Pub Date : 2026-01-06DOI: 10.1016/j.ymgmr.2025.101287
Connor J. Huck , Isabella Devaprasad , Blake R. Wilde
Variants of uncertain significance (VUS) in fumarate hydratase (FH) complicate the diagnosis of hereditary leiomyomatosis and renal cell carcinoma (HLRCC). The FH VUS p.Lys414Glu has been reported in patients with HLRCC features but additional evidence is needed to support an interpretation of pathogenicity. Here we show that p.Lys414Glu is completely inactive, supporting a classification of pathogenic and providing critical evidence for clinical care and surveillance of patients with germline FH p.Lys414Glu.
{"title":"Biochemical characterization of the FH variant p.Lys414Glu reveals loss of enzymatic function and disrupted multimerization","authors":"Connor J. Huck , Isabella Devaprasad , Blake R. Wilde","doi":"10.1016/j.ymgmr.2025.101287","DOIUrl":"10.1016/j.ymgmr.2025.101287","url":null,"abstract":"<div><div>Variants of uncertain significance (VUS) in fumarate hydratase (<em>FH</em>) complicate the diagnosis of hereditary leiomyomatosis and renal cell carcinoma (HLRCC). The FH VUS p.Lys414Glu has been reported in patients with HLRCC features but additional evidence is needed to support an interpretation of pathogenicity. Here we show that p.Lys414Glu is completely inactive, supporting a classification of pathogenic and providing critical evidence for clinical care and surveillance of patients with germline FH p.Lys414Glu.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"46 ","pages":"Article 101287"},"PeriodicalIF":1.9,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145898012","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 : 2026-01-06DOI: 10.1016/j.ymgmr.2025.101286
Vinh Phuc Kieu , Thang Van Viet Nguyen , Anh Duc Vu
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a rare genetic metabolic disorder involving impaired fatty acid β-oxidation. It is caused by mutations in the Acyl-CoA Dehydrogenase Very Long Chain (ACADVL) gene, which encodes the VLCAD enzyme. The clinical presentation is diverse, ranging from a severe neonatal-onset form to a milder adult-onset form. We describe the first reported case in Vietnam, which is a 20-year-old man who presented with exercise intolerance, myalgia, and recurrent rhabdomyolysis triggered by fasting and exertion. Acylcarnitine profiling suggested a fatty acid oxidation disorder, and whole-exome sequencing identified the diagnosis of VLCAD deficiency with c747G > T (p.Trp249Cys) mutation. It has not previously been reported in the Vietnamese population. This case highlights the important role of neonatal screening and genetic testing in the early diagnosis of metabolic myopathies. In addition, it raises awareness of genetic disorders among healthcare providers and the public in developing countries.
甚长链酰基辅酶a脱氢酶（VLCAD）缺乏症是一种罕见的遗传性代谢疾病，涉及脂肪酸β氧化受损。它是由编码VLCAD酶的酰基辅酶a脱氢酶长链（ACADVL）基因突变引起的。临床表现多种多样，从新生儿发病的严重形式到成人发病的轻微形式。我们描述了越南的第一例报告病例，这是一名20岁的男性，他表现为运动不耐受、肌痛和由禁食和运动引发的复发性横纹肌溶解。酰基肉碱分析提示脂肪酸氧化障碍，全外显子组测序确定了c747G >； T （p.Trp249Cys）突变的VLCAD缺陷诊断。以前没有在越南人群中报道过。本病例强调了新生儿筛查和基因检测在代谢性肌病早期诊断中的重要作用。此外，它还提高了发展中国家卫生保健提供者和公众对遗传疾病的认识。
{"title":"First reported case of adult-onset very long-chain acyl-coa dehydrogenase (vlcad) deficiency in Vietnam: a rare metabolic myopathy","authors":"Vinh Phuc Kieu , Thang Van Viet Nguyen , Anh Duc Vu","doi":"10.1016/j.ymgmr.2025.101286","DOIUrl":"10.1016/j.ymgmr.2025.101286","url":null,"abstract":"<div><div>Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a rare genetic metabolic disorder involving impaired fatty acid β-oxidation. It is caused by mutations in the Acyl-CoA Dehydrogenase Very Long Chain (ACADVL) gene, which encodes the VLCAD enzyme. The clinical presentation is diverse, ranging from a severe neonatal-onset form to a milder adult-onset form. We describe the first reported case in Vietnam, which is a 20-year-old man who presented with exercise intolerance, myalgia, and recurrent rhabdomyolysis triggered by fasting and exertion. Acylcarnitine profiling suggested a fatty acid oxidation disorder, and whole-exome sequencing identified the diagnosis of VLCAD deficiency with c747G > T (p.Trp249Cys) mutation. It has not previously been reported in the Vietnamese population. This case highlights the important role of neonatal screening and genetic testing in the early diagnosis of metabolic myopathies. In addition, it raises awareness of genetic disorders among healthcare providers and the public in developing countries.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"46 ","pages":"Article 101286"},"PeriodicalIF":1.9,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145898013","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 : 2025-12-01DOI: 10.1016/j.ymgmr.2025.101279
Alicia Guertin , Raoul Kanav Khanna , Marine Tardieu , Maud François , Hélène Blasco , Isabelle Benz de Bretagne , Jean-François Benoist , Adrien Bigot , Nathalie Tressel , François Maillot , François Labarthe
Background
Methylmalonic acidemia (MMA) caused by complete or partial deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (mut0 or mut- enzymatic subtype, respectively) leads to the accumulation of toxic organic acids, causing severe organ dysfunction and life-threatening complications. Despite appropriate treatment, optic neuropathy has been reported as a vision-threatening complication of MMA, often resulting in debilitating sequelae.
