Molecular Genetics and Metabolism Reports最新文献

Clinical expert opinion on the role of elosulfase alfa in non-ambulatory individuals with Morquio A syndrome 临床专家意见在非流动个体Morquio A综合征中的作用

IF 1.9 4区医学 Q3 GENETICS & HEREDITY

Molecular Genetics and Metabolism Reports

Pub Date : 2026-01-21 DOI: 10.1016/j.ymgmr.2026.101290

Carolina F.M. de Souza , Barbara K. Burton , Philippe M. Campeau , Roberto Giugliani , Nathalie Guffon , Christina Lampe , Nicole Muschol , Serap Sivri , Martha Solano , Karolina M. Stepien

Background

Morquio A syndrome is associated with progressive loss of ambulatory capacity. The impact of elosulfase alfa enzyme replacement therapy (ERT), the approved treatment for Morquio A, remains understudied in non-ambulatory patients.

Methods

A modified Delphi study explored international expert opinions on drivers for using elosulfase alfa in non-ambulatory patients, potential treatment benefits in this population, and strategies for monitoring treatment impact. The study consisted of an initial exploratory virtual advisory board, anonymous voting on statements, and a survey to collect additional information.

Results

Ten physicians with expertise in managing patients with Morquio A participated in the study. The experts reached ≥70% agreement on 14 statements; nine statements achieved 100% agreement. They agreed that mobility should not drive decisions to initiate, continue or discontinue treatment. ERT should be considered or continued as long as the benefits outweigh the burden of treatment. The decision to discontinue ERT should be based on clinician and patient/family consensus considering clinical status, health-related quality of life, and treatment burden. Clinical experience suggests that patients who cannot complete the 6MWT can still benefit from ERT. In these patients, treatment success may be measured using assessments of pulmonary function, hand dexterity, general functionality and pain, patient-reported symptoms, and quality of life assessments.

Conclusions

This explorative study offers valuable insights into drivers of ERT use in non-ambulatory patients with Morquio A, its potential benefits, and strategies for monitoring treatment outcomes in clinical practice. These findings may guide patient management, optimize treatment, and inform future research for this population.

背景：morquio A综合征与进行性活动能力丧失有关。经批准的Morquio A的治疗方法埃洛硫酶- α - α酶替代疗法（ERT）对非门诊患者的影响仍未得到充分研究。方法一项修正的德尔菲研究探讨了国际专家对非门诊患者使用埃洛硫酶的驱动因素、该人群的潜在治疗益处以及监测治疗效果的策略的意见。这项研究包括一个初步的探索性虚拟咨询委员会，对陈述进行匿名投票，以及收集额外信息的调查。结果10名具有管理Morquio A患者专业知识的医生参与了研究。专家对14项意见的一致度≥70%；9项声明100%一致。他们一致认为，流动性不应影响开始、继续或停止治疗的决定。只要ERT的益处大于治疗负担，就应考虑或继续ERT。停止ERT的决定应基于临床医生和患者/家属的共识，考虑临床状况、健康相关的生活质量和治疗负担。临床经验表明，不能完成6MWT的患者仍然可以从ERT中获益。在这些患者中，治疗成功可以通过评估肺功能、手灵活性、一般功能和疼痛、患者报告的症状和生活质量评估来衡量。结论：这项探索性研究为Morquio A非门诊患者使用ERT的驱动因素、其潜在益处以及临床实践中监测治疗结果的策略提供了有价值的见解。这些发现可以指导患者管理，优化治疗，并为该人群的未来研究提供信息。

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引用次数: 0

Congenital disorder of deglycosylation 2. Report of a novel MAN2C1 pathogenic variant and additional phenotypic implications 先天性去糖基化障碍2。一个新的MAN2C1致病变异和额外的表型意义的报告

IF 1.9 4区医学 Q3 GENETICS & HEREDITY

Molecular Genetics and Metabolism Reports

Pub Date : 2026-01-18 DOI: 10.1016/j.ymgmr.2026.101289

Rafael Luis Aguirre-Guillen , Luis Ángel Arredondo-Navarro , María Fernanda Hernández-Rodríguez , Martín-De La Torre Eduardo , Contreras Peregrina María del Rosario , Mayra Alejandra Arce-Lozoya , Estefanía Ochoa-Padilla , Víctor Ulises Rodríguez-Machuca

The MAN2C1 gene encodes an enzyme with alpha-mannosidase 2C1 activity, which is responsible for the degradation of defective glycoproteins in the cytoplasm. The purpose of this report is to present a novel MAN2C1 pathogenic variant in a patient with a congenital disorder of deglycosylation 2. We describe a case with 15q24.1q24.3 microdeletion syndrome which also presented a deleterious variant in the MAN2C1 gene located at the opposite allele. We discussed the phenotypic consequences when MAN2C1 gene transcript is missing.

