Pub Date : 2025-09-24DOI: 10.1016/j.ymgmr.2025.101255
Tiago Koppe , Franciele C. Pinheiro , Marina Siebert , Suelen Basgalupp , Liane E. Daudt , Ida Vanessa D. Schwartz
Gaucher disease (GD) is a lysosomal disorder associated with hyperferritinemia and altered hepcidin levels. This study evaluated the effect of GD-specific treatment on serum hepcidin and interleukin-6 (IL-6) in seven treatment-naïve Brazilian patients with type 1 GD. Concentrations were measured before and after initiation of treatment. Hepcidin levels significantly decreased and IL-6 showed a downward trend. These results suggest that hepcidin may also exert endocrine effects in GD-related iron metabolism.
{"title":"Serum hepcidin as a biomarker of treatment response in Gaucher disease","authors":"Tiago Koppe , Franciele C. Pinheiro , Marina Siebert , Suelen Basgalupp , Liane E. Daudt , Ida Vanessa D. Schwartz","doi":"10.1016/j.ymgmr.2025.101255","DOIUrl":"10.1016/j.ymgmr.2025.101255","url":null,"abstract":"<div><div>Gaucher disease (GD) is a lysosomal disorder associated with hyperferritinemia and altered hepcidin levels. This study evaluated the effect of GD-specific treatment on serum hepcidin and interleukin-6 (IL-6) in seven treatment-naïve Brazilian patients with type 1 GD. Concentrations were measured before and after initiation of treatment. Hepcidin levels significantly decreased and IL-6 showed a downward trend. These results suggest that hepcidin may also exert endocrine effects in GD-related iron metabolism.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101255"},"PeriodicalIF":1.9,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145118390","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 : 2025-09-23DOI: 10.1016/j.ymgmr.2025.101258
Troy K. Coody , Irene De Biase , Julie M. Porter , Marzia Pasquali , Brian J. Shayota
Prolidase deficiency (PD) is an autosomal recessive inborn error of metabolism, with an estimated incidence of 1 per 1.25 million births. Prolidase is critical for the turnover of proline and hydroxyproline-rich proteins, such as collagen. Collagen metabolism is essential for matrix regeneration during cellular proliferation and complex bodily functions such as wound healing and immunological cell differentiation. PD clinical manifestations include persistent skin ulcerations and poor wound healing, hypertelorism, high arched palate, depressed nasal bridge, micrognathia, splenomegaly, intellectual disability, recurring infections, and hematological abnormalities. Biochemically, a diagnosis of PD is supported by increased urinary excretion of glycyl-proline and other proline-containing iminopeptides detected by amino acid analysis. There are no current targeted therapies, but suggested interventions have included topical proline-glycine ointment, manganese supplementation, topical and oral steroids, and immunomodulation with monoclonal antibodies.
Here, we describe a 30-year-old patient with PD whose clinical course has been characterized by recurrent skin ulcerations/cysts with secondary scarring, recurrent infections, anemia, thrombocytopenia, lymphopenia, elevated liver enzymes, hirsutism, and seemingly unrelated papillary thyroid cancer. Skin manifestations were particularly severe due to the added complication of a diagnosis of hidradenitis suppurativa. Quantitative analysis of amino acids and related compounds revealed markedly elevated glycyl-proline in urine and plasma. To further characterize the biochemical phenotype, untargeted metabolomic analysis was sent on both plasma and urine. An increase was noted in several metabolites from the prolidase-dependent dipeptide recycling pathways. A better understanding of the pathophysiological mechanisms involved in prolidase deficiency may prove useful as different therapeutic approaches are being considered.
