Pub Date : 2026-03-01Epub Date: 2026-02-22DOI: 10.1016/j.ymgmr.2026.101299
Samira Nmer , Said Trhanint , Hanane Sayel , Sana Chaouki , Laila Bouguenouch , Karim Ouldim
Background
Spinal muscular atrophy (SMA) is a neuromuscular disorder caused in 95% of cases by homozygous SMN1 exon 7 deletion, with severity primarily determined by the modifier genes SMN2 and NAIP copy numbers.
Objective
This study, the first in the Moroccan population, simultaneously analyzed SMN1, SMN2, and NAIP copy numbers to investigate their relationship with SMA severity and their utility in predicting patients' phenotype.
Methods
RFLP-PCR was used to screen 214 patients for SMN1 exon 7 homozygous deletion. In patients with confirmed SMA, copy number variations (CNVs) of SMN1, SMN2, and NAIP were analyzed by MLPA.
Results
SMN1 exon 7 was deleted in 27% (58/214) of patients. Among those analyzed by MLPA (32/58), 75% (24/32) also carried an SMN1 exon 8 deletion. SMN2 exon 7 copy number ranged from 2 to 4, with lower copies correlating with greater disease severity. NAIP exon 5 deletion was primarily seen in type I SMA. Combined SMN1–SMN2–NAIP genotypes showed that 80% of type I patients (8/10) had 2 SMN2 copies and 0 NAIP; 66.7% of type II (4/6) had 3 SMN2 copies and ≥ 1 NAIP; and 75% of type III (12/16) had either 3 SMN2 copies with 1–2 NAIP or 4 SMN2 copies with variable NAIP status.
Conclusions
This study demonstrated an inverse correlation between SMN2 and NAIP copy numbers and SMA severity. Combined SMN1–SMN2–NAIP genotypes provided stronger predictive insights on disease severity than individual gene copy number. Implementing CNV analysis of these genes in Morocco could enhance SMA severity prediction and support genetic counseling.
{"title":"First combined analysis of SMN1, SMN2, and NAIP copy numbers in Moroccan SMA patients and their correlation with disease severity","authors":"Samira Nmer , Said Trhanint , Hanane Sayel , Sana Chaouki , Laila Bouguenouch , Karim Ouldim","doi":"10.1016/j.ymgmr.2026.101299","DOIUrl":"10.1016/j.ymgmr.2026.101299","url":null,"abstract":"<div><h3>Background</h3><div>Spinal muscular atrophy (SMA) is a neuromuscular disorder caused in 95% of cases by homozygous <em>SMN1</em> exon 7 deletion, with severity primarily determined by the modifier genes <em>SMN2</em> and <em>NAIP</em> copy numbers.</div></div><div><h3>Objective</h3><div>This study, the first in the Moroccan population, simultaneously analyzed <em>SMN1</em>, <em>SMN2</em>, and <em>NAIP</em> copy numbers to investigate their relationship with SMA severity and their utility in predicting patients' phenotype.</div></div><div><h3>Methods</h3><div>RFLP-PCR was used to screen 214 patients for <em>SMN1</em> exon 7 homozygous deletion. In patients with confirmed SMA, copy number variations (CNVs) of <em>SMN1</em>, <em>SMN2</em>, and <em>NAIP</em> were analyzed by MLPA.</div></div><div><h3>Results</h3><div><em>SMN1</em> exon 7 was deleted in 27% (58/214) of patients. Among those analyzed by MLPA (32/58), 75% (24/32) also carried an <em>SMN1</em> exon 8 deletion. <em>SMN2</em> exon 7 copy number ranged from 2 to 4, with lower copies correlating with greater disease severity. <em>NAIP</em> exon 5 deletion was primarily seen in type I SMA. Combined <em>SMN1</em>–<em>SMN2</em>–<em>NAIP</em> genotypes showed that 80% of type I patients (8/10) had 2 <em>SMN2</em> copies and 0 <em>NAIP</em>; 66.7% of type II (4/6) had 3 <em>SMN2</em> copies and ≥ 1 <em>NAIP</em>; and 75% of type III (12/16) had either 3 <em>SMN2</em> copies with 1–2 <em>NAIP</em> or 4 <em>SMN2</em> copies with variable <em>NAIP</em> status.</div></div><div><h3>Conclusions</h3><div>This study demonstrated an inverse correlation between <em>SMN2</em> and <em>NAIP</em> copy numbers and SMA severity. Combined <em>SMN1</em>–<em>SMN2</em>–<em>NAIP</em> genotypes provided stronger predictive insights on disease severity than individual gene copy number. Implementing CNV analysis of these genes in Morocco could enhance SMA severity prediction and support genetic counseling.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"46 ","pages":"Article 101299"},"PeriodicalIF":1.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147344724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-13DOI: 10.1016/j.ymgmr.2026.101295
