Pub Date : 2025-06-01Epub Date: 2025-04-12DOI: 10.1016/j.ymgmr.2025.101219
Candela Romano , Joel Wells , Nicholas Stanzione , Virginia Kimonis
Fabry disease is a rare X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene, which encodes for the α–galactosidase A enzyme responsible for degrading globotriaosylceramide. Its deficiency leads to the accumulation of GL3 in lysosomes, resulting in progressive multi-organ involvement, with predilection for the heart and kidneys.
Clinical features associated with Fabry disease include acroparesthesia, angiokeratomas, hypohidrosis, corneal whorls, chronic kidney disease, cardiomyopathy, and strokes. Osteopenia and osteoporosis are less known complications, with rare reported cases of avascular necrosis of the hips.
We report bilateral avascular necrosis in a 40-year-old-man diagnosed with Fabry at the age of 25 years. He carriers the familiar p.G328V GLA pathogenic variant. His Fabry features includes acroparesthesia, angiokeratomas, hypohidrosis, temperature and exercise intolerance, pain crises, abdominal pain and diarrhea, tinnitus, hearing loss, hypertrophic cardiomyopathy, palpitations, and chest pain. Family history reveals Fabry disease affecting multiple maternal relatives. The patient was recently diagnosed with avascular necrosis of the right hip requiring total arthroplasty due to failure of conservative treatment. Nine months later, he developed left hip pain attributed to avascular necrosis, also treated with total arthroplasty.
This case highlights a rare skeletal complication of Fabry disease, underscoring the need for early diagnosis, optimizing treatment of Fabry disease, managing atypical comorbidities, and vigilant monitoring of bone health.
{"title":"Bilateral avascular necrosis: A rare complication of Fabry disease","authors":"Candela Romano , Joel Wells , Nicholas Stanzione , Virginia Kimonis","doi":"10.1016/j.ymgmr.2025.101219","DOIUrl":"10.1016/j.ymgmr.2025.101219","url":null,"abstract":"<div><div>Fabry disease is a rare X-linked lysosomal storage disorder caused by pathogenic variants in the <em>GLA</em> gene, which encodes for the α–galactosidase A enzyme responsible for degrading globotriaosylceramide. Its deficiency leads to the accumulation of GL3 in lysosomes, resulting in progressive multi-organ involvement, with predilection for the heart and kidneys.</div><div>Clinical features associated with Fabry disease include acroparesthesia, angiokeratomas, hypohidrosis, corneal whorls, chronic kidney disease, cardiomyopathy, and strokes. Osteopenia and osteoporosis are less known complications, with rare reported cases of avascular necrosis of the hips.</div><div>We report bilateral avascular necrosis in a 40-year-old-man diagnosed with Fabry at the age of 25 years. He carriers the familiar p.G328V <em>GLA</em> pathogenic variant. His Fabry features includes acroparesthesia, angiokeratomas, hypohidrosis, temperature and exercise intolerance, pain crises, abdominal pain and diarrhea, tinnitus, hearing loss, hypertrophic cardiomyopathy, palpitations, and chest pain. Family history reveals Fabry disease affecting multiple maternal relatives. The patient was recently diagnosed with avascular necrosis of the right hip requiring total arthroplasty due to failure of conservative treatment. Nine months later, he developed left hip pain attributed to avascular necrosis, also treated with total arthroplasty.</div><div>This case highlights a rare skeletal complication of Fabry disease, underscoring the need for early diagnosis, optimizing treatment of Fabry disease, managing atypical comorbidities, and vigilant monitoring of bone health.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101219"},"PeriodicalIF":1.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143821376","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 : 2025-06-01Epub Date: 2025-04-16DOI: 10.1016/j.ymgmr.2025.101218
Roberto Giugliani , Juan Politei , Ana Martins , Nelson Murillo , Paula Rozenfeld , Mauricio Lopera , Sergio Salgado , Gustavo Quirós , Charles Marques , Osvaldo Vieira , Hernán Amartino , Fernando Perretta , Sandra Marques e Silva , Joseph Brooks , Laura Titievsky , Jacobo Villalobos , Cassiano Braga , Harris A. Peñaranda
Background
Fabry disease (FD) is an X-linked lysosomal sphingolipidosis. It is caused by pathogenic variants in the GLA gene with a consequent deficiency of the enzyme α-galactosidase A, resulting in the pathological accumulation of glycolipids - mainly globotriosyl ceramide (GL-3, GB3) and its deacylated product, globotriaosylsphingosine (Lyso-Gb-3) - in plasma and in a wide variety of cell types throughout the human body; it is characterized as a chronic, multisystemic disease with progressive evolution, which causes deterioration of the patient's quality of life and decreases survival and life expectancy.
