Journal of Inherited Metabolic Disease最新文献

{"title":"Gene replacement therapies for inherited disorders of neurotransmission: Current progress in succinic semialdehyde dehydrogenase deficiency","authors":"Henry H. C. Lee,&nbsp;Itay Tokatly Latzer,&nbsp;Mariarita Bertoldi,&nbsp;Guangping Gao,&nbsp;Phillip L. Pearl,&nbsp;Mustafa Sahin,&nbsp;Alexander Rotenberg","doi":"10.1002/jimd.12735","DOIUrl":"10.1002/jimd.12735","url":null,"abstract":"<p>Neurodevelopment is a highly organized and complex process involving lasting and often irreversible changes in the central nervous system. Inherited disorders of neurotransmission (IDNT) are a group of genetic disorders where neurotransmission is primarily affected, resulting in abnormal brain development from early life, manifest as neurodevelopmental disorders and other chronic conditions. In principle, IDNT (particularly those of monogenic causes) are amenable to gene replacement therapy via precise genetic correction. However, practical challenges for gene replacement therapy remain major hurdles for its translation from bench to bedside. We discuss key considerations for the development of gene replacement therapies for IDNT. As an example, we describe our ongoing work on gene replacement therapy for succinic semialdehyde dehydrogenase deficiency, a GABA catabolic disorder.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140588868","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":"Outcomes after newborn screening for propionic and methylmalonic acidemia and homocystinurias","authors":"Anna T. Reischl-Hajiabadi,&nbsp;Elena Schnabel,&nbsp;Florian Gleich,&nbsp;Katharina Mengler,&nbsp;Martin Lindner,&nbsp;Peter Burgard,&nbsp;Roland Posset,&nbsp;Svenja Lommer-Steinhoff,&nbsp;Sarah C. Grünert,&nbsp;Eva Thimm,&nbsp;Peter Freisinger,&nbsp;Julia B. Hennermann,&nbsp;Johannes Krämer,&nbsp;Gwendolyn Gramer,&nbsp;Dominic Lenz,&nbsp;Stine Christ,&nbsp;Friederike Hörster,&nbsp;Georg F. Hoffmann,&nbsp;Sven F. Garbade,&nbsp;Stefan Kölker,&nbsp;Ulrike Mütze","doi":"10.1002/jimd.12731","DOIUrl":"10.1002/jimd.12731","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>The current German newborn screening (NBS) panel includes 13 inherited metabolic diseases (IMDs). In addition, a NBS pilot study in Southwest Germany identifies individuals with propionic acidemia (PA), methylmalonic acidemia (MMA), combined and isolated remethylation disorders (e.g., cobalamin [cbl] C and methylenetetrahydrofolate reductase [MTHFR] deficiency), cystathionine β-synthase (CBS) deficiency, and neonatal cbl deficiency through one multiple-tier algorithm. The long-term health benefits of screened individuals are evaluated in a multicenter observational study. Twenty seven screened individuals with IMDs (PA [<i>N</i> = 13], MMA [<i>N</i> = 6], cblC deficiency [<i>N</i> = 5], MTHFR deficiency [<i>N</i> = 2] and CBS deficiency [<i>N</i> = 1]), and 42 with neonatal cbl deficiency were followed for a median of 3.6 years. Seventeen screened IMD patients (63%) experienced at least one metabolic decompensation, 14 of them neonatally and six even before the NBS report (PA, cbl-nonresponsive MMA). Three PA patients died despite NBS and immediate treatment. Fifteen individuals (79%) with PA or MMA and all with cblC deficiency developed permanent, mostly neurological symptoms, while individuals with MTHFR, CBS, and neonatal cbl deficiency had a favorable clinical outcome. Utilizing a combined multiple-tier algorithm, we demonstrate that NBS and specialized metabolic care result in substantial benefits for individuals with MTHFR deficiency, CBS deficiency, neonatal cbl deficiency, and to some extent, cbl-responsive MMA and cblC deficiency. However, its advantage is less evident for individuals with PA and cbl-nonresponsive MMA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Synopsis</h3>\u0000 \u0000 <p>Early detection through newborn screening and subsequent specialized metabolic care improve clinical outcomes and survival in individuals with MTHFR deficiency and cystathionine-β-synthase deficiency, and to some extent in cobalamin-responsive methylmalonic acidemia (MMA) and cblC deficiency while the benefit for individuals with propionic acidemia and cobalamin-nonresponsive MMA is less evident due to the high (neonatal) decompensation rate, mortality, and long-term complications.