Arturo Olivares-Rivera , Hilal Ersöz , Philipp Höger , Martina Veith , Timm Greulich , Kai Schlamp , Sabina Janciauskiene , Felix Herth , Franziska C. Trudzinski
Severe alpha-1 antitrypsin deficiency (AATD) is a rare genetic condition characterized by low levels of alpha-1 antitrypsin (AAT), leading to progressive lung and/or liver disease. Most severe cases are linked to the Z allele (c.1096G > A (p.Glu366Lys)) of the SERPINA1 gene but characterizing patients with rare mutations remains challenging. This case report discusses the clinical significance of a novel SERPINA1 variant, c.236 T > A (p.Val79Glu; ClinVar accession SCV007334878), and the challenges in profiling such cases. Two male siblings carried both the common Z allele mutation and the novel exon 2 mutation. Despite genetic similarities, their clinical courses diverged. The older brother, a 66-year-old patient, presented with very severe airflow obstruction (GOLD stage IV) and an AAT level of 0.32 g/L. After years of pharmacologic treatment and endoscopic lung volume reduction, his condition worsened, requiring a double lung transplant. In contrast, the younger brother, currently 58 years old, was diagnosed through family screening and had an AAT level of 0.4 g/L. His condition progressed to panlobular basal emphysema accompanied by bronchopathy and mild bronchiectasis, managed with pharmacologic therapy. Both siblings had a history of smoking, potentially influencing their clinical outcomes. This case highlights the complexity of assessing rare SERPINA1 mutations due to underlying biochemical complexities, genetic variability, and diagnostic limitations. It underscores the importance of combining biochemical analysis of variant AAT proteins with clinical evaluation to better understand disease expression, the value of genetic screening in family members, and the need for personalized clinical management to support timely and appropriate therapeutic interventions.
严重α -1抗胰蛋白酶缺乏症（AATD）是一种罕见的遗传性疾病，其特征是α -1抗胰蛋白酶（AAT）水平低，可导致进行性肺和/或肝脏疾病。大多数严重病例与SERPINA1基因的Z等位基因（c.1096G > A (p.Glu366Lys)）有关，但罕见突变患者的特征仍然具有挑战性。本病例报告讨论了一种新的SERPINA1变异的临床意义T > A (p.Val79Glu; ClinVar accession SCV007334878)，以及分析此类案例的挑战。两个男性兄弟姐妹同时携带了常见的Z等位基因突变和新的外显子2突变。尽管基因相似，但他们的临床过程却不同。哥哥66岁，表现为非常严重的气流阻塞（GOLD IV期），AAT水平为0.32 g/L。经过多年的药物治疗和内窥镜肺体积缩小，他的病情恶化，需要双肺移植。相比之下，弟弟，目前58岁，是通过家庭筛查诊断出来的，AAT水平为0.4 g/L。他的病情发展为全小叶性基底肺气肿，并伴有支气管病和轻度支气管扩张，经药物治疗。兄弟姐妹都有吸烟史，这可能会影响他们的临床结果。由于潜在的生化复杂性、遗传变异性和诊断局限性，该病例突出了评估罕见SERPINA1突变的复杂性。它强调了将变异AAT蛋白的生化分析与临床评估相结合的重要性，以更好地了解疾病表达，在家庭成员中进行遗传筛查的价值，以及个性化临床管理以支持及时和适当的治疗干预的必要性。
{"title":"Clinical implications of a novel SERPINA1 variant c.236 T > A: Challenges in characterizing new rare alpha-1 antitrypsin mutations","authors":"Arturo Olivares-Rivera , Hilal Ersöz , Philipp Höger , Martina Veith , Timm Greulich , Kai Schlamp , Sabina Janciauskiene , Felix Herth , Franziska C. Trudzinski","doi":"10.1016/j.ymgmr.2026.101295","DOIUrl":"10.1016/j.ymgmr.2026.101295","url":null,"abstract":"<div><div>Severe alpha-1 antitrypsin deficiency (AATD) is a rare genetic condition characterized by low levels of alpha-1 antitrypsin (AAT), leading to progressive lung and/or liver disease. Most severe cases are linked to the Z allele (c.1096G > A (p.Glu366Lys)) of the <em>SERPINA1</em> gene but characterizing patients with rare mutations remains challenging. This case report discusses the clinical significance of a novel <em>SERPINA1</em> variant, c.236 T > A (p.Val79Glu; ClinVar accession SCV007334878), and the challenges in profiling such cases. Two male siblings carried both the common Z allele mutation and the novel exon 2 mutation. Despite genetic similarities, their clinical courses diverged. The older brother, a 66-year-old patient, presented with very severe airflow obstruction (GOLD stage IV) and an AAT level of 0.32 g/L. After years of pharmacologic treatment and endoscopic lung volume reduction, his condition worsened, requiring a double lung transplant. In contrast, the younger brother, currently 58 years old, was diagnosed through family screening and had an AAT level of 0.4 g/L. His condition progressed to panlobular basal emphysema accompanied by bronchopathy and mild bronchiectasis, managed with pharmacologic therapy. Both siblings had a history of smoking, potentially influencing their clinical outcomes. This case highlights the complexity of assessing rare <em>SERPINA1</em> mutations due to underlying biochemical complexities, genetic variability, and diagnostic limitations. It underscores the importance of combining biochemical analysis of variant AAT proteins with clinical evaluation to better understand disease expression, the value of genetic screening in family members, and the need for personalized clinical management to support timely and appropriate therapeutic interventions.