Case report
We present the case of an 18-year-old woman with isolated mut° MMA and with chronic kidney disease stage 3 who presented with a rapid decline in distance and near visual acuity in both eyes. Goldmann visual field perimetry revealed bilateral central relative scotomas with preserved peripheral vision. Visual evoked potentials were unstructured in both eyes, despite normal retinal imaging, indicating optic neuropathy. Metabolic testing revealed elevated levels of methylmalonic acid in both plasma and urine, and increased lactate levels in the plasma and cerebrospinal fluid. Based on the hypothesis of subacute toxicity from methylmalonic acid metabolites, intensive intermittent hemodialysis was initiated, which rapidly decreased the patient's plasma methylmalonic acid level. We also added an oral supplement of coenzyme Q10 and vitamin E. With this treatment, the patient's vision rapidly recovered, and visual function normalized five months later. No progression of optic neuropathy occurred in the eight years follow up after a combined liver/kidney transplant procedure.
Conclusion
Optic neuropathy is a rare long-term complication of isolated MMA, presumably due to the chronic or subacute accumulation of toxic methylmalonic acid metabolites. This case report highlights the importance of early and intensive hemodialysis in achieving favorable visual outcomes by reducing toxic metabolite levels in both blood and central nervous system. In the long-term, liver or combined liver-kidney transplantation should be discussed.
{"title":"Full recovery of vision following early and intensive hemodialysis in an 18-year-old woman with methylmalonic acidemia-related optic neuropathy","authors":"Alicia Guertin , Raoul Kanav Khanna , Marine Tardieu , Maud François , Hélène Blasco , Isabelle Benz de Bretagne , Jean-François Benoist , Adrien Bigot , Nathalie Tressel , François Maillot , François Labarthe","doi":"10.1016/j.ymgmr.2025.101279","DOIUrl":"10.1016/j.ymgmr.2025.101279","url":null,"abstract":"<div><h3>Background</h3><div>Methylmalonic acidemia (MMA) caused by complete or partial deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (mut<sup>0</sup> or mut- enzymatic subtype, respectively) leads to the accumulation of toxic organic acids, causing severe organ dysfunction and life-threatening complications. Despite appropriate treatment, optic neuropathy has been reported as a vision-threatening complication of MMA, often resulting in debilitating sequelae.</div></div><div><h3>Case report</h3><div>We present the case of an 18-year-old woman with isolated mut° MMA and with chronic kidney disease stage 3 who presented with a rapid decline in distance and near visual acuity in both eyes. Goldmann visual field perimetry revealed bilateral central relative scotomas with preserved peripheral vision. Visual evoked potentials were unstructured in both eyes, despite normal retinal imaging, indicating optic neuropathy. Metabolic testing revealed elevated levels of methylmalonic acid in both plasma and urine, and increased lactate levels in the plasma and cerebrospinal fluid. Based on the hypothesis of subacute toxicity from methylmalonic acid metabolites, intensive intermittent hemodialysis was initiated, which rapidly decreased the patient's plasma methylmalonic acid level. We also added an oral supplement of coenzyme Q10 and vitamin E. With this treatment, the patient's vision rapidly recovered, and visual function normalized five months later. No progression of optic neuropathy occurred in the eight years follow up after a combined liver/kidney transplant procedure.</div></div><div><h3>Conclusion</h3><div>Optic neuropathy is a rare long-term complication of isolated MMA, presumably due to the chronic or subacute accumulation of toxic methylmalonic acid metabolites. This case report highlights the importance of early and intensive hemodialysis in achieving favorable visual outcomes by reducing toxic metabolite levels in both blood and central nervous system. In the long-term, liver or combined liver-kidney transplantation should be discussed.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101279"},"PeriodicalIF":1.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145614653","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}
Infantile-onset Pompe disease is a severe lysosomal storage disorder caused by biallelic pathogenic variants in GAA, leading to deficient acid α-glucosidase activity.
