Alkaptonuria (AKU) is a rare autosomal recessive disorder of amino acid metabolism caused by defects in the HGD gene. The diagnosis of AKU is often delayed or missed due to its insidiousness. AKU is far from well-known in China. This study aims to provide an epidemiological synthesis of Chinese AKU patients. Firstly, we reported a Chinese pediatric AKU patient who visited because of short stature. Her urinary organic acid analysis revealed a small amount of homogentisic acid (HGA). Whole exome sequencing and Sanger sequencing revealed that the patient carried a c.343-1G > A/c.1027 A > C(p.Met343Leu) compound heterozygous variant in the HGD gene, which was inherited from her parents, respectively. During 4-year follow-up, a small amount of HGA was persistently present in her urine, whereas her height exhibited catch-up growth and subsequently normalized. According to the literature, 91 Chinese AKU patients, including the present one, were included. Among them, the male-to-female ratio was approximately 2:1, and the average age at diagnosis was 36.99 ± 23.05 years. The most common clinical feature was darkened urine (100.00 %), followed by arthropathy (69.23 %) and pigmentation of the skin or sclera (58.24 %). Pigmentation of the skin or sclera and arthropathy occurred more frequently in adult patients. Eleven different variants in the HGD gene were identified, including 5 known variants and 6 not listed in HGMD. This study describes a new Chinese AKU patient and summarizes the clinical and molecular features of Chinese AKU patients, which will help enrich the knowledge of AKU and contribute to early recognition, diagnosis and treatment.
{"title":"Clinical and molecular characteristics of Chinese patients with alkaptonuria: 4-year follow-up of a pediatric patient and literature review","authors":"Xiaomei Qiu , Yuqing Liu, Yongxian Shao, Xiaojian Mao, Jingqi Zhang, Xiaodan Chen, Xi Yin, Huiying Sheng, Xiuzhen Li, Yunting Lin","doi":"10.1016/j.ymgmr.2025.101276","DOIUrl":"10.1016/j.ymgmr.2025.101276","url":null,"abstract":"<div><div>Alkaptonuria (AKU) is a rare autosomal recessive disorder of amino acid metabolism caused by defects in the <em>HGD</em> gene. The diagnosis of AKU is often delayed or missed due to its insidiousness. AKU is far from well-known in China. This study aims to provide an epidemiological synthesis of Chinese AKU patients. Firstly, we reported a Chinese pediatric AKU patient who visited because of short stature. Her urinary organic acid analysis revealed a small amount of homogentisic acid (HGA). Whole exome sequencing and Sanger sequencing revealed that the patient carried a c.343-1G > A/c.1027 A > C(p.Met343Leu) compound heterozygous variant in the <em>HGD</em> gene, which was inherited from her parents, respectively. During 4-year follow-up, a small amount of HGA was persistently present in her urine, whereas her height exhibited catch-up growth and subsequently normalized. According to the literature, 91 Chinese AKU patients, including the present one, were included. Among them, the male-to-female ratio was approximately 2:1, and the average age at diagnosis was 36.99 ± 23.05 years. The most common clinical feature was darkened urine (100.00 %), followed by arthropathy (69.23 %) and pigmentation of the skin or sclera (58.24 %). Pigmentation of the skin or sclera and arthropathy occurred more frequently in adult patients. Eleven different variants in the <em>HGD</em> gene were identified, including 5 known variants and 6 not listed in HGMD. This study describes a new Chinese AKU patient and summarizes the clinical and molecular features of Chinese AKU patients, which will help enrich the knowledge of AKU and contribute to early recognition, diagnosis and treatment.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101276"},"PeriodicalIF":1.9,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-10DOI: 10.1016/j.ymgmr.2025.101273
Dennis T. Famili , Gehad Elghazali , Emanuela Argili , Russell P. Saneto , Michael Harris , Oleg Gerasimenko , Julia Gerasimenko , Manolis Fanto , Hormos Salimi Dafsari , Heinz Jungbluth
Vici syndrome is a severe neurodevelopmental multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. There may be additional variable involvement of other organs. VS is caused by recessive mutations in EPG5, encoding a tethering factor with important roles in autophagy, an essential cellular homeostatic mechanism involved in metabolic adaptation, infection defence and quality control of proteins and organelles.
Acute pancreatitis is an inflammatory syndrome caused by an acute injury resulting in failure of safeguarding mechanisms preventing autodigestion. Chronic pancreatitis is characterized by replacement of pancreatic parenchyma with fibrotic tissue following repeated injury, resulting in endocrine and exocrine insufficiency. In addition to common causes such as excessive ethanol consumption, gallstones and pharmacological factors, there are likely to be additional genetic contributors.
Here we report 3 patients with EPG5-related Vici syndrome and not previously recognized pancreatic involvement, ranging from otherwise asymptomatic amylase elevations to acute pancreatitis and pancreatic insufficiency. A topical literature review on the role of autophagy and autophagy-related genes in the pancreas suggested that autophagy defects may affect critical pathological events involved in pancreatitis, in particular abnormal vacuole formation in acinar cells, inappropriate intra-acinar trypsinogen activation, mitochondrial dysfunction and disturbed calcium homeostasis.
These findings illustrate the importance of EPG5 and other autophagy-related genes in normal pancreatic function and expand the phenotypical spectrum of EPG5-related disorders.
