Molecular Genetics and Metabolism Reports最新文献_第10页

Genetic variations in the IDUA gene in Tunisian MPS I families: Identification of a novel microdeletion disrupting substrate binding and structural insights 突尼斯MPS I家族中IDUA基因的遗传变异：鉴定一种新的微缺失破坏底物结合和结构见解

IF 1.8 4区医学 Q3 GENETICS & HEREDITY

Molecular Genetics and Metabolism Reports

Pub Date : 2025-04-19 DOI: 10.1016/j.ymgmr.2025.101222

Mariem Rebai , Yessine Amri , Chaima Sahli , Hajer Foddha , Taieb Messaoud , Hela Boudabous , Hassen Ben Abdennebi , Salima Ferchichi , Latifa Chkioua

Background

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by a deficiency in alpha-L-iduronidase (IDUA), leading to the accumulation of glycosaminoglycans. MPS I presents with a broad spectrum of clinical phenotypes, ranging from severe to mild. This study aimed to identify genetic mutations in the IDUA gene among Tunisian families and assess their structural and functional implications.

Patients and methods

Genomic DNA was extracted from blood samples of four patients including two siblings from three Tunisian families. Polymerase chain reaction (PCR) followed by Sanger sequencing was performed to identify mutations in the IDUA gene. Bioinformatics tools, including the SWISS-MODEL server and DynaMut, were used for structural modeling and to predict the impact of the mutations on protein stability and flexibility.

Results

Two mutations in the IDUA gene were identified. A novel deletion mutation p.His356_Gln362del was discovered in two patients with severe MPS I phenotypes, while a previously reported missense mutation p.Pro533Arg was found in two patients with intermediate and mild phenotypes. Structural analysis revealed that the novel deletion disrupts the protein's substrate-binding site. This deletion causes structural deformation and leads to the elimination of the substrate binding site, resulting in a complete loss of enzymatic activity.

The missense mutation p.Pro533Arg affects the stability and flexibility of the protein, likely reducing substrate affinity. This substitution results in the introduction of a bulkier amino acid, requiring more space in the contact region between the β-sheet structure and the substrate-bound helix.

Conclusion

This study reports a novel deletion mutation in the IDUA gene in Tunisian MPS I patients, alongside a previously described mutation. The findings enhance understanding of the molecular basis of MPS I and provide insights into the structural effects of these mutations, which could aid in future diagnosis and therapeutic strategies. Future studies should explore the prevalence of the reported mutations in larger cohorts and investigate targeted therapies, such as pharmacological chaperones, to rescue enzymatic activity in patients carrying such mutations.

粘多糖病I型（MPS I）是由α - l -伊杜糖醛酸酶（IDUA）缺乏引起的溶酶体储存障碍，导致糖胺聚糖的积累。MPS I表现为广泛的临床表型，范围从严重到轻度。本研究旨在鉴定突尼斯家庭中IDUA基因的基因突变，并评估其结构和功能意义。患者和方法从四个患者的血液样本中提取基因组DNA，其中包括来自三个突尼斯家庭的两个兄弟姐妹。采用聚合酶链反应（PCR）和Sanger测序鉴定IDUA基因突变。使用生物信息学工具（包括SWISS-MODEL server和DynaMut）进行结构建模，并预测突变对蛋白质稳定性和灵活性的影响。结果鉴定出2个IDUA基因突变。在两名严重MPS I型患者中发现了一种新的缺失突变p.His356_Gln362del，而在两名中度和轻度表型患者中发现了先前报道的错义突变p.p pro533arg。结构分析显示，新的缺失破坏了蛋白质的底物结合位点。这种缺失导致结构变形，并导致底物结合位点的消除，导致酶活性完全丧失。错义突变p.p pro533arg影响蛋白质的稳定性和灵活性，可能降低底物亲和力。这种取代导致引入更大的氨基酸，在β-片结构和底物结合螺旋之间的接触区域需要更多的空间。本研究报告了突尼斯MPS I患者中IDUA基因的一种新的缺失突变，以及先前描述的突变。这些发现增强了对MPS I的分子基础的理解，并为这些突变的结构效应提供了见解，这可能有助于未来的诊断和治疗策略。未来的研究应该在更大的队列中探索已报道的突变的患病率，并研究靶向治疗，如药物伴侣，以挽救携带此类突变的患者的酶活性。

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引用次数: 0

Expert review in diagnostic, therapeutic and follow-up of Fabry disease in Latin America based on patient care standards 根据病人护理标准对拉丁美洲法布里病的诊断、治疗和随访进行专家审查

