Pub Date : 2025-10-08DOI: 10.1016/j.ymgme.2025.109260
Xueyang Pan , Yue Wang , Ning Liu , Xi Luo , V. Reid Sutton , William J. Craigen , Qin Sun
Large deletions in multi-copy mitochondrial DNA (mtDNA) are associated with chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre syndrome (KSS), and Pearson syndrome (PS), collectively referred to as single large-scale mtDNA deletion syndromes (SLSMDSs). These deletions are typically sporadic and heteroplasmic, yet the relationship between heteroplasmy levels and disease severity remains uncertain, particularly for low level deletions, making pathogenicity assessment challenging.
To evaluate the functional impact of mtDNA deletions in muscle, we retrospectively analyzed 1104 consecutive clinical cases with both mtDNA sequencing and mitochondrial electron transport chain (ETC) enzyme assays performed on the same muscle specimen. Fifteen cases (1.4 %) carried a single large mtDNA deletion and exhibited clinical features consistent with the CPEO/KSS spectrum. Of these, seven showed ETC deficiencies despite low deletion heteroplasmy levels (<10 % in all cases). Four had enzyme deficiencies defined to a single complex, while three had deficiencies in multiple complexes. Complex IV was most frequently impaired, whereas nuclear-encoded complex II activity remained normal in all samples. Notably, the pattern of ETC impairment did not fully correlate with the specific mitochondrial genes disrupted by the deletions.
These findings demonstrate that mitochondrial dysfunction can occur at mtDNA deletion heteroplasmy levels far below conventional pathogenic thresholds. This highlights the diagnostic relevance of low-level mtDNA deletions and supports the integration of molecular and functional testing in accurate SLSMDS diagnosis.
{"title":"Detecting mitochondrial electron transport chain enzyme defects in low-heteroplasmy single large-scale mtDNA deletion syndromes (SLSMDSs)","authors":"Xueyang Pan , Yue Wang , Ning Liu , Xi Luo , V. Reid Sutton , William J. Craigen , Qin Sun","doi":"10.1016/j.ymgme.2025.109260","DOIUrl":"10.1016/j.ymgme.2025.109260","url":null,"abstract":"<div><div>Large deletions in multi-copy mitochondrial DNA (mtDNA) are associated with chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre syndrome (KSS), and Pearson syndrome (PS), collectively referred to as single large-scale mtDNA deletion syndromes (SLSMDSs). These deletions are typically sporadic and heteroplasmic, yet the relationship between heteroplasmy levels and disease severity remains uncertain, particularly for low level deletions, making pathogenicity assessment challenging.</div><div>To evaluate the functional impact of mtDNA deletions in muscle, we retrospectively analyzed 1104 consecutive clinical cases with both mtDNA sequencing and mitochondrial electron transport chain (ETC) enzyme assays performed on the same muscle specimen. Fifteen cases (1.4 %) carried a single large mtDNA deletion and exhibited clinical features consistent with the CPEO/KSS spectrum. Of these, seven showed ETC deficiencies despite low deletion heteroplasmy levels (<10 % in all cases). Four had enzyme deficiencies defined to a single complex, while three had deficiencies in multiple complexes. Complex IV was most frequently impaired, whereas nuclear-encoded complex II activity remained normal in all samples. Notably, the pattern of ETC impairment did not fully correlate with the specific mitochondrial genes disrupted by the deletions.</div><div>These findings demonstrate that mitochondrial dysfunction can occur at mtDNA deletion heteroplasmy levels far below conventional pathogenic thresholds. This highlights the diagnostic relevance of low-level mtDNA deletions and supports the integration of molecular and functional testing in accurate SLSMDS diagnosis.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 3","pages":"Article 109260"},"PeriodicalIF":3.5,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145292996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-07DOI: 10.1016/j.ymgme.2025.109255
Andrés Felipe Leal , Luis Eduardo Prieto , Harry Pachajoa , Shunji Tomatsu
Mucopolysaccharidosis VI, also known as Maroteaux-Lamy syndrome, is a lysosomal storage disorder (LSD) caused by pathogenic mutations in the ARSB gene, resulting in arylsulfatase (ARSB) deficiency and the lysosomal accumulation of dermatan sulfate (DS) and chondroitin 4-sulfate (C4S). DS and C4S accumulation leads to multisystemic symptoms in MPS VI patients in cartilage, bone, heart valves, cornea, liver, and respiratory tract. Currently, enzyme replacement therapy (ERT) is the only approved treatment for patients with MPS VI, providing clinical benefits that include increased survival and improved quality of life. However, ERT has a limited impact on bone manifestations. Significant advances have been made in gene therapy (GT) using classical adeno-associated virus and the CRISPR/Cas9 system, providing promising alternatives in MPS VI. Importantly, hematopoietic stem cell transplantation (HSCT) in combination with GT may also offer a novel alternative. Additionally, substrate reduction therapy with odiparcil, immunomodulation, and stop codon read-through therapies have been explored in MPS VI. Future directions in MPS VI should include targeting cellular alterations, such as mitochondrial dysfunction, exploring cartilage-targeting alternatives, and implementing pharmacological chaperones. This manuscript highlights recent progress and emerging strategies for treating MPS VI.
