Molecular Genetics and Metabolism Reports最新文献

{"title":"Intrafamilial phenotypic heterogeneity in carriers of the m.3303C > T mutation cannot be explained solely by heteroplasmy levels","authors":"Josef Finsterer","doi":"10.1016/j.ymgmr.2026.101356","DOIUrl":"10.1016/j.ymgmr.2026.101356","url":null,"abstract":"","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"48 ","pages":"Article 101356"},"PeriodicalIF":1.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148934464","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}

{"title":"Changes in motor function, quality of life, and clinical manifestations in patients with Alpha-mannosidosis treated with Velmanase Alfa: Data from the French Étoile Alpha registry","authors":"Nathalie Guffon,&nbsp;Karine Mention-Mulliez,&nbsp;Francis Gaches,&nbsp;Daniela Garavaglia,&nbsp;Fabrizio Salomone,&nbsp;Bénédicte Héron","doi":"10.1016/j.ymgmr.2026.101351","DOIUrl":"10.1016/j.ymgmr.2026.101351","url":null,"abstract":"<div><div>Alpha-mannosidosis (AM) is a rare lysosomal storage disease with heterogeneous disease manifestations and a continuous spectrum of severity. The only specific treatment for AM is enzyme replacement therapy with velmanase alfa (VA). The focus of this analysis was to assess changes in physician-reported clinical manifestations of AM following VA treatment, using data from Étoile Alpha, a multicenter, non-interventional registry of AM patients treated with VA in France. The cohort included 16 patients (7 females [43.7%]) and 9 males [56.3%]), with a median (range) age at VA initiation and duration of VA treatment of 15.7 (6.1–49.4) and 3.3 (1.1–9.2) years, respectively. Clinical outcomes, including 3-minute stair climb test, 6-minute walk test, forced expiratory volume in 1 second and forced vital capacity, showed numerical improvements from baseline to the last assessment. VA treatment was associated with significant (<em>p</em> &lt; 0.0001) improvements in overall physician-assessed health assessment scores, encompassing motor, quality of life and psychological domains. Across all individual clinical manifestations, VA led to either improvement or stability, with no deteriorations reported. Lower patient age at inclusion, diagnosis and at VA initiation were significantly (<em>p</em> &lt; 0.05) associated with improvement of clinical manifestations. To complement these clinical data, physician-reported narratives recorded before and after VA treatment were evaluated using natural language processing. Sentiment analysis revealed that all pre-treatment narratives were negative, with shifting to positive sentiment in 81.3% of cases following treatment. This analysis highlights the varied clinical manifestations associated with AM and underscores the potential benefits of early intervention with enzyme replacement therapy.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"48 ","pages":"Article 101351"},"PeriodicalIF":1.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148934462","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}

{"title":"Spectrum of inherited metabolic disorders diagnosed through newborn screening and symptomatic referrals in Eastern Türkiye","authors":"Sezai Arslan,&nbsp;Filiz Ekinci Uğan,&nbsp;Oğuzhan Yaralı,&nbsp;Hasan Kahveci","doi":"10.1016/j.ymgmr.2026.101349","DOIUrl":"10.1016/j.ymgmr.2026.101349","url":null,"abstract":"<div><h3>Objective</h3><div>Inherited metabolic disorders (IMDs) are heterogeneous genetic diseases whose observed spectrum is influenced by population characteristics, newborn screening (NBS), and diagnostic pathways.This study aimed to characterize confirmed IMDs diagnosed through NBS and symptomatic referrals at a tertiary center in Eastern Türkiye and estimate the regional burden of selected disorders.</div></div><div><h3>Methods</h3><div>This retrospective study included patients evaluated between September 2022 and September 2024. IMDs were confirmed by biochemical and/or molecular genetic analyses. Population and live-birth data from the defined referral region were used to estimate regional and NBS-based birth prevalence.</div></div><div><h3>Results</h3><div>Among 9603 patients evaluated, 828 (8.6%) had a confirmed IMDs; 580 (70.0%) were identified through NBS, 230 (27.8%) through symptomatic referral, and 18 (2.2%) through family screening. Vitamin and cofactor metabolism (43.8%) and amino acid metabolism disorders (35.7%) predominated. Biotinidase deficiency was the most frequent disorder (<em>n</em> = 360, 43.4%), including 316 (87.8%) partial and 44 (12.2%) profound cases. Neurological manifestations were the most frequent presentation among symptomatic patients (23.2%). Based on 61,409 estimated live births, estimated birth prevalence was 1:627 for the hyperphenylalaninemia/phenylketonuria spectrum and 1:543 for biotinidase deficiency. Minimum estimated regional prevalence was 1.07 and 0.97 per 100,000 for mucopolysaccharidoses and alkaptonuria, respectively.</div></div><div><h3>Conclusion</h3><div>NBS and symptom-based evaluation are complementary diagnostic pathways for IMDs. The observed disease spectrum reflects the influence of screening strategies, while symptomatic referrals reveal broader clinical and genetic heterogeneity.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"48 ","pages":"Article 101349"},"PeriodicalIF":1.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148934463","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}

