Journal of Inherited Metabolic Disease最新文献

{"title":"Long-Read Sequencing Expands the Genotypic Spectrum of Patients With Mucopolysaccharidosis Type II","authors":"Na Hao,&nbsp;Fengxia Yao,&nbsp;Danhua Li,&nbsp;Jingwen Zhou,&nbsp;Weimin Zhang,&nbsp;Aiping Mao,&nbsp;Zhixin Tian,&nbsp;Fei Zhao,&nbsp;Juntao Liu","doi":"10.1002/jimd.70055","DOIUrl":"https://doi.org/10.1002/jimd.70055","url":null,"abstract":"<div>\u0000 \u0000 <p>The substantial genetic heterogeneity associated with mucopolysaccharidosis type II (MPS II) poses major challenges to current genetic testing. A comprehensive analysis of MPS II (CAMPS II), integrating long-range PCR with long-read sequencing (LRS), was established to identify <i>IDS</i> variants in 92 patients with clinically suspected MPS II. Comparative analysis against conventional genetic testing including multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing revealed concordant results in 75% (69/92) of cases, with discordant results in 25% (23/92) of cases. Among 23 discordant cases, CAMPS II newly identified <i>IDS</i> variants in 18 patients and enhanced variant detection in five patients. The diagnostic yield of CAMPS II for pathogenic variants was 82.6% (76/92), significantly higher than 66.3% (61/92) with conventional methods. CAMPS II expanded the genotypic spectrum in 92 probands, including 79.3% (73/92) SNVs/Indels, 15.2% (14/92) <i>IDS/IDSP1</i> inversions, 2.2% (2/92) complete <i>IDS</i> deletions, 2.2% (2/92) gross deletions/duplications, and 1.1% (1/92) <i>IDS/IDSP1</i> deletions. Moreover, 14.1% (13/92) of the patients carried novel variants. Junction characterization in 15 patients with complex rearrangement revealed hotspot regions prone to inversion and conversion events. Above all, this study highlights the advantages of CAMPS II in identifying diverse <i>IDS</i> variants, improving diagnostic yields, and identifying carrier status.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Outcome of Haemopoietic Stem Cell Transplantation in 21 Patients With Alpha-Mannosidosis","authors":"Robert Šáhó,&nbsp;Renata Formánková,&nbsp;Julie B. Eisengart,&nbsp;Allan Meldgaard Lund,&nbsp;Cecilie Videbaek,&nbsp;Berrak Bilginer Gürbüz,&nbsp;Namık Yaşar Özbek,&nbsp;Fatma Al Jasmi,&nbsp;Pavel Ješina,&nbsp;François Feillet,&nbsp;Cécile Pochon,&nbsp;Anne-Sophie Guémann,&nbsp;Moeenaldeen AlSayed,&nbsp;Sabine Laktina,&nbsp;Sema Kalkan Uçar,&nbsp;Serap Aksoylar,&nbsp;Troy C. Lund,&nbsp;Paul John Orchard,&nbsp;Fatma Tuba Eminoğlu,&nbsp;Talia İleri,&nbsp;Çiğdem Seher Kasapkara,&nbsp;Akif Yeşilipek,&nbsp;Ali Tunç Tuncel,&nbsp;Ansgar Schulz,&nbsp;Katarína Juríčková,&nbsp;Anna Hlavatá,&nbsp;Lucia Santoro,&nbsp;Martin Magner","doi":"10.1002/jimd.70047","DOIUrl":"https://doi.org/10.1002/jimd.70047","url":null,"abstract":"<div>\u0000 \u0000 <p>The outcomes of alpha-mannosidosis after hematopoietic stem cell transplantation (HSCT) are incompletely described. This retrospective multi-center study evaluated the outcomes of patients who underwent HSCT for their alpha-mannosidosis after 2010. Twenty-one children (11 females) with enzymatically and/or genetically confirmed alpha-mannosidosis, diagnosed at a mean age of 14 months (0–60 months), were included. The median age at HSCT was 3.9 years (10 months to 13.3 years) with a median follow-up of 2.3 years (0.3–14.1 years). Seventy-four percent (14/19) of patients received an unrelated graft while the rest had a matched sibling donor. Primary engraftment was reached in 17 of 21 patients; four patients required a second HSCT with successful subsequent engraftment. Nine patients had severe post-HSCT infections, five patients developed acute graft-versus-host disease (GvHD) (&gt; = grade II), and one patient had chronic GvHD. No patient died during follow-up. Seven out of ten patients received enzyme replacement therapy both pre- and post-HSCT. Among children with clinical symptoms, improvement was documented in hepatomegaly (40% of patients before HSCT, down to 10% after), recurrent infections (62%/30%), and hearing disorder (85%/65%). In 13 patients with developmental data, outcomes after HSCT suggested at least mild delays persisted post-HSCT in the majority (85%), with some trends of higher functioning with earlier treatment. Findings suggest HSCT has shown notable improvements in safety and is associated with clinical benefit in alpha-mannosidosis. Neurodevelopmental findings require longer-term study to account for phenotypic diversity.