{"title":"Clinical and biochemical characterization of a patient with prolidase deficiency, a rare disorder of collagen metabolism","authors":"Troy K. Coody , Irene De Biase , Julie M. Porter , Marzia Pasquali , Brian J. Shayota","doi":"10.1016/j.ymgmr.2025.101258","DOIUrl":"10.1016/j.ymgmr.2025.101258","url":null,"abstract":"<div><div>Prolidase deficiency (PD) is an autosomal recessive inborn error of metabolism, with an estimated incidence of 1 per 1.25 million births. Prolidase is critical for the turnover of proline and hydroxyproline-rich proteins, such as collagen. Collagen metabolism is essential for matrix regeneration during cellular proliferation and complex bodily functions such as wound healing and immunological cell differentiation. PD clinical manifestations include persistent skin ulcerations and poor wound healing, hypertelorism, high arched palate, depressed nasal bridge, micrognathia, splenomegaly, intellectual disability, recurring infections, and hematological abnormalities. Biochemically, a diagnosis of PD is supported by increased urinary excretion of glycyl-proline and other proline-containing iminopeptides detected by amino acid analysis. There are no current targeted therapies, but suggested interventions have included topical proline-glycine ointment, manganese supplementation, topical and oral steroids, and immunomodulation with monoclonal antibodies.</div><div>Here, we describe a 30-year-old patient with PD whose clinical course has been characterized by recurrent skin ulcerations/cysts with secondary scarring, recurrent infections, anemia, thrombocytopenia, lymphopenia, elevated liver enzymes, hirsutism, and seemingly unrelated papillary thyroid cancer. Skin manifestations were particularly severe due to the added complication of a diagnosis of hidradenitis suppurativa. Quantitative analysis of amino acids and related compounds revealed markedly elevated glycyl-proline in urine and plasma. To further characterize the biochemical phenotype, untargeted metabolomic analysis was sent on both plasma and urine. An increase was noted in several metabolites from the prolidase-dependent dipeptide recycling pathways. A better understanding of the pathophysiological mechanisms involved in prolidase deficiency may prove useful as different therapeutic approaches are being considered.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101258"},"PeriodicalIF":1.9,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145118391","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}
Type 1 Gaucher disease is a lysosomal storage disorder associated with marked phenotypic heterogeneity, including among individuals carrying genotypes historically defined as “mild”. Early diagnosis, workup and follow-up care are crucial to avoid irreversible complications. We present a case series of 5 pediatric patients with type 1 Gaucher disease who had been identified based on newborn screening (NBS), parental carrier status, or clinical presentation. They were followed over time for monitoring of clinical status, hematologic indices, biomarkers including glucopsychosine, and imaging studies. Enzyme replacement therapy (ERT) was started when rising trends of biomarkers and/or new clinical symptoms appeared. Three patients were identified by NBS, one at birth due to parental carrier status, and one after symptomatic presentation with femoral fracture. All patients required initiation of ERT between 9 months and 5 years of age due to evidence of disease progression. Early diagnosis via NBS and proactive monitoring enabled timely ERT initiation in four cases, preventing irreversible organ damage and clinical complications. In contrast, the unscreened case presented with severe skeletal and hematologic involvement at baseline. Rising glucopsychosine was a sensitive early marker of disease activity and MRI was more sensitive at detecting organomegaly than ultrasound. These cases emphasize the vital importance of NBS, regular biomarker surveillance, and early intervention, even in presumed mild cases based on genotype. Early diagnosis via NBS, individualized monitoring and timely treatment are fundamental to optimizing outcomes in Gaucher disease type 1.
{"title":"Early diagnosis and management in Gaucher disease: A case series emphasizing the critical role of newborn screening","authors":"Éliane Beauregard-Lacroix , Madeline Steffensen , Caitlin Menello , Can Ficicioglu","doi":"10.1016/j.ymgmr.2025.101256","DOIUrl":"10.1016/j.ymgmr.2025.101256","url":null,"abstract":"<div><div>Type 1 Gaucher disease is a lysosomal storage disorder associated with marked phenotypic heterogeneity, including among individuals carrying genotypes historically defined as “mild”. Early diagnosis, workup and follow-up care are crucial to avoid irreversible complications. We present a case series of 5 pediatric patients with type 1 Gaucher disease who had been identified based on newborn screening (NBS), parental carrier status, or clinical presentation. They were followed over time for monitoring of clinical status, hematologic indices, biomarkers including glucopsychosine, and imaging studies. Enzyme replacement therapy (ERT) was started when rising trends of biomarkers and/or new clinical symptoms appeared. Three patients were identified by NBS, one at birth due to parental carrier status, and one after symptomatic presentation with femoral fracture. All patients required initiation of ERT between 9 months and 5 years of age due to evidence of disease progression. Early diagnosis via NBS and proactive monitoring enabled timely ERT initiation in four cases, preventing irreversible organ damage and clinical complications. In contrast, the unscreened case presented with severe skeletal and hematologic involvement at baseline. Rising glucopsychosine was a sensitive early marker of disease activity and MRI was more sensitive at detecting organomegaly than ultrasound. These cases emphasize the vital importance of NBS, regular biomarker surveillance, and early intervention, even in presumed mild cases based on genotype. Early diagnosis via NBS, individualized monitoring and timely treatment are fundamental to optimizing outcomes in Gaucher disease type 1.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101256"},"PeriodicalIF":1.9,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145109136","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 : 2025-09-16DOI: 10.1016/j.ymgmr.2025.101252