IF 1.8 4区医学 Q3 GENETICS & HEREDITY

Molecular Genetics and Metabolism Reports

Pub Date : 2025-04-16 DOI: 10.1016/j.ymgmr.2025.101218

Roberto Giugliani , Juan Politei , Ana Martins , Nelson Murillo , Paula Rozenfeld , Mauricio Lopera , Sergio Salgado , Gustavo Quirós , Charles Marques , Osvaldo Vieira , Hernán Amartino , Fernando Perretta , Sandra Marques e Silva , Joseph Brooks , Laura Titievsky , Jacobo Villalobos , Cassiano Braga , Harris A. Peñaranda

Background

Fabry disease (FD) is an X-linked lysosomal sphingolipidosis. It is caused by pathogenic variants in the GLA gene with a consequent deficiency of the enzyme α-galactosidase A, resulting in the pathological accumulation of glycolipids - mainly globotriosyl ceramide (GL-3, GB3) and its deacylated product, globotriaosylsphingosine (Lyso-Gb-3) - in plasma and in a wide variety of cell types throughout the human body; it is characterized as a chronic, multisystemic disease with progressive evolution, which causes deterioration of the patient's quality of life and decreases survival and life expectancy.

In Latin America there are different limitations to the management of patients with Fabry disease, in most countries, access to diagnostic tools and treatment on time is complex and can sometimes suffer delays in its implementation. This situation is due to the high costs to health systems of follow-up and pharmacological therapy for Fabry patients, creating barriers to timely access.

Conclusions

Although medical criteria are fundamental in the choice of pharmacological therapy, the final decision should also rely on the patient's choice according to their expectations and the adherence and compliance with the treatment that they are willing to follow. As it has been described, there are currently three therapeutic options, for which the appropriate profile must be defined to achieve the best clinical outcomes, considering that it is a permanent treatment; experts consider that Fabry patients need comprehensive and interdisciplinary management to stop the progression and functional deterioration of the affected organs by its multiple systemic manifestations. In Latin-American countries, it is difficult to guarantee this comprehensive and coordinated management, due to limited public policies related to orphan diseases diagnosis, treatment and follow up.

It is considered crucial to structure support networks specialized in Fabry disease and generate partnerships with health institutions and other health system stakeholders, that would articulate and coordinate patients and relatives counseling and management, establish the specific pharmacological treatment to reduce the progression of the disease and the systemic involvement, deciding between the administration of enzyme replacement therapy or the most recent option of oral management with pharmacological chaperone both with proven effectiveness. This will be the decision of the attending physician, who will propose and advise the therapeutic choice that best suits the patient's needs.

背景法布里病（FD）是一种x连锁溶酶体鞘脂病。它是由GLA基因的致病性变异引起的，随之而来的α-半乳糖苷酶a的缺乏，导致糖脂的病理性积累，主要是globotrioyl神经酰胺（GL-3, GB3）及其脱酰基产物globotriosylsphingosine (Lyso-Gb-3)，在血浆和整个人体的各种细胞类型中；它的特点是一种进行性发展的慢性多系统疾病，可导致患者生活质量恶化，降低生存率和预期寿命。在拉丁美洲，对法布里病患者的管理存在不同的限制，在大多数国家，及时获得诊断工具和治疗是复杂的，有时在执行过程中可能会出现延误。这种情况是由于卫生系统对Fabry患者的随访和药物治疗费用高昂，造成了及时获得的障碍。结论医学标准是选择药物治疗的基础，但最终的决定还应取决于患者根据自己的期望和对治疗的依从性和依从性的选择。如前所述，目前有三种治疗方案，考虑到它是一种永久性治疗，必须确定适当的方案以达到最佳临床结果；专家认为Fabry患者由于其多系统表现，需要综合、跨学科的治疗，以阻止受累器官的进展和功能退化。在拉丁美洲国家，由于孤儿病的诊断、治疗和随访方面的公共政策有限，很难保证这种全面和协调的管理。构建专门针对法布里病的支持网络并与卫生机构和其他卫生系统利益相关者建立伙伴关系被认为是至关重要的，这将阐明和协调患者和亲属的咨询和管理，建立特定的药物治疗以减少疾病的进展和全身参与。决定是使用酶替代疗法还是最近选择口服药物伴侣治疗，两者都证明有效。这将是主治医生的决定，他将提出并建议最适合患者需要的治疗选择。

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引用次数: 0

Five years of newborn screening for Pompe, Mucopolysaccharidosis type I, Gaucher, and Fabry diseases in Oregon 俄勒冈州开展庞贝氏症、I 型粘多糖病、戈谢病和法布里病新生儿筛查五年来的情况

