Pub Date : 2024-10-29DOI: 10.1016/j.ymgme.2024.108598
Bernd C. Schwahn , Claire Hart , Louisa Ann Smith , Anthony Hart , Lynette Fairbanks , Monica Arenas-Hernandez , Charles Turner , Alistair Horman , Stewart Rust , José A. Santamaria-Araujo , Simon J. Mayr , Günter Schwarz , Mark Sharrard
We report the first, and so far, only index patient with neonatal onset MoCD type A who was diagnosed and treated early enough with cPMP to avoid severe brain injury and disability. The child presented with hypoglycemia at the age of 10 h and was diagnosed because of the incidental finding of severely decreased L-cystine in plasma. Due to a high level of awareness and excellent co-operation between metabolic laboratory and clinical services, cPMP substitution could be initiated before severe encephalopathy set in, and the child subsequently had a normal motor development. The child has been continued on daily substitution with cPMP until today (age 7 years) and has shown a satisfying long-term developmental outcome. Long-term follow-up, however, revealed significant communication difficulties and cognitive abilities in the range of mild to moderate learning disability. The severity of the metabolic disease was confirmed by the extent of biochemical abnormalities and further functional characterisation of the underlying genetic variants. This case provides further evidence that cPMP substitution does significantly alter the disease course when applied early enough. Postnatal treatment in this case was not sufficient to enable an entirely normal cognitive development, despite sustained complete normalization of the biochemical abnormalities.
{"title":"cPMP rescue of a neonate with severe molybdenum cofactor deficiency after serendipitous early diagnosis, and characterisation of a novel MOCS1 variant","authors":"Bernd C. Schwahn , Claire Hart , Louisa Ann Smith , Anthony Hart , Lynette Fairbanks , Monica Arenas-Hernandez , Charles Turner , Alistair Horman , Stewart Rust , José A. Santamaria-Araujo , Simon J. Mayr , Günter Schwarz , Mark Sharrard","doi":"10.1016/j.ymgme.2024.108598","DOIUrl":"10.1016/j.ymgme.2024.108598","url":null,"abstract":"<div><div>We report the first, and so far, only index patient with neonatal onset MoCD type A who was diagnosed and treated early enough with cPMP to avoid severe brain injury and disability. The child presented with hypoglycemia at the age of 10 h and was diagnosed because of the incidental finding of severely decreased L-cystine in plasma. Due to a high level of awareness and excellent co-operation between metabolic laboratory and clinical services, cPMP substitution could be initiated before severe encephalopathy set in, and the child subsequently had a normal motor development. The child has been continued on daily substitution with cPMP until today (age 7 years) and has shown a satisfying long-term developmental outcome. Long-term follow-up, however, revealed significant communication difficulties and cognitive abilities in the range of mild to moderate learning disability. The severity of the metabolic disease was confirmed by the extent of biochemical abnormalities and further functional characterisation of the underlying genetic variants. This case provides further evidence that cPMP substitution does significantly alter the disease course when applied early enough. Postnatal treatment in this case was not sufficient to enable an entirely normal cognitive development, despite sustained complete normalization of the biochemical abnormalities.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 4","pages":"Article 108598"},"PeriodicalIF":3.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-28DOI: 10.1016/j.ymgme.2024.108597
Rebecca A. Gibson , William R. Jeck , Rebecca L. Koch , Aarav Mehta , Su Jin Choi , Yajur Sriraman , Deeksha Bali , Sarah Young , Aravind Asokan , Jeong-A Lim , Priya S. Kishnani
Hepatic glycogen storage disease type IX γ2 (GSD IX γ2) is a severe, liver-specific subtype of GSD IX. While all patients with hepatic GSD IX present with similar symptoms, over 95 % of patients with GSD IX γ2 progress to liver fibrosis and cirrhosis. Despite disease severity, the long-term natural history of GSD IX γ2 liver disease progression is not known. Our lab previously characterized the Phkg2−/− mouse model at 3 months of age, demonstrating that the mouse recapitulates the early liver disease phenotype of GSD IX γ2. To understand how liver disease progresses in GSD IX γ2, we characterized the mouse model through 24 months of age. Our study showed for the first time that GSD IX γ2 mice develop liver fibrosis that progresses to cirrhosis. Importantly, we observed that the progression of liver fibrosis is associated with an initial elevation and subsequent decrease of key GSD biomarkers – the latter being a finding that is often considered to be an improvement of disease in patients. In recognition of the unique liver fibrosis pattern and to support future therapeutic investigations using this model, we developed a novel scoring system for GSD IX γ2 mouse liver pathology. Lastly, this work introduces evidence of a dysregulated glycogen metabolism pathway which can serve as an endpoint for future therapeutic evaluation. As we await longitudinal clinical natural history data, these findings greatly expand our understanding of liver disease manifestations in GSD IX γ2 and have notable clinical applications.