Case
We report a 6-month-old South Indian male with recurrent respiratory infections, feeding difficulty, generalized hypotonia, and delayed motor milestones. Dried blood spot(DBS) enzyme assay demonstrated markedly reduced acid α-glucosidase activity, and molecular testing identified a homozygous pathogenic variant in GAA (c.2560C > T; p.Arg854*). Parental segregation testing confirmed both parents as heterozygous carriers. Serum creatine phosphokinase was 853 U/L. A cardiac evaluation was recommended but not completed at the time of initial assessment.
Conclusion
This case underscores the diagnostic value of integrating enzyme and molecular testing when infantile-onset Pompe disease is suspected. While newborn screening for Pompe disease exists in some regions, it is not universally implemented, contributing to delays in diagnosis. Early identification allows appropriate counseling and consideration of available management pathways.
Key clinical message
Infantile-onset Pompe disease should be considered in infants presenting with hypotonia, recurrent respiratory infections, feeding difficulties, and delayed motor milestones. Combining dried blood spot enzyme assay with confirmatory molecular testing of the GAA gene enables timely diagnosis, informs counseling, and guides management even in settings where access to enzyme replacement therapy is limited.
{"title":"Integrating enzyme assay and molecular genetic testing for early diagnosis of infantile-onset Pompe disease: A case report","authors":"Anuradha Sharma, Minakshi Vashist, Rohit Kaushik, Gulshan Rohilla, Sonia Narwal","doi":"10.1016/j.ymgmr.2025.101283","DOIUrl":"10.1016/j.ymgmr.2025.101283","url":null,"abstract":"<div><h3>Background</h3><div>Infantile-onset Pompe disease is a severe lysosomal storage disorder caused by biallelic pathogenic variants in <strong><em>GAA</em></strong>, leading to deficient acid α-glucosidase activity.</div></div><div><h3>Case</h3><div>We report a 6-month-old South Indian male with recurrent respiratory infections, feeding difficulty, generalized hypotonia, and delayed motor milestones. <strong>Dried blood spot</strong>(DBS) enzyme assay demonstrated markedly reduced acid α-glucosidase activity, and molecular testing identified a homozygous pathogenic variant in <strong><em>GAA</em></strong> (c.2560C > T; p.Arg854*). Parental segregation testing confirmed both parents as heterozygous carriers. Serum creatine phosphokinase was 853 U/L. A cardiac evaluation was recommended but not completed at the time of initial assessment.</div></div><div><h3>Conclusion</h3><div>This case underscores the diagnostic value of integrating enzyme and molecular testing when infantile-onset Pompe disease is suspected. While newborn screening for Pompe disease exists in some regions, it is not universally implemented, contributing to delays in diagnosis. Early identification allows appropriate counseling and consideration of available management pathways.</div></div><div><h3>Key clinical message</h3><div>Infantile-onset Pompe disease should be considered in infants presenting with hypotonia, recurrent respiratory infections, feeding difficulties, and delayed motor milestones. Combining dried blood spot enzyme assay with confirmatory molecular testing of the <strong><em>GAA</em></strong> gene enables timely diagnosis, informs counseling, and guides management even in settings where access to enzyme replacement therapy is limited.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101283"},"PeriodicalIF":1.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733134","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 : 2025-12-01DOI: 10.1016/j.ymgmr.2025.101281
Saja Baheer Abdul Wahhab , Rabab Farhan Thejeal
Background
Mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome) is a rare lysosomal storage disorder that causes early-onset skeletal dysplasia and progressive multisystem involvement. Although international cohorts have been described, population-specific data from the Middle East remain limited.
Objective
This study aimed to characterize the clinical spectrum, functional status, and GALNS variant profile in Iraqi children with MPS IVA, and to assess diagnostic timing in comparison with international experience.
Methods
We retrospectively analyzed 33 children from 26 unrelated families with confirmed MPS IVA, recruited at the Children's Welfare Teaching Hospital in Baghdad between 2016 and 2022. Enzyme activity was measured on dried blood spots by LC-MS/MS, and GALNS variants were identified using next-generation sequencing with Sanger confirmation. Clinical evaluation included anthropometry, echocardiography, ophthalmologic and audiologic assessments, skeletal surveys, and functional endurance testing (6-min walk test and 3-min stair-climb).