Martina Tosi , Anne Daly , Catherine Ashmore , Alex Pinto , Suresh Vijay , Elvira Verduci , Sharon Evans , Anita MacDonald
In patients with phenylketonuria (PKU), sapropterin dihydrochloride (sapropterin) lowers blood phenylalanine (Phe) and may enhance Phe tolerance in sapropterin responsive patients. Attention to its administration, particularly the timing, and giving it with food with appropriate macronutrient composition, is important. We describe two boys with PKU who improved their Phe tolerance and metabolic control when they adjusted their method of sapropterin administration. Case 1: aged 7.25 years with mild PKU experienced a 40 % reduction in blood Phe after a 30-day sapropterin trial (20 mg/kg). Initially, he took sapropterin once daily dissolved in water. This increased his protein tolerance from 26 g to 50 g/day and reduced his protein equivalent from protein substitute to 20 g/day. His blood Phe was a median of 230 μmol/L (range: 130–300). After six months, twice-daily dosing further improved his protein tolerance to 60 g/day, with a lower median blood Phe (130 μmol/L, range: 80–220). By age 8 years, he swallowed tablets intact with meals, ate an unrestricted protein intake (∼80 g/day), stopped protein substitute, maintained excellent metabolic control with perceived cognitive improvement. Case 2: a boy who aged 4.992 years with mild PKU had a 33 % reduction in blood Phe after a 30-day sapropterin (20 mg/kg) trial. Initially, he took sapropterin once daily dissolved in water, increasing his protein tolerance from 14 g to 55 g/day, and reducing protein equivalent from protein substitute to 20 g/day. Median blood Phe was 240 μmol/L (range: 120–320). At age 6.92 years, twice-daily dosing and swallowing intact tablets further lowered his blood Phe, to a mean of 130 μmol/L (range: 100–130). He stopped dietary protein restriction and protein substitute intake. These case studies showed clinical and dietary benefits with adjustment of sapropterin administration. It was unclear if the improvements observed were associated with twice daily sapropterin administration, attention to taking it with fat containing meals, swallowing the tablets intact, or a combination of these. Further research to monitor the efficacy and safety of administration change is necessary.
{"title":"Improving sapropterin administration efficacy in PKU: Clinical practice case studies","authors":"Martina Tosi , Anne Daly , Catherine Ashmore , Alex Pinto , Suresh Vijay , Elvira Verduci , Sharon Evans , Anita MacDonald","doi":"10.1016/j.ymgmr.2025.101252","DOIUrl":"10.1016/j.ymgmr.2025.101252","url":null,"abstract":"<div><div>In patients with phenylketonuria (PKU), sapropterin dihydrochloride (sapropterin) lowers blood phenylalanine (Phe) and may enhance Phe tolerance in sapropterin responsive patients. Attention to its administration, particularly the timing, and giving it with food with appropriate macronutrient composition, is important. We describe two boys with PKU who improved their Phe tolerance and metabolic control when they adjusted their method of sapropterin administration. Case 1: aged 7.2<del>5</del> years with mild PKU experienced a 40 % reduction in blood Phe after a 30-day sapropterin trial (20 mg/kg). Initially, he took sapropterin once daily dissolved in water. This increased his protein tolerance from 26 g to 50 g/day and reduced his protein equivalent from protein substitute to 20 g/day. His blood Phe was a median of 230 μmol/L (range: 130–300). After six months, twice-daily dosing further improved his protein tolerance to 60 g/day, with a lower median blood Phe (130 μmol/L, range: 80–220). By age 8 years, he swallowed tablets intact with meals, ate an unrestricted protein intake (∼80 g/day), stopped protein substitute, maintained excellent metabolic control with perceived cognitive improvement. Case 2: a boy who aged 4.9<del>92</del> years with mild PKU had a 33 % reduction in blood Phe after a 30-day sapropterin (20 mg/kg) trial. Initially, he took sapropterin once daily dissolved in water, increasing his protein tolerance from 14 g to 55 g/day, and reducing protein equivalent from protein substitute to 20 g/day. Median blood Phe was 240 μmol/L (range: 120–320). At age 6.9<del>2</del> years, twice-daily dosing and swallowing intact tablets further lowered his blood Phe, to a mean of 130 μmol/L (range: 100–130). He stopped dietary protein restriction and protein substitute intake. These case studies showed clinical and dietary benefits with adjustment of sapropterin administration. It was unclear if the improvements observed were associated with twice daily sapropterin administration, attention to taking it with fat containing meals, swallowing the tablets intact, or a combination of these. Further research to monitor the efficacy and safety of administration change is necessary.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101252"},"PeriodicalIF":1.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096334","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 : 2025-09-13DOI: 10.1016/j.ymgmr.2025.101251
Sinziana Stanescu , Olatz Villate , Fernando Andrade , Domingo Gonzalez-Lamuño , Amaya Bélanger-Quintana , Francisco Arrieta , Maria-Luz Couce , Alfonso Muriel , Luis Aldamiz-Echevarria
Introduction
Isolated methylmalonic acidemia (MMA) is an inborn error of metabolism due to the deficiency of the methylmalonic mutase enzyme. Many patients develop chronic complications such as basal ganglia lesions or kidney impairment. A growing body of evidence supports secondary mitochondrial dysfunction as the main cause for the development of these long-term complications, even in patients with good metabolic control. Currently, available methods to study mitochondrial function are often invasive, such as muscular or skin biopsy.