In Latin America there are different limitations to the management of patients with Fabry disease, in most countries, access to diagnostic tools and treatment on time is complex and can sometimes suffer delays in its implementation. This situation is due to the high costs to health systems of follow-up and pharmacological therapy for Fabry patients, creating barriers to timely access.
Conclusions
Although medical criteria are fundamental in the choice of pharmacological therapy, the final decision should also rely on the patient's choice according to their expectations and the adherence and compliance with the treatment that they are willing to follow. As it has been described, there are currently three therapeutic options, for which the appropriate profile must be defined to achieve the best clinical outcomes, considering that it is a permanent treatment; experts consider that Fabry patients need comprehensive and interdisciplinary management to stop the progression and functional deterioration of the affected organs by its multiple systemic manifestations. In Latin-American countries, it is difficult to guarantee this comprehensive and coordinated management, due to limited public policies related to orphan diseases diagnosis, treatment and follow up.
It is considered crucial to structure support networks specialized in Fabry disease and generate partnerships with health institutions and other health system stakeholders, that would articulate and coordinate patients and relatives counseling and management, establish the specific pharmacological treatment to reduce the progression of the disease and the systemic involvement, deciding between the administration of enzyme replacement therapy or the most recent option of oral management with pharmacological chaperone both with proven effectiveness. This will be the decision of the attending physician, who will propose and advise the therapeutic choice that best suits the patient's needs.
{"title":"Expert review in diagnostic, therapeutic and follow-up of Fabry disease in Latin America based on patient care standards","authors":"Roberto Giugliani , Juan Politei , Ana Martins , Nelson Murillo , Paula Rozenfeld , Mauricio Lopera , Sergio Salgado , Gustavo Quirós , Charles Marques , Osvaldo Vieira , Hernán Amartino , Fernando Perretta , Sandra Marques e Silva , Joseph Brooks , Laura Titievsky , Jacobo Villalobos , Cassiano Braga , Harris A. Peñaranda","doi":"10.1016/j.ymgmr.2025.101218","DOIUrl":"10.1016/j.ymgmr.2025.101218","url":null,"abstract":"<div><h3>Background</h3><div>Fabry disease (FD) is an X-linked lysosomal sphingolipidosis. It is caused by pathogenic variants in the GLA gene with a consequent deficiency of the enzyme α-galactosidase A, resulting in the pathological accumulation of glycolipids - mainly globotriosyl ceramide (GL-3, GB3) and its deacylated product, globotriaosylsphingosine (Lyso-Gb-3) - in plasma and in a wide variety of cell types throughout the human body; it is characterized as a chronic, multisystemic disease with progressive evolution, which causes deterioration of the patient's quality of life and decreases survival and life expectancy.</div><div>In Latin America there are different limitations to the management of patients with Fabry disease, in most countries, access to diagnostic tools and treatment on time is complex and can sometimes suffer delays in its implementation. This situation is due to the high costs to health systems of follow-up and pharmacological therapy for Fabry patients, creating barriers to timely access.</div></div><div><h3>Conclusions</h3><div>Although medical criteria are fundamental in the choice of pharmacological therapy, the final decision should also rely on the patient's choice according to their expectations and the adherence and compliance with the treatment that they are willing to follow. As it has been described, there are currently three therapeutic options, for which the appropriate profile must be defined to achieve the best clinical outcomes, considering that it is a permanent treatment; experts consider that Fabry patients need comprehensive and interdisciplinary management to stop the progression and functional deterioration of the affected organs by its multiple systemic manifestations. In Latin-American countries, it is difficult to guarantee this comprehensive and coordinated management, due to limited public policies related to orphan diseases diagnosis, treatment and follow up.</div><div>It is considered crucial to structure support networks specialized in Fabry disease and generate partnerships with health institutions and other health system stakeholders, that would articulate and coordinate patients and relatives counseling and management, establish the specific pharmacological treatment to reduce the progression of the disease and the systemic involvement, deciding between the administration of enzyme replacement therapy or the most recent option of oral management with pharmacological chaperone both with proven effectiveness. This will be the decision of the attending physician, who will propose and advise the therapeutic choice that best suits the patient's needs.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101218"},"PeriodicalIF":1.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143833426","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 : 2025-06-01Epub Date: 2025-05-03DOI: 10.1016/j.ymgmr.2025.101226
María Arbelo Rodríguez , Elena Márquez Mesa , Cristina Lorenzo González , Marina Gutiérrez Vilar , Loredana Arhip , Mónica Ruiz Pons , José Pablo Suárez Llanos
Background
Glycogen Storage Disease Ib (GSD Ib) is a disease that associates both neutropenia and neutrophil dysfunction, thereby causing recurrent infections and inflammatory bowel disease (IBD). As of now, the standard treatment of these complications has been the administration of granulocyte-stimulating factor (GCSF). However, recent studies have found that the use of empagliflozin, an antidiabetic drug, may have benefits by reducing the levels of 1,5 anhydroglucitol-6-phosphate (1,5-AG6P), a metabolite that accumulates in the cytosol of neutrophils and blocks the use of glucose.