肝糖原贮积症 IX γ2型（GSD IX γ2）是 GSD IX 的一种严重的肝脏特异性亚型。虽然所有肝脏 GSD IX 患者的症状相似，但超过 95% 的 GSD IX γ2 患者会发展为肝纤维化和肝硬化。尽管疾病严重，但GSD IX γ2肝病进展的长期自然史尚不清楚。我们的实验室先前鉴定了3月龄的Phkg2-/-小鼠模型，证明该小鼠重现了GSD IX γ2的早期肝病表型。为了了解 GSD IX γ2肝病的发展过程，我们对该小鼠模型进行了长达 24 个月的鉴定。我们的研究首次表明，GSD IX γ2小鼠会出现肝纤维化并发展为肝硬化。重要的是，我们观察到肝纤维化的进展与 GSD 关键生物标志物最初的升高和随后的降低有关，后者通常被认为是患者病情的改善。鉴于这种独特的肝纤维化模式，并为了支持未来利用这种模型进行治疗研究，我们开发了一种新的 GSD IX γ2小鼠肝脏病理学评分系统。最后，这项工作引入了糖原代谢途径失调的证据，可作为未来治疗评估的终点。在我们等待纵向临床自然史数据的同时，这些发现极大地扩展了我们对 GSD IX γ2肝病表现的理解，并具有显著的临床应用价值。
{"title":"Progressive liver disease and dysregulated glycogen metabolism in murine GSD IX γ2 models human disease","authors":"Rebecca A. Gibson , William R. Jeck , Rebecca L. Koch , Aarav Mehta , Su Jin Choi , Yajur Sriraman , Deeksha Bali , Sarah Young , Aravind Asokan , Jeong-A Lim , Priya S. Kishnani","doi":"10.1016/j.ymgme.2024.108597","DOIUrl":"10.1016/j.ymgme.2024.108597","url":null,"abstract":"<div><div>Hepatic glycogen storage disease type IX γ2 (GSD IX γ2) is a severe, liver-specific subtype of GSD IX. While all patients with hepatic GSD IX present with similar symptoms, over 95 % of patients with GSD IX γ2 progress to liver fibrosis and cirrhosis. Despite disease severity, the long-term natural history of GSD IX γ2 liver disease progression is not known. Our lab previously characterized the <em>Phkg2</em><sup><em>−/−</em></sup> mouse model at 3 months of age, demonstrating that the mouse recapitulates the early liver disease phenotype of GSD IX γ2. To understand how liver disease progresses in GSD IX γ2, we characterized the mouse model through 24 months of age. Our study showed for the first time that GSD IX γ2 mice develop liver fibrosis that progresses to cirrhosis. Importantly, we observed that the progression of liver fibrosis is associated with an initial elevation and subsequent decrease of key GSD biomarkers – the latter being a finding that is often considered to be an improvement of disease in patients. In recognition of the unique liver fibrosis pattern and to support future therapeutic investigations using this model, we developed a novel scoring system for GSD IX γ2 mouse liver pathology. Lastly, this work introduces evidence of a dysregulated glycogen metabolism pathway which can serve as an endpoint for future therapeutic evaluation. As we await longitudinal clinical natural history data, these findings greatly expand our understanding of liver disease manifestations in GSD IX γ2 and have notable clinical applications.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 4","pages":"Article 108597"},"PeriodicalIF":3.7,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-22DOI: 10.1016/j.ymgme.2024.108596
Lorenzo Badenetti , Seok-Ho Yu , Maxwell B. Colonna , Rony Hull , Jennifer R. Bethard , Lauren Ball , Heather Flanagan-Steet , Richard Steet
Defining the molecular consequences of lysosomal dysfunction in neuronal cell types remains an area of investigation that is needed to understand many underappreciated phenotypes associated with lysosomal disorders. Here we characterize GNPTAB-knockout DAOY medulloblastoma cells using different genetic and proteomic approaches, with a focus on how altered gene expression and cell surface abundance of glycoproteins may explain emerging neurological issues in individuals with GNPTAB-related disorders, including mucolipidosis II (ML II) and mucolipidosis IIIα/β (ML IIIα/β). The two knockout clones characterized demonstrated all the biochemical hallmarks of this disease, including loss of intracellular glycosidase activity due to impaired mannose 6-phosphate-dependent lysosomal sorting, lysosomal cholesterol accumulation, and increased markers of autophagic dysfunction. RNA sequencing identified altered transcript abundance of several neuronal markers and genes involved in drug metabolism and transport, and neurodegeneration-related pathways. Using selective exo-enzymatic labeling (SEEL) coupled with proteomics to profile cell surface glycoproteins, we demonstrated altered abundance of several glycoproteins in the knockout cells. Most striking was increased abundance of the amyloid precursor protein and apolipoprotein B, indicating that loss of GNPTAB function in these cells corresponds with elevation in proteins associated with neurodegeneration. The implication of these findings on lysosomal disease pathogenesis and the emerging neurological manifestations of GNPTAB-related disorders is discussed.