{"title":"Pancreatic involvement in EPG5-related disorders","authors":"Dennis T. Famili , Gehad Elghazali , Emanuela Argili , Russell P. Saneto , Michael Harris , Oleg Gerasimenko , Julia Gerasimenko , Manolis Fanto , Hormos Salimi Dafsari , Heinz Jungbluth","doi":"10.1016/j.ymgmr.2025.101273","DOIUrl":"10.1016/j.ymgmr.2025.101273","url":null,"abstract":"<div><div>Vici syndrome is a severe neurodevelopmental multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. There may be additional variable involvement of other organs. <em>VS</em> is caused by recessive mutations in <em>EPG5</em>, encoding a tethering factor with important roles in autophagy, an essential cellular homeostatic mechanism involved in metabolic adaptation, infection defence and quality control of proteins and organelles.</div><div>Acute pancreatitis is an inflammatory syndrome caused by an acute injury resulting in failure of safeguarding mechanisms preventing autodigestion. Chronic pancreatitis is characterized by replacement of pancreatic parenchyma with fibrotic tissue following repeated injury, resulting in endocrine and exocrine insufficiency. In addition to common causes such as excessive ethanol consumption, gallstones and pharmacological factors, there are likely to be additional genetic contributors.</div><div>Here we report 3 patients with <em>EPG5</em>-related Vici syndrome and not previously recognized pancreatic involvement, ranging from otherwise asymptomatic amylase elevations to acute pancreatitis and pancreatic insufficiency. A topical literature review on the role of autophagy and autophagy-related genes in the pancreas suggested that autophagy defects may affect critical pathological events involved in pancreatitis, in particular abnormal vacuole formation in acinar cells, inappropriate intra-acinar trypsinogen activation, mitochondrial dysfunction and disturbed calcium homeostasis.</div><div>These findings illustrate the importance of <em>EPG5</em> and other autophagy-related genes in normal pancreatic function and expand the phenotypical spectrum of <em>EPG5</em>-related disorders.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101273"},"PeriodicalIF":1.9,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-08DOI: 10.1016/j.ymgmr.2025.101275
Marya S. Sabir , Kostantin Dobrenis , Allisandra K. Rha , Laura Pollard , Petcharat Leoyklang , Mariah Marrero , Carla Ciccone , Mary E. Hackbarth , Marjan Huizing , Raymond Y. Wang , William A. Gahl , Frances M. Platt , May Christine V. Malicdan
Free sialic acid storage disorder (FSASD) is an autosomal recessive lysosomal storage disease caused by biallelic pathogenic variants in SLC17A5, which encodes the lysosomal sialic acid transporter, sialin. FSASD is characterized by excessive lysosomal free sialic acid accumulation, leading to either a severe, early-onset lethal phenotype or a progressive neurodegenerative course. To characterize biochemical alterations in FSASD models, we performed comprehensive profiling of glycosphingolipids (GSLs), including sialylated species (i.e., gangliosides), in mouse embryonic fibroblasts (MEFs) derived from Slc17a5-R39C/R39C and Slc17a5-KO/KO mouse models, as well as in human SLC17A5-deficient HEK-293 T cells generated via CRISPR-Cas9-mediated non-homologous end joining. HPLC-based analyses demonstrated GM3 ganglioside accumulation in MEFs and significant reductions in a-series GSLs—including GM2, GM1a, and GD1a—in SLC17A5-deficient HEK-293 T cells. Analysis of neuraminidase 1/3/4 activities revealed consistently elevated activity across all cell models, while cytosolic neuraminidase 2 showed only a modest increase in Slc17a5-R39C/R39C MEFs. Preliminary quantification showed elevated free sialic acid across all models, consistent with the characteristic biochemical defect observed in FSASD and supporting their relevance for mechanistic studies. These findings highlight that free sialic acid storage leads to changes in GSL homeostasis in FSASD mouse (MEFs) and human (SLC17A5-deficient HEK-293T) cellular models, underscoring their utility as models for studying FSASD pathogenesis.