{"title":"A 53-week, open-label phase IIIb study of velaglucerase alfa in Chinese patients with type 1 Gaucher disease: Safety, efficacy, and pharmacokinetics","authors":"Lihui Zhang ,&nbsp;Xue-Qun Luo ,&nbsp;Yongjun Fang ,&nbsp;Fengkui Zhang ,&nbsp;Yan Meng ,&nbsp;Xiaoping Luo ,&nbsp;Liansheng Zhang ,&nbsp;Zhengqing Qiu ,&nbsp;Xiao Ge ,&nbsp;Jaco Botha ,&nbsp;Jenny Zhan ,&nbsp;Tianyou Wang","doi":"10.1016/j.ymgmr.2026.101324","DOIUrl":"10.1016/j.ymgmr.2026.101324","url":null,"abstract":"<div><h3>Background</h3><div>Velaglucerase alfa is approved in China for treating type 1 Gaucher disease (GD1), but data on its use in Chinese pediatric and adult patients are limited. This study evaluated the safety, efficacy, and pharmacokinetics of velaglucerase alfa in Chinese patients with GD1.</div></div><div><h3>Methods</h3><div>This was a phase IIIb, multicenter, open-label, single-arm, 53-week study (<span><span>NCT05529992</span><svg><path></path></svg></span>). Patients received intravenous velaglucerase alfa (60 U/kg) every 2 weeks. The primary endpoint was the incidence of serious treatment-emergent adverse events (TEAEs). Secondary endpoints evaluated safety (incidence of TEAEs), efficacy (changes in hemoglobin concentrations, platelet counts, liver and spleen volumes [as percent of body weight, % BW]), and quality of life (QoL).</div></div><div><h3>Results</h3><div>Twenty patients were enrolled (treatment-naïve, <em>n</em> = 16; previously treated, <em>n</em> = 4). Four patients experienced 4 serious TEAEs requiring hospitalization; none were treatment-related. Overall, 19 of 20 patients experienced 104 TEAEs, of which 9 were treatment-related (8.7%; all mild). No TEAEs or deaths led to discontinuation of treatment. Mean (SD) improvements in hemoglobin concentrations (baseline, 10.5 g/dL [2.2]; change, +2.3 g/dL [1.3]; +25.5%), platelet counts (baseline, 59.9 × 10⁹/L [23.4]; change, +42.1 × 10⁹/L [27.7]; +82.3%), normalized spleen (baseline, 5.2% BW [2.6]; change, −3.1% BW [1.6]; −58.4%), and liver volume (baseline, 4.6% BW [1.3]; change, −1.1% BW [0.9]; −21.5%) were observed through Week 53. Nineteen of 20 (95.0%) patients reported improved QoL.</div></div><div><h3>Conclusions</h3><div>Velaglucerase alfa was well-tolerated in Chinese patients with GD1, with no new safety signals, and resulted in improved hemoglobin and platelet levels, as well as liver and spleen volumes.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"47 ","pages":"Article 101324"},"PeriodicalIF":1.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148183945","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}