{"title":"Multi-omic analysis of a mucolipidosis II neuronal cell model uncovers involvement of pathways related to neurodegeneration and drug metabolism","authors":"Lorenzo Badenetti , Seok-Ho Yu , Maxwell B. Colonna , Rony Hull , Jennifer R. Bethard , Lauren Ball , Heather Flanagan-Steet , Richard Steet","doi":"10.1016/j.ymgme.2024.108596","DOIUrl":"10.1016/j.ymgme.2024.108596","url":null,"abstract":"<div><div>Defining the molecular consequences of lysosomal dysfunction in neuronal cell types remains an area of investigation that is needed to understand many underappreciated phenotypes associated with lysosomal disorders. Here we characterize <em>GNPTAB</em>-knockout DAOY medulloblastoma cells using different genetic and proteomic approaches, with a focus on how altered gene expression and cell surface abundance of glycoproteins may explain emerging neurological issues in individuals with <em>GNPTAB</em>-related disorders, including mucolipidosis II (ML II) and mucolipidosis IIIα/β (ML IIIα/β). The two knockout clones characterized demonstrated all the biochemical hallmarks of this disease, including loss of intracellular glycosidase activity due to impaired mannose 6-phosphate-dependent lysosomal sorting, lysosomal cholesterol accumulation, and increased markers of autophagic dysfunction. RNA sequencing identified altered transcript abundance of several neuronal markers and genes involved in drug metabolism and transport, and neurodegeneration-related pathways. Using selective <em>exo</em>-enzymatic labeling (SEEL) coupled with proteomics to profile cell surface glycoproteins, we demonstrated altered abundance of several glycoproteins in the knockout cells. Most striking was increased abundance of the amyloid precursor protein and apolipoprotein B, indicating that loss of <em>GNPTAB</em> function in these cells corresponds with elevation in proteins associated with neurodegeneration. The implication of these findings on lysosomal disease pathogenesis and the emerging neurological manifestations of <em>GNPTAB</em>-related disorders is discussed.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 3","pages":"Article 108596"},"PeriodicalIF":3.7,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-12DOI: 10.1016/j.ymgme.2024.108594
Johan L.K. Van Hove
The recognition of glycine as an endogenous ligand at the allosteric activation site of the NMDA-type glutamatergic receptor led to the assumption that the excess glycine in nonketotic hyperglycinemia would result in overactivation of these receptors, and of the proposed use of inhibitors such as dextromethorphan or ketamine as a therapeutic agent. Years later it was recognized that these same receptors have an alternative endogenous activator d-serine, which is markedly decreased in nonketotic hyperglycinemia. This may result in underactivation of these NMDA-type glutamatergic receptors, challenging the earlier hypothesis. Clear clinical evidence of an added therapeutic benefit beyond the use of glycine reduction strategies from use of either dextromethorphan or ketamine in nonketotic hyperglycinemia has not been documented. The systematic use of these NMDA-type receptor antagonists in nonketotic hyperglycinemia should be reevaluated, particularly in light of emerging potential adverse effects.