IF 1.8 4区医学 Q3 GENETICS & HEREDITY

Molecular Genetics and Metabolism Reports

Pub Date : 2025-04-15 DOI: 10.1016/j.ymgmr.2025.101221

Sarah Viall , Patrice Held

In October 2018, the Oregon newborn screening program began screening for four lysosomal storage disorders (LSDs) Pompe, Mucopolysaccharidosis Type I (MPSI), Gaucher, and Fabry. The laboratory used two different methodologies, digital microfluidics and tandem mass spectrometry, to measure the four LSD enzyme activities. Accuracy and precision were improved and lower false positive rates were observed with use of the Revvity NeoLSD assay on the mass spectrometry platform, as compared to the Baebies digital microfluidics method. All newborn specimens with screen positive results were reflexed to a second-tier molecular assay to identify variants in the target gene. Over the first five years of screening, 139 cases were referred for confirmatory testing and clinical evaluation due to presence of pathogenic/likely pathogenic variant(s)or variant(s) of unknown significance. These identified newborns were evaluated at the Oregon Health & Science University (OHSU) metabolic clinic in Portland, Oregon. However, due to the COVID-19 pandemic, clinicians had to pivot from in-person to virtual visits and triage on acuity, which impacted the time to diagnosis. Of referred babies, 3 are currently receiving treatment for their detected LSD. Over 50 babies have an inconclusive or possible late onset diagnosis with uncertain timeline for development of symptoms.

2018年10月，俄勒冈州新生儿筛查项目开始筛查四种溶酶体贮积症（LSDs）， Pompe，粘多糖病I型（MPSI）， Gaucher和Fabry。该实验室使用了两种不同的方法，数字微流体和串联质谱法，来测量四种LSD酶的活性。与Baebies数字微流体法相比，在质谱平台上使用Revvity NeoLSD法可以提高准确性和精密度，并且观察到更低的假阳性率。所有筛查结果呈阳性的新生儿标本都被反射到二级分子测定中，以确定目标基因的变异。在筛查的前5年，由于存在致病性/可能致病性变异或意义未知的变异，139例患者被转诊进行确认性检测和临床评估。这些被确认的新生儿在俄勒冈州健康&；俄勒冈州波特兰市科学大学（OHSU）代谢诊所。然而，由于COVID-19大流行，临床医生不得不从亲自就诊转向虚拟就诊，并根据视力进行分诊，这影响了诊断时间。在转介的婴儿中，有3名目前正在接受检测出的致幻剂治疗。超过50名婴儿有不确定的或可能的晚发性诊断，症状发展时间表不确定。

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引用次数: 0

Bilateral avascular necrosis: A rare complication of Fabry disease 双侧无血管坏死：法布里病的罕见并发症

IF 1.8 4区医学 Q3 GENETICS & HEREDITY

Molecular Genetics and Metabolism Reports

Pub Date : 2025-04-12 DOI: 10.1016/j.ymgmr.2025.101219

Candela Romano , Joel Wells , Nicholas Stanzione , Virginia Kimonis

Fabry disease is a rare X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene, which encodes for the α–galactosidase A enzyme responsible for degrading globotriaosylceramide. Its deficiency leads to the accumulation of GL3 in lysosomes, resulting in progressive multi-organ involvement, with predilection for the heart and kidneys.

Clinical features associated with Fabry disease include acroparesthesia, angiokeratomas, hypohidrosis, corneal whorls, chronic kidney disease, cardiomyopathy, and strokes. Osteopenia and osteoporosis are less known complications, with rare reported cases of avascular necrosis of the hips.

We report bilateral avascular necrosis in a 40-year-old-man diagnosed with Fabry at the age of 25 years. He carriers the familiar p.G328V GLA pathogenic variant. His Fabry features includes acroparesthesia, angiokeratomas, hypohidrosis, temperature and exercise intolerance, pain crises, abdominal pain and diarrhea, tinnitus, hearing loss, hypertrophic cardiomyopathy, palpitations, and chest pain. Family history reveals Fabry disease affecting multiple maternal relatives. The patient was recently diagnosed with avascular necrosis of the right hip requiring total arthroplasty due to failure of conservative treatment. Nine months later, he developed left hip pain attributed to avascular necrosis, also treated with total arthroplasty.

This case highlights a rare skeletal complication of Fabry disease, underscoring the need for early diagnosis, optimizing treatment of Fabry disease, managing atypical comorbidities, and vigilant monitoring of bone health.