MAN2C1基因编码一种具有α -甘露糖苷酶2C1活性的酶，该酶负责细胞质中缺陷糖蛋白的降解。本报告的目的是在患有先天性去糖基化2疾病的患者中提出一种新的MAN2C1致病变异。我们描述了一个15q24.1q24.3微缺失综合征的病例，该病例在位于相反等位基因的MAN2C1基因中也出现了有害变异。我们讨论了MAN2C1基因转录物缺失时的表型后果。

引用次数: 0

Branched-chain amino acid transferase 2 (BCAT2) deficiency: A case series and systematic review 支链氨基酸转移酶2 （BCAT2）缺乏：一个案例系列和系统回顾

IF 1.9 4区医学 Q3 GENETICS & HEREDITY

Molecular Genetics and Metabolism Reports

Pub Date : 2026-01-17 DOI: 10.1016/j.ymgmr.2026.101291

Maja Filipic , Ziga Iztok Remec , Ana Drole Torkar , Nataša Sustar , Vanja Cuk , Chiara Rodaro , Maruša Debeljak , Matej Mlinaric , Jaka Sikonja , Vesna Bancic Silva , Primoz Kotnik , Tadej Battelino , Mojca Zerjav Tansek , Urh Groselj , Barbka Repic Lampret

Background

Branched-chain amino acid transaminase 2 (BCAT2) deficiency is an autosomal recessive disorder that impairs branched-chain amino acid (BCAA) catabolism. Its clinical and metabolic features remain poorly understood due to limited reports in the literature.

Methods

We report three novel cases of BCAT2 deficiency from Slovenia: one diagnosed following symptom onset, one through cascade screening of parents, and one by newborn screening. Diagnosis was established through metabolic evaluation and confirmation of pathogenic variants in the BCAT2 gene. In addition, we performed a systematic review of all previously reported cases of BCAT2 deficiency.

Results

All three patients were homozygous for the NM_001190.4:c.600C > A (p.Tyr200Ter) variant, with valine concentrations at presentation of 2093, 2589, and 794 μmol/L. Only one patient was symptomatic, presenting with headaches, developmental delay, and intellectual disability, while the remaining two were largely asymptomatic. Notably, insulin resistance was observed in one of the three patients and may be associated with elevated BCAA levels. Systematic literature review identified 8 additional cases of BCAT2 deficiency. Genetic variant c.600C > A was also found in two Pakistani individuals, while the remaining variants were each reported in only a single individual. The most common clinical characteristics were intellectual disability (55%), developmental delay and other neurological symptoms (36%). Abnormal white matter findings on MRI were observed in all patients who underwent imaging. BCAA levels decreased in all patients receiving pyridoxine supplementation; however, only 50% showed clinical improvement.

Conclusion

BCAT2 deficiency displays marked interindividual heterogeneity, ranging from asymptomatic cases to severe neurological impairment, which renders its pathogenicity uncertain.