{"title":"Profiling glycosphingolipid changes in mouse and human cellular models of lysosomal free sialic acid storage disorder","authors":"Marya S. Sabir , Kostantin Dobrenis , Allisandra K. Rha , Laura Pollard , Petcharat Leoyklang , Mariah Marrero , Carla Ciccone , Mary E. Hackbarth , Marjan Huizing , Raymond Y. Wang , William A. Gahl , Frances M. Platt , May Christine V. Malicdan","doi":"10.1016/j.ymgmr.2025.101275","DOIUrl":"10.1016/j.ymgmr.2025.101275","url":null,"abstract":"<div><div>Free sialic acid storage disorder (FSASD) is an autosomal recessive lysosomal storage disease caused by biallelic pathogenic variants in <em>SLC17A5</em>, which encodes the lysosomal sialic acid transporter, sialin. FSASD is characterized by excessive lysosomal free sialic acid accumulation, leading to either a severe, early-onset lethal phenotype or a progressive neurodegenerative course. To characterize biochemical alterations in FSASD models, we performed comprehensive profiling of glycosphingolipids (GSLs), including sialylated species (i.e., gangliosides), in mouse embryonic fibroblasts (MEFs) derived from Slc17a5-R39C/R39C and Slc17a5-KO/KO mouse models, as well as in human SLC17A5-deficient HEK-293 T cells generated via CRISPR-Cas9-mediated non-homologous end joining. HPLC-based analyses demonstrated GM3 ganglioside accumulation in MEFs and significant reductions in a-series GSLs—including GM2, GM1a, and GD1a—in SLC17A5-deficient HEK-293 T cells. Analysis of neuraminidase 1/3/4 activities revealed consistently elevated activity across all cell models, while cytosolic neuraminidase 2 showed only a modest increase in Slc17a5-R39C/R39C MEFs. Preliminary quantification showed elevated free sialic acid across all models, consistent with the characteristic biochemical defect observed in FSASD and supporting their relevance for mechanistic studies. These findings highlight that free sialic acid storage leads to changes in GSL homeostasis in FSASD mouse (MEFs) and human (SLC17A5-deficient HEK-293T) cellular models, underscoring their utility as models for studying FSASD pathogenesis.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101275"},"PeriodicalIF":1.9,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145465582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-27DOI: 10.1016/j.ymgmr.2025.101270
Steven H. Lang , Andres Caceres Salgado , Matthew T. Snyder , Brandy Rawls-Castillo , Aaron Williams , Charul Gijavanekar , Sarah H. Elsea , Xia Wang , Mary Elizabeth M. Tessier , Claudia Soler-Alfonso , Fernando Scaglia
Introduction
Ethylmalonic encephalopathy (EE) is an often-severe inborn error of metabolism caused by biallelic variants in the ETHE1 gene leading to impaired detoxification of hydrogen sulfide (H2S). H2S is produced both exogenously by anerobic intestinal bacteria as well as by the endogenous catabolism of the sulfur-containing amino acids methionine and cysteine. Existing therapies including metronidazole, N-acetylcysteine (NAC), and orthotopic liver transplantation (OLT) have been pursued with the objective of reducing or detoxifying exogenously produced H2S. However, strategies to reduce endogenously produced H2S using a methionine and cysteine restricted diet are an understudied therapeutic avenue.
Methods
We performed an open-label, single-arm study to evaluate the effects of dietary intervention with a methionine and cysteine restricted diet (20–30 mg/kg/day) on biochemical parameters and overall clinical trajectory in three patients with molecularly confirmed ethylmalonic encephalopathy (two with attenuated phenotypes, one classically affected). All three patients were receiving a combination of medical therapy with metronidazole and NAC and were status-post OLT at the time of diet initiation. Plasma butyrylcarnitine (C4) levels were measured at diagnosis, serially following initiation of medical therapy and OLT, and at regular follow-up visits in a metabolic clinic after diet initiation. Additionally, we obtained untargeted metabolomics studies and directly evaluated ethylmalonate, butyrylcarnitine, isobutyrylcarnitine, isovalerylcarnitine, 2-methylbutyrylcarnitine, glutarylcarnitine, and methylsuccinate levels in the pre- OLT/medical therapy, post- OLT/medical therapy, and post- sulfur-restricted diet states.
Results
We observed a 20–38 % reduction in plasma C4 levels in all three patients following OLT and combination medical therapy with NAC and metronidazole. An 8–10 % reduction in C4 was observed following the introduction of dietary therapy in the two patients with attenuated phenotypes and an 82 % increase in C4 was seen in the patient with the classical phenotype. The metabolic profile as assessed by untargeted metabolomics analysis was largely unchanged in the pre-OLT/medical therapy, post-OLT/medical therapy, and post-diet states.
Conclusions
The modest biochemical response to a sulfur-restricted diet observed in our cohort likely reflects the relatively minor contribution of endogenous sulfur-containing amino acid catabolism to overall H2S production. Further work is needed to study the impact of dietary intervention on the natural history of EE including diet only trials in the animal model as well as in the pre-OLT period in human participants.
{"title":"Biochemical and clinical response to a sulfur-restricted diet in ethylmalonic encephalopathy","authors":"Steven H. Lang , Andres Caceres Salgado , Matthew T. Snyder , Brandy Rawls-Castillo , Aaron Williams , Charul Gijavanekar , Sarah H. Elsea , Xia Wang , Mary Elizabeth M. Tessier , Claudia Soler-Alfonso , Fernando Scaglia","doi":"10.1016/j.ymgmr.2025.101270","DOIUrl":"10.1016/j.ymgmr.2025.101270","url":null,"abstract":"<div><h3>Introduction</h3><div>Ethylmalonic encephalopathy (EE) is an often-severe inborn error of metabolism caused by biallelic variants in the <em>ETHE1</em> gene leading to impaired detoxification of hydrogen sulfide (H<sub>2</sub>S). H<sub>2</sub>S is produced both exogenously by anerobic intestinal bacteria as well as by the endogenous catabolism of the sulfur-containing amino acids methionine and cysteine. Existing therapies including metronidazole, <em>N</em>-acetylcysteine (NAC), and orthotopic liver transplantation (OLT) have been pursued with the objective of reducing or detoxifying exogenously produced H<sub>2</sub>S. However, strategies to reduce endogenously produced H<sub>2</sub>S using a methionine and cysteine restricted diet are an understudied therapeutic avenue.