</p>\u0000 </section>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12731","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140335915","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":"The clinical relevance of novel biomarkers as outcome parameter in adults with phenylketonuria","authors":"A. M. J. van Wegberg,&nbsp;J. C. van der Weerd,&nbsp;U. F. H. Engelke,&nbsp;K. L. M. Coene,&nbsp;R. Jahja,&nbsp;S. J. L. Bakker,&nbsp;S. C. J. Huijbregts,&nbsp;R. A. Wevers,&nbsp;M. R. Heiner-Fokkema,&nbsp;F. J. van Spronsen","doi":"10.1002/jimd.12732","DOIUrl":"10.1002/jimd.12732","url":null,"abstract":"<p>Recent studies in PKU patients identified alternative biomarkers in blood using untargeted metabolomics. To test the added clinical value of these novel biomarkers, targeted metabolomics of 11 PKU biomarkers (phenylalanine, glutamyl-phenylalanine, glutamyl-glutamyl-phenylalanine, N-lactoyl-phenylalanine, N-acetyl-phenylalanine, the dipeptides phenylalanyl-phenylalanine and phenylalanyl-leucine, phenylalanine–hexose conjugate, phenyllactate, phenylpyruvate, and phenylacetate) was performed in stored serum samples of the well-defined PKU patient-COBESO cohort and a healthy control group. Serum samples of 35 PKU adults and 20 healthy age- and sex-matched controls were analyzed using ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry. Group differences were tested using the Mann–Whitney <i>U</i> test. Multiple linear regression analyses were performed with these biomarkers as predictors of (neuro-)cognitive functions working memory, sustained attention, inhibitory control, and mental health. Compared to healthy controls, phenylalanine, glutamyl-phenylalanine, N-lactoyl-phenylalanine, N-acetyl-phenylalanine, phenylalanine–hexose conjugate, phenyllactate, phenylpyruvate, and phenylacetate were significant elevated in PKU adults (<i>p</i> &lt; 0.001). The remaining three were below limit of detection in PKU and controls. Both phenylalanine and N-lactoyl-phenylalanine were associated with DSM-VI Attention deficit/hyperactivity (<i>R</i>² = 0.195, <i>p</i> = 0.039 and <i>R</i>² = 0.335, <i>p</i> = 0.002, respectively) of the ASR questionnaire. In addition, N-lactoyl-phenylalanine showed significant associations with ASR DSM-VI avoidant personality (<i>R</i>² = 0.265, <i>p</i> = 0.010), internalizing (<i>R</i>² = 0.192, <i>p</i> = 0.046) and externalizing problems (<i>R</i>² = 0.217, <i>p</i> = 0.029) of the ASR questionnaire and multiple aspects of the MS2D and FI tests, reflecting working memory with <i>R</i>² between 0.178 (<i>p</i> = 0.048) and 0.204 (<i>p</i> = 0.033). Even though the strength of the models was not considered strong, N-lactoyl-phenylalanine outperformed phenylalanine in its association with working memory and mental health outcomes.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12732","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140331818","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":"What can pediatricians learn from adult inherited metabolic diseases?","authors":"Fanny Mochel","doi":"10.1002/jimd.12729","DOIUrl":"10.1002/jimd.12729","url":null,"abstract":"<p>The field of inherited metabolic diseases (IMD) has initially emerged and developed over decades in pediatric departments. Still, today, about 50% of patients with IMD are adults, and adult metabolic medicine (AMM) is getting more structured at national and international levels. There are several domains in which pediatricians can learn from AMM. First, long-term evolution of IMD patients, especially those treated since childhood, is critical to determine nutritional and neuropsychiatric outcomes in adults so that these outcomes can be better monitored, and patient care adjusted as much as possible from childhood. Conversely, the observation of attenuated phenotypes in adults of IMD known to present with severe phenotypes in children calls for caution in the development of newborn screening programs and, more largely, in the interpretation of next-generation sequencing data. Third, it is important for pediatricians to be familiar with adult-onset IMD as they expand our understanding of metabolism, including in children, such as oxysterols and glycogen metabolism. Last, the identification of common molecular and cellular mechanisms in neurodevelopment and neurodegeneration opens the way to synergistic therapeutic developments that will benefit both fields of pediatric and adult medicine. Overall, these observations underline the need of strong interdisciplinarity between pediatricians and adult specialists for the diagnosis and the treatment of IMD well beyond the issues of patient transition from pediatric to adult medicine.