{"title":"Mucopolysaccharidosis VI: Therapeutic strategies and perspectives","authors":"Andrés Felipe Leal , Luis Eduardo Prieto , Harry Pachajoa , Shunji Tomatsu","doi":"10.1016/j.ymgme.2025.109255","DOIUrl":"10.1016/j.ymgme.2025.109255","url":null,"abstract":"<div><div>Mucopolysaccharidosis VI, also known as Maroteaux-Lamy syndrome, is a lysosomal storage disorder (LSD) caused by pathogenic mutations in the <em>ARSB</em> gene, resulting in arylsulfatase (ARSB) deficiency and the lysosomal accumulation of dermatan sulfate (DS) and chondroitin 4-sulfate (C4S). DS and C4S accumulation leads to multisystemic symptoms in MPS VI patients in cartilage, bone, heart valves, cornea, liver, and respiratory tract. Currently, enzyme replacement therapy (ERT) is the only approved treatment for patients with MPS VI, providing clinical benefits that include increased survival and improved quality of life. However, ERT has a limited impact on bone manifestations. Significant advances have been made in gene therapy (GT) using classical adeno-associated virus and the CRISPR/Cas9 system, providing promising alternatives in MPS VI. Importantly, hematopoietic stem cell transplantation (HSCT) in combination with GT may also offer a novel alternative. Additionally, substrate reduction therapy with odiparcil, immunomodulation, and stop codon read-through therapies have been explored in MPS VI. Future directions in MPS VI should include targeting cellular alterations, such as mitochondrial dysfunction, exploring cartilage-targeting alternatives, and implementing pharmacological chaperones. This manuscript highlights recent progress and emerging strategies for treating MPS VI.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 3","pages":"Article 109255"},"PeriodicalIF":3.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mitochondrial aminoacyl tRNA synthetase (mt-ARS) related disorders represent a widely heterogeneous group of diseases affecting the efficiency of mitochondrial protein synthesis.
AARS2 and DARS2 biallelic mutations are associated with clinical syndromes prominently characterized by diffuse leukoencephalopathy with a highly variable age of onset, ranging from early infancy to adulthood.
Preliminary in vitro results on patients' fibroblasts and some anecdotal reports on patients affected by mt-ARS related disease have suggested a possible benefit of supplementation with the specific substrate amino acid of the defective mt-ARS.
Methods
We recruited 6 adult patients affected by AARS2 (n = 2) and DARS2 (n = 4) related leukoencephalopathies and started an oral supplementation with alanine and aspartate, respectively, for a total duration of 2 years. Therapeutic efficacy and safety were assessed through clinical examinations, standardized scales, functional tests, quality of life (QoL) scores, brain MRI, and laboratory analyses.
Results
Overall, the treatment was safe and well tolerated by all patients, but efficacy endpoints were not met as no significant improvements were observed in global, cognitive, or motor scores.; nonetheless, all patients but one remained clinically stable.
Conclusions
Despite inherent limitations of this pivotal trial, our findings suggest that specific amino acid supplementation is a safe intervention but do not yield a clear symptomatic benefit; nevertheless, we cannot exclude a potential role in stabilizing the clinical condition in adult patients with DARS2-related disorders.