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"46 ","pages":"Article 101295"},"PeriodicalIF":1.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146169979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-14DOI: 10.1016/j.ymgmr.2026.101297
Martin Magner , Robert Šáhó , Petra Slavíková , Radovan Bakaľár , Lenka Dvořáková , Karolína Pešková , Danijela Petković Ramadža , Ivo Barić , Nikola Ilic , Anna Čechová , Martin Řeboun , Hana Vlášková , Silvie Kelifová , Pavel Ješina , Dagmar Procházková , Hana Hansíková , Tomáš Honzík , Jiří Zeman
Glycogen storage disease type IX (GSD IX) arises from hepatic phosphorylase b kinase (PhK) deficiency attributable to pathogenic variants in the PHKA2, PHKB, and PHKG2 genes. This multicenter retrospective study evaluated clinical and biochemical data from 52 patients diagnosed across three European countries, with a median follow-up of 9.3 years (range: 1–49). In the cohort, 86.5% were classified as GSD IXa, whereas GSD IXb and IXc accounted for 7.7% and 3.8%, respectively; one diagnosis was based solely on enzymatic testing. Null variants in PHKA2 consistently resulted in severe PhK deficiency, whereas missense variants and in-frame deletions were associated with variable enzymatic impairment (8/19 tested cases). The median age at symptom onset was 1.6 years, and the mean age at diagnosis was 2.0 years. Predominant manifestations included hepatomegaly (82%), elevated aminotransferases (81%), hypertriglyceridemia (71%), hypercholesterolemia (67%), hypoglycemia (46%), hyperlactatemia (38%), and short stature (30%). Aberrant apolipoprotein C-III glycosylation was detected in 80% of analyzed samples. Nutritional intervention was associated with improved growth (height SD score − 0.8 ± 1.3 vs −0.2 ± 1.65; p = 0.031) and fewer documented fasting hypoglycemia episodes (20/44 vs 9/44; p = 0.012), although hepatomegaly frequently persisted. Liver biopsies showed steatosis, fibrosis, and/or chronic hepatitis in 52% of examined cases. A single hepatic adenoma was identified in a 14-year-old male. Overall, the clinical course of GSD IX was favorable, with hepatomegaly, elevated liver enzymes, and dyslipidemia as the most prevalent features. Severe hypoglycemic episodes were uncommon, and no clear genotype–phenotype correlation emerged.
糖原储存病IX型（GSD IX）是由PHKA2、PHKB和PHKG2基因致病性变异引起的肝磷酸化酶b激酶（PhK）缺乏引起的。这项多中心回顾性研究评估了来自三个欧洲国家的52名确诊患者的临床和生化数据，中位随访时间为9.3年（范围：1-49年）。在队列中，86.5%被归类为GSD IXa，而GSD IXb和IXc分别占7.7%和3.8%；一种诊断仅基于酶检测。PHKA2的零变异体始终导致严重的PhK缺陷，而错义变异体和帧内缺失与不同的酶损伤相关（8/19测试病例）。出现症状时的中位年龄为1.6岁，诊断时的平均年龄为2.0岁。主要表现为肝肿大（82%）、转氨酶升高（81%）、高甘油三酯血症（71%）、高胆固醇血症（67%）、低血糖症（46%）、高乳酸血症（38%）和身材矮小（30%）。在80%的分析样本中检测到异常载脂蛋白C-III糖基化。营养干预与改善生长（身高SD评分- 0.8±1.3 vs -0.2±1.65;p = 0.031）和较少记录的空腹低血糖发作（20/44 vs 9/44; p = 0.012）相关，尽管肝肥大经常持续存在。肝活检显示52%的病例有脂肪变性、纤维化和/或慢性肝炎。在一个14岁的男性身上发现了一个单一的肝腺瘤。总体而言，GSD IX的临床过程是有利的，肝肿大、肝酶升高和血脂异常是最普遍的特征。严重的低血糖发作不常见，没有明确的基因型-表型相关性出现。
{"title":"Glycogen storage disease type IX: Long-term follow-up of 52 patients from three European countries","authors":"Martin Magner , Robert Šáhó , Petra Slavíková , Radovan Bakaľár , Lenka Dvořáková , Karolína Pešková , Danijela Petković Ramadža , Ivo Barić , Nikola Ilic , Anna Čechová , Martin Řeboun , Hana Vlášková , Silvie Kelifová , Pavel Ješina , Dagmar Procházková , Hana Hansíková , Tomáš Honzík , Jiří Zeman","doi":"10.1016/j.ymgmr.2026.101297","DOIUrl":"10.1016/j.ymgmr.2026.101297","url":null,"abstract":"<div><div>Glycogen storage disease type IX (GSD IX) arises from hepatic phosphorylase b kinase (PhK) deficiency attributable to pathogenic variants in the PHKA2, PHKB, and PHKG2 genes. This multicenter retrospective study evaluated clinical and biochemical data from 52 patients diagnosed across three European countries, with a median follow-up of 9.3 years (range: 1–49). In the cohort, 86.5% were classified as GSD IXa, whereas GSD IXb and IXc accounted for 7.7% and 3.8%, respectively; one diagnosis