</div></div><div><h3>Methods</h3><div>We performed an open-label, single-arm study to evaluate the effects of dietary intervention with a methionine and cysteine restricted diet (20–30 mg/kg/day) on biochemical parameters and overall clinical trajectory in three patients with molecularly confirmed ethylmalonic encephalopathy (two with attenuated phenotypes, one classically affected). All three patients were receiving a combination of medical therapy with metronidazole and NAC and were status-post OLT at the time of diet initiation. Plasma butyrylcarnitine (C4) levels were measured at diagnosis, serially following initiation of medical therapy and OLT, and at regular follow-up visits in a metabolic clinic after diet initiation. Additionally, we obtained untargeted metabolomics studies and directly evaluated ethylmalonate, butyrylcarnitine, isobutyrylcarnitine, isovalerylcarnitine, 2-methylbutyrylcarnitine, glutarylcarnitine, and methylsuccinate levels in the pre- OLT/medical therapy, post- OLT/medical therapy, and post- sulfur-restricted diet states.</div></div><div><h3>Results</h3><div>We observed a 20–38 % reduction in plasma C4 levels in all three patients following OLT and combination medical therapy with NAC and metronidazole. An 8–10 % reduction in C4 was observed following the introduction of dietary therapy in the two patients with attenuated phenotypes and an 82 % increase in C4 was seen in the patient with the classical phenotype. The metabolic profile as assessed by untargeted metabolomics analysis was largely unchanged in the pre-OLT/medical therapy, post-OLT/medical therapy, and post-diet states.</div></div><div><h3>Conclusions</h3><div>The modest biochemical response to a sulfur-restricted diet observed in our cohort likely reflects the relatively minor contribution of endogenous sulfur-containing amino acid catabolism to overall H<sub>2</sub>S production. Further work is needed to study the impact of dietary intervention on the natural history of EE including diet only trials in the animal model as well as in the pre-OLT period in human participants.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101270"},"PeriodicalIF":1.9,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145415873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-19DOI: 10.1016/j.ymgmr.2025.101272
Jeongho Lee, Eun Sook Suh
Phenylketonuria (PKU) is one of the most common inherited metabolic disorders. If recognized and treated early, patients can avoid severe complications and maintain normal intellectual functioning. However, despite early and intensive treatment, several studies have reported an increased prevalence of psychiatric and behavioral symptoms, particularly in adulthood. The aim of this study was to investigate psychiatric manifestations in children and adolescents with PKU. The Korean version of the Child Behavior Checklist (K-CBCL) was used to assess psychopathology in 50 children with PKU and 50 healthy controls. Recent and mean phenylalanine (Phe) levels, as well as demographic information, were collected through retrospective chart review. Patients with PKU showed significantly higher scores in social, school, aggressive behavior, externalizing problems, and total behavior on the K-CBCL than healthy controls. Significant differences were found in total competence (p < 0.001), total behavior (p = 0.004), attention (p = 0.031), and emotional lability (p = 0.031) between clinical and non-clinical ranges. Later age at diagnosis was associated with increased anxiety, depression, thought problems, attention deficits, and emotional lability. Internalizing problems (p = 0.025), thought problems (p = 0.016), and delinquent behavior (p = 0.006) were positively correlated with recent and mean Phe levels. Internalizing problems (p = 0.004), attention (p = 0.008), and social problems (p = 0.016) were associated with variation in blood Phe levels. Children with PKU may experience greater psychosocial challenges than healthy children. Careful monitoring and control of Phe levels may reduce the risk of psychiatric symptoms in this population.
{"title":"Psychosocial adaptation of children and adolescents with phenylketonuria in Korea","authors":"Jeongho Lee, Eun Sook Suh","doi":"10.1016/j.ymgmr.2025.101272","DOIUrl":"10.1016/j.ymgmr.2025.101272","url":null,"abstract":"<div><div>Phenylketonuria (PKU) is one of the most common inherited metabolic disorders. If recognized and treated early, patients can avoid severe complications and maintain normal intellectual functioning. However, despite early and intensive treatment, several studies have reported an increased prevalence of psychiatric and behavioral symptoms, particularly in adulthood. The aim of this study was to investigate psychiatric manifestations in children and adolescents with PKU. The Korean version of the Child Behavior Checklist (K-CBCL) was used to assess psychopathology in 50 children with PKU and 50 healthy controls. Recent and mean phenylalanine (Phe) levels, as well as demographic information, were collected through retrospective chart review. Patients with PKU showed significantly higher scores in social, school, aggressive behavior, externalizing problems, and total behavior on the K-CBCL than healthy controls. Significant differences were found in total competence (<em>p</em> < 0.001), total behavior (<em>p</em> = 0.004), attention (<em>p</em> = 0.031), and emotional lability (p = 0.031) between clinical and non-clinical ranges. Later age at diagnosis was associated with increased anxiety, depression, thought problems, attention deficits, and emotional lability. Internalizing problems (<em>p</em> = 0.025), thought problems (<em>p</em> = 0.016), and delinquent behavior (<em>p</em> = 0.006) were positively correlated with recent and mean Phe levels. Internalizing problems (<em>p</em> = 0.004), attention (<em>p</em> = 0.008), and social problems (<em>p</em> = 0.016) were associated with variation in blood Phe levels. Children with PKU may experience greater psychosocial challenges than healthy children. Careful monitoring and control of Phe levels may reduce the risk of psychiatric symptoms in this population.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101272"},"PeriodicalIF":1.9,"publicationDate":"2025-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145325207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-17DOI: 10.1016/j.ymgmr.2025.101271
Hayaki Okamoto, Shunsuke Goto, Mika Fujita, Hideki Fujii
Background
Fabry disease (FD) is a rare X-linked lysosomal storage disorder characterized by globotriaosylceramide (Gb3) accumulation, resulting in kidney and cardiac dysfunction. Although enzyme replacement therapy (ERT) and chaperone therapy are the standard therapies, progression of renal decline persists. Sodium–glucose co-transporter 2 (SGLT2) inhibitors exert renoprotective effects in chronic kidney disease (CKD), but their efficacy in FD remains unknown.
