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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。

{"title":"Two decades of experience of the Fabry Outcome Survey provides further confirmation of the long-term effectiveness of agalsidase alfa enzyme replacement therapy","authors":"Uma Ramaswami , Guillem Pintos-Morell , Christoph Kampmann , Kathleen Nicholls , Dau-Ming Niu , Ricardo Reisin , Michael L. West , Christina Anagnostopoulou , Jaco Botha , Dalia Jazukeviciene , Jörn Schenk , Derralynn A. Hughes , Roberto Giugliani","doi":"10.1016/j.ymgmr.2025.101215","DOIUrl":"10.1016/j.ymgmr.2025.101215","url":null,"abstract":"<div><h3>Background</h3><div>Analyses of up to 20 years of data from the Fabry Outcome Survey (FOS) assessed the long-term effectiveness of agalsidase alfa enzyme replacement therapy.</div></div><div><h3>Methods</h3><div>The impact of agalsidase alfa treatment on renal, cardiac, morbidity, and mortality outcomes in FOS was compared with untreated external Fabry disease (FD) cohorts.</div></div><div><h3>Results</h3><div>A total of 2171 FOS patients (1014 men, 919 women, 163 boys, 75 girls) received agalsidase alfa (median [range] duration of treatment: 5.38 [0.0–20.8] years). Annual rates of decline in estimated glomerular filtration rate improved in treated patients versus untreated external cohorts regardless of sex or baseline urinary protein levels. Annual left ventricular mass index rates were stable in treated patients regardless of sex or baseline left ventricular hypertrophy status, and better than in untreated external cohorts. The mean age at which 50 % of patients had their first composite morbidity event was later in the agalsidase-alfa-treated population than in the untreated external cohort (51.7 vs 41 years [males]; 60.8 vs 53 years [females]). After 24 months of treatment, the probability of a composite morbidity event was ∼34 % in treated patients and ∼ 45 % in untreated patients. Treated patients were older at death than untreated patients (mean [range]: 61.7 [26.2–87.6] vs 50.3 [34.5–70.1] years). The mean age at which 50 % of male patients were still alive was higher in treated patients than in untreated external cohorts (75.5 vs 60.0 years).</div></div><div><h3>Conclusions</h3><div>Long-term treatment with agalsidase alfa may provide renal, cardiac, and overall survival protection in FD.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101215"},"PeriodicalIF":1.8,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143817548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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。

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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

Outcome of creatine supplementation therapy in phosphoglucomutase-1 deficiency associated congenital disorders of glycosylation: Novel insights 肌酸补充治疗与磷酸葡萄糖糖化酶-1缺乏相关的先天性糖基化疾病的结果：新的见解

IF 1.8 4区医学 Q3 GENETICS & HEREDITY

Molecular Genetics and Metabolism Reports

Pub Date : 2025-04-03 DOI: 10.1016/j.ymgmr.2025.101212

Anastasia Ambrose , Morganne McCabe , Clara Hung , Iveta Sosova , Peter Seres , Saadet Mercimek-Andrews

Background

Biallelic pathogenic variants in PGM1 result in phosphoglucomutase 1 (PGM1) deficiency that is one of the congenital disorders of glycosylation (CDG) (PGM1-CDG). Phenotypic spectrum includes congenital malformations, and muscular, cardiac, hepatic, endocrine and hematologic phenotypes. Current treatment consists of D-galactose therapy that results in clinical and biochemical improvements. To improve fatigue, and exercise intolerance, we started creatine supplementation therapy.

Material and methods

We reviewed electronic patient chart. We applied Nijmegen Pediatric CDG Rating Scale (NPCRS) and The Functional Assessment of Chronic Illness Therapy Fatigue scale (FACIT-F). We measured creatine metabolism biomarkers.

Results

This is a 29-year-old female with PGM1-CDG, confirmed diagnosis by clinical exome sequencing. She has been treated with D-galactose therapy which did not improve her fatigue and exercise intolerance. She was started on creatine supplementation therapy at the age of 27 years which led to decreased daytime sleeping, increased exercise capacity and improvements in her NPCRS, and FACIT-F. Her plasma guanidinoacetate was low. She had elevated urine galactitol on D-galactose therapy.

Discussion

PGM1-CDG associated myopathy is likely due to combination of several factors including abnormal muscle carbohydrate metabolism, abnormal N-glycosylation of proteins involved in the muscle functions and creatine transport and altered muscle energy homeostasis. It was previously shown that creatine supplementation therapy improves myopathy in patients with mitochondrial cytopathies. We think that the use of creatine supplementation therapy coincided with improvements in fatigue and exercise intolerance subjectively and objectively in our patient.