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12729","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140193986","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":"Clinical landscape of citrin deficiency: A global perspective on a multifaceted condition.","authors":"Jun Kido, Georgios Makris, Saikat Santra, Johannes Häberle","doi":"10.1002/jimd.12722","DOIUrl":"https://doi.org/10.1002/jimd.12722","url":null,"abstract":"<p><p>Citrin deficiency is an autosomal recessive disorder caused by a defect of citrin resulting from mutations in SLC25A13. The clinical manifestation is very variable and comprises three types: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD: OMIM 605814), post-NICCD including failure to thrive and dyslipidemia caused by citrin deficiency, and adult-onset type II citrullinemia (CTLN2: OMIM 603471). Frequently, NICCD can run with a mild clinical course and manifestations may resolve in the post-NICCD. However, a subset of patients may develop CTLN2 when they become more than 18 years old, and this condition is potentially life-threatening. Since a combination of diet with low-carbohydrate and high-fat content supplemented with medium-chain triglycerides is expected to ameliorate most manifestations and to prevent the progression to CTLN2, early detection and intervention are important and may improve long-term outcome in patients. Moreover, infusion of high sugar solution and/or glycerol may be life-threatening in patients with citrin deficiency, particularly CTLN2. The disease is highly prevalent in East Asian countries but is more and more recognized as a global entity. Since newborn screening for citrin deficiency has only been introduced in a few countries, the diagnosis still mainly relies on clinical suspicion followed by genetic testing or selective metabolic screening. This paper aims at describing (1) the different stages of the disease focusing on clinical aspects; (2) the current published clinical situation in East Asia, Europe, and North America; (3) current efforts in increasing awareness by establishing management guidelines and patient registries, hereby illustrating the ongoing development of a global network for this rare disease.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140175025","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":"T cell activation contributes to purifying selection against the MELAS-associated m.3243A>G pathogenic variant in blood","authors":"Melissa A. Walker,&nbsp;Shuqiang Li,&nbsp;Kenneth J. Livak,&nbsp;Amel Karaa,&nbsp;Catherine J. Wu,&nbsp;Vamsi K. Mootha","doi":"10.1002/jimd.12726","DOIUrl":"10.1002/jimd.12726","url":null,"abstract":"<p>T cells have been shown to maintain a lower percentage (heteroplasmy) of the pathogenic m.3243A&gt;G variant (<i>MT-TL1</i>, associated with maternally inherited diabetes and deafness [MIDD] and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes [MELAS]). The mechanism(s) underlying this purifying selection, however, remain unknown. Here we report that purified patient memory CD4+ T cells have lower bulk m.3243A&gt;G heteroplasmy compared to naïve CD4+ T cells. In vitro activation of naïve CD4+ m.3243A&gt;G patient T cells results in lower bulk m.3243A&gt;G heteroplasmy after proliferation. Finally, m.3243A&gt;G patient T cell receptor repertoire sequencing reveals relative oligoclonality compared to controls. These data support a role for T cell activation in peripheral, purifying selection against high m.3243A&gt;G heteroplasmy T cells at the level of the cell, in a likely cell-autonomous fashion.