was based solely on enzymatic testing. Null variants in PHKA2 consistently resulted in severe PhK deficiency, whereas missense variants and in-frame deletions were associated with variable enzymatic impairment (8/19 tested cases). The median age at symptom onset was 1.6 years, and the mean age at diagnosis was 2.0 years. Predominant manifestations included hepatomegaly (82%), elevated aminotransferases (81%), hypertriglyceridemia (71%), hypercholesterolemia (67%), hypoglycemia (46%), hyperlactatemia (38%), and short stature (30%). Aberrant apolipoprotein C-III glycosylation was detected in 80% of analyzed samples. Nutritional intervention was associated with improved growth (height SD score − 0.8 ± 1.3 vs −0.2 ± 1.65; <em>p</em> = 0.031) and fewer documented fasting hypoglycemia episodes (20/44 vs 9/44; <em>p</em> = 0.012), although hepatomegaly frequently persisted. Liver biopsies showed steatosis, fibrosis, and/or chronic hepatitis in 52% of examined cases. A single hepatic adenoma was identified in a 14-year-old male. Overall, the clinical course of GSD IX was favorable, with hepatomegaly, elevated liver enzymes, and dyslipidemia as the most prevalent features. Severe hypoglycemic episodes were uncommon, and no clear genotype–phenotype correlation emerged.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"46 ","pages":"Article 101297"},"PeriodicalIF":1.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147276786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-01-09DOI: 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。
{"title":"Unveiling alpha-mannosidosis in Iraqi children: A series of clinically and genetically characterized cases with novel MAN2B1 variant","authors":"Mays Riyadh Al Tai , Nebal Waill Saadi , Marwa Sabah Alothman , Ikhlas Ali Ahmed , Hala Sameh Arif , Saja Baheer Abdulwahhab","doi":"10.1016/j.ymgmr.2025.101282","DOIUrl":"10.1016/j.ymgmr.2025.101282","url":null,"abstract":"<div><h3>Background</h3><div>Alpha-mannosidosis is a rare lysosomal storage disorder caused by <em>MAN2B1</em> 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.</div></div><div><h3>Patients and methods</h3><div>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 <em>MAN2B1</em> testing. Clinical and imaging data were collected from medical records.</div></div><div><h3>Results</h3><div>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 <em>MAN2B1</em> variants, including one novel variant [c.830C > T (p.Pro277Leu)].</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"46 ","pages":"Article 101282"},"PeriodicalIF":1.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145929217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-03-07DOI: 10.1016/j.ymgmr.2026.101304
Didem Demirbas, Susan E. Waisbren, Olaf Bodamer, Christina Y. Hung, Farrah Rajabi , Gerard Berry, Harvey L. Levy
Intellectual disability is the cardinal clinical feature of untreated phenylketonuria (PKU). Nevertheless, there are rare individuals with untreated PKU who have had normal or near normal cognition despite having never been treated. We are reporting two adult sisters with untreated PKU who are strikingly discordant in cognition and the studies we conducted to determine whether there is a significant difference between the sisters that might explain the discordancy. The older sister has the expected moderate to severe cognitive disability while the younger sister is intellectually normal having graduated from college and serving as an executive secretary until retirement. Studies that include plasma phenylalanine (Phe) and other amino acids, urine organic acids, phenylalanine hydroxylase (PAH) genotype, in vivo PAH activity, brain MRI, and whole exome sequencing failed to reveal a significant difference between the sisters. The results of published studies comparing cognitively normal and abnormal individuals with untreated PKU also failed to reveal a significant difference with the exception of a single unconfirmed study reporting a lower brain Phe level in three adults with untreated PKU (Moller HE, Weglage J, Wiedermann D, Ullrich K, 1998). It is important to identify and study cognitively normal or near normal individuals with untreated PKU in search of a factor that might explain the discordancy in clinical outcome and lead to a further understanding of pathogenesis in PKU.