PGM1的双等位致病变异可导致磷酸葡萄糖糖化酶1 （PGM1）缺乏，这是先天性糖基化（PGM1-CDG）疾病之一。表型谱包括先天性畸形、肌肉、心脏、肝脏、内分泌和血液学表型。目前的治疗包括d -半乳糖治疗，结果临床和生化改善。为了改善疲劳和运动不耐受，我们开始了肌酸补充疗法。材料与方法回顾电子病历。我们采用奈梅亨儿童CDG评定量表（NPCRS）和慢性疾病治疗疲劳功能评定量表（FACIT-F）。我们测量了肌酸代谢生物标志物。结果29岁女性，PGM1-CDG，经临床外显子组测序确诊。她接受了d -半乳糖治疗，但并没有改善她的疲劳和运动不耐受。她在27岁时开始接受肌酸补充治疗，导致白天睡眠减少，运动能力增加，NPCRS和FACIT-F改善。血浆中胍丁酯含量低。她接受d -半乳糖治疗后尿中半乳糖醇升高。pgm1 - cdg相关肌病可能是由多种因素共同作用的结果，包括肌肉碳水化合物代谢异常、参与肌肉功能和肌酸运输的蛋白质n -糖基化异常以及肌肉能量稳态改变。先前的研究表明，肌酸补充疗法可改善线粒体细胞病变患者的肌病。我们认为肌酸补充疗法的使用与我们患者主观上和客观上的疲劳和运动不耐受的改善相一致。

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引用次数: 0

Benefits of early intervention with olipudase alfa in symptomatic children with acid sphingomyelinase deficiency: A sibling case-comparison study 对有症状的酸性鞘磷脂酶缺乏症儿童早期干预脂酶的益处：一项兄弟姐妹病例比较研究

IF 1.8 4区医学 Q3 GENETICS & HEREDITY

Molecular Genetics and Metabolism Reports

Pub Date : 2025-04-02 DOI: 10.1016/j.ymgmr.2025.101210

Drew B. Sinha , William L. Simpson , Andrew Ting , Louise Bier , Mary Freeman , Lauren Mackenzie Mason , George A. Diaz , Jaya Ganesh

Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disease with multisystem complications including neurodegeneration, hepatosplenomegaly, interstitial lung disease (ILD), bone marrow disease, and growth failure. Non-neurological manifestations of this disease are amenable to enzyme replacement therapy (ERT) with olipudase alfa in both adult and pediatric patients. In this study, we offer evidence for the role of intervention in early childhood pediatric cases. We present longitudinal follow-up for two siblings with ASMD (SMPD1 p.R498L/p.R610del compound heterozygous genotype) who were started on ERT at different ages (ages 3 and 7, duration of treatment >4 years). After initiation of ERT, both siblings demonstrated significant radiographic improvement of interstitial lung disease (ILD), organomegaly, and growth. Notably, the younger sibling who had started earlier on treatment did not experience any deceleration in growth parameters and has normal height and weight for age, while the older sibling showed a decline in growth velocity that improved once treatment was initiated. Similarly, the older sibling showed similar-to-worse ILD and more persistent organomegaly compared to the younger sibling. Treatment has resulted in sustained improvements in both patients. These findings suggest that early intervention with ERT in ASMD may have cumulative benefits for pediatric health and motivate early screening for ASMD in pediatric patients.

酸性鞘磷脂酶缺乏症（ASMD）是一种溶酶体贮积性疾病，具有多系统并发症，包括神经退行性变、肝脾肿大、间质性肺疾病（ILD）、骨髓疾病和生长衰竭。这种疾病的非神经系统表现适用于脂肪酶α - fa酶替代疗法（ERT）在成人和儿童患者。在本研究中，我们为干预在儿童早期病例中的作用提供证据。我们对两名患有ASMD （SMPD1 p.R498L/p）的兄弟姐妹进行了纵向随访。R610del复合杂合基因型)，在不同年龄（3岁和7岁，治疗时间为4年）开始ERT治疗。在ERT治疗开始后，两个兄弟姐妹在肺间质性疾病（ILD）、器官肿大和生长方面表现出显著的影像学改善。值得注意的是，较早开始治疗的弟弟妹妹的生长参数没有任何减速，身高和体重与年龄正常，而哥哥姐姐的生长速度下降，一旦开始治疗就有所改善。同样，与年幼的兄弟姐妹相比，年长的兄弟姐妹表现出类似或更严重的ILD和更持久的器官肿大。治疗使两名患者的病情持续改善。这些发现表明，对ASMD进行ERT早期干预可能对儿童健康具有累积益处，并激励儿童ASMD患者的早期筛查。