Objectives
This pilot study is aimed to develop a safe, non-invasive method to assess mitochondrial and glycolytic function in isolated MMA patients using lymphocytes.
Materials and methods
Mitochondrial bioenergetics and glycolysis were evaluated in lymphocytes from two mut0 MMA patients and two age- and sex-matched controls using Seahorse technology. In vitro treatments with triheptanoin, citrate, and resveratrol were performed.
Results
MMA lymphocytes showed significant impairment in mitochondrial respiration and glycolysis compared to healthy controls. Triheptanoin exposure improved ATP production and glycolytic flux (ECAR), but no significant changes were observed in oxygen consumption (OCR). Citrate and resveratrol had no measurable impact on bioenergetic parameters.
Conclusions
This exploratory study suggests that Seahorse technology can detect mitochondrial dysfunction in MMA lymphocytes. Further studies in larger cohorts are required to validate these findings and explore their clinical relevance.
{"title":"Mitochondrial dysfunction in methylmalonic acidemia: A pilot study using Seahorse technology in peripheral blood","authors":"Sinziana Stanescu , Olatz Villate , Fernando Andrade , Domingo Gonzalez-Lamuño , Amaya Bélanger-Quintana , Francisco Arrieta , Maria-Luz Couce , Alfonso Muriel , Luis Aldamiz-Echevarria","doi":"10.1016/j.ymgmr.2025.101251","DOIUrl":"10.1016/j.ymgmr.2025.101251","url":null,"abstract":"<div><h3>Introduction</h3><div>Isolated methylmalonic acidemia (MMA) is an inborn error of metabolism due to the deficiency of the methylmalonic mutase enzyme. Many patients develop chronic complications such as basal ganglia lesions or kidney impairment. A growing body of evidence supports secondary mitochondrial dysfunction as the main cause for the development of these long-term complications, even in patients with good metabolic control. Currently, available methods to study mitochondrial function are often invasive, such as muscular or skin biopsy.</div></div><div><h3>Objectives</h3><div>This pilot study is aimed to develop a safe, non-invasive method to assess mitochondrial and glycolytic function in isolated MMA patients using lymphocytes.</div></div><div><h3>Materials and methods</h3><div>Mitochondrial bioenergetics and glycolysis were evaluated in lymphocytes from two <em>mut</em><sup><em>0</em></sup> MMA patients and two age- and sex-matched controls using Seahorse technology. <em>In vitro</em> treatments with triheptanoin, citrate, and resveratrol were performed.</div></div><div><h3>Results</h3><div>MMA lymphocytes showed significant impairment in mitochondrial respiration and glycolysis compared to healthy controls. Triheptanoin exposure improved ATP production and glycolytic flux (ECAR), but no significant changes were observed in oxygen consumption (OCR). Citrate and resveratrol had no measurable impact on bioenergetic parameters.</div></div><div><h3>Conclusions</h3><div>This exploratory study suggests that Seahorse technology can detect mitochondrial dysfunction in MMA lymphocytes. Further studies in larger cohorts are required to validate these findings and explore their clinical relevance.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101251"},"PeriodicalIF":1.9,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145045619","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 : 2025-09-12DOI: 10.1016/j.ymgmr.2025.101250
Rafael Garrett , Sara Pickett , Melinda J. Peters , Khadija Belhassan , Adam S. Ptolemy , Roy W.A. Peake
The current approach for investigating patients with suspected inborn errors of metabolism (IEMs) involves traditional targeted biochemical assays such as amino/organic acid analyses. Although highly effective for confirmatory testing, they are less effective in identifying disorders not included in newborn screening (NBS) panels, and for patients with non-classical clinical presentations. Targeted assays analyze a narrow range of metabolites and are conducted across different analytical platforms, often requiring more than one specimen type. In contrast, comprehensive metabolic profiling using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) provides significantly more information from a single specimen, eliminating the need for multiple and time-consuming analyses across different platforms. We describe the use of LC-HRMS metabolic profiling in two patients with decompensated maple syrup urine disease (MSUD). In the first patient, a previously healthy 3-month-old infant presenting with altered mental status, apnea, and seizures, LC-HRMS analysis of plasma before treatment showed increased levels of branched-chain amino acids and their related 2-keto and hydroxy acids. The diagnosis of MSUD was confirmed by targeted amino acid analysis. Additionally, the treatment course, which included dialysis and nutritional management, was monitored using LC-HRMS. This approach was successfully applied to a second patient, a 1-week-old infant with classical MSUD identified through NBS. In conclusion, comprehensive metabolic profiling by LC-HRMS is a valuable investigative tool for patients with both classic and non-specific neurometabolic clinical phenotypes, providing additional insights into metabolite perturbations during acute management.