{"title":"The role of NMDA-receptor type glutamatergic antagonists dextromethorphan or ketamine in the treatment of nonketotic hyperglycinemia: A critical reassessment","authors":"Johan L.K. Van Hove","doi":"10.1016/j.ymgme.2024.108594","DOIUrl":"10.1016/j.ymgme.2024.108594","url":null,"abstract":"<div><div>The recognition of glycine as an endogenous ligand at the allosteric activation site of the NMDA-type glutamatergic receptor led to the assumption that the excess glycine in nonketotic hyperglycinemia would result in overactivation of these receptors, and of the proposed use of inhibitors such as dextromethorphan or ketamine as a therapeutic agent. Years later it was recognized that these same receptors have an alternative endogenous activator <span>d</span>-serine, which is markedly decreased in nonketotic hyperglycinemia. This may result in underactivation of these NMDA-type glutamatergic receptors, challenging the earlier hypothesis. Clear clinical evidence of an added therapeutic benefit beyond the use of glycine reduction strategies from use of either dextromethorphan or ketamine in nonketotic hyperglycinemia has not been documented. The systematic use of these NMDA-type receptor antagonists in nonketotic hyperglycinemia should be reevaluated, particularly in light of emerging potential adverse effects.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 3","pages":"Article 108594"},"PeriodicalIF":3.7,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142446819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-12DOI: 10.1016/j.ymgme.2024.108595
Nicola Longo , Laura Alane Voss , Marta Frigeni , Bijina Balakrishnan , Marzia Pasquali
Cerebral creatine deficiency syndromes (CCDS) are rare inherited metabolic disorders caused by defective biosynthesis or transport of creatine. These conditions are characterized by reduced accumulation of creatine in the brain, mild to severe intellectual disability, global developmental delay, and speech-language disorders. The amount of brain creatine reduction needed to cause symptoms is not known. Here we report a new patient with creatine transporter deficiency (CTD) who presented at 15 months of age with seizures and global delays with no speech at 3 years of age. Brain MRI was normal, but brain MRS indicated creatine levels reduced to about 20 % of normal. He had normal levels of creatine and guanidinoacetate in plasma, but increased creatine/creatinine ratio in urine. DNA sequencing identified a hemizygous c.832C > T (p.Arg278Cys) variant in the creatine transporter gene SLC6A8. Fibroblasts from this patient had about 25 % of normal creatine transport activity, a value much higher than that measured in patients whose variants introduced premature stop codons in SLC6A8. The child was started on supplements of creatine, glycine, and arginine. His speech improved dramatically, and he had no more seizures, even during episodes of fever. Despite the clinical improvement, a repeat MRS demonstrated similar levels of brain creatine. This study suggests that a reduction in creatine transporter activity to 25 % or less is sufficient to cause symptoms of brain creatine deficiency and that functionally milder forms of CTD might respond to supplements aimed at replenishing brain creatine.
{"title":"Response to therapy of creatine transporter deficiency caused by a hypomorphic variant in SLC6A8","authors":"Nicola Longo , Laura Alane Voss , Marta Frigeni , Bijina Balakrishnan , Marzia Pasquali","doi":"10.1016/j.ymgme.2024.108595","DOIUrl":"10.1016/j.ymgme.2024.108595","url":null,"abstract":"<div><div>Cerebral creatine deficiency syndromes (CCDS) are rare inherited metabolic disorders caused by defective biosynthesis or transport of creatine. These conditions are characterized by reduced accumulation of creatine in the brain, mild to severe intellectual disability, global developmental delay, and speech-language disorders. The amount of brain creatine reduction needed to cause symptoms is not known. Here we report a new patient with creatine transporter deficiency (CTD) who presented at 15 months of age with seizures and global delays with no speech at 3 years of age. Brain MRI was normal, but brain MRS indicated creatine levels reduced to about 20 % of normal. He had normal levels of creatine and guanidinoacetate in plasma, but increased creatine/creatinine ratio in urine. DNA sequencing identified a hemizygous c.832C > T (p.Arg278Cys) variant in the creatine transporter gene <em>SLC6A8.</em> Fibroblasts from this patient had about 25 % of normal creatine transport activity, a value much higher than that measured in patients whose variants introduced premature stop codons in <em>SLC6A8</em>. The child was started on supplements of creatine, glycine, and arginine. His speech improved dramatically, and he had no more seizures, even during episodes of fever. Despite the clinical improvement, a repeat MRS demonstrated similar levels of brain creatine. This study suggests that a reduction in creatine transporter activity to 25 % or less is sufficient to cause symptoms of brain creatine deficiency and that functionally milder forms of CTD might respond to supplements aimed at replenishing brain creatine.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 3","pages":"Article 108595"},"PeriodicalIF":3.7,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142446871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-12DOI: 10.1016/j.ymgme.2024.108593
Emily Groopman , Shruthi Mohan , Amber Waddell , Matheus Wilke , Raquel Fernandez , Meredith Weaver , Hongjie Chen , Hongbin Liu , Deeksha Bali , Heather Baudet , Lorne Clarke , Christina Hung , Rong Mao , Filippo Pinto e Vairo , Lemuel Racacho , Tatiana Yuzyuk , William J. Craigen , Jennifer Goldstein
Lysosomal diseases (LDs) are a heterogeneous group of rare genetic disorders that result in impaired lysosomal function, leading to progressive multiorgan system dysfunction. Accurate diagnosis is paramount to initiating targeted therapies early in the disease process in addition to providing prognostic information and appropriate support for families. In recent years, genomic sequencing technologies have become the first-line approach in the diagnosis of LDs. Understanding the clinical validity of the role of a gene in a disease is critical for the development of genomic technologies, such as which genes to include on next generation sequencing panels, and the interpretation of results from exome and genome sequencing. To this aim, the ClinGen Lysosomal Diseases Gene Curation Expert Panel utilized a semi-quantitative framework incorporating genetic and experimental evidence to assess the clinical validity of the 56 LD-associated genes on the Lysosomal Disease Network's list. Here, we describe the results, and the key themes and challenges encountered.