{"title":"Amino acid supplementation in patients affected by leukoencephalopathies associated with mitochondrial aminoacyl tRNA synthetase pathogenic variants: Pilot clinical trial in adults and review of literature","authors":"Alessia Catania , Silvia Marchet , Krisztina Einvag , Eleonora Lamantea , Ettore Salsano , Daniele Ghezzi , Costanza Lamperti","doi":"10.1016/j.ymgme.2025.109259","DOIUrl":"10.1016/j.ymgme.2025.109259","url":null,"abstract":"<div><h3>Background</h3><div>Mitochondrial aminoacyl tRNA synthetase (mt-ARS) related disorders represent a widely heterogeneous group of diseases affecting the efficiency of mitochondrial protein synthesis.</div><div><em>AARS2</em> and <em>DARS2</em> biallelic mutations are associated with clinical syndromes prominently characterized by diffuse leukoencephalopathy with a highly variable age of onset, ranging from early infancy to adulthood.</div><div>Preliminary in vitro results on patients' fibroblasts and some anecdotal reports on patients affected by mt-ARS related disease have suggested a possible benefit of supplementation with the specific substrate amino acid of the defective mt-ARS.</div></div><div><h3>Methods</h3><div>We recruited 6 adult patients affected by <em>AARS2</em> (<em>n</em> = 2) and <em>DARS2</em> (<em>n</em> = 4) related leukoencephalopathies and started an oral supplementation with alanine and aspartate, respectively, for a total duration of 2 years. Therapeutic efficacy and safety were assessed through clinical examinations, standardized scales, functional tests, quality of life (QoL) scores, brain MRI, and laboratory analyses.</div></div><div><h3>Results</h3><div>Overall, the treatment was safe and well tolerated by all patients, but efficacy endpoints were not met as no significant improvements were observed in global, cognitive, or motor scores.; nonetheless, all patients but one remained clinically stable.</div></div><div><h3>Conclusions</h3><div>Despite inherent limitations of this pivotal trial, our findings suggest that specific amino acid supplementation is a safe intervention but do not yield a clear symptomatic benefit; nevertheless, we cannot exclude a potential role in stabilizing the clinical condition in adult patients with <em>DARS2</em>-related disorders.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 3","pages":"Article 109259"},"PeriodicalIF":3.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145270248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-06DOI: 10.1016/j.ymgme.2025.109253
Francesco Gavazzi , Samuel R. Pierce , Vanessa Smith , Eric Yang , Julie Skorup , Kristy Pucci , Emma Kotes , Allan M. Glanzman , Stacy V. Cusack , Todd Levy , Holly Dubbs , Emma Wiener , Sarah Woidill , Joseph Vithayathil , Abbas Jawad , Nivedita Thakur , Laura A. Adang
Background
Beta-propeller Protein-Associated Neurodegeneration (BPAN) is a rare neurodevelopmental degenerative disorder caused by pathogenic variants in WDR45 leading to brain iron accumulation. Its rarity and complex clinical course make it difficult to select appropriate clinical outcome assessments (COAs). This study evaluates established COAs for feasibility and effectiveness in capturing BPAN's functional ability profiles exploring cognitive, motor, and behavioral features.
Methods
We performed an observational study. Children were recruited as part of the Myelin Disorders Biorepository Project at the Children's Hospital of Philadelphia. We administered the Gross Motor Function Measure-88 (GMFM-88), the Leiter International Performance Scale (Leiter-3), and the Vineland Adaptive Behavior Scale (VABS-3). A Rasch validated version of the GMFM-88, the GMFM-66, was derived from the GMFM-88 data. Descriptive statistics and Spearman's rank correlation were used to compare assessments. Statistical analyses were performed to compare performance across cohorts and assess correlations, with significance defined as p < 0.05.
Results
Fifty-three individuals (43 females, 10 males) with molecularly confirmed BPAN participated. The VABS-3 (n = 53) showed a decline in adaptive skills over time, with significant differences between Communication and Socialization Domain performance (Kruskal-Wallis test with Dunn's correction p < 0.0001). GMFM-88 assessments (n = 32) showed a median performance of 33.4 %. Patient participation/behavior affected data completeness. The more limited GMFM-66 correlated better with the VABS-3 Gross Motor subdomain than the GMFM-88 (r = 0.94, r = 0.73, respectively). The Leiter-3 (n = 36) demonstrated significant non-verbal cognitive impairment, although there were behavioral challenges which impacted implementation. Longitudinal VABS-3 data revealed a median − 2.9 points/year decline in Adaptive Behavior Composite scores, reflecting progressive functional loss.
Discussion
This study highlights key considerations for selecting COAs in BPAN. The panel of COAs should accommodate the behavioral challenges associated with BPAN that can limit participant compliance with testing. The abbreviated GMFM-66 was a more reliable tool to capture motor skills. Similarly, behavioral difficulties impacted Leiter-3 performance, which demonstrated general impairment in non-verbal cognitive skills. The VABS-3 effectively tracked adaptive function decline, demonstrating feasibility for longitudinal monitoring. Future studies should expand cohort size, refine assessment strategies, and align measures with disease progression to optimize clinical trial readiness.