{"title":"Application of high-resolution mass spectrometry profiling towards the diagnosis and acute management of maple syrup urine disease","authors":"Rafael Garrett , Sara Pickett , Melinda J. Peters , Khadija Belhassan , Adam S. Ptolemy , Roy W.A. Peake","doi":"10.1016/j.ymgmr.2025.101250","DOIUrl":"10.1016/j.ymgmr.2025.101250","url":null,"abstract":"<div><div>The current approach for investigating patients with suspected inborn errors of metabolism (IEMs) involves traditional targeted biochemical assays such as amino/organic acid analyses. Although highly effective for confirmatory testing, they are less effective in identifying disorders not included in newborn screening (NBS) panels, and for patients with non-classical clinical presentations. Targeted assays analyze a narrow range of metabolites and are conducted across different analytical platforms, often requiring more than one specimen type. In contrast, comprehensive metabolic profiling using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) provides significantly more information from a single specimen, eliminating the need for multiple and time-consuming analyses across different platforms. We describe the use of LC-HRMS metabolic profiling in two patients with decompensated maple syrup urine disease (MSUD). In the first patient, a previously healthy 3-month-old infant presenting with altered mental status, apnea, and seizures, LC-HRMS analysis of plasma before treatment showed increased levels of branched-chain amino acids and their related 2-keto and hydroxy acids. The diagnosis of MSUD was confirmed by targeted amino acid analysis. Additionally, the treatment course, which included dialysis and nutritional management, was monitored using LC-HRMS. This approach was successfully applied to a second patient, a 1-week-old infant with classical MSUD identified through NBS. In conclusion, comprehensive metabolic profiling by LC-HRMS is a valuable investigative tool for patients with both classic and non-specific neurometabolic clinical phenotypes, providing additional insights into metabolite perturbations during acute management.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101250"},"PeriodicalIF":1.9,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145045620","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 : 2025-08-26DOI: 10.1016/j.ymgmr.2025.101248
P. De Liso , R. Webster , B. Plecko , F. Vigevano
{"title":"Comment on: Lee J.Z.C. et al. Case report: Hepatocellular carcinoma in a patient with Pyridoxamine 5-phosphate oxidase (PNPO) deficiency undergoing pyridoxal 5-phosphate (PLP) treatment. Mol Genet Metab Rep. 2025;9;43:101224.","authors":"P. De Liso , R. Webster , B. Plecko , F. Vigevano","doi":"10.1016/j.ymgmr.2025.101248","DOIUrl":"10.1016/j.ymgmr.2025.101248","url":null,"abstract":"","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101248"},"PeriodicalIF":1.9,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144896732","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 : 2025-08-26DOI: 10.1016/j.ymgmr.2025.101249
Stephen G. Kaler , William Fyke , Angela Lignelli-Dipple , Valentina Emmanuele , Eun Bi Lee , Hyein Kathy Lee , Adiel Munk , Jose Andres Morales Corado , Alejandro Iglesias , Priyanka Mehrotra