{"title":"Homozygous variegate porphyria: Two cases misdiagnosed as erythropoietic protoporphyria","authors":"Chenqing Wang ,&nbsp;Narmene Bensaber ,&nbsp;Lina Rebeiz ,&nbsp;Benny Tran ,&nbsp;Silvia Tortorelli ,&nbsp;Kevin Kyle ,&nbsp;Lenore K. Yalom ,&nbsp;Akshata Moghe ,&nbsp;Karl E. Anderson ,&nbsp;Rebecca K. Leaf ,&nbsp;Amy K. Yeung","doi":"10.1016/j.ymgmr.2026.101325","DOIUrl":"10.1016/j.ymgmr.2026.101325","url":null,"abstract":"<div><div>Homozygous variegate porphyria (HVP) is an ultra-rare porphyria caused by biallelic pathogenic variants in <em>PPOX</em>. It typically presents with early childhood onset of cutaneous photosensitivity, including blistering, skin fragility, scarring, and poorly defined neurologic symptoms. We report two unrelated patients with childhood-onset photosensitivity, blistering, scarring, modest zinc-predominant erythrocyte protoporphyrin elevation, elevated plasma porphyrins that were predominantly protoporphyrin, and homozygous novel <em>PPOX</em> variants, findings consistent with homozygous variegate porphyria. Both patients had initially been diagnosed with erythropoietic protoporphyria because of photosensitivity and elevated total erythrocyte protoporphyrin, despite fractionation demonstrating a slight zinc predominance rather than metal-free predominance. Genetic testing revealed that both patients were homozygous for <em>PPOX</em> variants: c.223G&gt;T p.Val75Phe in Case 1 and c.1070A&gt;C p.Asp357Ala in Case 2. Neither variant was present in population genetic datasets nor previously reported in patients with variegate porphyria, and both were classified as variants of uncertain significance. A plasma fluorescence scan was performed for Case 2 and showed a peak at 624 nm, specific for variegate porphyria. A comprehensive porphyria gene panel, ideally with plasma fluorescence scanning, should be performed when total erythrocyte protoporphyrin is substantially elevated but predominantly zinc-chelated, to ensure accurate diagnosis of homozygous porphyrias such as HVP.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"47 ","pages":"Article 101325"},"PeriodicalIF":1.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148241595","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}

{"title":"Quality of life after diet liberalization in individuals with phenylketonuria treated with Pegvaliase","authors":"Chiara Cazzorla ,&nbsp;Giacomo Gaiga ,&nbsp;Jessica Carretta ,&nbsp;Vincenza Gragnaniello ,&nbsp;Christian Loro ,&nbsp;Daniela Gueraldi ,&nbsp;Andrea Dorigato ,&nbsp;Alessandro P. Burlina ,&nbsp;Alberto B. Burlina","doi":"10.1016/j.ymgmr.2026.101323","DOIUrl":"10.1016/j.ymgmr.2026.101323","url":null,"abstract":"<div><h3>Objective</h3><div>To assess the impact of pegvaliase treatment on quality of life and individuals' perception of and satisfaction with therapy in Italian individuals with classical phenylketonuria (PKU) after diet liberalization.</div></div><div><h3>Methods</h3><div>This longitudinal observational study included individuals with classical PKU and persistently poor dietary adherence who initiated treatment with pegvaliase and achieved diet liberalization. Blood Phe levels were measured at baseline and throughout treatment for up to 12 months following diet liberalization. Quality of life was assessed using the Phenylketonuria–Quality of Life (PKU-QOL) questionnaire at three time points (before treatment, and 6 and 12 months after diet liberalization); a qualitative satisfaction survey was also administered.</div></div><div><h3>Results</h3><div>Seven participants (1 male, 6 females; mean age 27.7 years) achieved diet liberalization within a mean of 61 weeks after maintenance period, with a mean reduction in blood Phe levels of 79.7%. At 6 and 12 months after diet liberalization, PKU-QOL scores showed a consistent decrease, indicating improved quality of life, particularly in the “PKU in general” subscale, assessing the emotional, practical, and social impact of PKU. Patient-reported outcomes highlighted improvements in energy levels, sleep quality, emotional well-being, and social functioning. Common challenges included injection-site discomfort and initial treatment-related anxiety.</div></div><div><h3>Conclusions</h3><div>Pegvaliase treatment was effective in reducing blood Phe levels and achieving diet liberalization, thereby improving quality of life in individuals with PKU who historically had poor dietary adherence. Despite initial treatment challenges, the therapy enabled substantial improvements in quality of life and dietary freedom.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"47 ","pages":"Article 101323"},"PeriodicalIF":1.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148183946","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}