{"title":"Functional ability profiles in beta-propeller protein-associated neurodegeneration (BPAN)","authors":"Francesco Gavazzi , Samuel R. Pierce , Vanessa Smith , Eric Yang , Julie Skorup , Kristy Pucci , Emma Kotes , Allan M. Glanzman , Stacy V. Cusack , Todd Levy , Holly Dubbs , Emma Wiener , Sarah Woidill , Joseph Vithayathil , Abbas Jawad , Nivedita Thakur , Laura A. Adang","doi":"10.1016/j.ymgme.2025.109253","DOIUrl":"10.1016/j.ymgme.2025.109253","url":null,"abstract":"<div><h3>Background</h3><div>Beta-propeller Protein-Associated Neurodegeneration (BPAN) is a rare neurodevelopmental degenerative disorder caused by pathogenic variants in <em>WDR45</em> leading to brain iron accumulation. Its rarity and complex clinical course make it difficult to select appropriate clinical outcome assessments (COAs). This study evaluates established COAs for feasibility and effectiveness in capturing BPAN's functional ability profiles exploring cognitive, motor, and behavioral features.</div></div><div><h3>Methods</h3><div>We performed an observational study. Children were recruited as part of the Myelin Disorders Biorepository Project at the Children's Hospital of Philadelphia. We administered the Gross Motor Function Measure-88 (GMFM-88), the Leiter International Performance Scale (Leiter-3), and the Vineland Adaptive Behavior Scale (VABS-3). A Rasch validated version of the GMFM-88, the GMFM-66, was derived from the GMFM-88 data. Descriptive statistics and Spearman's rank correlation were used to compare assessments. Statistical analyses were performed to compare performance across cohorts and assess correlations, with significance defined as <em>p</em> < 0.05.</div></div><div><h3>Results</h3><div>Fifty-three individuals (43 females, 10 males) with molecularly confirmed BPAN participated. The VABS-3 (<em>n</em> = 53) showed a decline in adaptive skills over time, with significant differences between Communication and Socialization Domain performance (Kruskal-Wallis test with Dunn's correction <em>p</em> < 0.0001). GMFM-88 assessments (<em>n</em> = 32) showed a median performance of 33.4 %. Patient participation/behavior affected data completeness. The more limited GMFM-66 correlated better with the VABS-3 Gross Motor subdomain than the GMFM-88 (<em>r</em> = 0.94, <em>r</em> = 0.73, respectively). The Leiter-3 (<em>n</em> = 36) demonstrated significant non-verbal cognitive impairment, although there were behavioral challenges which impacted implementation. Longitudinal VABS-3 data revealed a median − 2.9 points/year decline in Adaptive Behavior Composite scores, reflecting progressive functional loss.</div></div><div><h3>Discussion</h3><div>This study highlights key considerations for selecting COAs in BPAN. The panel of COAs should accommodate the behavioral challenges associated with BPAN that can limit participant compliance with testing. The abbreviated GMFM-66 was a more reliable tool to capture motor skills. Similarly, behavioral difficulties impacted Leiter-3 performance, which demonstrated general impairment in non-verbal cognitive skills. The VABS-3 effectively tracked adaptive function decline, demonstrating feasibility for longitudinal monitoring. Future studies should expand cohort size, refine assessment strategies, and align measures with disease progression to optimize clinical trial readiness.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 3","pages":"Article 109253"},"PeriodicalIF":3.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-06DOI: 10.1016/j.ymgme.2025.109254
Forbes D. Porter , Derek M. Alexander , Orsolya K. Albert , Kendall P. Robbins , Desiree A. Labor , Aiden J. Borruso , Nicole Y. Farhat , Xuntian Jiang , Elizabeth Berry-Kravis
Niemann-Pick disease, type C1 (NPC1) is a lysosomal disease characterized by endolysosomal storage of unesterified cholesterol. Individuals with NPC1 manifest progressive neurodegeneration. Identification and characterization of proximal biomarkers is essential for developing therapeutic interventions. Increased levels of 24(S)-hydroxycholesterol (24(S)OHC) after intrathecal administration of adrabetadex reflect correction of the biochemical defect in neurons. In this study, we show that 24(S)OHC remains a robust proximal biomarker in individuals treated with IT adrabetadex for over four years.