支链氨基酸转氨酶2 （BCAT2）缺乏症是一种常染色体隐性遗传病，损害支链氨基酸（BCAA）分解代谢。由于文献报道有限，其临床和代谢特征仍然知之甚少。方法我们报告了来自斯洛文尼亚的3例BCAT2缺乏症：1例在症状出现后诊断，1例通过父母级联筛查，1例通过新生儿筛查。通过代谢评估和确认BCAT2基因的致病变异来确定诊断。此外，我们对所有先前报告的BCAT2缺乏症病例进行了系统回顾。结果3例患者均为NM_001190.4:c纯合子。600C > A （p.t y200ter）变异，缬氨酸浓度分别为2093、2589和794 μmol/L。只有一名患者出现症状，表现为头痛、发育迟缓和智力残疾，而其余两名患者基本上没有症状。值得注意的是，三名患者中有一人出现胰岛素抵抗，这可能与BCAA水平升高有关。系统文献回顾确定了另外8例BCAT2缺乏症。遗传变异c.600C >； A也在两个巴基斯坦个体中被发现，而其余的变异仅在一个个体中被报道。最常见的临床特征是智力障碍（55%）、发育迟缓和其他神经系统症状（36%）。所有接受影像学检查的患者在MRI上均发现异常白质。补充吡哆醇的所有患者BCAA水平均下降；然而，只有50%的患者表现出临床改善。结论bcat2缺乏具有明显的个体间异质性，从无症状病例到严重神经功能障碍，其致病性不确定。

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引用次数: 0

Unveiling alpha-mannosidosis in Iraqi children: A series of clinically and genetically characterized cases with novel MAN2B1 variant 揭示伊拉克儿童α -甘露甘露病：一系列具有新型MAN2B1变异的临床和遗传特征的病例

IF 1.9 4区医学 Q3 GENETICS & HEREDITY

Molecular Genetics and Metabolism Reports

Pub Date : 2026-01-09 DOI: 10.1016/j.ymgmr.2025.101282

Mays Riyadh Al Tai , Nebal Waill Saadi , Marwa Sabah Alothman , Ikhlas Ali Ahmed , Hala Sameh Arif , Saja Baheer Abdulwahhab

Background

Alpha-mannosidosis is a rare lysosomal storage disorder caused by MAN2B1 mutations, leading to cognitive decline, hearing loss, infections, and skeletal abnormalities. Limited data exist from the Middle East; this study describes the clinical and genetic features of affected Iraqi children.

Patients and methods

This study was conducted at Children Welfare Teaching Hospital, and Al Emamayn Al Khadimiyan Medical City Baghdad, Iraq. We retrospectively reviewed children diagnosed with alpha-mannosidosis (2017–2025). Diagnosis was confirmed by enzyme assay and MAN2B1 testing. Clinical and imaging data were collected from medical records.

Results

A total of nine children from five unrelated families were identified. The cohort included seven males and two females. The mean age at symptoms onset was 1.1 ± 0.5 years, while the mean age at diagnosis was 10.7 ± 7.6 years, indicating a diagnostic delay of approximately 9.6 ± 7.4 years. All the patients were born to consanguineous parents. The most common clinical features included psychomotor delay, sensorineural hearing loss and coarse facial features (100 % for each). Neuroimaging of the brain revealed variable findings, and skeletal radiographs showed dysostosis multiplex in 4/9 patients. Genetic testing revealed three pathogenic/likely pathogenic MAN2B1 variants, including one novel variant [c.830C > T (p.Pro277Leu)].

Conclusion

Our findings represent the first clinical and molecular characterization of alpha-mannosidosis in Iraqi children and reveal previously unreported genetic features in this population. It highlights that clinical and laboratory findings in our patients were largely consistent with previously published regional and international data. It demonstrates notable diagnostic delay and identified novel variants, expanding the mutational spectrum associated with the disease.

甘露甘露病是一种罕见的由MAN2B1突变引起的溶酶体贮积疾病，可导致认知能力下降、听力丧失、感染和骨骼异常。来自中东的数据有限；这项研究描述了受影响的伊拉克儿童的临床和遗传特征。患者和方法本研究在伊拉克巴格达的儿童福利教学医院和Al Emamayn Al Khadimiyan医疗城进行。我们回顾性分析了2017-2025年诊断为α -甘露酸菌病的儿童。通过酶分析和MAN2B1检测确诊。临床和影像学资料收集自医疗记录。结果共鉴定出来自5个无血缘关系家庭的9名儿童。该队列包括7名男性和2名女性。出现症状时的平均年龄为1.1±0.5岁，而诊断时的平均年龄为10.7±7.6岁，表明诊断延迟约9.6±7.4年。所有病人的父母都是近亲。最常见的临床特征包括精神运动性延迟、感音神经性听力损失和粗糙的面部特征（每项100%）。脑神经影像学显示不同的结果，骨骼x线片显示4/9的患者多发性骨缺损。基因检测发现三种致病/可能致病的MAN2B1变异，包括一种新变异[c]。[qh] [p]；结论：我们的研究结果代表了伊拉克儿童α -甘露甘露病的第一个临床和分子特征，并揭示了该人群中以前未报道的遗传特征。它强调，我们患者的临床和实验室结果与以前发表的区域和国际数据基本一致。它显示了显著的诊断延迟和识别新的变异，扩大了与疾病相关的突变谱。