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144367274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First in Human Gene Editing for an Inherited Metabolic Disease","authors":"Shamima Rahman,&nbsp;Julien Baruteau","doi":"10.1002/jimd.70056","DOIUrl":"https://doi.org/10.1002/jimd.70056","url":null,"abstract":"&lt;p&gt;Last month, Musunuru et al. [&lt;span&gt;1&lt;/span&gt;] reported the first in vivo gene editing therapy for a baby with an inherited metabolic disease (IMD) in the &lt;i&gt;New England Journal of Medicine&lt;/i&gt;. The ‘n of 1’ study comprised a well planned and executed therapeutic pipeline culminating in delivery of a customised novel gene editing treatment to an infant less than 7 months after their diagnosis with neonatal onset carbamoyl phosphate synthase (CPS1) deficiency. This groundbreaking work impressed by its demonstration of feasibility and early successful data in a human but also by the rapidity by which this was achieved, 7 months from diagnosis to a novel personalised therapy designed from scratch.&lt;/p&gt;&lt;p&gt;The patient presented soon after birth with severe hyperammonaemia requiring nitrogen scavengers and renal replacement therapy. Targeted genome sequencing enabled a rapid diagnosis of CPS1 deficiency, identifying compound heterozygous pathogenic variants, one of which was particularly amenable to base editing. By 1 month, the patient's mutation had been introduced into a cell line and by 2 months screening had been completed for the most efficacious base editing strategy. By 3 months, a mouse model had been created incorporating the patient-specific mutation using CRISPR/Cas9 technology. Off-target analysis revealed low-level synonymous bystander editing in the &lt;i&gt;CPS1&lt;/i&gt; gene in keeping with a single base mismatch in the guide mRNA. After an initial meeting with the FDA at 4 months, a toxicology batch of the base editor was manufactured and delivered to the mouse model and to non-human primates (NHPs) (5–6 months).&lt;/p&gt;&lt;p&gt;Satisfied by the lack of toxicity in the mice and NHPs, a clinical batch of the lipid nanoparticle mRNA gene editing treatment, named k-abe, was manufactured (6 months). Off-target editing analyses of the clinical batch were acceptable, and an IND application was approved by the FDA at 7 months. Two doses were administered to the infant, at 7 and 8 months of age, together with concomitant prophylactic immunosuppression (sirolimus and tacrolimus) to prevent immunisation against the transgenic enzyme. Partial efficacy was evidenced by good control of plasma ammonia and glutamine levels during a period of clinical stability and during two viral illnesses, an increase of orotic acid allowing a well-tolerated normalisation of dietary protein intake and a halved dose of nitrogen scavenger. No safety issues were reported, but only two low doses were delivered (0.1 and 0.3 mg/kg respectively), and clearly longer-term follow-up is needed.&lt;/p&gt;&lt;p&gt;This was an ideal candidate disease to trial this type of innovative therapy for the first time—a severe neonatal presentation of a disease with predictable consequences and lack of alternative therapeutic options other than liver transplantation in infancy. The patient remained stable with no major hyperammonaemic decompensation before dosing. As the authors of the article stated, mortality of neon","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70056","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144273550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Minor Haplotype Variant Determines the Pathogenicity of the p.Ile279Thr Substitution in the Primary Hyperoxaluria Type 1 Gene, AGXT","authors":"Luana Ruta,&nbsp;Andrea G. Cogal,&nbsp;Gioena Pampalone,&nbsp;David J. Sas,&nbsp;John C. Lieske,&nbsp;Gill Rumsby,&nbsp;Barbara Cellini,&nbsp;Peter C. Harris","doi":"10.1002/jimd.70052","DOIUrl":"https://doi.org/10.1002/jimd.70052","url":null,"abstract":"<p>Human alanine:glyoxylate aminotransferase (AGT) is a liver peroxisomal enzyme that metabolizes glyoxylate, the oxalate precursor, to glycine. AGT deficiency, due to recessive pathogenic changes in the <i>AGXT</i> gene, results in calcium oxalate accumulation and kidney stones, a condition known as primary hyperoxaluria type 1 (PH1). Most missense variants lead to PH1 by causing AGT misfolding, but their effects manifest differently based on the presence of two polymorphic variants, p.Pro11Leu (p.P11L) and p.Ile340Met (p.I340M), which are usually present in linkage disequilibrium and generate the minor haplotype. While the p.P11L substitution reduces AGT global stability and worsens the effects of pathogenic changes, the p.I340M exerts a stabilizing effect whose role on PH1 pathogenesis has never been elucidated. The p.Ile279Thr (p.I279T) variant is frequent in healthy populations (0.29%), mainly on the major allele, but we present data from six PH1 families (eight patients) suggesting p.I279T as a PH1 pathogenic allele. Interestingly, in these families, p.Thr279 is always associated with p.Leu11 and p.Ile340, thus with a split <i>AGXT</i> haplotype. Analysis of the effects of the p.I279T mutation by in silico predictions, biochemical analyses on purified proteins, and expression in two cellular models of disease (<i>AGXT1</i>-KO HepG2 and CHO cells) shows that it causes a folding defect that is exacerbated by p.P11L but mitigated by p.I340M, thus explaining why p.Thr279 is pathogenic just on the p.Leu11–p.Ile340 haplotype. These data indicate that genetic screenings for PH1 should document the <i>AGXT</i> haplotype, including its components, to obtain an accurate diagnosis and possible prognostic information.