Methods
We retrospectively analyzed data of 10 patients with FD treated with SGLT2 inhibitors and compared their renal outcomes to 18 patients with CKD without FD. The estimated glomerular filtration rate (eGFR) slope, urinary albumin-to-creatinine ratio (UACR), and plasma brain natriuretic peptide (BNP) levels were assessed 1 year before and after initiating SGLT2 inhibitor therapy. Linear mixed-effects models were employed for statistical analysis.
Results
In patients with FD, the annual eGFR decline significantly improved from −4.38 mL/min/1.73 m2/year (IQR: −10.57 to 0.59) before treatment to 1.25 (IQR: −4.16 to 9.74) after treatment (p < 0.05). This improvement remained significant after adjusting for confounding factors. In contrast, the annual eGFR decline in patients with CKD without FD also tended to improve, albeit without significance. Notably, the initial eGFR decline usually seen with SGLT2 inhibitors in CKD was not observed in the FD cohort. UACR and plasma BNP levels remained unchanged after SGLT2 inhibitor therapy.
Conclusions
SGLT2 inhibitors substantially attenuated the decline in eGFR in patients with FD. These findings support their potential as a renoprotective adjunct in the management of FD.
{"title":"Renoprotective effects of SGLT2 inhibitors in patients with Fabry disease","authors":"Hayaki Okamoto, Shunsuke Goto, Mika Fujita, Hideki Fujii","doi":"10.1016/j.ymgmr.2025.101271","DOIUrl":"10.1016/j.ymgmr.2025.101271","url":null,"abstract":"<div><h3>Background</h3><div>Fabry disease (FD) is a rare X-linked lysosomal storage disorder characterized by globotriaosylceramide (Gb3) accumulation, resulting in kidney and cardiac dysfunction. Although enzyme replacement therapy (ERT) and chaperone therapy are the standard therapies, progression of renal decline persists. Sodium–glucose co-transporter 2 (SGLT2) inhibitors exert renoprotective effects in chronic kidney disease (CKD), but their efficacy in FD remains unknown.</div></div><div><h3>Methods</h3><div>We retrospectively analyzed data of 10 patients with FD treated with SGLT2 inhibitors and compared their renal outcomes to 18 patients with CKD without FD. The estimated glomerular filtration rate (eGFR) slope, urinary albumin-to-creatinine ratio (UACR), and plasma brain natriuretic peptide (BNP) levels were assessed 1 year before and after initiating SGLT2 inhibitor therapy. Linear mixed-effects models were employed for statistical analysis.</div></div><div><h3>Results</h3><div>In patients with FD, the annual eGFR decline significantly improved from −4.38 mL/min/1.73 m<sup>2</sup>/year (IQR: −10.57 to 0.59) before treatment to 1.25 (IQR: −4.16 to 9.74) after treatment (<em>p</em> < 0.05). This improvement remained significant after adjusting for confounding factors. In contrast, the annual eGFR decline in patients with CKD without FD also tended to improve, albeit without significance. Notably, the initial eGFR decline usually seen with SGLT2 inhibitors in CKD was not observed in the FD cohort. UACR and plasma BNP levels remained unchanged after SGLT2 inhibitor therapy.</div></div><div><h3>Conclusions</h3><div>SGLT2 inhibitors substantially attenuated the decline in eGFR in patients with FD. These findings support their potential as a renoprotective adjunct in the management of FD.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101271"},"PeriodicalIF":1.9,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145325206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-16DOI: 10.1016/j.ymgmr.2025.101268
Ping Pang , Lin Wan , Yan Liang , Xia Zhao , Guang Yang
Nonketotic hyperglycinaemia (NKH) is an autosomal recessive neurometabolic disorder resulting from deficient glycine cleavage system activity, causing severe neurological impairment. While NKH is typically associated with pathogenic variants in glycine decarboxylase (GLDC) or aminomethyltransferase, the role of synonymous variants remains uncertain. To date, no cases of NKH caused by GLDC homozygous synonymous variants have been reported. Herein, a female infant born to consanguineous parents who developed refractory seizures, progressing to infantile epileptic spasms syndrome at 2 months is reported. Initial genetic testing identified a homozygous synonymous GLDC variant (c.1023G > A, p.Val341=), previously classified as “likely benign” in ClinVar (variation identification number: 1108119). Minigene splicing analysis revealed that the c.1023G > A variant caused a 38-base pair deletion in exon 7 (r.1021_1058del), Given the phenotypic characteristics of the child, we predict that this may resulting in a frameshift mutation (p.Val341ArgfsTer56) and a truncated protein. This functional evidence confirmed the pathogenicity of the variant.