{"title":"Utility of 24(S)-hydroxycholesterol as a proximal biomarker to monitor long-term intrathecal adrabetadex therapy in individuals with Niemann-Pick disease, type C1","authors":"Forbes D. Porter , Derek M. Alexander , Orsolya K. Albert , Kendall P. Robbins , Desiree A. Labor , Aiden J. Borruso , Nicole Y. Farhat , Xuntian Jiang , Elizabeth Berry-Kravis","doi":"10.1016/j.ymgme.2025.109254","DOIUrl":"10.1016/j.ymgme.2025.109254","url":null,"abstract":"<div><div>Niemann-Pick disease, type C1 (NPC1) is a lysosomal disease characterized by endolysosomal storage of unesterified cholesterol. Individuals with NPC1 manifest progressive neurodegeneration. Identification and characterization of proximal biomarkers is essential for developing therapeutic interventions. Increased levels of 24(<em>S</em>)-hydroxycholesterol (24(S)OHC) after intrathecal administration of adrabetadex reflect correction of the biochemical defect in neurons. In this study, we show that 24(S)OHC remains a robust proximal biomarker in individuals treated with IT adrabetadex for over four years.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 4","pages":"Article 109254"},"PeriodicalIF":3.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145557207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-06DOI: 10.1016/j.ymgme.2025.109257
Marisa W. Friederich , Johan L.K. Van Hove
Complex V catalyzes the formation of ATP from ADP and Pi through the dissipation of the proton gradient generated during the process of oxidative phosphorylation. Most complex V genetic disorders are caused by missense mutations in the mtDNA-encoded subunits, a (MT-ATP6) and A6L (MT-ATP8). Nuclear DNA-encoded gene mutations are increasingly recognized as causes of complex V defects and exhibited both autosomal recessive and autosomal dominant inheritance. Most identified variants are novel and confirmation by functional assays is important especially for variants demonstrating autosomal dominant inheritance. A kinetic spectrophotometric assay of the Complex V enzymatic hydrolysis activity has been reported. Here we report the clinical utility of this assay for the diagnosis of complex V deficiency after optimization and validation for the diagnosis of isolated complex V disorders due to both nuclear and mitochondrial DNA encoded variants and also for use in combined respiratory chain deficiencies. This assay was able to identify all nuclear DNA-encoded complex V deficiencies, whereas a decrease in complex V activity was observed in some patient cell lines with combined deficiencies. However, this assay only identified 50% of the mitochondrial DNA-encoded complex V deficiencies due to pathogenic variants in MT-ATP6/8. In conclusion, the enzymatic assay of complex V has best clinical utility for nuclear DNA-encoded complex V defects.
{"title":"Clinical utility of the ATP hydrolysis assay for the diagnosis of complex V deficiency in cultured skin fibroblasts","authors":"Marisa W. Friederich , Johan L.K. Van Hove","doi":"10.1016/j.ymgme.2025.109257","DOIUrl":"10.1016/j.ymgme.2025.109257","url":null,"abstract":"<div><div>Complex V catalyzes the formation of ATP from ADP and P<sub>i</sub> through the dissipation of the proton gradient generated during the process of oxidative phosphorylation. Most complex V genetic disorders are caused by missense mutations in the mtDNA-encoded subunits, a (<em>MT-ATP6</em>) and A6L (<em>MT-ATP8</em>). Nuclear DNA-encoded gene mutations are increasingly recognized as causes of complex V defects and exhibited both autosomal recessive and autosomal dominant inheritance. Most identified variants are novel and confirmation by functional assays is important especially for variants demonstrating autosomal dominant inheritance. A kinetic spectrophotometric assay of the Complex V enzymatic hydrolysis activity has been reported. Here we report the clinical utility of this assay for the diagnosis of complex V deficiency after optimization and validation for the diagnosis of isolated complex V disorders due to both nuclear and mitochondrial DNA encoded variants and also for use in combined respiratory chain deficiencies. This assay was able to identify all nuclear DNA-encoded complex V deficiencies, whereas a decrease in complex V activity was observed in some patient cell lines with combined deficiencies. However, this assay only identified 50% of the mitochondrial DNA-encoded complex V deficiencies due to pathogenic variants in MT-ATP6/8. In conclusion, the enzymatic assay of complex V has best clinical utility for nuclear DNA-encoded complex V defects.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 3","pages":"Article 109257"},"PeriodicalIF":3.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145346207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-02DOI: 10.1016/j.ymgme.2025.109251
Francis Rossignol , Kristen S. Pan , Monique B. Perry , Joy C. Bryant , Kevin J. O'Brien , Irene J. Castillo , Kathryn R. Spears , Carlos R. Ferreira , Mark D. Murphey , Matthew J. Minn , William A. Gahl , Wendy J. Introne
Alkaptonuria is associated with progressive spine disease beginning in young adulthood. Characteristic radiographic changes in the intervertebral discs are often the earliest detectable skeletal manifestations. We developed a radiographic severity score measuring spine disease at 13 levels (C2-C7, T10-S1) based upon three parameters: 1) narrowing; 2) calcification; 3) vacuum disc phenomenon. 409 sets of radiographs from 136 participants were scored and divided into: 1) a cross-sectional cohort, with the most recent visit of each individual; 2) a longitudinal cohort, for participants with multiple visits. Correlations with age, sex, clinical measurements and patient-reported outcomes were performed. Both cohorts showed correlation of spinal disease score with age. Correlations were found with pain (SF-36, Pain Disability Index) and physical function (Schober's test, SF-36, Human Activity Profile). Intra- and inter-rater reliability were high for the total score (ICC > 0.95, p < 0.001), with a minimal detectable change of 2.6 points out of a total possible score of 78. This radiographic severity score is highly reliable, correlates with age, sex, and several clinical measures of physical function and pain, and allows for the detection of clinically meaningful changes. It can also be used as an outcome measure to monitor disease progression and response to therapy.