{"title":"Assessment of genes involved in lysosomal diseases using the ClinGen clinical validity framework","authors":"Emily Groopman , Shruthi Mohan , Amber Waddell , Matheus Wilke , Raquel Fernandez , Meredith Weaver , Hongjie Chen , Hongbin Liu , Deeksha Bali , Heather Baudet , Lorne Clarke , Christina Hung , Rong Mao , Filippo Pinto e Vairo , Lemuel Racacho , Tatiana Yuzyuk , William J. Craigen , Jennifer Goldstein","doi":"10.1016/j.ymgme.2024.108593","DOIUrl":"10.1016/j.ymgme.2024.108593","url":null,"abstract":"<div><div>Lysosomal diseases (LDs) are a heterogeneous group of rare genetic disorders that result in impaired lysosomal function, leading to progressive multiorgan system dysfunction. Accurate diagnosis is paramount to initiating targeted therapies early in the disease process in addition to providing prognostic information and appropriate support for families. In recent years, genomic sequencing technologies have become the first-line approach in the diagnosis of LDs. Understanding the clinical validity of the role of a gene in a disease is critical for the development of genomic technologies, such as which genes to include on next generation sequencing panels, and the interpretation of results from exome and genome sequencing. To this aim, the ClinGen Lysosomal Diseases Gene Curation Expert Panel utilized a semi-quantitative framework incorporating genetic and experimental evidence to assess the clinical validity of the 56 LD-associated genes on the Lysosomal Disease Network's list. Here, we describe the results, and the key themes and challenges encountered.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 3","pages":"Article 108593"},"PeriodicalIF":3.7,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-11DOI: 10.1016/j.ymgme.2024.108590
Kelly A. George, Allyson L. Anding, Arjan van der Flier, Giulio S. Tomassy, Kenneth I. Berger, Tracy Y. Zhang, S. Pablo Sardi
Pompe disease is a debilitating and life-threatening disease caused by aberrant accumulation of glycogen resulting from reduced acid alpha-glucosidase activity. The first treatment for Pompe disease, the enzyme replacement therapy, Myozyme® (recombinant human acid alpha-glucosidase, alglucosidase alfa), is a lifesaving treatment for the most severe form of the disease and provided clinically meaningful benefits to patients with milder phenotypes. Nonetheless, many patients display suboptimal responses or clinical decline following years of alglucosidase alfa treatment. The approval of avalglucosidase alfa (Nexviazyme®) and cipaglucosidase alfa (Pombiliti®) with miglustat (Opfolda®) represents a new generation of enzyme replacement therapies seeking to further improve patient outcomes beyond alglucosidase alfa. However, the emergence of a complicated new phenotype with central nervous system involvement following long-term treatment, coupled with known and anticipated unmet needs of patients receiving enzyme replacement therapy, has prompted development of innovative new treatments.
This review provides an overview of the challenges of existing treatments and a summary of emerging therapies currently in preclinical or clinical development for Pompe disease and related lysosomal storage disorders. Key treatments include tissue-targeted enzyme replacement therapy, which seeks to enhance enzyme concentration in target tissues such as the central nervous system; substrate reduction therapy, which reduces intracellular glycogen concentrations via novel mechanisms; and gene therapy, which may restore endogenous production of deficient acid alpha-glucosidase. Each of these proposed treatments shows promise as a future therapeutic option to improve quality of life in Pompe disease by more efficiently treating the underlying cause of disease progression: glycogen accumulation.