非酮症型高甘氨酸血症（NKH）是一种常染色体隐性神经代谢疾病，由甘氨酸裂解系统活性不足引起，可导致严重的神经功能损害。虽然NKH通常与甘氨酸脱羧酶（GLDC）或氨基甲基转移酶的致病变异有关，但同义变异的作用仍不确定。迄今为止，还没有由GLDC纯合同义变异体引起的NKH病例的报道。本文报告了一位近亲父母所生的女婴，在2个月时发生难治性癫痫发作，进展为婴儿癫痫痉挛综合征。最初的基因检测发现了一种纯合同义GLDC变异（c.1023G > a, p.Val341=），该变异先前在ClinVar中被归类为“可能良性”（变异识别号：1108119）。Minigene剪接分析显示，c.1023G >； A变异导致第7外显子38个碱基对缺失（r.1021_1058del），考虑到儿童的表型特征，我们预测这可能导致移码突变（p.Val341ArgfsTer56）和截断蛋白。这一功能证据证实了该变异的致病性。
{"title":"Severe nonketotic hyperglycinaemia due to a synonymous variant","authors":"Ping Pang , Lin Wan , Yan Liang , Xia Zhao , Guang Yang","doi":"10.1016/j.ymgmr.2025.101268","DOIUrl":"10.1016/j.ymgmr.2025.101268","url":null,"abstract":"<div><div>Nonketotic hyperglycinaemia (NKH) is an autosomal recessive neurometabolic disorder resulting from deficient glycine cleavage system activity, causing severe neurological impairment. While NKH is typically associated with pathogenic variants in glycine decarboxylase (<em>GLDC</em>) or aminomethyltransferase, the role of synonymous variants remains uncertain. To date, no cases of NKH caused by <em>GLDC</em> homozygous synonymous variants have been reported. Herein, a female infant born to consanguineous parents who developed refractory seizures, progressing to infantile epileptic spasms syndrome at 2 months is reported. Initial genetic testing identified a homozygous synonymous <em>GLDC</em> variant (c.1023G > A, p.Val341=), previously classified as “likely benign” in ClinVar (variation identification number: 1108119). Minigene splicing analysis revealed that the c.1023G > A variant caused a 38-base pair deletion in exon 7 (r.1021_1058del), Given the phenotypic characteristics of the child, we predict that this may resulting in a frameshift mutation (p.Val341ArgfsTer56) and a truncated protein. This functional evidence confirmed the pathogenicity of the variant.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101268"},"PeriodicalIF":1.9,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145325209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-15DOI: 10.1016/j.ymgmr.2025.101269
Laila Kazem , Wafaa Al-Qabandi , Buthaina Albash , Reem Elshafie , Miao He , Hind Alsharhan
Introduction
Biallelic pathogenic variants in SCYL1 have been reported in 22 individuals to date. Also referred to as CALFAN syndrome (cholestasis, acute liver failure, and neurodegeneration), this condition is characterized by recurrent episodic acute liver failure (ALF) with low-GGT cholestasis and variable neurological manifestations. SCYL1 deficiency disrupts intracellular vesicular trafficking, leading to hepatopathy and, in some cases, abnormal glycosylation.
Results
We report two Kuwaiti siblings homozygous for a pathogenic splice site variant in SCYL1(NM_020680.4):c.1386 + 1G > A p.?. The younger sibling, an 8-year-old female presented at 16 months with ALF, hepatosplenomegaly, global developmental delay, hypotonia, and gait instability. During liver crises, she demonstrated biochemical features including low-GGT cholestasis, coagulopathy, and transient glycosylation abnormalities. Liver biopsy revealed peri-sinusoidal fibrosis and mild steatosis. She experienced two additional ALF episodes at 26 months and 3 years, both resolving completely. Follow-up biochemical testing at age 5.5 years showed normalization of glycosylation patterns following hepatic recovery. In contrast, her 9-year-old brother, who carries the same homozygous variant, remains asymptomatic, with normal development, liver function and imaging.
Conclusion
To our knowledge, this is the first description of an asymptomatic individual homozygous for a pathogenic SCYL1 variant. Our findings highlight striking intrafamilial variability in SCYL1-deficiency and emphasize the reversibility of glycosylation abnormalities and liver dysfunction upon clinical recovery.
{"title":"SCYL1 deficiency and intrafamilial variability: Two cases from Kuwait","authors":"Laila Kazem , Wafaa Al-Qabandi , Buthaina Albash , Reem Elshafie , Miao He , Hind Alsharhan","doi":"10.1016/j.ymgmr.2025.101269","DOIUrl":"10.1016/j.ymgmr.2025.101269","url":null,"abstract":"<div><h3>Introduction</h3><div>Biallelic pathogenic variants in <em>SCYL1</em> have been reported in 22 individuals to date. Also referred to as CALFAN syndrome (cholestasis, acute liver failure, and neurodegeneration), this condition is characterized by recurrent episodic acute liver failure (ALF) with low-GGT cholestasis and variable neurological manifestations. <em>SCYL1</em> deficiency disrupts intracellular vesicular trafficking, leading to hepatopathy and, in some cases, abnormal glycosylation.</div></div><div><h3>Results</h3><div>We report two Kuwaiti siblings homozygous for a pathogenic splice site variant in <em>SCYL1</em>(NM_020680.4):c.1386 + 1G > A p.?. The younger sibling, an 8-year-old female presented at 16 months with ALF, hepatosplenomegaly, global developmental delay, hypotonia, and gait instability. During liver crises, she demonstrated biochemical features including low-GGT cholestasis, coagulopathy, and transient glycosylation abnormalities. Liver biopsy revealed peri-sinusoidal fibrosis and mild steatosis. She experienced two additional ALF episodes at 26 months and 3 years, both resolving completely. Follow-up biochemical testing at age 5.5 years showed normalization of glycosylation patterns following hepatic recovery. In contrast, her 9-year-old brother, who carries the same homozygous variant, remains asymptomatic, with normal development, liver function and imaging.</div></div><div><h3>Conclusion</h3><div>To our knowledge, this is the first description of an asymptomatic individual homozygous for a pathogenic <em>SCYL1</em> variant. Our findings highlight striking intrafamilial variability in <em>SCYL1</em>-deficiency and emphasize the reversibility of glycosylation abnormalities and liver dysfunction upon clinical recovery.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101269"},"PeriodicalIF":1.9,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145325208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-10DOI: 10.1016/j.ymgmr.2025.101260