尿酸尿与从青年期开始的进行性脊柱疾病有关。椎间盘的特征性影像学改变通常是最早可发现的骨骼表现。我们开发了一种基于三个参数的脊柱疾病严重程度评分，分为13个级别（C2-C7, T10-S1）： 1)狭窄；2)钙化;3)真空盘现象。对136名参与者的409组x光片进行评分并分为：1)横断面队列，每个人最近一次访问；2)纵向队列，用于多次访问的参与者。与年龄、性别、临床测量和患者报告的结果进行相关性分析。两个队列均显示脊柱疾病评分与年龄相关。疼痛（SF-36，疼痛残疾指数）和身体功能（Schober's test, SF-36, Human Activity Profile）之间存在相关性。评分者内部和评分者之间的信度很高（ICC > 0.95, p < 0.001），在78分的总分中，可检测到的最小变化为2.6分。这种x线严重程度评分是高度可靠的，与年龄、性别、身体功能和疼痛的几种临床测量相关，并允许检测临床有意义的变化。它也可以作为监测疾病进展和治疗反应的结果指标。
{"title":"Development of a radiographic vertebral severity score for evaluation of disease progression in alkaptonuria","authors":"Francis Rossignol , Kristen S. Pan , Monique B. Perry , Joy C. Bryant , Kevin J. O'Brien , Irene J. Castillo , Kathryn R. Spears , Carlos R. Ferreira , Mark D. Murphey , Matthew J. Minn , William A. Gahl , Wendy J. Introne","doi":"10.1016/j.ymgme.2025.109251","DOIUrl":"10.1016/j.ymgme.2025.109251","url":null,"abstract":"<div><div>Alkaptonuria is associated with progressive spine disease beginning in young adulthood. Characteristic radiographic changes in the intervertebral discs are often the earliest detectable skeletal manifestations. We developed a radiographic severity score measuring spine disease at 13 levels (C2-C7, T10-S1) based upon three parameters: 1) narrowing; 2) calcification; 3) vacuum disc phenomenon. 409 sets of radiographs from 136 participants were scored and divided into: 1) a cross-sectional cohort, with the most recent visit of each individual; 2) a longitudinal cohort, for participants with multiple visits. Correlations with age, sex, clinical measurements and patient-reported outcomes were performed. Both cohorts showed correlation of spinal disease score with age. Correlations were found with pain (SF-36, Pain Disability Index) and physical function (Schober's test, SF-36, Human Activity Profile). Intra- and inter-rater reliability were high for the total score (ICC > 0.95, <em>p</em> < 0.001), with a minimal detectable change of 2.6 points out of a total possible score of 78. This radiographic severity score is highly reliable, correlates with age, sex, and several clinical measures of physical function and pain, and allows for the detection of clinically meaningful changes. It can also be used as an outcome measure to monitor disease progression and response to therapy.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 3","pages":"Article 109251"},"PeriodicalIF":3.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145270249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-29DOI: 10.1016/j.ymgme.2025.109248
Barbara K. Burton , Daniel Fertek , Peter S. Chin , Carole Ho , Roberto Giugliani , Johanna M.P. van den Hout , Martin Magner , Fatih Ezgü , Moeenaldeen AlSayed , Joseph Muenzer , Torayuki Okuyama , Simon A. Jones
Introduction
All people with the rare, inherited, lysosomal disease mucopolysaccharidosis type II (MPS II) experience somatic manifestations, and approximately two-thirds develop neurological and cognitive impairment. There is a well-documented need for novel therapies that target the central nervous system, but it is also clear that, despite enzyme replacement therapy having been available since 2006, somatic manifestations continue to have a substantial impact on quality of life, morbidity, and life expectancy. We conducted a targeted literature review to characterize the unmet needs related to the diagnosis, treatment, and monitoring of the somatic aspects of MPS II.