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引用次数: 0

Atypical case of neonatal-onset Gaucher disease type 3b: A case report 新生儿发病3b型戈谢病不典型病例1例

IF 1.8 4区医学 Q3 GENETICS & HEREDITY

Molecular Genetics and Metabolism Reports

Pub Date : 2025-03-29 DOI: 10.1016/j.ymgmr.2025.101211

Takanori Onuki , Kinuko Kojima , Kentaro Sawano , Nao Shibata , Yohei Ogawa , Go Hasegawa , Aya Narita , Hiromi Nyuzuki

Neonatal-onset Gaucher disease (nGD) is considered perinatal lethal GD, a variant of GD type 2 (GD2), and is associated with collodion skin or hydrops fetalis, hepatosplenomegaly, and involvement of central nervous system (CNS). Pulmonary involvement (PI) and lymphadenopathy (LD) are reported GD complications and have unknown incidence, pathogenesis, and response to treatments. Here, we report the case of a patient diagnosed with nGD with collodion skin who developed only mild neurological symptoms and later died in early childhood due to treatment-resistant PI and LD. A female neonate was born at 38 weeks of gestation (weight: approximately 2012 g, height: 45 cm). She had a collodion skin, hepatosplenomegaly, hemorrhagic plaques, and cholestatic liver disease at birth. She was diagnosed with GD based on decreased glucocerebrosidase enzyme activity, and genetic analysis of GBA1 revealed compound heterozygous mutations of c.1193G > T (p.Arg398Leu) and c.1265_1319del (p.Leu422fs). Intravenous enzyme replacement therapy (ERT) was initiated at the 15 days of age. At the age of 2 years and 2 months, she had a Developmental Quotient of 88 but developed horizontal gaze palsy. At 2 years 8 months of age, she developed mesenteric LD and PI because of which she failed to gain weight and developed tachypnea. She was started on oxygen therapy but died of respiratory failure and malnutrition due to PI and LD at the age of 3 years and 8 months. Pathological autopsy did not reveal the presence of Gaucher cells (GCs) in the liver, spleen, and bone marrow, but all lung macrophages had been transformed to GCs that were draining the alveoli, LD was observed in the mesenteric and mediastinal lymph nodes, and nodules of GCs were formed in bilateral kidneys. In conclusion, nGD with collodion skin is not always classified GD2. Although her phenotype may be classified as GD3b, her clinical course was like severe GD1. In addition, PI and LD are difficult to treat with adequate ERT.

新生儿性戈谢病（nGD）被认为是围产期致死性GD，是GD2型（GD2）的一种变体，与皮肤胶凝或胎儿水肿、肝脾肿大和中枢神经系统（CNS）受累有关。肺受累（PI）和淋巴结病（LD）是GD的并发症，发病率、发病机制和治疗效果尚不清楚。在这里，我们报告了一例被诊断为胶质皮肤的nGD患者，该患者仅出现轻微的神经系统症状，后来因治疗难治性PI和LD而在儿童早期死亡。一名女性新生儿在妊娠38周出生（体重：约2012克，身高：45厘米）。她出生时皮肤胶凝，肝脾肿大，出血性斑块和胆汁淤积性肝病。根据葡萄糖脑苷酶活性降低诊断为GD， GBA1基因分析显示c.1193G >复合杂合突变；T （p.Arg398Leu）和c.1265_1319del （p.Leu422fs）。15日龄时开始静脉注射酶替代治疗（ERT）。在2岁零2个月时，她的发育商为88，但出现了水平凝视麻痹。在2岁8个月大时，她出现了肠系膜LD和PI，因为她的体重没有增加，并且出现了呼吸急促。她开始吸氧治疗，但在3岁零8个月时死于PI和LD引起的呼吸衰竭和营养不良。病理解剖未发现肝、脾和骨髓中存在戈歇细胞（GCs），但所有肺巨噬细胞均转化为引流肺泡的戈歇细胞，在肠系膜和纵隔淋巴结中观察到LD，双侧肾脏形成戈歇细胞结节。总之，胶质皮肤的nGD并不总是被归类为GD2。虽然她的表型可能归类为GD3b，但她的临床过程类似于严重的GD1。此外，PI和LD很难通过适当的ERT治疗。

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引用次数: 0