Marina Bottino , Monica Boyer , Maija R. Steenari , Rebekah Barrick , Jose E. Abdenur
<div><div>Pyridoxine-Dependent Epilepsy (PDE) is an autosomal recessive disorder caused by biallelic variants in ALDH7A1. The most common presentation is intractable seizures in the neonatal/early infantile period, which respond to pyridoxine. Other manifestations include perinatal asphyxia, hypoglycemia, and neuroimaging abnormalities. Despite early treatment, patients often have neurodevelopmental abnormalities. Treatment guidelines recommend triple therapy with pyridoxine, dietary lysine restriction, and arginine supplementation.</div><div>We report an individual presenting with laboratory abnormalities suggestive of mitochondrial disease. Born full-term, via NSVD, with normal Apgar scores and cord gases. At 30 min, grunting developed, and at 4 h of life, jerky movements with eye deviation were noted. Laboratory results revealed acidosis (pH 7.15) and increased lactate (11.4 mMol/L, rr <2.1). The patient was started on IV fluids, given 1 mEq/kg of sodium bicarbonate, and transferred for higher-level care. Upon arrival, the evaluation was notable for hypotonia, non-rhythmic jerking movements, rapid eye blinking, and a critically low pH (6.92), high lactate (15.3 mMol/L), hyperammonemia (153 μMol/L, rr < 75), and a creatine kinase level of 15,742 U/L (rr 35–230). A single dose of phenobarbital was given, and the baby was intubated and ventilated. Video electroencephalogram (vEEG) showed a discontinuous background with abnormal, sharply contoured bursts alternating with suppression, with no clinical correlation. The patient was treated with continuous sodium bicarbonate drip and IV fluids, restricting glucose. Abnormal movements, lactic acidosis, and hyperammonemia resolved within 24 h. An electroencephalogram (EEG) at 5 days of life (DOL) showed a mildly discontinuous background with no epileptic activity, and MRI showed a thin corpus callosum, cysts, and cerebellar hypoplasia. Creatine kinase peaked at 30,995 U/L and normalized on DOL 8. Organic acids revealed significant increases in lactate, 2-OH-butyrate, pyruvate, 3-OH-butyrate, 2-OH-isovalerate, and a mild increase in Krebs-cycle intermediates.</div><div>Rapid whole genome sequence (rWGS) was available on DOL 9, disclosing two variants in <em>ALDH7A1</em>: c.1559C > T p.Ser520Phe, previously reported, and c.1540 A > G p.Lys514Glu, considered a VUS. Treatment with pyridoxine started at 30 mg/kg/day. Pre-treatment biomarkers were consistent with the diagnosis of PDE-ALDH7A1: urine Pipecolate 117.8 mMol/mol, RR ≤10, 6-oxo-Pipecolate 8.4 mMol/mol, RR ≤2.0 and plasma alpha-aminoadipic semialdehyde (AASA) 5.2 uMol/L, RR <0.4. Treatment with arginine was added on DOL 10 (200 mg/kg/day) and a lysine-restricted diet on DOL 12, after TPN was discontinued. Clinical exam improved, no seizures were observed, and EEG normalized. PDE biomarkers decreased, and the patient was discharged home on DOL 25.</div><div>Elevated lactic acid has been reported in up to 70.3 % of PDE-ALDH7A1 patients
{"title":"Lactic acidosis, rhabdomyolysis, and hyperammonemia: Atypical presentation in a new patient with PDE-ALDH7A1 defect","authors":"Marina Bottino , Monica Boyer , Maija R. Steenari , Rebekah Barrick , Jose E. Abdenur","doi":"10.1016/j.ymgmr.2025.101260","DOIUrl":"10.1016/j.ymgmr.2025.101260","url":null,"abstract":"<div><div>Pyridoxine-Dependent Epilepsy (PDE) is an autosomal recessive disorder caused by biallelic variants in ALDH7A1. The most common presentation is intractable seizures in the neonatal/early infantile period, which respond to pyridoxine. Other manifestations include perinatal asphyxia, hypoglycemia, and neuroimaging abnormalities. Despite early treatment, patients often have neurodevelopmental abnormalities. Treatment guidelines recommend triple therapy with pyridoxine, dietary lysine restriction, and arginine supplementation.</div><div>We report an individual presenting with laboratory abnormalities suggestive of mitochondrial disease. Born full-term, via NSVD, with normal Apgar scores and cord gases. At 30 min, grunting developed, and at 4 h of life, jerky movements with eye deviation were noted. Laboratory results revealed acidosis (pH 7.15) and increased lactate (11.4 mMol/L, rr <2.1). The patient was started on IV fluids, given 1 mEq/kg of sodium bicarbonate, and transferred for higher-level care. Upon arrival, the evaluation was notable for hypotonia, non-rhythmic jerking movements, rapid eye blinking, and a critically low pH (6.92), high lactate (15.3 mMol/L), hyperammonemia (153 μMol/L, rr < 75), and a creatine kinase level of 15,742 U/L (rr 35–230). A single dose of phenobarbital was given, and the baby was intubated and ventilated. Video electroencephalogram (vEEG) showed a discontinuous background with abnormal, sharply contoured bursts alternating with suppression, with no clinical correlation. The patient was treated with continuous sodium bicarbonate drip and IV fluids, restricting glucose. Abnormal movements, lactic acidosis, and hyperammonemia resolved within 24 h. An electroencephalogram (EEG) at 5 days of life (DOL) showed a mildly discontinuous background with no epileptic activity, and MRI showed a thin corpus callosum, cysts, and cerebellar hypoplasia. Creatine kinase peaked at 30,995 U/L and normalized on DOL 8. Organic acids revealed significant increases in lactate, 2-OH-butyrate, pyruvate, 3-OH-butyrate, 2-OH-isovalerate, and a mild increase in Krebs-cycle intermediates.