法布里病是一种罕见的 X 连锁溶酶体贮积症，由 GLA 基因的致病变体引起，该基因编码负责降解球糖基甘油酰胺的 α-半乳糖苷酶 A。法布里病的临床特征包括尖锐湿疣、血管角化瘤、多汗症、角膜轮纹、慢性肾病、心肌病和中风。骨质疏松和骨质疏松症是较少为人所知的并发症，髋关节血管性坏死的病例也鲜有报道。我们报告了一名 40 岁的男性患者的双侧髋关节血管性坏死病例，他在 25 岁时被诊断为法布里病。我们报告了一名 40 岁的法布里患者的双侧髋关节血管性坏死病例。他的法布里病特征包括尖锐湿疣、血管角化瘤、多汗症、体温和运动不耐受、疼痛危机、腹痛和腹泻、耳鸣、听力损失、肥厚性心肌病、心悸和胸痛。家族史显示，患者的多个母系亲属患有法布里病。患者最近被诊断为右髋关节血管性坏死，由于保守治疗无效，需要进行全关节置换术。九个月后，他出现了左髋关节疼痛，归因于血管性坏死，也接受了全关节成形术治疗。本病例突出了法布里病罕见的骨骼并发症，强调了早期诊断、优化法布里病治疗、管理非典型合并症和警惕监测骨骼健康的必要性。

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引用次数: 0

A study of Iraqi patients with homocysteine remethylation disorders in a tertiary pediatric centre 伊拉克同型半胱氨酸再甲基化障碍患者在三级儿科中心的研究

IF 1.8 4区医学 Q3 GENETICS & HEREDITY

Molecular Genetics and Metabolism Reports

Pub Date : 2025-04-11 DOI: 10.1016/j.ymgmr.2025.101217

Mays R. Al-Tai , Adel A. Kareem , Nebal W. Saadi , Tawfig Ben Omran , Ban A. Abdul Majeed , Ibrahim F. Ibrahim , Lamia A. Alattar

Background

Hyperhomocysteinemia is a group of inherited homocysteine metabolism disorders characterised by elevated blood homocysteine levels (total homocysteine >15 μM). Homocystinuria is classified into two main homocysteine metabolism disorders. Classical Homocystinuria is caused by a deficiency of the pyridoxine-dependent enzyme cystathionine beta-synthase in the trans‑sulfuration pathway. Non-classical Homocystinuria is a group of disorders affecting the interconversion of methionine to homocysteine through the re-methylation pathway.

Aim

This study aims to describe the clinical, biochemical, and genetic profiles of patients with re-methylation disorders.

Patients and methods

A cohort study was conducted at the metabolic clinic of Children Welfare Teaching Hospital in Baghdad from the 1st of December 2021 to the 1st of December 2022. The study included fifteen patients who met the following criteria: (1) elevated serum homocysteine levels (>15 μmol/L); (2) low or normal blood methionine levels (12–40 μmol/L). Results: fourteen MTHFR patients underwent statistical analysis, and one CblC patient was assessed separately. MTHFR patients comprised nine females and five males. The mean age at presentation was 7.1 years ±4.5, ranging from 1 to 16 years. Consanguineous marriages were reported in 13 patients. A family history of a similar disorder was documented in 73 % of cases. Among the families, four had two affected siblings. The two main reported clinical manifestations were gait disturbance (10/14, 71.4 %) and cognitive impairment/intellectual disability (6/14, 42.8 %). Brain MRI was conducted for all studied patients, with leukodystrophy being the most common finding (8/14, 57.1 %). Molecular testing revealed variants in MTHFR in 14 patients, and MMACHC in one patient.

Conclusion

According to this study, individuals with homocysteine re-methylation disorders can manifest symptomatology such as neuroregression, psychomotor delay, and whiter matter changes earlier than anticipated. And these disorders are amenable to treatment. Genetic testing is crucial in identifying the specific mutation type and guiding definitive treatment.

高同型半胱氨酸血症是一组遗传性同型半胱氨酸代谢疾病，其特征是血液中同型半胱氨酸水平升高（总同型半胱氨酸水平>；15 μM）。同型半胱氨酸尿分为两种主要的同型半胱氨酸代谢紊乱。经典的同型半胱氨酸尿是由反硫途径中吡哆醇依赖的酶-胱硫氨酸-合成酶的缺乏引起的。非经典同型半胱氨酸尿是一组通过重甲基化途径影响蛋氨酸向同型半胱氨酸相互转化的疾病。目的本研究旨在描述重甲基化障碍患者的临床、生化和遗传特征。患者与方法于2021年12月1日至2022年12月1日在巴格达儿童福利教学医院代谢门诊进行队列研究。本研究纳入了15例符合以下标准的患者：(1)血清同型半胱氨酸水平升高（15 μmol/L）；(2)血中蛋氨酸水平低或正常（12 ~ 40 μmol/L）。结果：14例MTHFR患者进行统计分析，1例CblC患者单独评估。MTHFR患者包括9名女性和5名男性。平均发病年龄7.1岁±4.5岁，年龄范围1 ~ 16岁。13例患者报告近亲结婚。73%的病例有类似疾病的家族史。在这些家庭中，有四个家庭有两个患病的兄弟姐妹。两种主要临床表现为步态障碍（10/14,71.4%）和认知障碍/智力障碍（6/14,42.8%）。对所有研究的患者进行脑MRI检查，最常见的发现是脑白质营养不良（8/14,57.1%）。分子检测显示14例患者MTHFR变异，1例患者MMACHC变异。结论同型半胱氨酸再甲基化障碍患者可比预期更早出现神经退化、精神运动延迟和白质改变等症状。这些疾病是可以治疗的。基因检测在确定特定突变类型和指导最终治疗方面至关重要。