NDUFV1 encodes NADH: ubiquinone oxidoreductase core subunit V1, a key component of mitochondrial Complex 1. Biallelic pathogenic variants in this gene produce a broad and variable phenotypic spectrum in affected individuals, including ophthalmoplegia, developmental delays, brain imaging abnormalities, and recurrent episodes of emesis and lactic acidemia. We report female siblings compound heterozygous for two missense variants (Arg40Gln, Val245Met) in NDUFV1 with unusual presentations of this condition. The 6-year-old proband showed normal growth and neurodevelopment until recently when weight loss and recurrent vomiting were noticed and brain imaging abnormalities consistent with Complex 1 deficiency were documented. She developed lactic acidemia without a clear precipitating factor and that, incongruously, was associated with profound alkalosis with blood pH as high as 7.83. We describe management of her acute illness during a hospital admission with aggressive sodium bicarbonate and sodium acetate replacement, and eventual recognition that anxiety-related hyperventilation contributed substantially to her transient profound alkalosis. We review the complex interplay of lactic acidemia due to mitochondrial Complex 1 deficiency, metabolic acidosis from acute loss of bicarbonate, respiratory alkalosis from hyperventilation and hypocapnia, and other concomitant medical issues, as well as her distinctive neuroradiological findings. Her 14-year-old sister was diagnosed retrospectively despite an earlier initial presentation, and manifests greater neurocognitive effects, similar neuroradiological signs, but no history of acute metabolic decompensation. These cases expand the phenotypic spectrum of this rare inherited illness, provide new information about its presentation and intrafamilial variability, and offer insight relevant to management of life-threatening metabolic crises associated with this disorder.
{"title":"Acute profound lactic alkalosis associated with NDUFV1 compound heterozygosity in a previously healthy 6-year-old female","authors":"Stephen G. Kaler , William Fyke , Angela Lignelli-Dipple , Valentina Emmanuele , Eun Bi Lee , Hyein Kathy Lee , Adiel Munk , Jose Andres Morales Corado , Alejandro Iglesias , Priyanka Mehrotra","doi":"10.1016/j.ymgmr.2025.101249","DOIUrl":"10.1016/j.ymgmr.2025.101249","url":null,"abstract":"<div><div><em>NDUFV1</em> encodes NADH: ubiquinone oxidoreductase core subunit V1, a key component of mitochondrial Complex 1. Biallelic pathogenic variants in this gene produce a broad and variable phenotypic spectrum in affected individuals, including ophthalmoplegia, developmental delays, brain imaging abnormalities, and recurrent episodes of emesis and lactic acidemia. We report female siblings compound heterozygous for two missense variants (Arg40Gln, Val245Met) in <em>NDUFV1</em> with unusual presentations of this condition. The 6-year-old proband showed normal growth and neurodevelopment until recently when weight loss and recurrent vomiting were noticed and brain imaging abnormalities consistent with Complex 1 deficiency were documented. She developed lactic acidemia without a clear precipitating factor and that, incongruously, was associated with profound alkalosis with blood pH as high as 7.83. We describe management of her acute illness during a hospital admission with aggressive sodium bicarbonate and sodium acetate replacement, and eventual recognition that anxiety-related hyperventilation contributed substantially to her transient profound alkalosis. We review the complex interplay of lactic acidemia due to mitochondrial Complex 1 deficiency, metabolic acidosis from acute loss of bicarbonate, respiratory alkalosis from hyperventilation and hypocapnia, and other concomitant medical issues, as well as her distinctive neuroradiological findings. Her 14-year-old sister was diagnosed retrospectively despite an earlier initial presentation, and manifests greater neurocognitive effects, similar neuroradiological signs, but no history of acute metabolic decompensation. These cases expand the phenotypic spectrum of this rare inherited illness, provide new information about its presentation and intrafamilial variability, and offer insight relevant to management of life-threatening metabolic crises associated with this disorder.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101249"},"PeriodicalIF":1.9,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144896731","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 : 2025-08-21DOI: 10.1016/j.ymgmr.2025.101247
P. Tanpaiboon, D. Salazar, M. Pan, L. Xu, R. Sharma
Objectives
Quality control (QC) in clinical laboratory is critical to ensuring quality and accuracy of patient results. However, QC monitoring is complicated in the multi-analyte, multi-instrument assays common to biochemical genetics laboratories. Comprehensive off-the-shelf QC management systems optimized for such highly complex assays and platforms are relatively scarce. A manual QC review process can impact laboratory productivity and increase risk of errors. Here we describe a novel software application that integrates, processes, and displays QC statistical parameters from multiple instruments in near real-time results by automated processor.
