>n</i> = 329), 12 to &lt;18 years (<i>n</i> = 141), and ≥18 years (<i>n</i> = 95) at enrolment. Overall, 401 (69.6%) participants experienced a total of 1960 adverse events; 61 events in 42 participants were serious, and two were considered sapropterin-related by the investigator. Mean (standard deviation) actual dietary Phe intake increased from baseline across all age groups: 957 (799) mg/day to a maximum of 1959 (1121) mg/day over a total study period of 11 years. Most participants exhibited an increase in Phe tolerance while blood Phe levels remained in the target range for their age (120–360 μmol/L for &lt;12 years; 120–600 μmol/L for ≥12 years). Most participants exhibited normal growth for height, weight, and body mass index. No additional safety concerns were identified. As an observational study, limitations include variability in routine care practices and inconsistent availability of data. Long-term sapropterin use demonstrates a favourable safety profile in real-world settings and increases Phe tolerance in participants with PAH deficiency while maintaining blood Phe levels in the target ranges.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intra- and extracellular real-time analysis of perfused fibroblasts using an NMR bioreactor: A pilot study","authors":"Christian Urzì,&nbsp;Christoph Meyer,&nbsp;Déborah Mathis,&nbsp;Peter Vermathen,&nbsp;Jean-Marc Nuoffer","doi":"10.1002/jimd.12794","DOIUrl":"10.1002/jimd.12794","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Introduction&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Metabolomic discrimination of different mitochondrial defects is challenging. We describe an NMR-based bioreactor allowing real-time intra- and extracellular metabolic investigation of perfused fibroblasts.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Objectives&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The objective of this study is (I) determining whether metabolic investigations of perfused fibroblasts overall and separated for intra- and extracellular contributions by real-time NMR allows for discrimination of different representative mitochondrial defects in a feasibility study and (II) gaining insight into physiological consequences of mitochondrial dysfunction in basal condition and during glycolysis inhibition.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Overall, intra- and extracellular metabolomes of malate dehydrogenase 2 (MDH2), pyruvate dehydrogenase (PDH), complex I (CI) deficient fibroblasts, and control fibroblasts were investigated under standard culture conditions and under glycolysis inhibition. In addition to “overall” metabolite quantification, intra- and extracellular metabolic contributions were separated based on diffusion rate differences.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results and Discussion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Overall metabolites: Chemometric analysis of the entire metabolome revealed good separation between control, PDH and MDH2, while CI was less well separated. However, mixed intra- and extracellular changes complicated interpretation of the cellular metabolism. Intra- and extracellular metabolites: Compartment specific chemometrics revealed possibly augmenting metabolomic separation between control and deficient cell lines under basal and inhibition condition. All mitochondrial defects exhibited upregulation of glycolytic metabolism compared to controls. Inhibition of glycolysis resulted in perturbations of other metabolic pathways such as glutaminolysis, alanine, arginine, glutamate, and proline metabolism. MDH2 showed upregulation of alanine and glutamate metabolism, while the CI defect revealed lower intracellular arginine and downregulation of glutamate and arginine-dependent proline synthesis.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Discrimination of intra- and extracellular metabolic contributions helps understanding the underlying mechanisms of mitochondrial disorders, uncovers potential metabolic biomarkers, and unravels metabolic pathway-specific adaptations in response to metabolic perturbations.