Methods
This review was conducted between July and September 2024. Peer-reviewed publications, abstracts, reports, and posters published between 2006 and 2024 were included. Records were identified from Embase, MEDLINE, and expert sources. Abstracts were screened, and full-text review, citation cross-check, and data extraction were performed.
Results
Of 1293 records identified, 365 were included for data extraction. The analysis identified four major unmet needs: (1) a lack of guidelines and recommendations to help enable early diagnosis and treatment initiation, and to advise on monitoring of disease progression and treatment effectiveness; (2) limitations in the ability of current treatments to address somatic manifestations that can lead to premature death, significant morbidity, and impaired quality of life; (3) a lack of strategies and guidelines for the transition from pediatric care to adult care; and (4) significant treatment- and disease-associated burden that affects people with MPS II and their caregivers.
Conclusions
Significant unmet needs persist in the management of somatic manifestations of MPS II, despite the availability of approved therapies and irrespective of cognitive status. Consideration of these needs should help guide the development of novel disease management strategies, ultimately improving care for people with MPS II.
{"title":"Unmet needs in the treatment and care of somatic manifestations in mucopolysaccharidosis type II: A targeted literature review","authors":"Barbara K. Burton , Daniel Fertek , Peter S. Chin , Carole Ho , Roberto Giugliani , Johanna M.P. van den Hout , Martin Magner , Fatih Ezgü , Moeenaldeen AlSayed , Joseph Muenzer , Torayuki Okuyama , Simon A. Jones","doi":"10.1016/j.ymgme.2025.109248","DOIUrl":"10.1016/j.ymgme.2025.109248","url":null,"abstract":"<div><h3>Introduction</h3><div>All people with the rare, inherited, lysosomal disease mucopolysaccharidosis type II (MPS II) experience somatic manifestations, and approximately two-thirds develop neurological and cognitive impairment. There is a well-documented need for novel therapies that target the central nervous system, but it is also clear that, despite enzyme replacement therapy having been available since 2006, somatic manifestations continue to have a substantial impact on quality of life, morbidity, and life expectancy. We conducted a targeted literature review to characterize the unmet needs related to the diagnosis, treatment, and monitoring of the somatic aspects of MPS II.</div></div><div><h3>Methods</h3><div>This review was conducted between July and September 2024. Peer-reviewed publications, abstracts, reports, and posters published between 2006 and 2024 were included. Records were identified from Embase, MEDLINE, and expert sources. Abstracts were screened, and full-text review, citation cross-check, and data extraction were performed.</div></div><div><h3>Results</h3><div>Of 1293 records identified, 365 were included for data extraction. The analysis identified four major unmet needs: (1) a lack of guidelines and recommendations to help enable early diagnosis and treatment initiation, and to advise on monitoring of disease progression and treatment effectiveness; (2) limitations in the ability of current treatments to address somatic manifestations that can lead to premature death, significant morbidity, and impaired quality of life; (3) a lack of strategies and guidelines for the transition from pediatric care to adult care; and (4) significant treatment- and disease-associated burden that affects people with MPS II and their caregivers.</div></div><div><h3>Conclusions</h3><div>Significant unmet needs persist in the management of somatic manifestations of MPS II, despite the availability of approved therapies and irrespective of cognitive status. Consideration of these needs should help guide the development of novel disease management strategies, ultimately improving care for people with MPS II.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 3","pages":"Article 109248"},"PeriodicalIF":3.5,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145270247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-22DOI: 10.1016/j.ymgme.2025.109236
J. Ganesh , C. Donnelly , A. Ligezka , G. Preston , E. Morava , M. Breilyn , I. Marin-Valencia , H. Raynes , N. Bansal , J. Lamour , C. Mintz , T. Kozicz
Pathogenic variants TOP3A gene have been recently described to cause a multisystem disorder associated with mitochondrial dysfunction in adults (Nicholls et al., 2018 [1]) and with a Bloom syndrome-like disorder in children (Martin et al., 2018 [2]).
We present the case of an 11-year-old male with homozygosity for a novel variant in TOP3A with myopathy, ataxia, and atrioventricular conduction defect similar to the adult cases described in the literature. He developed dilated cardiomyopathy and presented in acute decompensated heart failure requiring left ventricular assist device support as a bridge to heart transplantation. Clinical and laboratory features showed mitochondrial dysfunction confirming pathogenicity of the TOP3A variants. However, unlike the other pediatric cases of TOP3A related disease reported so far, the features of Bloom syndrome were not evident in this patient.