{"title":"POLG-related disorders: Clinical and molecular Spectrum in the Saudi population","authors":"Fuad Al Mutairi ,&nbsp;Faisal Joueidi ,&nbsp;Ziyad A. Al Mutairi ,&nbsp;Maha Alshalan ,&nbsp;Wafaa Eyaid ,&nbsp;Aziza M. Mushiba ,&nbsp;Malak AlGhamdi ,&nbsp;Brahim Tabarki ,&nbsp;Abdulaziz AlGhamdi ,&nbsp;Ruqaiah AlTassan ,&nbsp;Hamad Alzaidan ,&nbsp;Abubakar Sharif ,&nbsp;Hesham Aldhalaan ,&nbsp;Muhammad Umair ,&nbsp;Majid Alfadhel","doi":"10.1016/j.ymgmr.2026.101322","DOIUrl":"10.1016/j.ymgmr.2026.101322","url":null,"abstract":"<div><h3>Background</h3><div>POLG-related disorders are a group of mitochondrial diseases caused by variants in the <em>POLG</em> gene, which is essential for mitochondrial DNA replication and repair. These disorders encompass a wide spectrum of clinical manifestations, ranging from severe, early-onset conditions to milder, adult-onset syndromes.</div></div><div><h3>Methods</h3><div>We conducted a retrospective study of 19 molecularly confirmed cases with POLG-related disorders from 16 unrelated families in six different referral centers. Clinical, radiological, and molecular analysis were performed following standard methods.</div></div><div><h3>Results</h3><div>Most of the patients in this study presented with variable neurological symptoms before the age of 12 years (80%); commonly, these symptoms included developmental delay and encephalopathy (63%), seizures (58%), ataxia and dysphagia (42% each). Molecular analysis revealed eight different disease-causing variants in the <em>POLG</em> gene. The most frequently observed variant was c.3286C &gt; T; p.(Arg1096Cys). Notably, the <em>POLG</em> c.1957G &gt; A; p.(Glu653Lys) variant has not been reported in the literature previously, and might impact protein folding and stability.</div></div><div><h3>Conclusion</h3><div>Despite the management of these conditions remaining largely supportive, advances in understanding the molecular mechanisms of POLG-related disorders offer promise for future therapeutic strategies targeting mitochondrial function and stability. This study highlights the complexity of POLG-related disorders and underscores the need for continued research into their pathophysiology and treatment.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"47 ","pages":"Article 101322"},"PeriodicalIF":1.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148157471","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}

{"title":"First combined analysis of SMN1, SMN2, and NAIP copy numbers in Moroccan SMA patients and their correlation with disease severity","authors":"Samira Nmer ,&nbsp;Said Trhanint ,&nbsp;Hanane Sayel ,&nbsp;Sana Chaouki ,&nbsp;Laila Bouguenouch ,&nbsp;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}

{"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 ,&nbsp;Hilal Ersöz ,&nbsp;Philipp Höger ,&nbsp;Martina Veith ,&nbsp;Timm Greulich ,&nbsp;Kai Schlamp ,&nbsp;Sabina Janciauskiene ,&nbsp;Felix Herth ,&nbsp;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 &gt; 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 &gt; 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}

{"title":"Glycogen storage disease type IX: Long-term follow-up of 52 patients from three European countries","authors":"Martin Magner ,&nbsp;Robert Šáhó ,&nbsp;Petra Slavíková ,&nbsp;Radovan Bakaľár ,&nbsp;Lenka Dvořáková ,&nbsp;Karolína Pešková ,&nbsp;Danijela Petković Ramadža ,&nbsp;Ivo Barić ,&nbsp;Nikola Ilic ,&nbsp;Anna Čechová ,&nbsp;Martin Řeboun ,&nbsp;Hana Vlášková ,&nbsp;Silvie Kelifová ,&nbsp;Pavel Ješina ,&nbsp;Dagmar Procházková ,&nbsp;Hana Hansíková ,&nbsp;Tomáš Honzík ,&nbsp;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}