{"title":"Two adult sisters with untreated phenylketonuria: Strikingly discordant clinical phenotype","authors":"Didem Demirbas, Susan E. Waisbren, Olaf Bodamer, Christina Y. Hung, Farrah Rajabi , Gerard Berry, Harvey L. Levy","doi":"10.1016/j.ymgmr.2026.101304","DOIUrl":"10.1016/j.ymgmr.2026.101304","url":null,"abstract":"<div><div>Intellectual disability is the cardinal clinical feature of untreated phenylketonuria (PKU). Nevertheless, there are rare individuals with untreated PKU who have had normal or near normal cognition despite having never been treated. We are reporting two adult sisters with untreated PKU who are strikingly discordant in cognition and the studies we conducted to determine whether there is a significant difference between the sisters that might explain the discordancy. The older sister has the expected moderate to severe cognitive disability while the younger sister is intellectually normal having graduated from college and serving as an executive secretary until retirement. Studies that include plasma phenylalanine (Phe) and other amino acids, urine organic acids, phenylalanine hydroxylase (<em>PAH</em>) genotype, <em>in vivo</em> PAH activity, brain MRI, and whole exome sequencing failed to reveal a significant difference between the sisters. The results of published studies comparing cognitively normal and abnormal individuals with untreated PKU also failed to reveal a significant difference with the exception of a single unconfirmed study reporting a lower brain Phe level in three adults with untreated PKU (Moller HE, Weglage J, Wiedermann D, Ullrich K, 1998). It is important to identify and study cognitively normal or near normal individuals with untreated PKU in search of a factor that might explain the discordancy in clinical outcome and lead to a further understanding of pathogenesis in PKU.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"46 ","pages":"Article 101304"},"PeriodicalIF":1.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147397688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-10DOI: 10.1016/j.ymgmr.2026.101292
GuLing Qian , Chen Liu , YanHua Xu , Duo Zhou , Chi Chen , BenQing Wu , XinWen Huang
Objective
This study aimed to delineate the neonatal screening landscape, incidence, tandem mass spectrometry (MS/MS)-based metabolic signatures, ACADS gene variant spectrum, and long-term clinical outcomes of short-chain acyl-CoA dehydrogenase deficiency (SCADD) in newborns from Zhejiang Province, China.
Methods
A retrospective cohort study was conducted on 4,667,883 newborns in Zhejiang screened between November 2013 and August 2025. Acylcarnitine profiles in dried blood spots were analyzed by MS/MS. Urinary organic acids and ACADS gene variants were detected via gas chromatography–mass spectrometry (GC–MS) and high-throughput sequencing, respectively. Confirmed SCADD patients underwent longitudinal follow-up to evaluate growth, neurodevelopment, and biochemical parameters.
Results
Initial screening identified 500 infants with elevated butyrylcarnitine (C4) or C4/ propionylcarnitine (C3) ratios; 89 were confirmed as SCADD, corresponding to an incidence of 1 in 52,448 (1.9 per 100,000). All patients were asymptomatic during the neonatal period. Among the 26 patients who underwent urinary GC/MS, 25 (96.2%) presented with elevated ethylmalonic acid (EMA) levels. Fifty-one ACADS variants were identified, with missense variants (46/51, 90.2%) being the most prevalent; the top three variants were c.1031 A > G (28.1%), c.164C > T (13.5%), and c.1130C > T (11.2%).
Conclusions
The incidence of SCADD in Zhejiang is 1 in 52,448, with c.1031 A > G and c.164C > T as the most frequent ACADS variants; and most screen-detected SCADD cases remain asymptomatic.