Results
We therefore report our experience with three patients, one of them being a liver and kidney transplant recipient, with promising results. Morbidity has been greatly reduced in all cases consisting in weight gain, better neutrophil count and management of respiratory, osteoarticular and gastrointestinal comorbidities. Overall, an improvement in quality of life has been observed.
Conclusion
SGLT2 inhibitors, and specifically empagliflozin offer promising results in improving morbidity and quality of life in patients with GSD Ib. In the cases presented, including a patient with double liver-kidney transplant, a good profile of tolerance, safety and effectiveness has been observed.
Synopsis
Empagliflozin offers promising results in improving morbidity and quality of life in patients with GSD Ib, including the first double organ transplant patient treated with this drug.
{"title":"Empagliflozin as treatment in glycogen storage disease type IB patients","authors":"María Arbelo Rodríguez , Elena Márquez Mesa , Cristina Lorenzo González , Marina Gutiérrez Vilar , Loredana Arhip , Mónica Ruiz Pons , José Pablo Suárez Llanos","doi":"10.1016/j.ymgmr.2025.101226","DOIUrl":"10.1016/j.ymgmr.2025.101226","url":null,"abstract":"<div><h3>Background</h3><div>Glycogen Storage Disease Ib (GSD Ib) is a disease that associates both neutropenia and neutrophil dysfunction, thereby causing recurrent infections and inflammatory bowel disease (IBD). As of now, the standard treatment of these complications has been the administration of granulocyte-stimulating factor (GCSF). However, recent studies have found that the use of empagliflozin, an antidiabetic drug, may have benefits by reducing the levels of 1,5 anhydroglucitol-6-phosphate (1,5-AG6P), a metabolite that accumulates in the cytosol of neutrophils and blocks the use of glucose.</div></div><div><h3>Results</h3><div>We therefore report our experience with three patients, one of them being a liver and kidney transplant recipient, with promising results. Morbidity has been greatly reduced in all cases consisting in weight gain, better neutrophil count and management of respiratory, osteoarticular and gastrointestinal comorbidities. Overall, an improvement in quality of life has been observed.</div></div><div><h3>Conclusion</h3><div>SGLT2 inhibitors, and specifically empagliflozin offer promising results in improving morbidity and quality of life in patients with GSD Ib. In the cases presented, including a patient with double liver-kidney transplant, a good profile of tolerance, safety and effectiveness has been observed.</div></div><div><h3>Synopsis</h3><div>Empagliflozin offers promising results in improving morbidity and quality of life in patients with GSD Ib, including the first double organ transplant patient treated with this drug.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101226"},"PeriodicalIF":1.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901911","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 : 2025-06-01Epub Date: 2025-04-11DOI: 10.1016/j.ymgmr.2025.101215
Uma Ramaswami , Guillem Pintos-Morell , Christoph Kampmann , Kathleen Nicholls , Dau-Ming Niu , Ricardo Reisin , Michael L. West , Christina Anagnostopoulou , Jaco Botha , Dalia Jazukeviciene , Jörn Schenk , Derralynn A. Hughes , Roberto Giugliani
Background
Analyses of up to 20 years of data from the Fabry Outcome Survey (FOS) assessed the long-term effectiveness of agalsidase alfa enzyme replacement therapy.
Methods
The impact of agalsidase alfa treatment on renal, cardiac, morbidity, and mortality outcomes in FOS was compared with untreated external Fabry disease (FD) cohorts.