Results
Fifteen distinct GALNS variants were identified, including five novel variants (three missense, two frameshift). The most common allele was c.949G > A (p.Gly317Arg), consistently associated with severe phenotypes and absent enzyme activity. Universal skeletal dysplasia was observed, with frequent corneal clouding, cardiac valve disease, and reduced functional endurance. Symptoms typically appeared in early childhood, but definitive diagnosis was often delayed until later childhood or adolescence. Allele-specific genotype–phenotype trends were observed, though no statistically significant correlations could be established due to limited cohort size.
Conclusion
This first Iraqi cohort expands the GALNS variant spectrum and highlights persistent diagnostic delays despite early clinical manifestations. Early molecular confirmation, establishment of national registries, and multidisciplinary surveillance are essential to reduce long-term morbidity.
背景：粘多糖病型IVA （MPS IVA； Morquio A综合征）是一种罕见的溶酶体沉积疾病，可导致早发性骨骼发育不良和进行性多系统受累。虽然已经描述了国际队列，但来自中东的特定人群数据仍然有限。目的本研究旨在描述伊拉克MPS IVA患儿的临床谱、功能状态和GALNS变异谱，并与国际经验进行比较，评估诊断时机。方法回顾性分析2016年至2022年在巴格达儿童福利教学医院招募的26个非亲属家庭确诊MPS IVA的33名儿童。用LC-MS/MS测定干血斑上的酶活性，并采用Sanger确认的下一代测序方法鉴定GALNS变异。临床评估包括人体测量、超声心动图、眼科和听力学评估、骨骼调查和功能耐力测试（6分钟步行测试和3分钟爬楼梯）。结果鉴定出15种不同的GALNS变异，包括5种新变异（3种错义，2种移码）。最常见的等位基因是c.949G > A (p.Gly317Arg)，与严重表型和缺乏酶活性一致相关。观察到普遍的骨骼发育不良，角膜混浊，心脏瓣膜疾病和功能耐力降低。症状通常出现在儿童早期，但明确的诊断往往延迟到儿童后期或青春期。观察到等位基因特异性基因型-表型趋势，但由于队列规模有限，无法建立统计学上显著的相关性。结论：第一个伊拉克队列扩展了GALNS变异谱，突出了尽管早期临床表现，但持续的诊断延迟。早期分子确认、建立国家登记和多学科监测对于降低长期发病率至关重要。
{"title":"Clinical and molecular spectrum of mucopolysaccharidosis IVA in Iraqi children: Allele-specific genotype–phenotype trends and novel GALNS variants","authors":"Saja Baheer Abdul Wahhab , Rabab Farhan Thejeal","doi":"10.1016/j.ymgmr.2025.101281","DOIUrl":"10.1016/j.ymgmr.2025.101281","url":null,"abstract":"<div><h3>Background</h3><div>Mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome) is a rare lysosomal storage disorder that causes early-onset skeletal dysplasia and progressive multisystem involvement. Although international cohorts have been described, population-specific data from the Middle East remain limited.</div></div><div><h3>Objective</h3><div>This study aimed to characterize the clinical spectrum, functional status, and <em>GALNS</em> variant profile in Iraqi children with MPS IVA, and to assess diagnostic timing in comparison with international experience.</div></div><div><h3>Methods</h3><div>We retrospectively analyzed 33 children from 26 unrelated families with confirmed MPS IVA, recruited at the Children's Welfare Teaching Hospital in Baghdad between 2016 and 2022. Enzyme activity was measured on dried blood spots by LC-MS/MS, and <em>GALNS</em> variants were identified using next-generation sequencing with Sanger confirmation. Clinical evaluation included anthropometry, echocardiography, ophthalmologic and audiologic assessments, skeletal surveys, and functional endurance testing (6-min walk test and 3-min stair-climb).</div></div><div><h3>Results</h3><div>Fifteen distinct <em>GALNS</em> variants were identified, including five novel variants (three missense, two frameshift). The most common allele was c.949G > A (p.Gly317Arg), consistently associated with severe phenotypes and absent enzyme activity. Universal skeletal dysplasia was observed, with frequent corneal clouding, cardiac valve disease, and reduced functional endurance. Symptoms typically appeared in early childhood, but definitive diagnosis was often delayed until later childhood or adolescence. Allele-specific genotype–phenotype trends were observed, though no statistically significant correlations could be established due to limited cohort size.</div></div><div><h3>Conclusion</h3><div>This first Iraqi cohort expands the <em>GALNS</em> variant spectrum and highlights persistent diagnostic delays despite early clinical manifestations. Early molecular confirmation, establishment of national registries, and multidisciplinary surveillance are essential to reduce long-term morbidity.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101281"},"PeriodicalIF":1.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145614652","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 : 2025-12-01DOI: 10.1016/j.ymgmr.2025.101284
Francesca Cappozzo , Mariasavina Severino , Elena Gennaro , Francesca Faravelli , Marina Martinez Popple , Maria Cristina Schiaffino , Annalisa Madeo , Alessandro La Rosa
Infantile sialic acid storage disorder (ISSD) represents the most severe form of free sialic acid storage disease (FSASD), a rare lysosomal storage disorder caused by mutations in SLC17A5, which encodes the lysosomal sialic acid transporter sialin. These mutations lead to the accumulation of free sialic acid within lysosomes, resulting in multisystemic involvement. Through a case report and literature review, we explored the phenotypic spectrum of FSASD, with a particular focus on neurological manifestations and characteristic neuroimaging findings of ISSD. Our patient exhibited severe hypotonia shortly after birth, dysmorphic features, and hyporegenerative anemia, a clinical presentation that has not previously described in ISSD. Brain MRI revealed hypomyelination, periventricular white matter T1-hyperintensity and T2-hypointensity, callosal thinning, and optic atrophy, providing critical diagnostic clues. MR spectroscopy showed an elevated NAA-like peak, further supporting the suspicion of ISSD. Laboratory tests demonstrated increased chitotriosidase activity and elevated urinary excretion of free sialic acid. Next-generation sequencing identified compound heterozygosity for a known pathogenic variant and a previously unreported SLC17A5 variant (c.709G>A), affecting a highly conserved transmembrane domain residue and predicted to be pathogenic.