&lt;/p&gt;\u0000 &lt;","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-risk screening for late-onset Pompe disease in China: An expanded multicenter study","authors":"Kexin Jiao,&nbsp;Bochen Zhu,&nbsp;Xueli Chang,&nbsp;Junhong Guo,&nbsp;Jun Fu,&nbsp;Xueqin Song,&nbsp;Xuen Yu,&nbsp;Xiaoge Zhang,&nbsp;Jihong Dong,&nbsp;Wang Yan,&nbsp;Xinghua Luan,&nbsp;Zhiqiang Wang,&nbsp;Hong Han,&nbsp;Lijun Du,&nbsp;Liqiang Yu,&nbsp;Yali Zhang,&nbsp;Jingjing Zhang,&nbsp;Yan Chen,&nbsp;Jing Hu,&nbsp;Zhe Zhao,&nbsp;Juan Kang,&nbsp;Song Tan,&nbsp;Zhiyun Wang,&nbsp;Shanshan Mao,&nbsp;Fangyuan Qian,&nbsp;Ronghua Luo,&nbsp;Changxia Liu,&nbsp;Zhengyu Huang,&nbsp;Gang Li,&nbsp;Xia Li,&nbsp;Lijun Luo,&nbsp;Dong Li,&nbsp;Yuanlin Zhou,&nbsp;Xiafei Hu,&nbsp;Xuefan Yu,&nbsp;Yongguang Shi,&nbsp;Jianming Jiang,&nbsp;Jialong Zhang,&nbsp;Nachuan Cheng,&nbsp;Ningning Wang,&nbsp;Xingyu Xia,&nbsp;Dongyue Yue,&nbsp;Mingshi Gao,&nbsp;Jianying Xi,&nbsp;Sushan Luo,&nbsp;Jiahong Lu,&nbsp;Chongbo Zhao,&nbsp;Qing Ke,&nbsp;Mingming Ma,&nbsp;Wenhua Zhu","doi":"10.1002/jimd.12793","DOIUrl":"10.1002/jimd.12793","url":null,"abstract":"<p>Late-onset Pompe disease (LOPD) is caused by a genetic deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA), leading to progressive limb-girdle weakness and respiratory impairment. The insidious onset of non-specific early symptoms often prohibits timely diagnosis. This study aimed to validate the high-risk screening criteria for LOPD in the Chinese population. A total of 726 patients were included, including 96 patients under 14 years of age. Dried blood spots (DBS) and tandem mass spectrometry (MS/MS) were employed to evaluate serum GAA activity. Forty-four patients exhibited a decreased GAA activity, 16 (2.2%) of which were confirmed as LOPD by genetic testing. Three previously unreported GAA mutations were also identified. The median diagnostic delay was shortened to 3 years, which excelled the previous retrospective studies. At diagnosis, most patients exhibited impaired respiratory function and/or limb-girdle weakness. Elevated serum creatine kinase (CK) levels were more frequently observed in patients who manifested before age 16. Overall, high-risk screening is a feasible and efficient method to identify LOPD patients at an early stage. Patients over 1 year of age with either weakness in axial and/or proximal limb muscles, or unexplained respiratory distress shall be subject to GAA enzymatic test, while CK levels above 2 times the upper normal limit shall be an additional criterion for patients under 16. This modified high-risk screening criteria for LOPD requires further validation in larger Chinese cohorts.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Parental and child's psychosocial and financial burden living with an inherited metabolic disease identified by newborn screening","authors":"Elena Schnabel-Besson,&nbsp;Sven F. Garbade,&nbsp;Florian Gleich,&nbsp;Sarah C. Grünert,&nbsp;Johannes Krämer,&nbsp;Eva Thimm,&nbsp;Julia B. Hennermann,&nbsp;Peter Freisinger,&nbsp;Peter Burgard,&nbsp;Gwendolyn Gramer,&nbsp;Marina A. Morath,&nbsp;A. Tunç Tuncel,&nbsp;Svenja Keßler,&nbsp;Georg F. Hoffmann,&nbsp;Stefan Kölker,&nbsp;Ulrike Mütze","doi":"10.1002/jimd.12784","DOIUrl":"10.1002/jimd.12784","url":null,"abstract":"<p>Newborn screening (NBS) is one of the most effective measures of secondary prevention. While the benefit of NBS on the clinical long-term outcomes of children with inherited metabolic diseases (IMD) has been demonstrated, the potential burden of families living with an early diagnosed and treated child with an IMD has not been thoroughly investigated. The aim of this longitudinal questionnaire-based study on 369 families living with a child with an IMD was to investigate the psychosocial and financial burden following a true-positive NBS. The reported psychosocial burden differed between children and their parents, and was associated with the child's age, diagnosis, and treatment. At younger ages, parent-reported burden was higher for the parents than for the individual child, while it increased for children and decreased for parents as the child grew older. Furthermore, psychosocial burden increased if the child required a strict dietary treatment and was at risk of metabolic decompensation. Regardless of diagnosis and treatment, the developmental delay of their child independently increased the parental psychosocial burden. Financial burden was reported by 24% of all families, and was higher in low-income families and in families whose children required dietary treatment. In conclusion, a substantial psychosocial and financial burden was revealed for children and their families after true-positive NBS. Since this burden is likely to have a negative impact on the long-term individual health benefits of NBS, this study underlines the importance of regularly assessing the psychosocial and financial needs of these families.