</div><div>Rapid whole genome sequence (rWGS) was available on DOL 9, disclosing two variants in <em>ALDH7A1</em>: c.1559C > T p.Ser520Phe, previously reported, and c.1540 A > G p.Lys514Glu, considered a VUS. Treatment with pyridoxine started at 30 mg/kg/day. Pre-treatment biomarkers were consistent with the diagnosis of PDE-ALDH7A1: urine Pipecolate 117.8 mMol/mol, RR ≤10, 6-oxo-Pipecolate 8.4 mMol/mol, RR ≤2.0 and plasma alpha-aminoadipic semialdehyde (AASA) 5.2 uMol/L, RR <0.4. Treatment with arginine was added on DOL 10 (200 mg/kg/day) and a lysine-restricted diet on DOL 12, after TPN was discontinued. Clinical exam improved, no seizures were observed, and EEG normalized. PDE biomarkers decreased, and the patient was discharged home on DOL 25.</div><div>Elevated lactic acid has been reported in up to 70.3 % of PDE-ALDH7A1 patients ","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101260"},"PeriodicalIF":1.9,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145266533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-10DOI: 10.1016/j.ymgmr.2025.101267
Joo-Hyun Seo , Wakana Sou , Yasutsugu Chinen , Torayuki Okuyama
Abstract
Mucopolysaccharidosis type III (MPS III) is an autosomal recessive lysosomal storage disorder characterized by severe progressive neurocognitive deterioration. Currently, no definitive treatment for MPS III is available, although novel therapies are being developed. This retrospective study characterized the natural history, clinical symptoms, treatment strategies, and cognitive development of MPS III in Japan, which will provide the basis for evaluating the efficacy of new therapies. Twelve patients (three with MPS IIIA, nine with MPS IIIB) registered in the Japan Registration System for Metabolic & Inherited Diseases or their parents completed survey questions on patient background, diagnostic information, treatment history, and developmental age (DA). Mean age at diagnosis was 4 years and 7 months (standard deviation: 1 year and 6 months), with no notable difference between MPS IIIA and IIIB. All 12 patients had substantial developmental delay and progressive decline, as demonstrated by plotting DA against chronological age, as well as bone deformity, dysmorphic facial features (hirsutism), impaired motor and language development (language delay, hyperactivity, gait disorder), and sleep disturbance. Developmental delay had begun by approximately 3 years old when DA was usually first assessed, with regression occurring thereafter; regression was more gradual in MPS IIIB than in MPS IIIA. Most patients received daily care (e.g., tubal feeding) and medications to control symptoms (e.g., anticonvulsants). This was the first study to evaluate changes in DA, clinical symptoms, and treatment of patients with MPS III in Japan. These results can be used as natural history data in the future evaluation of new treatments.
{"title":"Natural history, clinical symptoms, and cognitive development of Japanese patients with mucopolysaccharidosis III","authors":"Joo-Hyun Seo , Wakana Sou , Yasutsugu Chinen , Torayuki Okuyama","doi":"10.1016/j.ymgmr.2025.101267","DOIUrl":"10.1016/j.ymgmr.2025.101267","url":null,"abstract":"<div><h3>Abstract</h3><div>Mucopolysaccharidosis type III (MPS III) is an autosomal recessive lysosomal storage disorder characterized by severe progressive neurocognitive deterioration. Currently, no definitive treatment for MPS III is available, although novel therapies are being developed. This retrospective study characterized the natural history, clinical symptoms, treatment strategies, and cognitive development of MPS III in Japan, which will provide the basis for evaluating the efficacy of new therapies. Twelve patients (three with MPS IIIA, nine with MPS IIIB) registered in the Japan Registration System for Metabolic & Inherited Diseases or their parents completed survey questions on patient background, diagnostic information, treatment history, and developmental age (DA). Mean age at diagnosis was 4 years and 7 months (standard deviation: 1 year and 6 months), with no notable difference between MPS IIIA and IIIB. All 12 patients had substantial developmental delay and progressive decline, as demonstrated by plotting DA against chronological age, as well as bone deformity, dysmorphic facial features (hirsutism), impaired motor and language development (language delay, hyperactivity, gait disorder), and sleep disturbance. Developmental delay had begun by approximately 3 years old when DA was usually first assessed, with regression occurring thereafter; regression was more gradual in MPS IIIB than in MPS IIIA. Most patients received daily care (e.g., tubal feeding) and medications to control symptoms (e.g., anticonvulsants). This was the first study to evaluate changes in DA, clinical symptoms, and treatment of patients with MPS III in Japan. These results can be used as natural history data in the future evaluation of new treatments.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101267"},"PeriodicalIF":1.9,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145266532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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