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引用次数: 0

Molecular characterization of Alkaptonuria in Brazilian patients 巴西患者尿酸钠的分子特征

IF 1.9 4区医学 Q3 GENETICS & HEREDITY

Molecular Genetics and Metabolism Reports

Pub Date : 2026-01-06 DOI: 10.1016/j.ymgmr.2025.101288

Carolina Araújo Moreno , Ruy Pires de Oliveira Sobrinho , Josep Jorente , Simone Appenzeller , Nelma Gláucia Silva Meira , Lucas Cadete Caldeira Costa , Angelina Xavier Acosta , The Brazilian Rare Genomes Project Consortium , Mara Sanches Guaragna , Carlos Eduardo Steiner

Objective

Alkaptonuria is a rare inborn error of metabolism, with few reports from Brazil and typically lacking genotype descriptions in the Brazilian population.

Methods

A retrospective study of clinical and molecular data of individuals with alkaptonuria submitted to whole genome sequencing.

Results

Five individuals from four unrelated families were enrolled, with ages ranging from 8 months to 61 years at first evaluation and currently ranging from 26 to 65 years. All presented a history of dark urine since infancy and accentuated elevation of homogentisic acid excretion in urine samples. In two consanguineous families from the State of Bahia, the c.847 A > T and c.899 T > G variants were identified in homozygous status in the HGD gene; one of the individuals also had a history of infertility and presented the homozygous c.537 + 1G > A variant in the STX2 gene. The two remaining families without consanguinity, both from the State of São Paulo, presented with a combination of the heterozygous variants c.508G > A and c.899 T > G in one individual, and deletion of exon 13 of the HGD gene in trans with the c.1007-172 A > G deep intronic variant as a possible causative variant in another patient.

Conclusions

Although small, the present series represents the first cohort of Brazilian individuals with alkaptonuria investigated by genomic sequencing, identifying a common variant (c.899 T > G) in two families and three exonic and one deep intronic variant in the HGD gene, besides a possible double diagnosis comprising infertility due to a homozygous variant of uncertain significance in the STX2 gene.

目的尿酸钠是一种罕见的先天性代谢错误，在巴西很少有报道，在巴西人群中通常缺乏基因型描述。方法采用全基因组测序方法对尿酸尿患者的临床和分子资料进行回顾性分析。结果入选的5例患者来自4个无血缘关系的家庭，首次评估时年龄为8个月~ 61岁，目前年龄为26 ~ 65岁。所有患者均表现为婴儿期以来尿色深，尿样均质酸排泄增高。在巴伊亚州的两个近亲家庭中，公元847年A >； T和c.899在HGD基因中发现了纯合状态的T >； G变异；其中1例患者有不育史，STX2基因为c.537 + 1G >； a纯合子变异。其余两个无血缘关系的家庭，均来自圣保罗州，表现出c.508G >； a和c.899的杂合变异组合在另一名患者中，c.1007-172 A >； G深内含子变异的HGD基因13外显子缺失可能是一种致病变异。结论：虽然规模很小，但本系列研究是巴西首例尿酸尿患者基因组测序研究，发现了一种常见变异（c.899）T >； G)在两个家族和HGD基因的三个外显子和一个深内含子变异，除了可能的双重诊断包括不孕不育由于STX2基因的纯合子变异的不确定意义。