{"title":"Cardiac transplant outcomes in a pediatric patient with novel homozygous variants in TOP3Α causing mitochondrial dysfunction","authors":"J. Ganesh , C. Donnelly , A. Ligezka , G. Preston , E. Morava , M. Breilyn , I. Marin-Valencia , H. Raynes , N. Bansal , J. Lamour , C. Mintz , T. Kozicz","doi":"10.1016/j.ymgme.2025.109236","DOIUrl":"10.1016/j.ymgme.2025.109236","url":null,"abstract":"<div><div>Pathogenic variants <em>TOP3A</em> gene have been recently described to cause a multisystem disorder associated with mitochondrial dysfunction in adults (Nicholls et al., 2018 [1]) and with a Bloom syndrome-like disorder in children (Martin et al., 2018 [2]).</div><div>We present the case of an 11-year-old male with homozygosity for a novel variant in <em>TOP3A</em> with myopathy, ataxia, and atrioventricular conduction defect similar to the adult cases described in the literature. He developed dilated cardiomyopathy and presented in acute decompensated heart failure requiring left ventricular assist device support as a bridge to heart transplantation. Clinical and laboratory features showed mitochondrial dysfunction confirming pathogenicity of the <em>TOP3A</em> variants. However, unlike the other pediatric cases of <em>TOP3A</em> related disease reported so far, the features of Bloom syndrome were not evident in this patient.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 3","pages":"Article 109236"},"PeriodicalIF":3.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145270250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-19DOI: 10.1016/j.ymgme.2025.109235
Courtney Berrios , Randi Gadea , Meghan Strenk , Twisha Nadella , Jennifer Gannon , Janelle Noel-MacDonnell
Purpose
This study explores the psychosocial impact of a positive newborn screen (NBS) result for four lysosomal storage disorders (LSDs) (Fabry disease, Krabbe disease, Mucopolysaccharidosis Type I, Pompe disease) across confirmatory results.
Methods
Parents whose child who had a positive NBS for one of the included LSDs were recruited for a retrospective cohort (n = 80) or prospective, longitudinal cohorts (n = 50). Surveys assessed uncertainty, anxiety, intrusive or avoidant thoughts, and perceived vulnerability of their child's health. In-depth interviews explored the NBS experience and psychosocial response.
Results
Participants experienced uncertainty and anxiety during confirmatory testing that improved as parents received more information. Retrospective cohort surveys showed ongoing levels of anxiety and perceived vulnerability in parents of children with carrier or pseudodeficiency results closer to those with true positive or inconclusive results than to false positives of undetermined cause. Interviews indicated some parents across cohorts and confirmatory results held uncertainty about their child's health, frequent thoughts about NBS, and vulnerable views of their child.
Conclusion
This mixed-methods study provides evidence that NBS for LSDs may be associated with extended psychosocial impacts for some families, even if their child does not have an LSD. Lower false positive rates and additional counseling may limit the burden.
{"title":"Parental psychosocial outcomes after a positive newborn screen for a lysosomal storage disorder","authors":"Courtney Berrios , Randi Gadea , Meghan Strenk , Twisha Nadella , Jennifer Gannon , Janelle Noel-MacDonnell","doi":"10.1016/j.ymgme.2025.109235","DOIUrl":"10.1016/j.ymgme.2025.109235","url":null,"abstract":"<div><h3>Purpose</h3><div>This study explores the psychosocial impact of a positive newborn screen (NBS) result for four lysosomal storage disorders (LSDs) (Fabry disease, Krabbe disease, Mucopolysaccharidosis Type I, Pompe disease) across confirmatory results.</div></div><div><h3>Methods</h3><div>Parents whose child who had a positive NBS for one of the included LSDs were recruited for a retrospective cohort (<em>n</em> = 80) or prospective, longitudinal cohorts (<em>n</em> = 50). Surveys assessed uncertainty, anxiety, intrusive or avoidant thoughts, and perceived vulnerability of their child's health. In-depth interviews explored the NBS experience and psychosocial response.</div></div><div><h3>Results</h3><div>Participants experienced uncertainty and anxiety during confirmatory testing that improved as parents received more information. Retrospective cohort surveys showed ongoing levels of anxiety and perceived vulnerability in parents of children with carrier or pseudodeficiency results closer to those with true positive or inconclusive results than to false positives of undetermined cause. Interviews indicated some parents across cohorts and confirmatory results held uncertainty about their child's health, frequent thoughts about NBS, and vulnerable views of their child.</div></div><div><h3>Conclusion</h3><div>This mixed-methods study provides evidence that NBS for LSDs may be associated with extended psychosocial impacts for some families, even if their child does not have an LSD. Lower false positive rates and additional counseling may limit the burden.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 3","pages":"Article 109235"},"PeriodicalIF":3.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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