Results
A total of 2171 FOS patients (1014 men, 919 women, 163 boys, 75 girls) received agalsidase alfa (median [range] duration of treatment: 5.38 [0.0–20.8] years). Annual rates of decline in estimated glomerular filtration rate improved in treated patients versus untreated external cohorts regardless of sex or baseline urinary protein levels. Annual left ventricular mass index rates were stable in treated patients regardless of sex or baseline left ventricular hypertrophy status, and better than in untreated external cohorts. The mean age at which 50 % of patients had their first composite morbidity event was later in the agalsidase-alfa-treated population than in the untreated external cohort (51.7 vs 41 years [males]; 60.8 vs 53 years [females]). After 24 months of treatment, the probability of a composite morbidity event was ∼34 % in treated patients and ∼ 45 % in untreated patients. Treated patients were older at death than untreated patients (mean [range]: 61.7 [26.2–87.6] vs 50.3 [34.5–70.1] years). The mean age at which 50 % of male patients were still alive was higher in treated patients than in untreated external cohorts (75.5 vs 60.0 years).
Conclusions
Long-term treatment with agalsidase alfa may provide renal, cardiac, and overall survival protection in FD.
{"title":"Two decades of experience of the Fabry Outcome Survey provides further confirmation of the long-term effectiveness of agalsidase alfa enzyme replacement therapy","authors":"Uma Ramaswami , Guillem Pintos-Morell , Christoph Kampmann , Kathleen Nicholls , Dau-Ming Niu , Ricardo Reisin , Michael L. West , Christina Anagnostopoulou , Jaco Botha , Dalia Jazukeviciene , Jörn Schenk , Derralynn A. Hughes , Roberto Giugliani","doi":"10.1016/j.ymgmr.2025.101215","DOIUrl":"10.1016/j.ymgmr.2025.101215","url":null,"abstract":"<div><h3>Background</h3><div>Analyses of up to 20 years of data from the Fabry Outcome Survey (FOS) assessed the long-term effectiveness of agalsidase alfa enzyme replacement therapy.</div></div><div><h3>Methods</h3><div>The impact of agalsidase alfa treatment on renal, cardiac, morbidity, and mortality outcomes in FOS was compared with untreated external Fabry disease (FD) cohorts.</div></div><div><h3>Results</h3><div>A total of 2171 FOS patients (1014 men, 919 women, 163 boys, 75 girls) received agalsidase alfa (median [range] duration of treatment: 5.38 [0.0–20.8] years). Annual rates of decline in estimated glomerular filtration rate improved in treated patients versus untreated external cohorts regardless of sex or baseline urinary protein levels. Annual left ventricular mass index rates were stable in treated patients regardless of sex or baseline left ventricular hypertrophy status, and better than in untreated external cohorts. The mean age at which 50 % of patients had their first composite morbidity event was later in the agalsidase-alfa-treated population than in the untreated external cohort (51.7 vs 41 years [males]; 60.8 vs 53 years [females]). After 24 months of treatment, the probability of a composite morbidity event was ∼34 % in treated patients and ∼ 45 % in untreated patients. Treated patients were older at death than untreated patients (mean [range]: 61.7 [26.2–87.6] vs 50.3 [34.5–70.1] years). The mean age at which 50 % of male patients were still alive was higher in treated patients than in untreated external cohorts (75.5 vs 60.0 years).</div></div><div><h3>Conclusions</h3><div>Long-term treatment with agalsidase alfa may provide renal, cardiac, and overall survival protection in FD.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101215"},"PeriodicalIF":1.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143817548","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 : 2025-06-01Epub Date: 2025-04-03DOI: 10.1016/j.ymgmr.2025.101212
Anastasia Ambrose , Morganne McCabe , Clara Hung , Iveta Sosova , Peter Seres , Saadet Mercimek-Andrews
Background
Biallelic pathogenic variants in PGM1 result in phosphoglucomutase 1 (PGM1) deficiency that is one of the congenital disorders of glycosylation (CDG) (PGM1-CDG). Phenotypic spectrum includes congenital malformations, and muscular, cardiac, hepatic, endocrine and hematologic phenotypes. Current treatment consists of D-galactose therapy that results in clinical and biochemical improvements. To improve fatigue, and exercise intolerance, we started creatine supplementation therapy.
Material and methods
We reviewed electronic patient chart. We applied Nijmegen Pediatric CDG Rating Scale (NPCRS) and The Functional Assessment of Chronic Illness Therapy Fatigue scale (FACIT-F). We measured creatine metabolism biomarkers.