Our findings underscore the role of neuroimaging in the early diagnosis of ISSD and suggest a potential link between sialic acid metabolism and erythropoiesis, suggesting further investigation. Despite the lack of targeted therapies, recognizing FSASD remains essential for patient management and genetic counselling, ensuring appropriate clinical care and family support.
{"title":"A novel SLC17A5 variant in infantile sialic acid storage disease with hyporegenerative anemia: Neuroimaging insights and literature review","authors":"Francesca Cappozzo , Mariasavina Severino , Elena Gennaro , Francesca Faravelli , Marina Martinez Popple , Maria Cristina Schiaffino , Annalisa Madeo , Alessandro La Rosa","doi":"10.1016/j.ymgmr.2025.101284","DOIUrl":"10.1016/j.ymgmr.2025.101284","url":null,"abstract":"<div><div>Infantile sialic acid storage disorder (ISSD) represents the most severe form of free sialic acid storage disease (FSASD), a rare lysosomal storage disorder caused by mutations in <em>SLC17A5</em>, which encodes the lysosomal sialic acid transporter sialin. These mutations lead to the accumulation of free sialic acid within lysosomes, resulting in multisystemic involvement. Through a case report and literature review, we explored the phenotypic spectrum of FSASD, with a particular focus on neurological manifestations and characteristic neuroimaging findings of ISSD. Our patient exhibited severe hypotonia shortly after birth, dysmorphic features, and hyporegenerative anemia, a clinical presentation that has not previously described in ISSD. Brain MRI revealed hypomyelination, periventricular white matter T1-hyperintensity and T2-hypointensity, callosal thinning, and optic atrophy, providing critical diagnostic clues. MR spectroscopy showed an elevated NAA-like peak, further supporting the suspicion of ISSD. Laboratory tests demonstrated increased chitotriosidase activity and elevated urinary excretion of free sialic acid. Next-generation sequencing identified compound heterozygosity for a known pathogenic variant and a previously unreported <em>SLC17A5</em> variant (c.709G>A), affecting a highly conserved transmembrane domain residue and predicted to be pathogenic.</div><div>Our findings underscore the role of neuroimaging in the early diagnosis of ISSD and suggest a potential link between sialic acid metabolism and erythropoiesis, suggesting further investigation. Despite the lack of targeted therapies, recognizing FSASD remains essential for patient management and genetic counselling, ensuring appropriate clinical care and family support.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101284"},"PeriodicalIF":1.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733129","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}
The mucopolysaccharidoses are a heterogeneous group of lysosomal storage disorders caused by deficiencies of enzymes involved in degradation of glycosaminoglycans. This study aimed to share our experience with biochemical investigations of these disorders under resource-limited conditions. Harmine extract was obtained from Peganum harmala seeds, and chromatography plates were homemade. Biochemical analysis involved urinary tests, including the Berry Spot test, the quantification of the glycosaminoglycans, as well as their characterization, and the analysis of deficient enzymes. The reference range values of glycosaminoglycans and activities of seven lysosomal enzymes, six of which are associated with these disorders were initially determined in samples of healthy subjects. The assay for β-galactosidase was described. These biochemical markers were then, evaluated in 29 patients, including 23 who were suspected of having different types of mucopolysaccharidoses and six who were diagnosed with the type I and undergoing enzymotherapy. The reference values of glycosaminoglycans and enzymes activities align with those reported in the literature. The reference value of β-galactosidase ranges from 83 to 311 nmol/17 h/mg. All the studied patients have shown the same positive pattern of Berry Spot Test in contrast of the healthy subjects. The level of GAGs was elevated by 1.1 to more than six fold but is decreased by more than six fold in patients with mucopolysaccharidosis type 1 undergoing enzymotherapy. The patients were categorized as follows: Hurler syndrome 34 %, Hunter syndrome 7 %, Sanfilippo syndrome 17 %, and Morquio syndrome 41 %. In patients for whom molecular defects were characterized, the mutations were correlated with the biochemical markers.