{"title":"Pompe disease: Unmet needs and emerging therapies","authors":"Kelly A. George, Allyson L. Anding, Arjan van der Flier, Giulio S. Tomassy, Kenneth I. Berger, Tracy Y. Zhang, S. Pablo Sardi","doi":"10.1016/j.ymgme.2024.108590","DOIUrl":"10.1016/j.ymgme.2024.108590","url":null,"abstract":"<div><div>Pompe disease is a debilitating and life-threatening disease caused by aberrant accumulation of glycogen resulting from reduced acid alpha-glucosidase activity. The first treatment for Pompe disease, the enzyme replacement therapy, Myozyme® (recombinant human acid alpha-glucosidase, alglucosidase alfa), is a lifesaving treatment for the most severe form of the disease and provided clinically meaningful benefits to patients with milder phenotypes. Nonetheless, many patients display suboptimal responses or clinical decline following years of alglucosidase alfa treatment. The approval of avalglucosidase alfa (Nexviazyme®) and cipaglucosidase alfa (Pombiliti®) with miglustat (Opfolda®) represents a new generation of enzyme replacement therapies seeking to further improve patient outcomes beyond alglucosidase alfa. However, the emergence of a complicated new phenotype with central nervous system involvement following long-term treatment, coupled with known and anticipated unmet needs of patients receiving enzyme replacement therapy, has prompted development of innovative new treatments.</div><div>This review provides an overview of the challenges of existing treatments and a summary of emerging therapies currently in preclinical or clinical development for Pompe disease and related lysosomal storage disorders. Key treatments include tissue-targeted enzyme replacement therapy, which seeks to enhance enzyme concentration in target tissues such as the central nervous system; substrate reduction therapy, which reduces intracellular glycogen concentrations via novel mechanisms; and gene therapy, which may restore endogenous production of deficient acid alpha-glucosidase. Each of these proposed treatments shows promise as a future therapeutic option to improve quality of life in Pompe disease by more efficiently treating the underlying cause of disease progression: glycogen accumulation.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 3","pages":"Article 108590"},"PeriodicalIF":3.7,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142446818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Acyl-CoA Oxidase-1 (ACOX1) deficiency (MIM 264470) is an autosomal recessive disease characterized by impairments in the desaturation of acyl-CoAs to 2-trans-enoyl-CoAs, which is the first step in the catalysis of the β-oxidative breakdown of very long chain fatty acids (VLCFA) occuring in peroxisomes. The deleterious accumulation of VLCFA in several organs, including the brain, is a key biochemical feature of this disease which has devastating neurological consequences. ACOX1 deficiency is ultra-rare; as such, few studies have been conducted to determine the leading causes of symptoms or uncover new therapeutics. When confronted with one such case, we decided to bring drug discovery tools to the patient's bedside in an attempt to identify a cure. A skin biopsy was performed on a young patient with ACOX1 deficiency, following which screening technologies and mass spectrometry analysis techniques were applied to design a cellular assay that enabled the direct measurement of the effect of small molecules on the patient's primary fibroblasts. This approach is particularly well adapted to inherited metabolic disorders such as ACOX1 deficiency. Through the evaluation of a proprietary library of repurposable drugs, we found that the anthelmintic drug niclosamide led to a significant reduction in VLCFA in vitro. This drug was subsequently administered to the patient for more than six years. This study outlines the screening and drug selection processes. Additionally, we present our comprehensive clinical and biochemical findings that aided in understanding the patient's natural history and analysis of the progression of the patient's symptoms throughout the treatment period. Although the patient's overall lifespan was extended compared to the average age at death in severe early onset cases of ACOX1 deficiency, we did not observe any definitive evidence of clinical or biochemical improvement during niclosamide treatment. Nonetheless, our study shows a good safety profile of long-term niclosamide administration in a child with a rare neurodegenerative disease, and illustrates the potential of individualized therapeutic strategies in the management of inherited metabolic disorders, which could benefit both patients and the broader scientific and medical communities.