Results
This is a 29-year-old female with PGM1-CDG, confirmed diagnosis by clinical exome sequencing. She has been treated with D-galactose therapy which did not improve her fatigue and exercise intolerance. She was started on creatine supplementation therapy at the age of 27 years which led to decreased daytime sleeping, increased exercise capacity and improvements in her NPCRS, and FACIT-F. Her plasma guanidinoacetate was low. She had elevated urine galactitol on D-galactose therapy.
Discussion
PGM1-CDG associated myopathy is likely due to combination of several factors including abnormal muscle carbohydrate metabolism, abnormal N-glycosylation of proteins involved in the muscle functions and creatine transport and altered muscle energy homeostasis. It was previously shown that creatine supplementation therapy improves myopathy in patients with mitochondrial cytopathies. We think that the use of creatine supplementation therapy coincided with improvements in fatigue and exercise intolerance subjectively and objectively in our patient.
{"title":"Outcome of creatine supplementation therapy in phosphoglucomutase-1 deficiency associated congenital disorders of glycosylation: Novel insights","authors":"Anastasia Ambrose , Morganne McCabe , Clara Hung , Iveta Sosova , Peter Seres , Saadet Mercimek-Andrews","doi":"10.1016/j.ymgmr.2025.101212","DOIUrl":"10.1016/j.ymgmr.2025.101212","url":null,"abstract":"<div><h3>Background</h3><div>Biallelic pathogenic variants in <em>PGM1</em> result in phosphoglucomutase 1 (PGM1) deficiency that is one of the congenital disorders of glycosylation (CDG) (PGM1-CDG). Phenotypic spectrum includes congenital malformations, and muscular, cardiac, hepatic, endocrine and hematologic phenotypes. Current treatment consists of D-galactose therapy that results in clinical and biochemical improvements. To improve fatigue, and exercise intolerance, we started creatine supplementation therapy.</div></div><div><h3>Material and methods</h3><div>We reviewed electronic patient chart. We applied Nijmegen Pediatric CDG Rating Scale (NPCRS) and The Functional Assessment of Chronic Illness Therapy Fatigue scale (FACIT-F). We measured creatine metabolism biomarkers.</div></div><div><h3>Results</h3><div>This is a 29-year-old female with PGM1-CDG, confirmed diagnosis by clinical exome sequencing. She has been treated with D-galactose therapy which did not improve her fatigue and exercise intolerance. She was started on creatine supplementation therapy at the age of 27 years which led to decreased daytime sleeping, increased exercise capacity and improvements in her NPCRS, and FACIT-F. Her plasma guanidinoacetate was low. She had elevated urine galactitol on D-galactose therapy.</div></div><div><h3>Discussion</h3><div>PGM1-CDG associated myopathy is likely due to combination of several factors including abnormal muscle carbohydrate metabolism, abnormal N-glycosylation of proteins involved in the muscle functions and creatine transport and altered muscle energy homeostasis. It was previously shown that creatine supplementation therapy improves myopathy in patients with mitochondrial cytopathies. We think that the use of creatine supplementation therapy coincided with improvements in fatigue and exercise intolerance subjectively and objectively in our patient.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101212"},"PeriodicalIF":1.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143768682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-01Epub Date: 2025-02-28DOI: 10.1016/j.ymgmr.2025.101202
Kirkland A. Wilson , Yun Zhou , Gary Cunningham , Kimberly Chapman , Marshall Summar , Debra Regier
Objectives
An assessment of amino acid and amine concentrations is important for the diagnosis and management of inherited metabolic disorders (IMDs). Methods exist that measure these biologically important metabolites but are cost-prohibitive and/or time consuming. We therefore sought to develop a novel methodology, applicable to IMDs, that is both high-throughput and low cost.
Methods
Previously, we developed a methodology for rapid, repeatable, and cost-efficient separation of approximately 20 amines as a proof of concept and now expand it to amines relevant to IMDs. We describe our separation methodology using reverse phase high performance liquid chromatography with ultraviolet-visible spectrum absorbance paired with pre-column derivatization with o-pthalaldehyde.
Results
We show reproducibility via concentration assessments, in triplicate, for each amine. We assess amines in prepared standard solutions and in biologic samples from patients with IMDs. We also detected and assessed the amino group containing compounds glutathione (oxidized and reduced forms) and ammonia. Validation was established using absolute area under the curve (AUC) and via comparison using a single internal standard.