{"title":"Mucopolysaccharidoses: A biochemical study under limited resources","authors":"Fadoua Bouzid , Houda El Fissi , Khadija Karim , Mohamed Said Sebbar , Bouchaib Jabir , Nouzha Chuis , Fouad Msanda , Najat Alif","doi":"10.1016/j.ymgmr.2025.101280","DOIUrl":"10.1016/j.ymgmr.2025.101280","url":null,"abstract":"<div><div>The mucopolysaccharidoses are a heterogeneous group of lysosomal storage disorders caused by deficiencies of enzymes involved in degradation of glycosaminoglycans. This study aimed to share our experience with biochemical investigations of these disorders under resource-limited conditions. Harmine extract was obtained from <em>Peganum harmala</em> seeds, and chromatography plates were homemade. Biochemical analysis involved urinary tests, including the Berry Spot test, the quantification of the glycosaminoglycans, as well as their characterization, and the analysis of deficient enzymes. The reference range values of glycosaminoglycans and activities of seven lysosomal enzymes, six of which are associated with these disorders were initially determined in samples of healthy subjects. The assay for β-galactosidase was described. These biochemical markers were then, evaluated in 29 patients, including 23 who were suspected of having different types of mucopolysaccharidoses and six who were diagnosed with the type I and undergoing enzymotherapy. The reference values of glycosaminoglycans and enzymes activities align with those reported in the literature. The reference value of β-galactosidase ranges from 83 to 311 nmol/17 h/mg. All the studied patients have shown the same positive pattern of Berry Spot Test in contrast of the healthy subjects. The level of GAGs was elevated by 1.1 to more than six fold but is decreased by more than six fold in patients with mucopolysaccharidosis type 1 undergoing enzymotherapy. The patients were categorized as follows: Hurler syndrome 34 %, Hunter syndrome 7 %, Sanfilippo syndrome 17 %, and Morquio syndrome 41 %. In patients for whom molecular defects were characterized, the mutations were correlated with the biochemical markers.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101280"},"PeriodicalIF":1.9,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145568413","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 : 2025-11-14DOI: 10.1016/j.ymgmr.2025.101277
Louise Robertson , Simon Tapley , Alexa Sparks , Joy McDonald , Ellen Condie , Sarah Bailey
Classical Galactosaemia is a rare, inherited metabolic disorder requiring lifelong dietary management. Despite increasing numbers of adults living with this condition, there is currently no formalised training or standardised guidance for United Kingdom (UK) dietitians managing adult patients. In response to this gap, a group of experienced UK dietitians specialising in inherited metabolic disorders collaboratively developed the first UK consensus document for the dietetic management of adults with Classical Galactosaemia. The guidance was formulated over a 12-month period through structured virtual meetings, with the objective of promoting consistency in clinical practice, supporting equitable service provision, and enhancing patient outcomes. Key areas addressed include dietary interventions, nutritional adequacy, bone health, dietary management with cognitive impairment, and reproductive health. The document also highlights critical gaps in the evidence base, particularly regarding individual galactose tolerance, the identification of sensitive biomarkers for monitoring, and the potential for dietary liberalisation in adulthood. This consensus guidance serves as a foundational resource for clinical practice and professional development, aiming to improve the quality and consistency of dietetic care for adults with Classical Galactosaemia across the UK.