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引用次数: 0

Cardiac manifestations in adult patients with inherited metabolic disease: A single-center experience 成年遗传性代谢性疾病患者的心脏表现：单中心研究

IF 1.8 4区医学 Q3 GENETICS & HEREDITY

Molecular Genetics and Metabolism Reports

Pub Date : 2025-04-11 DOI: 10.1016/j.ymgmr.2025.101216

Flutura Sadiku , Tobias Rutz , Andrea Superti-Furga , Pierre Monney , Christel Tran

Background

Inherited metabolic diseases (IMDs) can affect the heart, but data on cardiac manifestations in adults are scarce. This study examines the clinical and radiological features of cardiac complications in adults with IMDs.

Methods

This retrospective study included adult patients at our metabolic clinic with a biochemical and/or genetic diagnosis of IMD who underwent cardiac investigations. Records were reviewed for clinical features, echocardiograms, electrocardiograms, and treatment. Patients were categorized into three IMD subgroups: disorders of small molecules, complex molecules, and energy production.

Results

Of the 115 adult patients with IMD, 48 underwent cardiac testing (mean age 39.1 ± 14.8 years). Abnormal cardiac findings were reported in 23 of these patients (47.9 %, 14 men). Five (21.7 %) were symptomatic with dyspnea, peripheral edema, or chest pain. Fourteen patients (60.9 %) had heart muscle disease, 6 (26.1 %) had valvular involvement, and 5 (21.7 %) had arrhythmia. Valvular and heart muscle disease predominated in complex and small molecule disorders (3/4 and 7/9 respectively). Energy production disorders showed mixed involvement: heart muscle disease (5/10) and arrhythmia (5/10). Twelve of the 23 patients with abnormal findings (52.2 %) received specific cardiac therapy. All but one patient remained stable under treatment.

Discussion

In this cohort, cardiac disease was diagnosed in 23 of 115 adults with IMD (20 %), including structural heart defects and arrhythmia. The pattern and severity of cardiac involvement varied between disorders, with arrhythmia mainly associated with energy production disorders. Outcomes were favorable in most cases, likely due to collaboration between metabolic physicians and cardiologists and timely follow-up and treatment.

背景：遗传性代谢性疾病（IMDs）可影响心脏，但关于成人心脏表现的资料很少。本研究探讨成人imd患者心脏并发症的临床和影像学特征。方法本回顾性研究纳入了在我们的代谢诊所接受心脏检查的生化和/或遗传诊断为IMD的成年患者。回顾了临床特征、超声心动图、心电图和治疗记录。患者被分为三个IMD亚组：小分子、复杂分子和能量产生障碍。结果115例成年IMD患者中，48例接受心脏检查（平均年龄39.1±14.8岁）。其中23例（47.9%，14例男性）出现心脏异常。5例（21.7%）有呼吸困难、周围水肿或胸痛症状。14例（60.9%）有心肌疾病，6例（26.1%）有瓣膜受累，5例（21.7%）有心律失常。复杂和小分子疾病以瓣膜病和心肌病为主（分别为3/4和7/9）。能量产生障碍表现为混合参与：心肌疾病（5/10）和心律失常（5/10）。23例异常患者中有12例（52.2%）接受了特异性心脏治疗。除一名患者外，其余患者在治疗过程中保持稳定。在这一队列中，115例成人IMD中有23例（20%）被诊断为心脏病，包括结构性心脏缺陷和心律失常。心脏受累的模式和严重程度因疾病而异，心律失常主要与能量产生障碍有关。结果在大多数情况下是有利的，可能是由于代谢内科医生和心脏病专家之间的合作和及时的随访和治疗。

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引用次数: 0

Disease profile in a cohort of Brazilian patients diagnosed with alpha-mannosidosis 一组巴西α-甘露糖苷酶病患者的疾病概况

IF 1.8 4区医学 Q3 GENETICS & HEREDITY

Molecular Genetics and Metabolism Reports

Pub Date : 2025-04-11 DOI: 10.1016/j.ymgmr.2025.101220

Fabiano de Oliveira Poswar , Tamires Silva Alves , Daniel Rocha de Carvalho , Hélio van der Linden Jr , Charles Marques Lourenço , Dafne Dain Gandelman Horovitz , Anneliese Barth , Carmen Silvia Curiati Mendes , Ana Maria Martins , Roberto Giugliani

Alpha-mannosidosis (AM) is an ultrarare multisystemic disorder caused by alpha-mannosidase deficiency. This is the first comprehensive report on AM in Brazil, analyzing clinical and laboratory data from 14 patients diagnosed between 2001 and 2021. We summarize the patient diagnostic journey in the country, including the most common presenting symptoms, the time from disease onset to diagnosis and discuss other disease manifestations. Our findings may improve the disease awareness and understanding in the country.