Conclusions
We report good separation of 40 primary amino group containing metabolites, in a single, 53 min run. This rapid, low cost, and accurate methodology only requires a small volume of sample and can greatly increase availability and access. Finally, the numerous amines and unique compounds detected in our single run has large utility and can potentially increase clinical efficiency and broaden access to research, both important as the need for analysis of amines grows globally.
{"title":"A novel, high throughput, and low-cost method for the detection of 40 amines relevant to inborn errors of metabolism, in under 60 min, using reverse phase high performance liquid chromatography","authors":"Kirkland A. Wilson , Yun Zhou , Gary Cunningham , Kimberly Chapman , Marshall Summar , Debra Regier","doi":"10.1016/j.ymgmr.2025.101202","DOIUrl":"10.1016/j.ymgmr.2025.101202","url":null,"abstract":"<div><h3>Objectives</h3><div>An assessment of amino acid and amine concentrations is important for the diagnosis and management of inherited metabolic disorders (IMDs). Methods exist that measure these biologically important metabolites but are cost-prohibitive and/or time consuming. We therefore sought to develop a novel methodology, applicable to IMDs, that is both high-throughput and low cost.</div></div><div><h3>Methods</h3><div>Previously, we developed a methodology for rapid, repeatable, and cost-efficient separation of approximately 20 amines as a proof of concept and now expand it to amines relevant to IMDs. We describe our separation methodology using reverse phase high performance liquid chromatography with ultraviolet-visible spectrum absorbance paired with pre-column derivatization with <em>o</em>-pthalaldehyde.</div></div><div><h3>Results</h3><div>We show reproducibility via concentration assessments, in triplicate, for each amine. We assess amines in prepared standard solutions and in biologic samples from patients with IMDs. We also detected and assessed the amino group containing compounds glutathione (oxidized and reduced forms) and ammonia. Validation was established using absolute area under the curve (AUC) and via comparison using a single internal standard.</div></div><div><h3>Conclusions</h3><div>We report good separation of 40 primary amino group containing metabolites, in a single, 53 min run. This rapid, low cost, and accurate methodology only requires a small volume of sample and can greatly increase availability and access. Finally, the numerous amines and unique compounds detected in our single run has large utility and can potentially increase clinical efficiency and broaden access to research, both important as the need for analysis of amines grows globally.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101202"},"PeriodicalIF":1.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143511048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-01Epub Date: 2025-03-22DOI: 10.1016/j.ymgmr.2025.101208
Fei Li , Qin Cai , Wei Ji , Miao Xu , Guoli Tian , Fanyi Zeng
Carbamoyl phosphate synthetase I (CPS1) deficiency is a rare autosomal recessive metabolic abnormality cause by dysfunctionality of CPS1 and often result in unfavorable outcome. In this study, we presented the detailed laboratory features and genetic analysis of two patients with heterozygous variants of CPS1, c.1927 A > G (p.Asn643Asp), c.2375 T > G (p.Met792Arg), c.3443 T > A (p.Met1148Lys) in patient 1; c.3784C > T (p.Arg1262Ter), c.3734 T > A (p.Leu1245His) in patient 2, respectively. c.1927 A > G (p.Asn643Asp) and c.2375 T > G (p.Met792Arg) are novel out of 5 variants and classified as variants of uncertain significance (VUS) under the guidelines of ACMG/AMP-ClinGen. Structure-based analysis of 4 missense variants indicates deleterious alterations to the protein. Since the employment of genetic testing as a clinical diagnostic tool, distinguishing pathogenic from polymorphic changes poses significant problems for geneticists. As recommendation for PP3/BP4, the computational tools for missense variant have been published, we performed a comparative evaluation for pathogenicity interpretation in our patients and in ClinVar database regarding CPS1 missense variants under the updated guidelines of ACMG/AMP-ClinGen. The application of computational tools under the ACMG/AMP-ClinGen criteria revealed an increased sensitivity for pathogenicity evaluation, from variants of uncertain significance (VUS) to likely pathogenic (LP) in previously reported cases; while for variants without clinic information in the ClinVar database, the pathogenicity assessment of VUS remained, and shows a more optimistic and reliable clinical application in molecular diagnosis.