{"title":"Dietetic management of adults with Classical Galactosaemia in the UK: A care consensus document","authors":"Louise Robertson , Simon Tapley , Alexa Sparks , Joy McDonald , Ellen Condie , Sarah Bailey","doi":"10.1016/j.ymgmr.2025.101277","DOIUrl":"10.1016/j.ymgmr.2025.101277","url":null,"abstract":"<div><div>Classical Galactosaemia is a rare, inherited metabolic disorder requiring lifelong dietary management. Despite increasing numbers of adults living with this condition, there is currently no formalised training or standardised guidance for United Kingdom (UK) dietitians managing adult patients. In response to this gap, a group of experienced UK dietitians specialising in inherited metabolic disorders collaboratively developed the first UK consensus document for the dietetic management of adults with Classical Galactosaemia. The guidance was formulated over a 12-month period through structured virtual meetings, with the objective of promoting consistency in clinical practice, supporting equitable service provision, and enhancing patient outcomes. Key areas addressed include dietary interventions, nutritional adequacy, bone health, dietary management with cognitive impairment, and reproductive health. The document also highlights critical gaps in the evidence base, particularly regarding individual galactose tolerance, the identification of sensitive biomarkers for monitoring, and the potential for dietary liberalisation in adulthood. This consensus guidance serves as a foundational resource for clinical practice and professional development, aiming to improve the quality and consistency of dietetic care for adults with Classical Galactosaemia across the UK.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101277"},"PeriodicalIF":1.9,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516858","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 : 2025-11-14DOI: 10.1016/j.ymgmr.2025.101278
Iskren Menkovic , Neelam Makhijani , Ludmila Francescatto , Surekha Pendyal , Christine Stanley , Sarah P. Young , Dwight D. Koeberl , Dmitriy Niyazov , Ashlee R. Stiles
3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency is a rare autosomal recessive metabolic disease caused by variants in the HMGCL gene leading to an impairment in leucine catabolism and ketone synthesis. In the United States, HMG-CoA lyase deficiency is listed on the recommended uniform screening panel as a core condition for newborn screening. A positive newborn screen will typically show an elevation of C5-hydroxylated species on the acylcarnitine profile using a dried-blood spot collected between 24 and 48 h of life. Initial follow-up testing generally includes a plasma acylcarnitine profile and a urine organic acid profile. Clinically, this metabolic alteration can lead to severe metabolic decompensation, presenting as hypoketotic hypoglycemia and, when left untreated, potential long-term neurological impairments. This report highlights the case of a 38-day-old male with an initial abnormal newborn screen. Follow-up testing showed moderate elevations of C5-hydroxylated and C6-dicarboxylated species on the plasma acylcarnitine profile and marked elevations of 3-hydroxy-3-methylglutaric acid, 3-methylglutaconic acid, 3-methylglutaric and 3-hydroxyisovaleric acid detected by urine organic acid analysis. These findings were consistent with a biochemical diagnosis of HMG-CoA lyase deficiency. Confirmatory molecular testing included targeted HMGCL sequencing including deletion/duplication analysis; the results of which were negative. Genome sequencing was then requested which identified a deep intronic complex variant of unknown significance within intron 1 of HGMCL. RNA sequencing studies were sent as follow-up which revealed that the level of expression of the HMGCL gene was negligible in comparison with tissue-matched controls, thus confirming the biochemical diagnosis of HMG-CoA lyase deficiency.
{"title":"Timely intervention in HMG-CoA Lyase deficiency: The role of newborn screening, metabolic management, and genomic sequencing","authors":"Iskren Menkovic , Neelam Makhijani , Ludmila Francescatto , Surekha Pendyal , Christine Stanley , Sarah P. Young , Dwight D. Koeberl , Dmitriy Niyazov , Ashlee R. Stiles","doi":"10.1016/j.ymgmr.2025.101278","DOIUrl":"10.1016/j.ymgmr.2025.101278","url":null,"abstract":"<div><div>3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency is a rare autosomal recessive metabolic disease caused by variants in the HMGCL gene leading to an impairment in leucine catabolism and ketone synthesis. In the United States, HMG-CoA lyase deficiency is listed on the recommended uniform screening panel as a core condition for newborn screening. A positive newborn screen will typically show an elevation of C5-hydroxylated species on the acylcarnitine profile using a dried-blood spot collected between 24 and 48 h of life. Initial follow-up testing generally includes a plasma acylcarnitine profile and a urine organic acid profile. Clinically, this metabolic alteration can lead to severe metabolic decompensation, presenting as hypoketotic hypoglycemia