Methods
A customizable, cloud-based software application was developed to centralize the information, automate an extra review step in the QC review process and increase clinical utility. We monitored time spent on each step of QC review and QC range assignments before and one year after implementing the program and documented quality improvements.
Results
This QC program has modules for different assay platforms. The program's functions include automated collection and assay data analysis, Levey-Jennings charts with integrated data from multiple instruments, graphical data visualization, instrument data centralization, assay monitoring, and a QC audit trail. The program also generates email notifications for QC lot expiration, QC review reminder, and critical results alert enabling prompt communication to providers. After the first year, this program provided 81 %-time reduction of hands-on time.
Conclusion
This program improves assay quality and provides considerable time savings. One benefit of this software is the ease of updating program capabilities and customizing them to meet specific and changing needs, especially for high-complexity testing.
{"title":"Development of an automated quality control and assay performance management system for biochemical genetics laboratory","authors":"P. Tanpaiboon, D. Salazar, M. Pan, L. Xu, R. Sharma","doi":"10.1016/j.ymgmr.2025.101247","DOIUrl":"10.1016/j.ymgmr.2025.101247","url":null,"abstract":"<div><h3>Objectives</h3><div>Quality control (QC) in clinical laboratory is critical to ensuring quality and accuracy of patient results. However, QC monitoring is complicated in the multi-analyte, multi-instrument assays common to biochemical genetics laboratories. Comprehensive off-the-shelf QC management systems optimized for such highly complex assays and platforms are relatively scarce. A manual QC review process can impact laboratory productivity and increase risk of errors. Here we describe a novel software application that integrates, processes, and displays QC statistical parameters from multiple instruments in near real-time results by automated processor.</div></div><div><h3>Methods</h3><div>A customizable, cloud-based software application was developed to centralize the information, automate an extra review step in the QC review process and increase clinical utility. We monitored time spent on each step of QC review and QC range assignments before and one year after implementing the program and documented quality improvements.</div></div><div><h3>Results</h3><div>This QC program has modules for different assay platforms. The program's functions include automated collection and assay data analysis, Levey-Jennings charts with integrated data from multiple instruments, graphical data visualization, instrument data centralization, assay monitoring, and a QC audit trail. The program also generates email notifications for QC lot expiration, QC review reminder, and critical results alert enabling prompt communication to providers. After the first year, this program provided 81 %-time reduction of hands-on time.</div></div><div><h3>Conclusion</h3><div>This program improves assay quality and provides considerable time savings. One benefit of this software is the ease of updating program capabilities and customizing them to meet specific and changing needs, especially for high-complexity testing.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"44 ","pages":"Article 101247"},"PeriodicalIF":1.9,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144878157","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 : 2025-08-13DOI: 10.1016/j.ymgmr.2025.101246
Alessandro La Rosa , Alessia Pepe , Barbara Tappino , Fabio Corsolini , Andrea Chiaro , Annalisa Madeo
Background
Mucolipidosis (ML) is a rare autosomal recessive lysosomal disorder with variable onset and severity: MLII, characterized by early onset and rapid progression, and MLIII, milder with late onset and prolonged survival. ML is due to mutations in the Golgi enzyme uridine diphosphate-N-acetylglucosamine-1-phosphotransferase, whose subunits are encoded by GNPTAB and GNPTG genes. This report presents a particular case of infantile early-onset MLIII-gamma and emphasizes that articular manifestations can be a sign of a metabolic disease rather than a rheumatological or orthopedic one.
Case report
A 5.7-years-old girl presented with progressive hand stiffness and joint pain, exhibiting symptoms from 6 months of age. She displayed claw-hand deformity and joint stiffness but normal growth and neurodevelopment. Biochemical testing revealed normal activities of alpha-L-iduronidase and arylsulfatase-B in leukocytes, excluding mucopolysaccharidosis I and VI, while beta-hexosaminidase and alpha-L-fucosidase activities in plasma were elevated, suggesting ML. Genetic analysis of GNPTAB and GNPTG identified two pathogenic variants in the GNPTG gene, confirming MLIII-gamma diagnosis. Despite early onset, the patient exhibited a less severe skeletal phenotype and showed mild cardiac and ocular involvement, occasionally described in classic MLIII-gamma.