{"title":"Findings from the individualized management of a patient with Acyl-CoA Oxidase-1 (ACOX1) deficiency: A bedside-to-bench-to-bedside strategy","authors":"Camille Moreau , Adrien Paquot , Gustavo Soto Ares , Anne-Frédérique Dessein , Benoit Deprez , Terence Beghyn , Dries Dobbelaere","doi":"10.1016/j.ymgme.2024.108581","DOIUrl":"10.1016/j.ymgme.2024.108581","url":null,"abstract":"<div><div>Acyl-CoA Oxidase-1 (ACOX1) deficiency (MIM <span><span>264470</span><svg><path></path></svg></span>) is an autosomal recessive disease characterized by impairments in the desaturation of acyl-CoAs to 2-<em>trans</em>-enoyl-CoAs, which is the first step in the catalysis of the β-oxidative breakdown of very long chain fatty acids (VLCFA) occuring in peroxisomes. The deleterious accumulation of VLCFA in several organs, including the brain, is a key biochemical feature of this disease which has devastating neurological consequences. ACOX1 deficiency is ultra-rare; as such, few studies have been conducted to determine the leading causes of symptoms or uncover new therapeutics. When confronted with one such case, we decided to bring drug discovery tools to the patient's bedside in an attempt to identify a cure. A skin biopsy was performed on a young patient with ACOX1 deficiency, following which screening technologies and mass spectrometry analysis techniques were applied to design a cellular assay that enabled the direct measurement of the effect of small molecules on the patient's primary fibroblasts. This approach is particularly well adapted to inherited metabolic disorders such as ACOX1 deficiency. Through the evaluation of a proprietary library of repurposable drugs, we found that the anthelmintic drug niclosamide led to a significant reduction in VLCFA <em>in vitro</em>. This drug was subsequently administered to the patient for more than six years. This study outlines the screening and drug selection processes. Additionally, we present our comprehensive clinical and biochemical findings that aided in understanding the patient's natural history and analysis of the progression of the patient's symptoms throughout the treatment period. Although the patient's overall lifespan was extended compared to the average age at death in severe early onset cases of ACOX1 deficiency, we did not observe any definitive evidence of clinical or biochemical improvement during niclosamide treatment. Nonetheless, our study shows a good safety profile of long-term niclosamide administration in a child with a rare neurodegenerative disease, and illustrates the potential of individualized therapeutic strategies in the management of inherited metabolic disorders, which could benefit both patients and the broader scientific and medical communities.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 3","pages":"Article 108581"},"PeriodicalIF":3.7,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-23DOI: 10.1016/j.ymgme.2024.108580
Monika A. Sigg , Christopher Wilson , Gillian E. Clague , Huiyu Zhou , Cheng Su , Geoffrey Y. Berguig
Phenylketonuria (PKU) is caused by deficient activity of phenylalanine hydroxylase (PAH), the enzyme that converts phenylalanine (Phe) to tyrosine (Tyr), leading to a toxic accumulation of Phe and reduced Tyr in the blood and brain. Abnormal Phe and Tyr levels in the brain disrupt normal neurotransmitter biosynthesis and may contribute to the cognitive and psychiatric deficits observed in individuals with PKU. Blood neurotransmitter metabolites (NTMs) may serve as biomarkers that reflect neurotransmitter levels in the brain. In this study, blood NTMs correlated with brain NTMs and neurotransmitters in wild-type and PAH-deficient mice treated with PAH gene therapy. Pegvaliase is an enzyme substitution therapy that lowers blood Phe levels and is approved for individuals with PKU and uncontrolled blood Phe concentrations (>600 μmol/L) despite prior management. The current work evaluated the relationship between blood NTMs and blood Phe in pegvaliase-treated, Phase 3, PRISM-1 (NCT01819727) and PRISM-2 (NCT01889862) study participants (Pegvaliase Group; N = 109). At baseline, individuals in the Pegvaliase Group had lower levels of the NTMs homovanillic acid (HVA), 3-methoxy-4-hydroxyphenyl glycol (MOPEG), and 5-hydroxyindoleacetic acid (5HIAA), and higher levels of the NTM phenylacetylglutamine (PAG) than age- and sex-matched healthy controls. PAG levels correlated positively with Phe levels (r = 0.833; p < 0.001), while HVA, MOPEG, and 5HIAA levels correlated negatively with Phe levels (r = −0.588, −0.561, and −0.857, respectively; all p < 0.001) across all timepoints. In participants with longitudinal NTM measurements available at baseline, 12 months, and 24 months (Pegvaliase Subgroup; n = 91), blood NTM levels improved from baseline with pegvaliase treatment at 12 months and 24 months, and median levels were normalized with blood Phe level reductions below 360 μmol/L after 24 months of treatment with pegvaliase, including in participants with blood Phe <30 μmol/L. In conclusion, blood NTM levels correlated with blood Phe levels, and pegvaliase improved blood NTM levels in a large cohort of individuals with PKU.