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70052","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144256037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired Proteostasis is Linked to Neurological Pathology in a Zebrafish NGLY1 Deficiency Model","authors":"Aviv Mesika,&nbsp;Golan Nadav,&nbsp;Sapir Ben-David,&nbsp;Limor Kalfon,&nbsp;Chen Shochat,&nbsp;Rana Nasra,&nbsp;Alejandro Livoff,&nbsp;David Karasik,&nbsp;Tzipora C. Falik-Zaccai","doi":"10.1002/jimd.70050","DOIUrl":"https://doi.org/10.1002/jimd.70050","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>NGLY1 is a key enzyme in the process of misfolded protein deglycosylation. Bi-allelic pathogenic variants in <i>NGLY1</i> cause N-glycanase deficiency, also known as congenital disorder of deglycosylation (NGLY1-CDDG). This rare and multisystem autosomal recessive disorder is linked to a variable phenotype of global developmental delay, neuromuscular abnormalities, and alacrima, and it lacks effective treatment. We have studied the possible underlying mechanisms for the neuromuscular and ophthalmic phenotypes in an <i>ngly1-</i>deficient zebrafish model carrying a similar genetic variant that has also been identified in previously reported patients. We investigated phenotypic, biochemical, and molecular details underlying ngly1 deficiency using a zebrafish model. <i>ngly1-</i>deficient zebrafish phenotypes were characterized using histological staining, transmission electron microscopy (TEM), and micro-CT imaging. Furthermore, fish brain molecular and biochemical characterization was performed by gene expression analysis and immunoblotting techniques. Impaired proteostasis was evident in the brain of the mutant zebrafish, including accumulation of poly-ubiquitinated proteins and amyloid fibril aggregation. The mutant fish featured neuromuscular abnormalities and significant aquaporin1-protein reduction in the eyes and brain. The zebrafish model of NGLY1 deficiency provides an ideal platform for studying the molecular and biochemical mechanisms underlying NGLY1-CDDG in humans. Our novel findings of impaired protein homeostasis encompassing amyloid fibril aggregation (folding) and poly-ubiquitinated protein accumulation (degradation) in the brains of mutant zebrafish offer new insights into the brain pathology associated with NGLY1 deficiency. These discoveries may also advance our understanding of other neurodegenerative disorders and facilitate the identification of potential therapeutic targets.</p>\u0000 </section>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70050","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144213829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizing Diagnostic Delays in Metachromatic Leukodystrophy: A Real-World Data Approach","authors":"Ali Mohajer,&nbsp;Anjana Sevagamoorthy,&nbsp;Karen Bean,&nbsp;Sylvia Mutua,&nbsp;Francis Pang,&nbsp;Laura Ann Adang","doi":"10.1002/jimd.70049","DOIUrl":"https://doi.org/10.1002/jimd.70049","url":null,"abstract":"<p>Neurodegeneration in metachromatic leukodystrophy (MLD) may be preceded by systemic complications. Characterization of these features is critical to define barriers to early diagnosis and treatment eligibility for gene therapy. We utilized medical billing (claims) datasets and a natural history study to capture pre-diagnosis MLD-related events. MLD-related events (ICD-10-CM codes) were aggregated into system-based diagnosis clusters, and time to MLD diagnosis (TTD) computed for each organ-system diagnosis cluster. Differences in TTD distribution, instantaneous diagnosis hazard, and survival to MLD diagnosis were compared by sex and payor type. TTD and regression from onset of first symptoms were described using median and inter-quartile range. The claims dataset identified 174 MLD cases (diagnosis ≤ 6 years old) with 14 diagnosed within the first year of life. General neurologic concerns (<i>n</i> = 138; median 257 days pre-diagnosis), gastrointestinal (<i>n</i> = 137; 231 days), seizures (<i>n</i> = 48; 236 days), ophthalmologic (<i>n</i> = 46; 362 days), and language-related events (<i>n</i> = 41; 267 days) were common. Time to MLD diagnosis from onset of prodromal clusters was longer for children with non-commercial insurance: most prominent with seizures (survival logrank <i>p</i> value &lt; 0.02) and non-degenerative neurological symptoms (survival logrank <i>p</i> value &lt; 0.04). Similar findings were noted in our analysis of a second claims dataset. The natural history cohort demonstrated a similar pattern of prodromal disease features and delayed diagnosis. This study defines barriers to MLD diagnosis and highlights prodromal periods of pre-regression symptomatology, further supporting the need for early screening in this fatal disorder of childhood.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70049","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144197371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liver-Directed Gene Therapy Mitigates Early Nephropathy in Murine Glycogen Storage Disease Type Ia","authors":"Cheol Lee,&nbsp;Kunal Pratap,&nbsp;Lisa Zhang,&nbsp;Hung Dar Chen,&nbsp;Irina Arnaoutova,&nbsp;Matthew F. Starost,&nbsp;Brian C. Mansfield,&nbsp;Janice Y. Chou","doi":"10.1002/jimd.70048","DOIUrl":"https://doi.org/10.1002/jimd.70048","url":null,"abstract":"<p>Nephropathy is a complication of glycogen storage disease type Ia (GSD-Ia), a metabolic disorder caused by pathogenic variants in glucose-6-phosphatase-α (G6Pase-α or G6PC1). While maintaining blood glucose homeostasis can delay the progression of renal disease in GSD-Ia, the benefits of liver-directed G6PC1 gene therapy on nephropathy remain unclear. This study evaluates the effects of low- and high-dose G6PC1 liver gene augmentation therapy on kidney function. The <i>G6pc</i>−/− mice, which lack G6Pase-α activity in both liver and kidney, were treated with G6PC1 gene therapy to restore either low or near-normal levels of liver G6Pase-α activity, and renal phenotype was examined at age 12 weeks. Both groups exhibited impaired renal glucose homeostasis, altered renal glucose reabsorption, acute kidney injury, and early signs of renal fibrosis. However, mice with near-normal liver G6Pase-α activity had better renal glucose reabsorption and homeostasis with lower serum levels of cystatin C and blood urea nitrogen, key markers of kidney function. These findings highlight the potential of liver-directed G6PC1 gene therapy to enhance metabolic control and mitigate early kidney disease in GSD-Ia.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70048","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144171615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Multiomic Network Approach to Uncover Disease Modifying Mechanisms of Inborn Errors of Metabolism","authors":"Aaron Bender,&nbsp;Pablo Ranea-Robles,&nbsp;Evan G. Williams,&nbsp;Mina Mirzaian,&nbsp;J. Alexander Heimel,&nbsp;Christiaan N. Levelt,&nbsp;Ronald J. Wanders,&nbsp;Johannes M. Aerts,&nbsp;Jun Zhu,&nbsp;Johan Auwerx,&nbsp;Sander M. Houten,&nbsp;Carmen A. Argmann","doi":"10.1002/jimd.70045","DOIUrl":"https://doi.org/10.1002/jimd.70045","url":null,"abstract":"<div>\u0000 \u0000 <p>For many inborn errors of metabolism (IEM) the understanding of disease mechanisms remains limited, in part explaining their unmet medical needs. The expressivity of IEM disease phenotypes is affected by disease-modifying factors, including rare and common polygenic variation. We hypothesize that we can identify these modulating pathways using molecular signatures of IEM in combination with multiomic data and gene regulatory networks generated from non-IEM animal and human populations. We tested this approach by identifying and subsequently validating glucocorticoid signaling as a candidate modifier of mitochondrial fatty acid oxidation disorders, and recapitulating complement signaling as a modifier of inflammation in Gaucher disease. Our work describes a novel approach that can overcome the rare disease–rare data dilemma and reveal new IEM pathophysiology and potential drug targets using multiomics data in seemingly healthy populations.