Discussion
The natural history of MLIII remains poorly understood and mainly based on sporadic case reports/series. Our case presents a typical MLIII-gamma phenotype but with an unexpectedly early onset, expanding the clinical spectrum of this disease. It emphasizes the need for increased awareness among pediatric rheumatologists regarding metabolic disorders. Further case studies are essential to enhance understanding and improve diagnostic and therapeutic approaches for ML.
粘液脂质沉积症（MLII）是一种罕见的常染色体隐性溶酶体疾病，其发病和严重程度各不相同：MLII的特点是发病早，进展迅速，而MLIII的症状较轻，发病晚，生存期长。ML是由于高尔基酶尿苷二磷酸- n -乙酰氨基葡萄糖-1-磷酸转移酶的突变，其亚基由GNPTAB和GNPTG基因编码。本报告提出了一个特殊的婴儿早发mliii - γ病例，并强调关节表现可能是代谢性疾病的征兆，而不是风湿病或骨科疾病的征兆。病例报告一名5.7岁女孩，表现为进行性手部僵硬和关节疼痛，从6个月大开始出现症状。她表现出爪手畸形和关节僵硬，但生长和神经发育正常。生化检测显示白细胞α - l -伊杜糖醛酸酶和芳基磺化酶- b活性正常，排除粘多糖病I和VI，血浆β -己糖氨基酶和α - l -集中酶活性升高，提示ML。GNPTAB和GNPTG遗传分析发现GNPTG基因中有两个致病变异，证实了mliii - γ诊断。尽管发病早，但患者表现出不太严重的骨骼表型，并表现出轻微的心脏和眼部受累，偶尔在经典MLIII-gamma中描述。MLIII的自然历史仍然知之甚少，主要基于零星的病例报告/系列。本病例呈现典型的mliii - γ表型，但出乎意料地早发，扩大了该疾病的临床范围。它强调需要提高儿科风湿病学家对代谢紊乱的认识。进一步的病例研究对于加强对ML的理解和改进诊断和治疗方法至关重要。
{"title":"Hand stiffness not only a rheumatological sign: A case of early onset mucolipidosis III-gamma with literature review","authors":"Alessandro La Rosa , Alessia Pepe , Barbara Tappino , Fabio Corsolini , Andrea Chiaro , Annalisa Madeo","doi":"10.1016/j.ymgmr.2025.101246","DOIUrl":"10.1016/j.ymgmr.2025.101246","url":null,"abstract":"<div><h3>Background</h3><div>Mucolipidosis (ML) is a rare autosomal recessive lysosomal disorder with variable onset and severity: MLII, characterized by early onset and rapid progression, and MLIII, milder with late onset and prolonged survival. ML is due to mutations in the Golgi enzyme uridine diphosphate-<em>N</em>-acetylglucosamine-1-phosphotransferase, whose subunits are encoded by <em>GNPTAB</em> and <em>GNPTG</em> genes. This report presents a particular case of infantile early-onset MLIII-gamma and emphasizes that articular manifestations can be a sign of a metabolic disease rather than a rheumatological or orthopedic one.</div></div><div><h3>Case report</h3><div>A 5.7-years-old girl presented with progressive hand stiffness and joint pain, exhibiting symptoms from 6 months of age. She displayed claw-hand deformity and joint stiffness but normal growth and neurodevelopment. Biochemical testing revealed normal activities of alpha-L-iduronidase and arylsulfatase-B in leukocytes, excluding mucopolysaccharidosis I and VI, while beta-hexosaminidase and alpha-L-fucosidase activities in plasma were elevated, suggesting ML. Genetic analysis of <em>GNPTAB</em> and <em>GNPTG</em> identified two pathogenic variants in the <em>GNPTG</em> gene, confirming MLIII-gamma diagnosis. Despite early onset, the patient exhibited a less severe skeletal phenotype and showed mild cardiac and ocular involvement, occasionally described in classic MLIII-gamma.</div></div><div><h3>Discussion</h3><div>The natural history of MLIII remains poorly understood and mainly based on sporadic case reports/series. Our case presents a typical MLIII-gamma phenotype but with an unexpectedly early onset, expanding the clinical spectrum of this disease. It emphasizes the need for increased awareness among pediatric rheumatologists regarding metabolic disorders. Further case studies are essential to enhance understanding and improve diagnostic and therapeutic approaches for ML.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"44 ","pages":"Article 101246"},"PeriodicalIF":1.9,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144829086","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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