{"title":"Pegvaliase treatment normalizes blood neurotransmitter metabolites in adults with phenylketonuria","authors":"Monika A. Sigg , Christopher Wilson , Gillian E. Clague , Huiyu Zhou , Cheng Su , Geoffrey Y. Berguig","doi":"10.1016/j.ymgme.2024.108580","DOIUrl":"10.1016/j.ymgme.2024.108580","url":null,"abstract":"<div><div>Phenylketonuria (PKU) is caused by deficient activity of phenylalanine hydroxylase (PAH), the enzyme that converts phenylalanine (Phe) to tyrosine (Tyr), leading to a toxic accumulation of Phe and reduced Tyr in the blood and brain. Abnormal Phe and Tyr levels in the brain disrupt normal neurotransmitter biosynthesis and may contribute to the cognitive and psychiatric deficits observed in individuals with PKU. Blood neurotransmitter metabolites (NTMs) may serve as biomarkers that reflect neurotransmitter levels in the brain. In this study, blood NTMs correlated with brain NTMs and neurotransmitters in wild-type and <em>PAH</em>-deficient mice treated with <em>PAH</em> gene therapy. Pegvaliase is an enzyme substitution therapy that lowers blood Phe levels and is approved for individuals with PKU and uncontrolled blood Phe concentrations (>600 μmol/L) despite prior management. The current work evaluated the relationship between blood NTMs and blood Phe in pegvaliase-treated, Phase 3, PRISM-1 (<span><span>NCT01819727</span><svg><path></path></svg></span>) and PRISM-2 (<span><span>NCT01889862</span><svg><path></path></svg></span>) study participants (Pegvaliase Group; <em>N =</em> 109). At baseline, individuals in the Pegvaliase Group had lower levels of the NTMs homovanillic acid (HVA), 3-methoxy-4-hydroxyphenyl glycol (MOPEG), and 5-hydroxyindoleacetic acid (5HIAA), and higher levels of the NTM phenylacetylglutamine (PAG) than age- and sex-matched healthy controls. PAG levels correlated positively with Phe levels (<em>r</em> = 0.833; <em>p</em> < 0.001), while HVA, MOPEG, and 5HIAA levels correlated negatively with Phe levels (<em>r</em> = −0.588, −0.561, and −0.857, respectively; all <em>p</em> < 0.001) across all timepoints. In participants with longitudinal NTM measurements available at baseline, 12 months, and 24 months (Pegvaliase Subgroup; <em>n =</em> 91), blood NTM levels improved from baseline with pegvaliase treatment at 12 months and 24 months, and median levels were normalized with blood Phe level reductions below 360 μmol/L after 24 months of treatment with pegvaliase, including in participants with blood Phe <30 μmol/L. In conclusion, blood NTM levels correlated with blood Phe levels, and pegvaliase improved blood NTM levels in a large cohort of individuals with PKU.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 3","pages":"Article 108580"},"PeriodicalIF":3.7,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01DOI: 10.1016/j.ymgme.2024.108567
Dulce Quelhas , Jaak Jaeken
While the identification and diagnosis of congenital disorders of glycosylation (CDG) have rapidly progressed, the available treatment options are still quite limited. Mostly, we are only able to manage the disease symptoms rather than to address the underlying cause. However, recent years have brought about remarkable advances in treatment approaches for some CDG. Innovative therapies, targeting both the root cause and resulting manifestations, have transitioned from the research stage to practical application. The present paper aims to provide a detailed overview of these exciting developments and the rising concepts that are used to treat these ultra-rare diseases.
{"title":"Treatment of congenital disorders of glycosylation: An overview","authors":"Dulce Quelhas , Jaak Jaeken","doi":"10.1016/j.ymgme.2024.108567","DOIUrl":"10.1016/j.ymgme.2024.108567","url":null,"abstract":"<div><p>While the identification and diagnosis of congenital disorders of glycosylation (CDG) have rapidly progressed, the available treatment options are still quite limited. Mostly, we are only able to manage the disease symptoms rather than to address the underlying cause. However, recent years have brought about remarkable advances in treatment approaches for some CDG. Innovative therapies, targeting both the root cause and resulting manifestations, have transitioned from the research stage to practical application. The present paper aims to provide a detailed overview of these exciting developments and the rising concepts that are used to treat these ultra-rare diseases.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 1","pages":"Article 108567"},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224004517/pdfft?md5=11fe9626a95e4fd00999824a20760034&pid=1-s2.0-S1096719224004517-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142137123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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