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144171633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Audiovestibular Findings in Gaucher Disease Types I and III: Evidence of Vestibular Involvement in GD1","authors":"Elvan Onan,&nbsp;Fatma Derya Bulut,&nbsp;Deniz Kor,&nbsp;Muhammed Dagkiran,&nbsp;Caglar Eker,&nbsp;Ozgur Surmelioglu,&nbsp;Neslihan Önenli Mungan","doi":"10.1002/jimd.70046","DOIUrl":"https://doi.org/10.1002/jimd.70046","url":null,"abstract":"<p>Gaucher disease (GD), the most prevalent lysosomal storage disorder, is characterized by varying levels of systemic and neurological involvement. This study aims to investigate audiovestibular system involvement in patients with Gaucher disease type I (GD1) and type III (GD3) using audiometric and vestibular evaluations. We conducted a retrospective analysis of 42 patients diagnosed with GD who presented to the Department of Otorhinolaryngology at Çukurova University Faculty of Medicine between January 2001 and September 2023. The evaluations included pure tone audiometry (PTA), speech discrimination scores (SDS), acoustic impedance tests, and Video Head Impulse Test (vHIT) assessments. Of the 42 patients, 18 were diagnosed with GD1, and 24 with GD3. Audiovestibular anomalies were identified in 11 patients (26.2%). Sensorineural hearing loss (SNHL) was detected in 9 patients, including 4 GD1 and 5 GD3 patients, with bilateral involvement in 5 cases. The severity of hearing loss ranged from mild to moderately severe. Vestibular impairment, demonstrated by reduced vestibulo-ocular reflex (VOR) gain and catch-up saccades (CUS), was observed in 5 patients, predominantly among GD3 cases. Notably, concurrent audiovestibular dysfunction was observed in three patients, one with GD1 and two with GD3. This study is the first to describe the vestibular involvement in GD1. Audiovestibular abnormalities can manifest in both GD1 and GD3 patients, with distinct patterns of involvement. Regular auditory and vestibular assessments are essential to identify sensory deficits early, guide rehabilitation strategies, and enhance the quality of life for GD patients.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70046","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144171632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulatory News: Chenodiol for the Treatment of Cerebrotendinous Xanthomatosis: FDA Approval Summary","authors":"Theresa Bourne","doi":"10.1002/jimd.70051","DOIUrl":"https://doi.org/10.1002/jimd.70051","url":null,"abstract":"<p>Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by pathogenic variants in the <i>CYP27A1</i> gene which encodes the mitochondrial enzyme sterol 27-hydroxylase. This enzyme deficiency leads to abnormalities in bile acid synthesis, including deficient production of the primary bile acid chenodeoxycholic acid (CDCA) and loss of feedback inhibition on the enzyme 7α-hydroxylase, resulting in increased production of abnormal bile acids and bile alcohols, and accumulation of cholestanol, a toxic cholesterol metabolite, in various organs and tissues. Clinical manifestations of CTX include chronic diarrhea, juvenile-onset bilateral cataracts, tendon xanthomas, and progressive neurological dysfunction (pyramidal and cerebellar signs, seizures, dementia, and psychiatric disturbances).</p><p>Chenodiol is an orally administered exogenous CDCA that replaces the deficient bile acid in CTX. Chenodiol has been approved in the United States since 1983 for the treatment of radiolucent gallstones in adults and has been used off-label for the treatment of CTX for over 40 years. Although chenodiol is considered standard of care for the treatment of CTX worldwide, there have been no prospective, randomized, controlled trials to confirm the treatment benefit.</p><p>The FDA requires substantial evidence of effectiveness for drug approval, with benefits outweighing risks. Substantial evidence of effectiveness for chenodiol in patients with CTX was established using data from one adequate and well-controlled trial with confirmatory evidence. The recommended dosing regimen of 250 mg three times per day for adults was evaluated in a single trial in 14 patients aged 16 years and older with CTX. Chenodiol treatment resulted in lower levels of cholestanol compared to when treatment was withdrawn, which the review team considered clinically meaningful based on available literature supporting the role of cholestanol reduction and normalization in stabilizing or improving clinical symptoms for CTX patients. The confirmatory evidence providing strong mechanistic support includes the well-established etiology of the disease and the mechanism of action of chenodiol in replacing the deficient bile acid and restoring normal bile acid synthesis homeostasis. Since chenodiol treatment has been associated with hepatotoxicity, product labeling recommends monitoring liver transaminase and bilirubin levels and considering interrupting treatment if levels are significantly elevated. With all factors and limitations considered, the benefits of chenodiol were determined to outweigh the risks for adult patients with CTX.</p><p>The author declares no conflicts of interest.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70051","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144171566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}