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A 6-month randomized controlled trial for vitamin E supplementation in pediatric patients with Gaucher disease: Effect on oxidative stress, disease severity and hepatic complications","authors":"Amira Abdel Moneam Adly,&nbsp;Eman Abdel Rahman Ismail,&nbsp;Fatma A. Ibrahim,&nbsp;Mira Atef,&nbsp;Khaled Anwar El Sayed,&nbsp;Nihal Hussien Aly","doi":"10.1002/jimd.12792","DOIUrl":"10.1002/jimd.12792","url":null,"abstract":"<p>Enzymatic deficiency in Gaucher disease (GD) may induce oxidative stress. Vitamin E is the nature's most effective lipid-soluble antioxidant. This prospective clinical trial assessed the oxidant-antioxidant status in Egyptian patients with GD and the efficacy and safety and of vitamin E as an adjuvant antioxidant therapy. Forty children and adolescents with GD on stable doses of enzyme replacement therapy (ERT) were enrolled. Abdominal ultrasonography and transient elastography were performed. Malondialdehyde (MDA), vitamin E, and antioxidant enzymes (reduced glutathione [GSH], superoxide dismutase [SOD], glutathione peroxidase [GPx], and peroxiredoxin 2 [PRDX2]) were assessed. Patients were compared with 40 age- and sex-matched healthy controls. Patients with GD were randomized either to receive oral vitamin E for 6 months or not. All patients with GD had significantly higher MDA levels with lower levels of vitamin E and antioxidant enzymes compared with healthy controls (<i>p</i> &lt; 0.001). Vitamin E and PRDX2 were negatively correlated to severity score index (SSI), lyso GL1, and MDA. After 6 months of vitamin E supplementation, SSI and liver and spleen volumes and liver stiffness were significantly lower. Lyso GL1 and MDA were significantly decreased post-vitamin E therapy while antioxidant enzymes were significantly higher compared with baseline levels and with patients without vitamin E therapy. Oxidative stress is related to disease severity in pediatric patients with GD. A 6-month vitamin E supplementation for those patients represents a safe therapeutic adjuvant agent increasing the efficacy of ERT, reducing oxidative stress, and improving outcomes.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural disease course of chronic visceral acid sphingomyelinase deficiency in adults: A first step toward treatment criteria","authors":"Eline C. B. Eskes,&nbsp;Laura van Dussen,&nbsp;Marion M. M. G. Brands,&nbsp;Frédéric M. Vaz,&nbsp;Johannes M. F. G. Aerts,&nbsp;André B. P. van Kuilenburg,&nbsp;Barbara Sjouke,&nbsp;Carla E. M. Hollak","doi":"10.1002/jimd.12789","DOIUrl":"10.1002/jimd.12789","url":null,"abstract":"<p>Acid sphingomyelinase deficiency (ASMD) is an ultra-rare lysosomal storage disease with a broad spectrum of manifestations ranging from severe neuropathic forms to attenuated, chronic visceral forms. Manifestations of the chronic visceral subtype are variable and encompass different degrees of hepatosplenomegaly, pulmonary disease and dyslipidemia. The aim of this study was to provide insights into the natural course of adult patients with the chronic visceral subtype. Based on these insights, we proposed tentative criteria for initiation and follow-up of enzyme replacement therapy (ERT). The data of 23 adult patients were collected in a prospective study. Clinical, genetic and demographic data, plasma measurements, abdominal imaging, pulmonary imaging, pulmonary function tests and quality of life questionnaires were collected. Stability of disease based on several clinical, biochemical and radiological markers (i.e., spleen volume, platelet levels, liver volume, alanine aminotransferase [ALT] levels, diffusion capacity of the lungs for carbon monoxide [DLCO] chitotriosidase activity and lysosphingomyelin [LSM]) was assessed. Cardiovascular risk was estimated based on sex, age, smoking, systolic blood pressure and lipid profile. Quality of life was evaluated with the 36-Item Short Form Health Survey and the Health Assessment Questionnaire. Median follow-up was 6.1 years (range 1.3–19.5 years). The most common manifestations were splenomegaly (100%), decreased high-density lipoprotein cholesterol (HDL-C) plasma levels (83%), (signs of) steatosis measured with transient elastography (82%), thrombocytopenia (64%), hepatomegaly (52%) and decreased diffusion capacity (45%). The majority of markers remained stable during follow-up. Twelve patients showed progression of disease: four for spleen volume, two for liver volume, three for DLCO, seven for chitotriosidase activity and three for LSM. One patient showed progression of disease based on four markers, although this patient did not report any problems at the last visit. Cardiovascular risk was estimated and was increased in half of the patients older than 40 years. Patient-reported quality of life did not differ from the general population, but differences in median 36-Item Short Form Health Survey (SF-36) scores of patients with severe pulmonary involvement and those of patients without pulmonary involvement were observed. Tentative criteria for initiation and effect of therapy were proposed. In conclusion, the chronic visceral subtype of ASMD showed a predominantly stable disease course in this cohort. We propose that ERT should be initiated on an individual basis and only in case of progression or symptomatic disease. Collection and analysis of real world data are necessary to refine start, stop and follow-up criteria in the future.