甘露糖苷病（AM）是由甘露糖苷酶缺乏引起的一种罕见的多系统疾病。这是巴西关于AM的第一份综合报告，分析了2001年至2021年期间诊断的14名患者的临床和实验室数据。我们总结了国内患者的诊断历程，包括最常见的表现症状，从发病到诊断的时间，并讨论了其他疾病表现。我们的发现可能会提高国家对疾病的认识和理解。

引用次数: 0

Two decades of experience of the Fabry Outcome Survey provides further confirmation of the long-term effectiveness of agalsidase alfa enzyme replacement therapy 法布里结果调查二十年的经验进一步证实了琼脂苷酶- α酶替代疗法的长期有效性

IF 1.8 4区医学 Q3 GENETICS & HEREDITY

Molecular Genetics and Metabolism Reports

Pub Date : 2025-04-11 DOI: 10.1016/j.ymgmr.2025.101215

Uma Ramaswami , Guillem Pintos-Morell , Christoph Kampmann , Kathleen Nicholls , Dau-Ming Niu , Ricardo Reisin , Michael L. West , Christina Anagnostopoulou , Jaco Botha , Dalia Jazukeviciene , Jörn Schenk , Derralynn A. Hughes , Roberto Giugliani

Background

Analyses of up to 20 years of data from the Fabry Outcome Survey (FOS) assessed the long-term effectiveness of agalsidase alfa enzyme replacement therapy.

Methods

The impact of agalsidase alfa treatment on renal, cardiac, morbidity, and mortality outcomes in FOS was compared with untreated external Fabry disease (FD) cohorts.

Results

A total of 2171 FOS patients (1014 men, 919 women, 163 boys, 75 girls) received agalsidase alfa (median [range] duration of treatment: 5.38 [0.0–20.8] years). Annual rates of decline in estimated glomerular filtration rate improved in treated patients versus untreated external cohorts regardless of sex or baseline urinary protein levels. Annual left ventricular mass index rates were stable in treated patients regardless of sex or baseline left ventricular hypertrophy status, and better than in untreated external cohorts. The mean age at which 50 % of patients had their first composite morbidity event was later in the agalsidase-alfa-treated population than in the untreated external cohort (51.7 vs 41 years [males]; 60.8 vs 53 years [females]). After 24 months of treatment, the probability of a composite morbidity event was ∼34 % in treated patients and ∼ 45 % in untreated patients. Treated patients were older at death than untreated patients (mean [range]: 61.7 [26.2–87.6] vs 50.3 [34.5–70.1] years). The mean age at which 50 % of male patients were still alive was higher in treated patients than in untreated external cohorts (75.5 vs 60.0 years).

Conclusions

Long-term treatment with agalsidase alfa may provide renal, cardiac, and overall survival protection in FD.

对Fabry结局调查（FOS）长达20年的数据进行分析，评估了agalsidase - alfa酶替代疗法的长期有效性。方法：与未治疗的外源性法布里病（FD）队列比较胆碱苷酶治疗对FOS患者肾脏、心脏、发病率和死亡率的影响。结果共有2171例FOS患者（男性1014例，女性919例，男孩163例，女孩75例）接受了agalsidase - α - fa治疗（中位[范围]:5.38[0.0-20.8]年）。无论性别或基线尿蛋白水平如何，与未经治疗的外部队列相比，接受治疗的患者估计肾小球滤过率的年下降率有所改善。在接受治疗的患者中，不论性别或基线左心室肥厚状态，年左心室质量指数率都是稳定的，并且优于未经治疗的外部队列。在agalsidase-alfa治疗人群中，50%的患者发生首次复合发病事件的平均年龄比未治疗的外部队列晚(51.7岁vs 41岁[男性]；60.8 vs 53岁[女性])。治疗24个月后，接受治疗的患者发生复合发病事件的概率为~ 34%，未接受治疗的患者为~ 45%。接受治疗的患者比未接受治疗的患者死亡时年龄大（平均[范围]:61.7[26.2-87.6]岁vs 50.3[34.5-70.1]岁）。在接受治疗的患者中，50%男性患者仍然存活的平均年龄高于未接受治疗的外部队列（75.5岁对60.0岁）。结论长期应用琼脂苷酶可对FD患者的肾脏、心脏和总体生存提供保护。

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引用次数: 0

Branched-chain amino acid transferase type 2 (BCAT2) deficiency: Report of an eighth case and literature review 支链氨基酸转移酶2型（BCAT2）缺乏：第8例报告及文献复习