{"title":"Molecular characterization of Alkaptonuria in Brazilian patients","authors":"Carolina Araújo Moreno , Ruy Pires de Oliveira Sobrinho , Josep Jorente , Simone Appenzeller , Nelma Gláucia Silva Meira , Lucas Cadete Caldeira Costa , Angelina Xavier Acosta , The Brazilian Rare Genomes Project Consortium , Mara Sanches Guaragna , Carlos Eduardo Steiner","doi":"10.1016/j.ymgmr.2025.101288","DOIUrl":"10.1016/j.ymgmr.2025.101288","url":null,"abstract":"<div><h3>Objective</h3><div>Alkaptonuria is a rare inborn error of metabolism, with few reports from Brazil and typically lacking genotype descriptions in the Brazilian population.</div></div><div><h3>Methods</h3><div>A retrospective study of clinical and molecular data of individuals with alkaptonuria submitted to whole genome sequencing.</div></div><div><h3>Results</h3><div>Five individuals from four unrelated families were enrolled, with ages ranging from 8 months to 61 years at first evaluation and currently ranging from 26 to 65 years. All presented a history of dark urine since infancy and accentuated elevation of homogentisic acid excretion in urine samples. In two consanguineous families from the State of Bahia, the c.847 A > T and c.899 T > G variants were identified in homozygous status in the <em>HGD</em> gene; one of the individuals also had a history of infertility and presented the homozygous c.537 + 1G > A variant in the <em>STX2</em> gene. The two remaining families without consanguinity, both from the State of São Paulo, presented with a combination of the heterozygous variants c.508G > A and c.899 T > G in one individual, and deletion of exon 13 of the <em>HGD</em> gene in trans with the c.1007-172 A > G deep intronic variant as a possible causative variant in another patient.</div></div><div><h3>Conclusions</h3><div>Although small, the present series represents the first cohort of Brazilian individuals with alkaptonuria investigated by genomic sequencing, identifying a common variant (c.899 T > G) in two families and three exonic and one deep intronic variant in the <em>HGD</em> gene, besides a possible double diagnosis comprising infertility due to a homozygous variant of uncertain significance in the <em>STX2</em> gene.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"46 ","pages":"Article 101288"},"PeriodicalIF":1.9,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897978","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}

引用次数: 0

Identification of Multiple Sulfatase Deficiency (MSD) in newborn screening: A case study 在新生儿筛查中识别多重磺胺脂酶缺乏症（MSD）：一个案例研究

IF 1.9 4区医学 Q3 GENETICS & HEREDITY

Molecular Genetics and Metabolism Reports

Pub Date : 2026-01-06 DOI: 10.1016/j.ymgmr.2025.101285

Taraka R. Donti, James C. DiPerna, Madhuri R. Hegde, Revvity Omics, Inc

A patient with multiple sulfatase deficiency (MSD) was identified through a lysosomal storage disorder enzyme analysis panel, based on a characteristic pattern of reduced activities across multiple sulfatases. Newborn screening laboratories implement various quality control protocols to assess the integrity of received samples. The quality control policy for identifying heat-denatured samples evaluates several enzyme activity levels to determine if a sample has been compromised by excessive heat. A new quality control policy has been established to differentiate heat-denatured samples from those affected by Multiple Sulfatase Deficiency.

通过溶酶体储存障碍酶分析小组，根据多种硫酸酯酶活性降低的特征模式，确定了多发性硫酸酯酶缺乏症（MSD）患者。新生儿筛查实验室实施各种质量控制方案，以评估收到的样本的完整性。鉴定热变性样品的质量控制政策评估几种酶活性水平，以确定样品是否因过热而受损。建立了一种新的质量控制政策，以区分热变性样品和多种硫酸盐酶缺乏症样品。

引用次数: 0

Biochemical characterization of the FH variant p.Lys414Glu reveals loss of enzymatic function and disrupted multimerization FH变体p.Lys414Glu的生化特性揭示了酶功能的丧失和多聚性的破坏

IF 1.9 4区医学 Q3 GENETICS & HEREDITY

Molecular Genetics and Metabolism Reports

Pub Date : 2026-01-06 DOI: 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.