{"title":"Newborn screening, genetic analysis, and long-term follow-up of 89 cases with short-chain acyl-CoA dehydrogenase deficiency (SCADD)","authors":"GuLing Qian , Chen Liu , YanHua Xu , Duo Zhou , Chi Chen , BenQing Wu , XinWen Huang","doi":"10.1016/j.ymgmr.2026.101292","DOIUrl":"10.1016/j.ymgmr.2026.101292","url":null,"abstract":"<div><h3>Objective</h3><div>This study aimed to delineate the neonatal screening landscape, incidence, tandem mass spectrometry (MS/MS)-based metabolic signatures, ACADS gene variant spectrum, and long-term clinical outcomes of short-chain acyl-CoA dehydrogenase deficiency (SCADD) in newborns from Zhejiang Province, China.</div></div><div><h3>Methods</h3><div>A retrospective cohort study was conducted on 4,667,883 newborns in Zhejiang screened between November 2013 and August 2025. Acylcarnitine profiles in dried blood spots were analyzed by MS/MS. Urinary organic acids and ACADS gene variants were detected via gas chromatography–mass spectrometry (GC–MS) and high-throughput sequencing, respectively. Confirmed SCADD patients underwent longitudinal follow-up to evaluate growth, neurodevelopment, and biochemical parameters.</div></div><div><h3>Results</h3><div>Initial screening identified 500 infants with elevated butyrylcarnitine (C4) or C4/ propionylcarnitine (C3) ratios; 89 were confirmed as SCADD, corresponding to an incidence of 1 in 52,448 (1.9 per 100,000). All patients were asymptomatic during the neonatal period. Among the 26 patients who underwent urinary GC/MS, 25 (96.2%) presented with elevated ethylmalonic acid (EMA) levels. Fifty-one ACADS variants were identified, with missense variants (46/51, 90.2%) being the most prevalent; the top three variants were c.1031 A > G (28.1%), c.164C > T (13.5%), and c.1130C > T (11.2%).</div></div><div><h3>Conclusions</h3><div>The incidence of SCADD in Zhejiang is 1 in 52,448, with c.1031 A > G and c.164C > T as the most frequent ACADS variants; and most screen-detected SCADD cases remain asymptomatic.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"46 ","pages":"Article 101292"},"PeriodicalIF":1.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146169977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-12DOI: 10.1016/j.ymgmr.2026.101296
Wiebke Hahn , Karla Erffmeier , Maximilian Schulze , Felix Zahnert , Susanne Knake , Panagiota-Eleni Tsalouchidou
Background
Mutations in COQ8A cause primary coenzyme Q10 deficiency, which can present clinically heterogeneously: Symptoms range from cerebellar ataxia, epilepsy, encephalomyopathy, macular degeneration to nephropathy. High-dose coenzyme Q10 supplementation is widely used, yet there is little evidence on complementary strategies, particularly for non-epileptic features such as cerebellar ataxia.
Case presentation
We report a 46-year-old female with genetically confirmed COQ8A-related coenzyme Q10 (CoQ10) deficiency, presenting with ataxia and epilepsy characterized by myoclonic and bilateral tonic–clonic seizures, who participated in a clinical protocol of ketogenic intermittent fasting, a method of intermittent fasting combined with medium-chain triglycerides (MCT) primarily designed for seizure management. The patient followed a 16:8 intermittent fasting regime combined with MCT intake for three months, followed by three months of all-alone intermittent fasting. Routine blood markers and brain MRI, including diffusion imaging were obtained before and after ketogenic fasting.
Results
During the study protocol, while no seizure reduction in myoclonic seizures could be observed, ataxia - quantified by the Scale for the Assessment and Rating of Ataxia (SARA) - improved significantly from 8.5 to 6.0 during the interventions. MRI showed a trend suggesting improved cerebellar microstructural integrity.
Conclusions
This case highlights the potential of ketogenic intermittent fasting as an adjunct therapy for mitochondrial ataxia. Ketogenic intermittent fasting was associated with clinically meaningful improvement of ataxia in a patient with COQ8A-related CoQ10 deficiency, suggesting that ketogenic dietary strategies may represent a promising adjunct therapeutic approach for mitochondrial ataxia. Future research should assess this intervention in larger patient cohorts to confirm its potential benefits.