IF 1.8 4区医学 Q3 GENETICS & HEREDITY

Molecular Genetics and Metabolism Reports

Pub Date : 2025-04-09 DOI: 10.1016/j.ymgmr.2025.101213

Etienne Mondésert , Juliette Bouchereau , Manuel Schiff , Jean-François Benoist , Guilia Barcia , Boris Keren , Inès Mannes , Clément Pontoizeau , Charlotte Mansat , Apolline Imbard

Branched-chain amino acid transferase type 2 (BCAT2) deficiency is a rare autosomal recessive genetic condition, with only seven cases described to date. It results in an elevation of branched-chain amino acid (BCAA) plasma concentrations, predominantly on valine, with normal concentration of plasma allo-isoleucine and urine branched-chain α-keto acids (BCKA). Despite this constant biochemical feature, clinical consequences remain unclear with heterogeneous and far less severe than maple syrup urine disease (MSUD) reported phenotypes, one individual being even asymptomatic.

We report herein the eighth case of genetically confirmed BCAT2 deficiency, accompanied by a literature review and a discussion about the potential pathogenicity of this condition.

An 11-year-old boy presented with a rapidly reversible initial acute neurological episode suggesting an epileptic seizure. Abnormalities on cerebral magnetic resonance imaging and suspicion of cognitive impairment led to further metabolic investigations. BCAT2 deficiency has been mentioned in front of increased BCAAs (valine = 1667 μmol/L, leucine = 701 μmol/L, isoleucine = 561 μmol/L). A homozygous novel nonsense variant on BCAT2 (c.34C > T, p.Arg12*) was found on whole exome sequencing. After oral pyridoxine supplementation (200 mg/day), a decrease in BCAA concentrations was observed (valine = 984 μmol/L, leucine = 462 μmol/L, isoleucine = 302 μmol/L).

Laboratory and imaging findings were consistent with previously reported cases. However, clinical presentation of this case was atypical and could be related with epilepsy, although no other variant on epilepsy genes have been found. The relation between BCAT2 deficiency and these clinical findings is at this stage debated with regard to phenotypic variability. Further case-studies are needed to expand the knowledge about this condition.

支链氨基酸转移酶2型（BCAT2）缺乏症是一种罕见的常染色体隐性遗传疾病，迄今为止仅报道了7例。它导致支链氨基酸（BCAA）血浆浓度升高，主要是缬氨酸，血浆异亮氨酸和尿支链α-酮酸（BCKA）浓度正常。尽管这种恒定的生化特征，临床后果仍不清楚，异质性和远不如枫糖浆尿病（MSUD）报道的表型严重，一个人甚至无症状。我们在此报告第8例遗传证实的BCAT2缺乏症，并附有文献综述和对这种情况的潜在致病性的讨论。一个11岁的男孩提出了一个快速可逆的初始急性神经发作提示癫痫发作。脑磁共振成像异常和怀疑认知障碍导致进一步的代谢调查。BCAT2缺乏症出现在BCAAs升高前（缬氨酸= 1667 μmol/L，亮氨酸= 701 μmol/L，异亮氨酸= 561 μmol/L）。BCAT2基因纯合无义新变异(c.34C >；在全外显子组测序中发现了T， p.Arg12*)。口服吡哆醇（200 mg/d）后，BCAA浓度降低（缬氨酸= 984 μmol/L，亮氨酸= 462 μmol/L，异亮氨酸= 302 μmol/L）。实验室和影像学检查结果与先前报告的病例一致。然而，该病例的临床表现不典型，可能与癫痫有关，尽管没有发现癫痫基因的其他变异。BCAT2缺乏与这些临床表现之间的关系在现阶段还存在表型变异性方面的争论。需要进一步的案例研究来扩大对这种情况的了解。