{"title":"Identification of novel variants in carbamoyl phosphate synthetase 1 gene and comparative pathogenicity assessments of CPS1 missense variants following ACMG/AMP-ClinGen recommendation for computational tools","authors":"Fei Li , Qin Cai , Wei Ji , Miao Xu , Guoli Tian , Fanyi Zeng","doi":"10.1016/j.ymgmr.2025.101208","DOIUrl":"10.1016/j.ymgmr.2025.101208","url":null,"abstract":"<div><div>Carbamoyl phosphate synthetase I (CPS1) deficiency is a rare autosomal recessive metabolic abnormality cause by dysfunctionality of CPS1 and often result in unfavorable outcome. In this study, we presented the detailed laboratory features and genetic analysis of two patients with heterozygous variants of CPS1, c.1927 A > G (p.Asn643Asp), c.2375 T > G (p.Met792Arg), c.3443 T > A (p.Met1148Lys) in patient 1; c.3784C > T (p.Arg1262Ter), c.3734 T > A (p.Leu1245His) in patient 2, respectively. c.1927 A > G (p.Asn643Asp) and c.2375 T > G (p.Met792Arg) are novel out of 5 variants and classified as variants of uncertain significance (VUS) under the guidelines of ACMG/AMP-ClinGen. Structure-based analysis of 4 missense variants indicates deleterious alterations to the protein. Since the employment of genetic testing as a clinical diagnostic tool, distinguishing pathogenic from polymorphic changes poses significant problems for geneticists. As recommendation for PP3/BP4, the computational tools for missense variant have been published, we performed a comparative evaluation for pathogenicity interpretation in our patients and in ClinVar database regarding CPS1 missense variants under the updated guidelines of ACMG/AMP-ClinGen. The application of computational tools under the ACMG/AMP-ClinGen criteria revealed an increased sensitivity for pathogenicity evaluation, from variants of uncertain significance (VUS) to likely pathogenic (LP) in previously reported cases; while for variants without clinic information in the ClinVar database, the pathogenicity assessment of VUS remained, and shows a more optimistic and reliable clinical application in molecular diagnosis.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101208"},"PeriodicalIF":1.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143685375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-01Epub Date: 2025-05-23DOI: 10.1016/j.ymgmr.2025.101234
Dolat Singh Shekhawat , Amit Mittal , Kuldeep Singh
{"title":"Cost analysis of newborn screening for spinal muscular atrophy using digital PCR vs. MLPA","authors":"Dolat Singh Shekhawat , Amit Mittal , Kuldeep Singh","doi":"10.1016/j.ymgmr.2025.101234","DOIUrl":"10.1016/j.ymgmr.2025.101234","url":null,"abstract":"","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101234"},"PeriodicalIF":1.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123973","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 : 2025-06-01Epub Date: 2025-03-13DOI: 10.1016/j.ymgmr.2025.101205
Parsa Forouhar , Mohammad Amin Eghtedari , Maryam Taraz , Mahsa Abdullahpour , Mohammad Mehrpouyan , Zhale Askarzade
We report an 18-month-old female diagnosed with Vici syndrome, a rare congenital disorder characterized by developmental delay, albinism, cataracts, agenesis of the corpus callosum, hypotonia, and immunological anomalies. The patient, the second child of healthy first-cousin parents, presented with hypotonia at birth and subsequently developed bilateral cataracts, feeding difficulties, and multiple systemic manifestations, including kidney, bladder, and gallstones, as well as cardiomegaly and seizures. Genetic testing identified homozygous mutations in the EPG5 gene, confirming the diagnosis of Vici syndrome. The cardiac evaluation revealed a unique finding: serial echocardiograms initially detected multiple masses, which later regressed spontaneously, suggestive of a cardiac rhabdomyoma.
{"title":"An 18-month-old girl with Vici syndrome: A case report study","authors":"Parsa Forouhar , Mohammad Amin Eghtedari , Maryam Taraz , Mahsa Abdullahpour , Mohammad Mehrpouyan , Zhale Askarzade","doi":"10.1016/j.ymgmr.2025.101205","DOIUrl":"10.1016/j.ymgmr.2025.101205","url":null,"abstract":"<div><div>We report an 18-month-old female diagnosed with Vici syndrome, a rare congenital disorder characterized by developmental delay, albinism, cataracts, agenesis of the corpus callosum, hypotonia, and immunological anomalies. The patient, the second child of healthy first-cousin parents, presented with hypotonia at birth and subsequently developed bilateral cataracts, feeding difficulties, and multiple systemic manifestations, including kidney, bladder, and gallstones, as well as cardiomegaly and seizures. Genetic testing identified homozygous mutations in the EPG5 gene, confirming the diagnosis of Vici syndrome. The cardiac evaluation revealed a unique finding: serial echocardiograms initially detected multiple masses, which later regressed spontaneously, suggestive of a cardiac rhabdomyoma.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101205"},"PeriodicalIF":1.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143611308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-01Epub Date: 2025-04-09DOI: 10.1016/j.ymgmr.2025.101213
Etienne Mondésert , Juliette Bouchereau , Manuel Schiff , Jean-François Benoist , Guilia Barcia , Boris Keren , Inès Mannes , Clément Pontoizeau , Charlotte Mansat , Apolline Imbard
Branched-chain amino acid transferase type 2 (BCAT2) deficiency is a rare autosomal recessive genetic condition, with only seven cases described to date. It results in an elevation of branched-chain amino acid (BCAA) plasma concentrations, predominantly on valine, with normal concentration of plasma allo-isoleucine and urine branched-chain α-keto acids (BCKA). Despite this constant biochemical feature, clinical consequences remain unclear with heterogeneous and far less severe than maple syrup urine disease (MSUD) reported phenotypes, one individual being even asymptomatic.