富马酸水合酶（FH）的不确定意义变异（VUS）使遗传性平滑肌瘤病和肾细胞癌（HLRCC）的诊断复杂化。FH VUS p.Lys414Glu在具有HLRCC特征的患者中有报道，但需要额外的证据来支持对致病性的解释。本研究显示p.Lys414Glu完全失活，支持病原分类，并为种系FH p.Lys414Glu患者的临床护理和监测提供关键证据。

引用次数: 0

First reported case of adult-onset very long-chain acyl-coa dehydrogenase (vlcad) deficiency in Vietnam: a rare metabolic myopathy 越南首次报道成人发病的甚长链酰基辅酶a脱氢酶（vlcad）缺乏症：一种罕见的代谢性肌病

IF 1.9 4区医学 Q3 GENETICS & HEREDITY

Molecular Genetics and Metabolism Reports

Pub Date : 2026-01-06 DOI: 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。

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引用次数: 0

Full recovery of vision following early and intensive hemodialysis in an 18-year-old woman with methylmalonic acidemia-related optic neuropathy 18岁女性甲基丙二酸血症相关视神经病变患者早期强化血液透析后视力完全恢复

IF 1.9 4区医学 Q3 GENETICS & HEREDITY

Molecular Genetics and Metabolism Reports

Pub Date : 2025-12-01 DOI: 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.

甲基丙二酸血症（MMA）是由线粒体酶甲基丙二酰辅酶a（分别为mut0或mut-酶亚型）的完全或部分缺乏引起的，可导致有毒有机酸的积累，导致严重的器官功能障碍和危及生命的并发症。尽管有适当的治疗，视神经病变已被报道为MMA的视力威胁并发症，通常导致衰弱的后遗症。病例报告：我们报告一例18岁女性孤立性MMA伴慢性肾脏疾病3期，表现为双眼远近视力迅速下降。Goldmann视野检查显示双侧中央相对暗斑，周围视力保留。尽管视网膜成像正常，但两只眼睛的视觉诱发电位未结构化，表明视神经病变。代谢测试显示血浆和尿液中甲基丙二酸水平升高，血浆和脑脊液中乳酸水平升高。基于甲基丙二酸代谢物亚急性毒性的假设，开始强化间歇性血液透析，迅速降低患者血浆甲基丙二酸水平。我们还口服辅酶Q10和维生素e。通过这种治疗，患者的视力迅速恢复，视力功能在5个月后恢复正常。在肝/肾联合移植手术后的8年随访中，视神经病变未发生进展。结论视神经病变是孤立性MMA的一种罕见的长期并发症，可能是由于毒性甲基丙二酸代谢物的慢性或亚急性积累。本病例报告强调了早期和强化血液透析的重要性，通过降低血液和中枢神经系统中有毒代谢物的水平来获得良好的视力结果。从长期来看，应考虑肝移植或肝肾联合移植。

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引用次数: 0

Integrating enzyme assay and molecular genetic testing for early diagnosis of infantile-onset Pompe disease: A case report 结合酶测定和分子基因检测早期诊断婴儿起病庞贝病1例

IF 1.9 4区医学 Q3 GENETICS & HEREDITY

Molecular Genetics and Metabolism Reports

Pub Date : 2025-12-01 DOI: 10.1016/j.ymgmr.2025.101283

Anuradha Sharma, Minakshi Vashist, Rohit Kaushik, Gulshan Rohilla, Sonia Narwal

Background

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.

背景：早发性庞贝病是由GAA双等位基因致病变异引起的一种严重的溶酶体贮积症，导致酸性α-葡萄糖苷酶活性不足。病例：我们报告一个6个月大的南印度男性复发性呼吸道感染，进食困难，全身性肌张力低下，和延迟运动里程碑。干血斑（DBS）酶检测结果显示酸性α-葡萄糖苷酶活性明显降低，分子检测发现GAA纯合子致病变异（c.2560C >； T; p.Arg854*）。亲本分离试验证实双亲均为杂合携带者。血清肌酸磷酸激酶为853 U/L。建议进行心脏评估，但在最初评估时未完成。结论本病例强调了整合酶和分子检测对婴幼儿起病庞贝病的诊断价值。虽然在一些地区存在新生儿庞贝病筛查，但并未普遍实施，导致诊断延误。早期识别允许适当的咨询和考虑可用的管理途径。主要临床信息：在出现张力低下、反复呼吸道感染、喂养困难和运动发育迟缓的婴儿中，应考虑婴儿期起病的庞贝病。将干血斑酶测定与GAA基因的确证性分子检测相结合，即使在酶替代治疗有限的情况下，也能及时诊断，提供咨询，指导管理。

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引用次数: 0