{"title":"Intermittent ketogenic fasting with medium-chain triglycerides improves ataxia in COQ8A-related coenzyme Q10 deficiency: A case report","authors":"Wiebke Hahn , Karla Erffmeier , Maximilian Schulze , Felix Zahnert , Susanne Knake , Panagiota-Eleni Tsalouchidou","doi":"10.1016/j.ymgmr.2026.101296","DOIUrl":"10.1016/j.ymgmr.2026.101296","url":null,"abstract":"<div><h3>Background</h3><div>Mutations in COQ8A cause primary coenzyme Q10 deficiency, which can present clinically heterogeneously: Symptoms range from cerebellar ataxia, epilepsy, encephalomyopathy, macular degeneration to nephropathy. High-dose coenzyme Q10 supplementation is widely used, yet there is little evidence on complementary strategies, particularly for non-epileptic features such as cerebellar ataxia.</div></div><div><h3>Case presentation</h3><div>We report a 46-year-old female with genetically confirmed COQ8A-related coenzyme Q10 (CoQ10) deficiency, presenting with ataxia and epilepsy characterized by myoclonic and bilateral tonic–clonic seizures, who participated in a clinical protocol of ketogenic intermittent fasting, a method of intermittent fasting combined with medium-chain triglycerides (MCT) primarily designed for seizure management. The patient followed a 16:8 intermittent fasting regime combined with MCT intake for three months, followed by three months of all-alone intermittent fasting. Routine blood markers and brain MRI, including diffusion imaging were obtained before and after ketogenic fasting.</div></div><div><h3>Results</h3><div>During the study protocol, while no seizure reduction in myoclonic seizures could be observed, ataxia - quantified by the Scale for the Assessment and Rating of Ataxia (SARA) - improved significantly from 8.5 to 6.0 during the interventions. MRI showed a trend suggesting improved cerebellar microstructural integrity.</div></div><div><h3>Conclusions</h3><div>This case highlights the potential of ketogenic intermittent fasting as an adjunct therapy for mitochondrial ataxia. Ketogenic intermittent fasting was associated with clinically meaningful improvement of ataxia in a patient with COQ8A-related CoQ10 deficiency, suggesting that ketogenic dietary strategies may represent a promising adjunct therapeutic approach for mitochondrial ataxia. Future research should assess this intervention in larger patient cohorts to confirm its potential benefits.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"46 ","pages":"Article 101296"},"PeriodicalIF":1.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146169978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-11DOI: 10.1016/j.ymgmr.2026.101293
Nehal Abdelaziz Arafa , Aml Mahfouz , Shimaa Anwar , Iman Marzouk
Objectives
To present key features of pediatric acid sphingomyelinase deficiency (ASMD) and assess the clinical and safety outcomes of enzyme replacement therapy with olipudase alfa.
Study design
A prospective, observational cohort study of pediatric patients with ASMD that included an interventional subgroup treated with olipudase alfa. Patients presenting to the Alexandria University Children's Hospital in Egypt from June 2022 to May 2023 underwent clinical examination and genetic testing. Clinical and safety outcomes were assessed in patients who received biweekly infusions of olipudase alfa for 12 months.
Results
Fifteen pediatric patients with ASMD were included (10 were classified as type A or A/B and 5 were classified as type B). Patients with ASMD type A or A/B presented earlier and more severely, with a higher rate of mortality than patients with type B. Qualitative improvements in developmental and neurocognitive outcomes, clinical presentation, and laboratory parameters were observed among the patients with ASMD type A/B or type B treated with olipudase alfa (n = 6), with only mild safety events recorded. Treated patients with type B (n = 4) demonstrated significantly improved weight (p = 0.031, η2 = 0.757) and height/length Z-scores (p = 0.009, η2 = 0.707), and liver size (p = 0.025, η2 = 0.839) compared with baseline.
Conclusions
This case series contributes to the clinical and biochemical understanding of ASMD and may help reduce diagnostic delays and improve clinical management. Olipudase alfa was generally well tolerated, and promising clinical improvements were observed.
{"title":"Olipudase alfa treatment for pediatric acid sphingomyelinase deficiency in Egypt: A prospective, observational cohort study with an interventional subgroup","authors":"Nehal Abdelaziz Arafa , Aml Mahfouz , Shimaa Anwar , Iman Marzouk","doi":"10.1016/j.ymgmr.2026.101293","DOIUrl":"10.1016/j.ymgmr.2026.101293","url":null,"abstract":"<div><h3>Objectives</h3><div>To present key features of pediatric acid sphingomyelinase deficiency (ASMD) and assess the clinical and safety outcomes of enzyme replacement therapy with olipudase alfa.</div></div><div><h3>Study design</h3><div>A prospective, observational cohort study of pediatric patients with ASMD that included an interventional subgroup treated with olipudase alfa. Patients presenting to the Alexandria University Children's Hospital in Egypt from June 2022 to May 2023 underwent clinical examination and genetic testing. Clinical and safety outcomes were assessed in patients who received biweekly infusions of olipudase alfa for 12 months.</div></div><div><h3>Results</h3><div>Fifteen pediatric patients with ASMD were included (10 were classified as type A or A/B and 5 were classified as type B). Patients with ASMD type A or A/B presented earlier and more severely, with a higher rate of mortality than patients with type B. Qualitative improvements in developmental and neurocognitive outcomes, clinical presentation, and laboratory parameters were observed among the patients with ASMD type A/B or type B treated with olipudase alfa (<em>n</em> = 6), with only mild safety events recorded. Treated patients with type B (<em>n</em> = 4) demonstrated significantly improved weight (<em>p</em> = 0.031, <em>η</em><sup>2</sup> = 0.757) and height/length <em>Z</em>-scores (<em>p</em> = 0.009, <em>η</em><sup>2</sup> = 0.707), and liver size (<em>p</em> = 0.025, <em>η</em><sup>2</sup> = 0.839) compared with baseline.</div></div><div><h3>Conclusions</h3><div>This case series contributes to the clinical and biochemical understanding of ASMD and may help reduce diagnostic delays and improve clinical management. Olipudase alfa was generally well tolerated, and promising clinical improvements were observed.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"46 ","pages":"Article 101293"},"PeriodicalIF":1.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146169976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-17DOI: 10.1016/j.ymgmr.2026.101294
Maryam F. Bin Hadyan , Mohammed A. Saleh , Saad Aldalaqan , Aziza M. Mushiba , Ali M. Alasmari , Eissa A. Faqeih , Abdul A. Peer-Zada
Background
Carbonic anhydrase VA deficiency is a rare autosomal recessive disorder caused by biallelic mutations in the CA5A gene. Patients present with acute metabolic decompensation including hyperammonemia in infancy albeit a good outcome.