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11251844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140158348","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":"Genetic aetiologies of acute liver failure","authors":"Robert Hegarty,&nbsp;Richard J. Thompson","doi":"10.1002/jimd.12733","DOIUrl":"10.1002/jimd.12733","url":null,"abstract":"<p>Acute liver failure (ALF) is a rare, rapidly evolving, clinical syndrome with devastating consequences where definitive treatment is by emergency liver transplantation. Establishing a diagnosis can be challenging and, historically, the cause of ALF was unidentified in up to half of children. However, recent technological and clinical advances in genomic medicine have led to an increasing proportion being diagnosed with monogenic aetiologies of ALF. The conditions encountered include a diverse group of inherited metabolic disorders each with prognostic and treatment implications. Often these disorders are clinically indistinguishable and may even mimic disorders of immune regulation or red cell disorders. Rapid genomic sequencing for children with ALF is, therefore, a key component in the diagnostic work up today. This review focuses on the monogenic aetiologies of ALF.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140158347","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":"The continuously evolving phenotype of succinic semialdehyde dehydrogenase deficiency","authors":"Natalia Alexandra Julia-Palacios,&nbsp;Oya Kuseyri Hübschmann,&nbsp;Mireia Olivella,&nbsp;Roser Pons,&nbsp;Gabriella Horvath,&nbsp;Thomas Lücke,&nbsp;Cheuk-Wing Fung,&nbsp;Suet-Na Wong,&nbsp;Elisenda Cortès-Saladelafont,&nbsp;M. Mar Rovira-Remisa,&nbsp;Yılmaz Yıldız,&nbsp;Saadet Mercimek-Andrews,&nbsp;Birgit Assmann,&nbsp;Galina Stevanović,&nbsp;Filippo Manti,&nbsp;Heiko Brennenstuhl,&nbsp;Sabine Jung-Klawitter,&nbsp;Kathrin Jeltsch,&nbsp;H. Serap Sivri,&nbsp;Sven F. Garbade,&nbsp;Àngels García-Cazorla,&nbsp;Thomas Opladen","doi":"10.1002/jimd.12723","DOIUrl":"10.1002/jimd.12723","url":null,"abstract":"<p>The objective of the study is to evaluate the evolving phenotype and genetic spectrum of patients with succinic semialdehyde dehydrogenase deficiency (SSADHD) in long-term follow-up. Longitudinal clinical and biochemical data of 22 pediatric and 9 adult individuals with SSADHD from the patient registry of the International Working Group on Neurotransmitter related Disorders (iNTD) were studied with in silico analyses, pathogenicity scores and molecular modeling of <i>ALDH5A1</i> variants. Leading initial symptoms, with onset in infancy, were developmental delay and hypotonia. Year of birth and specific initial symptoms influenced the diagnostic delay. Clinical phenotype of 26 individuals (median 12 years, range 1.8–33.4 years) showed a diversifying course in follow-up: 77% behavioral problems, 76% coordination problems, 73% speech disorders, 58% epileptic seizures and 40% movement disorders. After ataxia, dystonia (19%), chorea (11%) and hypokinesia (15%) were the most frequent movement disorders. Involvement of the dentate nucleus in brain imaging was observed together with movement disorders or coordination problems. Short attention span (78.6%) and distractibility (71.4%) were the most frequently behavior traits mentioned by parents while impulsiveness, problems communicating wishes or needs and compulsive behavior were addressed as strongly interfering with family life. Treatment was mainly aimed to control epileptic seizures and psychiatric symptoms. Four new pathogenic variants were identified. In silico scoring system, protein activity and pathogenicity score revealed a high correlation. A genotype/phenotype correlation was not observed, even in siblings. This study presents the diversifying characteristics of disease phenotype during the disease course, highlighting movement disorders, widens the knowledge on the genotypic spectrum of SSADHD and emphasizes a reliable application of in silico approaches.