We report herein the eighth case of genetically confirmed BCAT2 deficiency, accompanied by a literature review and a discussion about the potential pathogenicity of this condition.
An 11-year-old boy presented with a rapidly reversible initial acute neurological episode suggesting an epileptic seizure. Abnormalities on cerebral magnetic resonance imaging and suspicion of cognitive impairment led to further metabolic investigations. BCAT2 deficiency has been mentioned in front of increased BCAAs (valine = 1667 μmol/L, leucine = 701 μmol/L, isoleucine = 561 μmol/L). A homozygous novel nonsense variant on BCAT2 (c.34C > T, p.Arg12*) was found on whole exome sequencing. After oral pyridoxine supplementation (200 mg/day), a decrease in BCAA concentrations was observed (valine = 984 μmol/L, leucine = 462 μmol/L, isoleucine = 302 μmol/L).
Laboratory and imaging findings were consistent with previously reported cases. However, clinical presentation of this case was atypical and could be related with epilepsy, although no other variant on epilepsy genes have been found. The relation between BCAT2 deficiency and these clinical findings is at this stage debated with regard to phenotypic variability. Further case-studies are needed to expand the knowledge about this condition.
{"title":"Branched-chain amino acid transferase type 2 (BCAT2) deficiency: Report of an eighth case and literature review","authors":"Etienne Mondésert , Juliette Bouchereau , Manuel Schiff , Jean-François Benoist , Guilia Barcia , Boris Keren , Inès Mannes , Clément Pontoizeau , Charlotte Mansat , Apolline Imbard","doi":"10.1016/j.ymgmr.2025.101213","DOIUrl":"10.1016/j.ymgmr.2025.101213","url":null,"abstract":"<div><div>Branched-chain amino acid transferase type 2 (BCAT2) deficiency is a rare autosomal recessive genetic condition, with only seven cases described to date. It results in an elevation of branched-chain amino acid (BCAA) plasma concentrations, predominantly on valine, with normal concentration of plasma allo-isoleucine and urine branched-chain α-keto acids (BCKA). Despite this constant biochemical feature, clinical consequences remain unclear with heterogeneous and far less severe than maple syrup urine disease (MSUD) reported phenotypes, one individual being even asymptomatic.</div><div>We report herein the eighth case of genetically confirmed BCAT2 deficiency, accompanied by a literature review and a discussion about the potential pathogenicity of this condition.</div><div>An 11-year-old boy presented with a rapidly reversible initial acute neurological episode suggesting an epileptic seizure. Abnormalities on cerebral magnetic resonance imaging and suspicion of cognitive impairment led to further metabolic investigations. BCAT2 deficiency has been mentioned in front of increased BCAAs (valine = 1667 μmol/L, leucine = 701 μmol/L, isoleucine = 561 μmol/L). A homozygous novel nonsense variant on <em>BCAT2</em> (c.34C > T, p.Arg12*) was found on whole exome sequencing. After oral pyridoxine supplementation (200 mg/day), a decrease in BCAA concentrations was observed (valine = 984 μmol/L, leucine = 462 μmol/L, isoleucine = 302 μmol/L).</div><div>Laboratory and imaging findings were consistent with previously reported cases. However, clinical presentation of this case was atypical and could be related with epilepsy, although no other variant on epilepsy genes have been found. The relation between BCAT2 deficiency and these clinical findings is at this stage debated with regard to phenotypic variability. Further case-studies are needed to expand the knowledge about this condition.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101213"},"PeriodicalIF":1.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143799309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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