Objective
We report three children from the same Saudi tribe with a novel homozygous deletion in CA5A gene, manifesting predominantly as developmental delay without hyperammonemia and major metabolic crises.
Methods
Diagnostic work-up included clinical, biochemical, neuroimaging, and genetic analyses through WES and WGS with family segregation analysis.
Results
The first patient, a 3-year-old girl, presented with global developmental delay, corpus callosum thinning, and mild periventricular leukomalacia on brain MRI. The second patient, a 7-year-old girl born to consanguineous parents, had delayed motor and language milestones with persistent speech delay, microcephaly, and mild to moderate intellectual disability, but normal metabolic and neuroimaging findings. Her younger sister, aged 4 years, showed mild speech delay without additional clinical abnormalities with biochemical investigations in both siblings unremarkable. None presented with classic neonatal hyperammonemia. A pathogenic homozygous loss of 16.5 kb (exons 3–7) in CA5A gene (chr16:87921735–87,938,510 NM_001739.2) was identified in all the three children with the parents and healthy siblings carrying the variant in heterozygous state.
Conclusion
CA-VA deficiency may present with non-specific neurodevelopmental delay without metabolic decompensation. Genetic analysis remains the cornerstone for identifying atypical cases with novel mutations in a rare disease and recognition of this atypical presentation is essential for awareness of the disease.
{"title":"A novel homozygous CA5A gene deletion in carbonic anhydrase VA deficiency presenting as developmental delay without metabolic crisis","authors":"Maryam F. Bin Hadyan , Mohammed A. Saleh , Saad Aldalaqan , Aziza M. Mushiba , Ali M. Alasmari , Eissa A. Faqeih , Abdul A. Peer-Zada","doi":"10.1016/j.ymgmr.2026.101294","DOIUrl":"10.1016/j.ymgmr.2026.101294","url":null,"abstract":"<div><h3>Background</h3><div>Carbonic anhydrase VA deficiency is a rare autosomal recessive disorder caused by biallelic mutations in the CA5A gene. Patients present with acute metabolic decompensation including hyperammonemia in infancy albeit a good outcome.</div></div><div><h3>Objective</h3><div>We report three children from the same Saudi tribe with a novel homozygous deletion in CA5A gene, manifesting predominantly as developmental delay without hyperammonemia and major metabolic crises.</div></div><div><h3>Methods</h3><div>Diagnostic work-up included clinical, biochemical, neuroimaging, and genetic analyses through WES and WGS with family segregation analysis.</div></div><div><h3>Results</h3><div>The first patient, a 3-year-old girl, presented with global developmental delay, corpus callosum thinning, and mild periventricular leukomalacia on brain MRI. The second patient, a 7-year-old girl born to consanguineous parents, had delayed motor and language milestones with persistent speech delay, microcephaly, and mild to moderate intellectual disability, but normal metabolic and neuroimaging findings. Her younger sister, aged 4 years, showed mild speech delay without additional clinical abnormalities with biochemical investigations in both siblings unremarkable. None presented with classic neonatal hyperammonemia. A pathogenic homozygous loss of 16.5 kb (exons 3–7) in CA5A gene (chr16:87921735–87,938,510 NM_001739.2) was identified in all the three children with the parents and healthy siblings carrying the variant in heterozygous state.</div></div><div><h3>Conclusion</h3><div>CA-VA deficiency may present with non-specific neurodevelopmental delay without metabolic decompensation. Genetic analysis remains the cornerstone for identifying atypical cases with novel mutations in a rare disease and recognition of this atypical presentation is essential for awareness of the disease.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"46 ","pages":"Article 101294"},"PeriodicalIF":1.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147284104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-01-21DOI: 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.
{"title":"Clinical expert opinion on the role of elosulfase alfa in non-ambulatory individuals with Morquio A syndrome","authors":"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","doi":"10.1016/j.ymgmr.2026.101290","DOIUrl":"10.1016/j.ymgmr.2026.101290","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusions</h3><div>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.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"46 ","pages":"Article 101290"},"PeriodicalIF":1.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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