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mild/moderate phenotypes in AADC deficiency: Focus on the aromatic amino acid decarboxylase protein","authors":"Giovanni Bisello,&nbsp;Rossella Franchini,&nbsp;Cristian Andres Carmona Carmona,&nbsp;Mariarita Bertoldi","doi":"10.1002/jimd.12791","DOIUrl":"10.1002/jimd.12791","url":null,"abstract":"<p>AADC deficiency is a severe neurometabolic inherited rare disorder due to the absence or decrease of dopamine and serotonin levels, causing deep motor and neurodevelopmental impairments. The disease is often fatal in the first decade of life, and pharmacological treatments (dopamine agonists, pyridoxine, and monoamine oxidase inhibitors as the first-line choices) can only alleviate the symptoms. Gene therapy surgery is now available for severe patients in the European Union and the United Kingdom, and follow-up data witness encouraging improvements. In the past few years, mostly due to the increased awareness and knowledge of AADC deficiency, together with newborn screening programs and advancements in methods for genetic diagnosis, the number of mild/moderate phenotypes of AADC deficiency patients has increased to 12% of the total. A review of the genotypes (homozygous/compound heterozygous) of AADC deficiency mild/moderate patients is presented here. The pathogenicity classification of each genetic variant is discussed. Then, we focused on the type of AADC protein possessed by patients and on the predictable structural score of the homodimeric/heterodimeric species of each protein variant. Since the terminology used for genetic and protein variants is the same, we highlighted how it could be misleading. We analyzed the loss-of-function as a fold-change decrease of activity of the recombinant purified AADC enzyme(s) theoretically synthesized by mild/moderate patients. A minimal residual <i>k</i>_<i>cat</i> of 8% and/or <i>k</i>_<i>cat</i>/K_m of 1% seems necessary to avoid a severe disease manifestation. Overall, this cluster of mild/moderate patients needs consideration for a more appropriate and aimed therapeutic approach.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improved biochemical and neurodevelopmental profiles with high-dose hydroxocobalamin therapy in cobalamin C defect","authors":"Giorgia Olivieri,&nbsp;Benedetta Greco,&nbsp;Sara Cairoli,&nbsp;Giulio Catesini,&nbsp;Francesca Romana Lepri,&nbsp;Lorenzo Orazi,&nbsp;Maria Mallardi,&nbsp;Diego Martinelli,&nbsp;Daniela Ricci,&nbsp;Raffaele Simeoli,&nbsp;Carlo Dionisi-Vici","doi":"10.1002/jimd.12787","DOIUrl":"10.1002/jimd.12787","url":null,"abstract":"<p>Cobalamin C (Cbl-C) defect causes methylmalonic acidemia, homocystinuria, intellectual disability and visual impairment, despite treatment adherence. While international guidelines recommend parenteral hydroxocobalamin (OH-Cbl) as effective treatment, dose adjustments remain unclear. We assessed OH-Cbl therapy impact on biochemical, neurocognitive and visual outcomes in early-onset Cbl-C patients treated with different OH-Cbl doses over 3 years. Group A (<i>n</i> = 5), diagnosed via newborn screening (NBS), received high-dose OH-Cbl (median 0.55 mg/kg/day); Group B1 (<i>n</i> = 3), NBS-diagnosed, received low-dose OH-Cbl (median 0.09 mg/kg/day); Group B2 (<i>n</i> = 12), diagnosed on clinical bases, received low-dose OH-Cbl (median 0.06 mg/kg/day). Biochemical analyses revealed better values of homocysteine, methionine and methylmalonic acid in Group A compared to Group B1 (<i>p</i> &lt; 0.01, <i>p</i> &lt; 0.05 and <i>p</i> &lt; 0.01, respectively) and B2 (<i>p</i> &lt; 0.001, <i>p</i> &lt; 0.01 and <i>p</i> &lt; 0.001, respectively). Neurodevelopmental assessment showed better outcome in Group A compared to low-dose treated Groups B1 and B2, especially in Developmental Quotient, Hearing and Speech and Performance subscales without significant differences between Group B2 and Group B1. Maculopathy was detected in 100%, 66% and 83% of patients in the three groups, respectively. This study showed that “high-dose” OH-Cbl treatment in NBS-diagnosed children with severe early-onset Cbl-C defect led to a significant improvement in the metabolic profile and in neurocognitive outcome, compared to age-matched patients treated with a “low-dose” regimen. Effects on maculopathy seem unaffected by OH-Cbl dosage. Our findings, although observed in a limited number of patients, may contribute to improve the long-term outcome of Cbl-C patients.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}