and, when left untreated, potential long-term neurological impairments. This report highlights the case of a 38-day-old male with an initial abnormal newborn screen. Follow-up testing showed moderate elevations of C5-hydroxylated and C6-dicarboxylated species on the plasma acylcarnitine profile and marked elevations of 3-hydroxy-3-methylglutaric acid, 3-methylglutaconic acid, 3-methylglutaric and 3-hydroxyisovaleric acid detected by urine organic acid analysis. These findings were consistent with a biochemical diagnosis of HMG-CoA lyase deficiency. Confirmatory molecular testing included targeted <em>HMGCL</em> sequencing including deletion/duplication analysis; the results of which were negative. Genome sequencing was then requested which identified a deep intronic complex variant of unknown significance within intron 1 of <em>HGMCL</em>. RNA sequencing studies were sent as follow-up which revealed that the level of expression of the HMGCL gene was negligible in comparison with tissue-matched controls, thus confirming the biochemical diagnosis of HMG-CoA lyase deficiency.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101278"},"PeriodicalIF":1.9,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516857","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 : 2025-11-13DOI: 10.1016/j.ymgmr.2025.101274
Mohammad Elahimanesh , Reza Ganjali , Mohammad Najafi
Gaucher disease (GD) is a lysosomal storage disorder caused by the failure of GBA1 (Glucosylceramidase Beta 1). The aim of study was to analyze and enrich signaling pathways with transcriptomic profiles in cultured skin fibroblasts of GD subtypes (GD1, GD2, GD3) using GEO datasets. Differentially expressed genes (DEGs) were identified using the Limma package in R with a significance threshold (adjusted p-value <0.05 and |log2FC| > 1) and were used in gene networks constructed by Cytoscape. In GD1, up regulated genes (TP53, COL4A1) were found in mRNA splicing and ECM organization, while down regulated genes (IL6, TGFBR2) were linked to cytokine and TGF-β signaling pathways. GD2 showed upregulation of MMP1, CXCL8, and interferon-related genes (ISG15, MX1), associated with interleukin-4/13 signaling and ECM dysregulation, reflecting severe neuroinflammation. GD3 exhibited upregulation of FOS, AKT1 (>5 years), and POSTN, EGR2 (<5 years), found in PI3K/AKT and myelination signaling pathways, alongside down regulated CXCL8 and PTGS2 linked to receptor tyrosine kinase signaling pathway. Gene networks identified hub genes (PSAP, CTSB for GD1; LAMP2, GAA for GD2/GD3) and enriched pathways (glycosphingolipid metabolism, lysosomal function). Top 5 % DEGs, including KDM5D (GD1), MMP1 (GD2), and FOSB (GD3), were proposed as subtype-specific markers. The findings highlighted distinct molecular signatures between GD1 (immune/ECM-focused) and GD2/GD3 (neuroinflammatory/neurodevelopmental), informing targeted diagnostics.
{"title":"Transcriptomic signatures in Gaucher disease subtypes: A systems biology perspective","authors":"Mohammad Elahimanesh , Reza Ganjali , Mohammad Najafi","doi":"10.1016/j.ymgmr.2025.101274","DOIUrl":"10.1016/j.ymgmr.2025.101274","url":null,"abstract":"<div><div>Gaucher disease (GD) is a lysosomal storage disorder caused by the failure of <em>GBA1</em> (Glucosylceramidase Beta 1). The aim of study was to analyze and enrich signaling pathways with transcriptomic profiles in cultured skin fibroblasts of GD subtypes (GD1, GD2, GD3) using GEO datasets. Differentially expressed genes (DEGs) were identified using the Limma package in R with a significance threshold (adjusted <em>p</em>-value <0.05 and |log2FC| > 1) and were used in gene networks constructed by Cytoscape. In GD1, up regulated genes (<em>TP53</em>, <em>COL4A1</em>) were found in mRNA splicing and ECM organization, while down regulated genes (<em>IL6</em>, <em>TGFBR2</em>) were linked to cytokine and TGF-β signaling pathways. GD2 showed upregulation of <em>MMP1</em>, <em>CXCL8</em>, and interferon-related genes (<em>ISG15</em>, <em>MX1</em>), associated with interleukin-4/13 signaling and ECM dysregulation, reflecting severe neuroinflammation. GD3 exhibited upregulation of <em>FOS</em>, <em>AKT1</em> (>5 years), and <em>POSTN</em>, <em>EGR2</em> (<5 years), found in PI3K/AKT and myelination signaling pathways, alongside down regulated <em>CXCL8</em> and <em>PTGS2</em> linked to receptor tyrosine kinase signaling pathway. Gene networks identified hub genes (<em>PSAP</em>, <em>CTSB</em> for GD1; <em>LAMP2</em>, <em>GAA</em> for GD2/GD3) and enriched pathways (glycosphingolipid metabolism, lysosomal function). Top 5 % DEGs, including KDM5D (GD1), MMP1 (GD2), and FOSB (GD3), were proposed as subtype-specific markers. The findings highlighted distinct molecular signatures between GD1 (immune/ECM-focused) and GD2/GD3 (neuroinflammatory/neurodevelopmental), informing targeted diagnostics.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101274"},"PeriodicalIF":1.9,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516747","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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