{"title":"Branched-chain amino acid transferase type 2 (BCAT2) deficiency: Report of an eighth case and literature review","authors":"Etienne Mondésert , Juliette Bouchereau , Manuel Schiff , Jean-François Benoist , Guilia Barcia , Boris Keren , Inès Mannes , Clément Pontoizeau , Charlotte Mansat , Apolline Imbard","doi":"10.1016/j.ymgmr.2025.101213","DOIUrl":"10.1016/j.ymgmr.2025.101213","url":null,"abstract":"<div><div>Branched-chain amino acid transferase type 2 (BCAT2) deficiency is a rare autosomal recessive genetic condition, with only seven cases described to date. It results in an elevation of branched-chain amino acid (BCAA) plasma concentrations, predominantly on valine, with normal concentration of plasma allo-isoleucine and urine branched-chain α-keto acids (BCKA). Despite this constant biochemical feature, clinical consequences remain unclear with heterogeneous and far less severe than maple syrup urine disease (MSUD) reported phenotypes, one individual being even asymptomatic.</div><div>We report herein the eighth case of genetically confirmed BCAT2 deficiency, accompanied by a literature review and a discussion about the potential pathogenicity of this condition.</div><div>An 11-year-old boy presented with a rapidly reversible initial acute neurological episode suggesting an epileptic seizure. Abnormalities on cerebral magnetic resonance imaging and suspicion of cognitive impairment led to further metabolic investigations. BCAT2 deficiency has been mentioned in front of increased BCAAs (valine = 1667 μmol/L, leucine = 701 μmol/L, isoleucine = 561 μmol/L). A homozygous novel nonsense variant on <em>BCAT2</em> (c.34C > T, p.Arg12*) was found on whole exome sequencing. After oral pyridoxine supplementation (200 mg/day), a decrease in BCAA concentrations was observed (valine = 984 μmol/L, leucine = 462 μmol/L, isoleucine = 302 μmol/L).</div><div>Laboratory and imaging findings were consistent with previously reported cases. However, clinical presentation of this case was atypical and could be related with epilepsy, although no other variant on epilepsy genes have been found. The relation between BCAT2 deficiency and these clinical findings is at this stage debated with regard to phenotypic variability. Further case-studies are needed to expand the knowledge about this condition.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101213"},"PeriodicalIF":1.8,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143799309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The recurrent p.Glu3Lys variant in EHHADH is responsible for Fanconi syndrome with early liver dysfunction and mitochondrial abnormalities 在EHHADH中反复出现的p.g ul3lys变异是范可尼综合征伴早期肝功能障碍和线粒体异常的原因

IF 1.8 4区医学 Q3 GENETICS & HEREDITY

Molecular Genetics and Metabolism Reports

Pub Date : 2025-04-04 DOI: 10.1016/j.ymgmr.2025.101214

P. Rollier , A. Cospain , M. Barth , V. Milon , N. Gueguen , C. Homedan , V. Desquiret , C. Bris , E. Colin , L. Damaj , A. Ryckewaert , P. Reynier , S. Odent , P. Amati-Bonneau , V. Procaccio , D. Bonneau , A. Ziegler

Background

The recurrent pathogenic variant c.7G>A p.Glu3Lys in the EHHADH gene is responsible for an autosomal dominant form of Fanconi renotubular syndrome. This variant leads to mislocalization of peroxisomal EHHADH protein to the mitochondria, thereby impairing mitochondrial function. To date, this variant has been reported in only two unrelated families, with affected individuals presenting with isolated renotubular Fanconi syndrome. No other pathogenic variant has been documented in this gene.

Methods

A boy followed from four months-old to twelve years-old underwent clinical evaluation, mitochondrial analyses and exome sequencing.

Results

The four-month-old infant boy presented with hypoglycemia, ketonuria, lactic acidosis and hepatic cytolysis. Three months later, a Fanconi tubulopathy with nephrocalcinosis appeared. Mitochondrial respiratory chain analyses performed on hepatocytes showed a decreased activity of complex I and IV of the mitochondrial respiratory chain and a quantitative decrease of these complexes. Exome sequencing revealed the missense variant c.7G>A p.Glu3Lys, inherited from his father who was asymptomatic at 54 years old. A diet supplemented in medium-chain fatty acids was experimented.

Conclusion

This case widens the phenotypic spectrum of the recurrent p.Glu3Lys variant in EHHADH, which may be responsible for Fanconi syndrome and early onset hepatic dysfunction with cytolysis and hypoglycemia. Medium-chain fatty acids supplemented diet did not improve the disease.

背景：EHHADH基因中的复发致病性变异c.7G>A . glu3lys可导致常染色体显性范可尼肾小管综合征。这种变异导致过氧化物酶体EHHADH蛋白错定位到线粒体，从而损害线粒体功能。迄今为止，仅在两个不相关的家族中报道了这种变异，受影响的个体表现为孤立性肾小管范可尼综合征。该基因未发现其他致病变异。方法对一名4个月大至12岁的男孩进行临床评估、线粒体分析和外显子组测序。结果4月龄男婴表现为低血糖、尿酮、乳酸酸中毒、肝细胞溶解。3个月后，出现范可尼肾小管病变伴肾钙质沉着症。对肝细胞进行的线粒体呼吸链分析显示，线粒体呼吸链复合体I和IV的活性降低，这些复合体的数量减少。外显子组测序显示错义变体c.7G>A p.g u3lys，遗传自他的父亲，他在54岁时无症状。试验了添加中链脂肪酸的日粮。结论本病例拓宽了EHHADH复发性p.g ul3lys变异的表型谱，该变异可能与Fanconi综合征和早发性肝功能障碍伴细胞溶解和低血糖有关。中链脂肪酸补充饮食没有改善疾病。

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引用次数: 0