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12723","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140158349","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":"Hepatobiliary circulation and dominant urinary excretion of homogentisic acid in a mouse model of alkaptonuria","authors":"B. P. Norman,&nbsp;H. Sutherland,&nbsp;P. J. M. Wilson,&nbsp;D. A. Rutland,&nbsp;A. M. Milan,&nbsp;A. T. Hughes,&nbsp;A. S. Davison,&nbsp;M. Khedr,&nbsp;J. C. Jarvis,&nbsp;J. A. Gallagher,&nbsp;G. Bou-Gharios,&nbsp;L. R. Ranganath","doi":"10.1002/jimd.12728","DOIUrl":"10.1002/jimd.12728","url":null,"abstract":"<p>Altered activity of specific enzymes in phenylalanine-tyrosine (phe-tyr) metabolism results in incomplete breakdown of various metabolite substrates in this pathway. Increased biofluid concentration and tissue accumulation of the phe-tyr pathway metabolite homogentisic acid (HGA) is central to pathophysiology in the inherited disorder alkaptonuria (AKU). Accumulation of metabolites upstream of HGA, including tyrosine, occurs in patients on nitisinone, a licenced drug for AKU and hereditary tyrosinaemia type 1, which inhibits the enzyme responsible for HGA production. The aim of this study was to investigate the phe-tyr metabolite content of key biofluids and tissues in AKU mice on and off nitisinone to gain new insights into the biodistribution of metabolites in these altered metabolic states. The data show for the first time that HGA is present in bile in AKU (mean [±SD] = 1003[±410] μmol/L; nitisinone-treated AKU mean [±SD] = 45[±23] μmol/L). Biliary tyrosine, 3(4-hydroxyphenyl)pyruvic acid (HPPA) and 3(4-hydroxyphenyl)lactic acid (HPLA) are also increased on nitisinone. Urine was confirmed as the dominant elimination route of HGA in untreated AKU, but with indication of biliary excretion. These data provide new insights into pathways of phe-tyr metabolite biodistribution and metabolism, showing for the first time that hepatobiliary excretion contributes to the total pool of metabolites in this pathway. Our data suggest that biliary elimination of organic acids and other metabolites may play an underappreciated role in disorders of metabolism. We propose that our finding of approximately 3.8 times greater urinary HGA excretion in AKU mice compared with patients is one reason for the lack of extensive tissue ochronosis in the AKU mouse model.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12728","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140131748","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":"Open-label, single-center, clinical study evaluating the safety, tolerability and clinical effects of pentosan polysulfate sodium in subjects with mucopolysaccharidosis I","authors":"Drago Bratkovic,&nbsp;Curtis Gravance,&nbsp;David Ketteridge,&nbsp;Ravi Krishnan,&nbsp;Divya Navuru,&nbsp;Michael Sheehan,&nbsp;Donna Skerrett,&nbsp;Michael Imperiale","doi":"10.1002/jimd.12715","DOIUrl":"10.1002/jimd.12715","url":null,"abstract":"<p>Lysosomal enzyme deficiency in mucopolysaccharidosis (MPS) I results in glycosaminoglycan (GAG) accumulation leading to pain and limited physical function. Disease-modifying treatments for MPS I, enzyme replacement, and hematopoietic stem cell therapy (HSCT), do not completely resolve MPS I symptoms, particularly skeletal manifestations. The GAG reduction, anti-inflammatory, analgesic, and tissue remodeling properties of pentosan polysulfate sodium (PPS) may provide disease-modifying treatment for musculoskeletal symptoms and joint inflammation in MPS I following ERT and/or HSCT. The safety and efficacy of PPS were evaluated in four subjects with MPS I aged 14–19 years, previously treated with ERT and/or HSCT. Subjects received doses of 0.75 mg/kg or 1.5 mg/kg PPS via subcutaneous injections weekly for 12 weeks, then every 2 weeks for up to 72 weeks. PPS was well tolerated at both doses with no serious adverse events. MPS I GAG fragment (UA-HNAc [1S]) levels decreased at 73 weeks. Cartilage degradation biomarkers serum C-telopeptide of crosslinked collagen (CTX) type I (CTX-I) and type II (CTX-II) and urine CTX-II decreased in all subjects through 73 weeks. PROMIS scores for pain interference, pain behavior, and fatigue decreased in all subjects through 73 weeks. Physical function, measured by walking distance and dominant hand function, improved at 49 and 73 weeks. Decreased GAG fragments and cartilage degradation biomarkers, and positive PROMIS outcomes support continued study of PPS as a potential disease-modifying treatment for MPS I with improved pain and function outcomes.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140101782","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}