JIMD Podcasts

A child with severe developmental delay and an early-onset tumour sets the stage for a remarkable case of genetic investigation. In this episode, Sally Ann Lynch and Alfonso D’Alessio uncover how functional testing transformed an uncertain variant into a key diagnostic insight.

Read the article: https://doi.org/10.1002/ajmg.a.64275

Krista Casazza talks about validating key biomarkers in Niemann-Pick type C and why they are essential for future clinical trials and regulatory approval. The discussion focuses on emerging candidates such as 24-hydroxycholesterol, neurofilament light chain, and calbindin-D, alongside the urgent need for data harmonisation and collaboration across the NPC community.

Biomarker Validation in NPC1: Foundations for Clinical Trials and Regulatory Alignment

Krista Casazza, et al

https://doi.org/10.1002/jimd.70075

In this JIMD Shortcast, Allyson Terrell and Katie Sapp explore the real-world challenges of newborn screening for lysosomal storage disorders, based on a survey of healthcare professionals working at the front line of implementation. The study highlights the limitations of single-tier screening, the value of multi-tier testing, and the growing importance of multidisciplinary collaboration to improve diagnostic clarity and patient outcomes.

Exploratory Study on the Challenges of Newborn Screening for Lysosomal Storage Disorders Emphasizes the Need for Multitier Testing and Collaborative Approaches to Management

A. Terrell, et al

https://doi.org/10.1002/jmd2.70027

A nationwide CTX study, a critical treatment window, and a conversation with the lead author. Dr Tanyel Zübarioğlu joins the JIMD Podcast to unpack the long-term impact of CDCA therapy and why timing matters more than ever.

Long-Term Outcomes of Chenodeoxycholic Acid Therapy for Cerebrotendinous Xanthomatosis: A Nationwide Study on Prognostic Factors and Treatment Tanyel Zubarioglu, et al

https://doi.org/10.1002/jimd.70069

Editorial Comment to Regulatory News

Carla E. M. Hollak, Natalja Bouwhuis

https://doi.org/10.1002/jimd.70071

The Research Round-Up returns! Hosts Silvia Radenkovic and Rodrigo Starosta are joined by Dr Hilary Vernon and Dr Austin Larson for a deep dive into the latest discoveries in mitochondrial disease.

Together they explore how new biomarkers like FGF21 and GDF15 are reshaping diagnosis, how multi-omics approaches are accelerating precision care, and what large-scale data from gnomAD to stem-cell models is revealing about disease mechanisms and therapeutic opportunities.

A lively, expert-led discussion connecting science, diagnostics, and patient impact across the mitochondrial field.

Laricchia KM, et al

Mitochondrial DNA variation across 56,434 individuals in gnomAD. Genome Res. 2022 Mar;32(3):569-582. doi: 10.1101/gr.276013.121. Epub 2022 Jan 24. PMID: 35074858; PMCID: PMC8896463.

Liu O, et al

FGF21 and GDF15 are elevated in Barth Syndrome and are correlated to important clinical measures. Mol Genet Metab. 2023 Nov;140(3):107676. doi: 10.1016/j.ymgme.2023.107676. Epub 2023 Aug 2. PMID: 37549445.

Van Hove JLK, et al

Protein biomarkers GDF15 and FGF21 to differentiate mitochondrial hepatopathies from other pediatric liver diseases. Hepatol Commun. 2024 Jan 5;8(1):e0361. doi: 10.1097/HC9.0000000000000361. Erratum in: Hepatol Commun. 2024 Jan 29;8(2):e0390. doi: 10.1097/HC9.0000000000000390. PMID: 38180987; PMCID: PMC10781130.

Starosta RT, et al

An integrated multi-omics approach allowed ultra-rapid diagnosis of a deep intronic pathogenic variant in PDHX and precision treatment in a neonate critically ill with lactic acidosis. Mitochondrion. 2024 Nov;79:101973. doi: 10.1016/j.mito.2024.101973. Epub 2024 Oct 15. PMID: 39413893; PMCID: PMC11578067.

Jain IH, et al

Hypoxia as a therapy for mitochondrial disease. Science. 2016 Apr 1;352(6281):54-61. doi: 10.1126/science.aad9642. Epub 2016 Feb 25. PMID: 26917594; PMCID: PMC4860742

Sandlers Y, et al

Metabolomics Reveals New Mechanisms for Pathogenesis in Barth Syndrome and Introduces Novel Roles for Cardiolipin in Cellular Function. PLoS One. 2016 Mar 25;11(3):e0151802. doi: 10.1371/journal.pone.0151802. PMID: 27015085; PMCID: PMC4807847.

Sniezek Carney O, et al.

Stem cell models of TAFAZZIN deficiency reveal novel tissue-specific pathologies in Barth syndrome. Hum Mol Genet. 2025 Jan 23;34(1):101-115. doi: 10.1093/hmg/ddae152. PMID: 39535077; PMCID: PMC11756277.

Here’s a polished podcast blurb suitable for LinkedIn, BlueSky, or Apple Podcasts listings — written in the JIMD Podcast tone and style:

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It’s one of the most talked-about breakthroughs of 2025, a first-in-human demonstration of in vivo gene editing to treat an inherited metabolic disease.

In this episode, Kiran Musunuru and Rebecca Ahrens-Nicklas are joined by Julien Baruteau to unpack what this means for the field. They explore the science behind gene editing, the importance of ethical design, and the emotional weight of stopping therapy once enzyme function is restored.

The conversation bridges the NEJM landmark paper (Musunuru et al., 2025) and the accompanying JIMD editorial (Rahman & Baruteau, 2025), reflecting on what this moment tells us about the future of metabolic medicine and how ready we are for it.

First in Human Gene Editing for an Inherited Metabolic Disease

Shamima Rahman, Julien Baruteau

https://doi.org/10.1002/jimd.70056

Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease

Kiran Musunuru, et al

https://www.nejm.org/doi/10.1056/NEJMoa2504747

Dr Samuel Mackenzie discusses the perplexing presentation of a 61-year-old man with rhabdomyolysis and a prolonged QT interval. Further exploration reveals a lifetime of episodic fatigue with illnesses.

https://doi.org/10.1016/j.ymgmr.2025.101241

Inherited metabolic diseases aren’t just for the young.

James Nurse talks with François Maillot and Ida Schwartz about their systematic review revealing how IMDs can first be diagnosed well into older age. From Fabry disease to alkaptonuria, they discuss diagnostic delays, missed clues, and why it’s time to think about geriatric metabolic medicine.

Diagnosis of Inherited Metabolic Disease in Older Patients: A Systematic Literature Review

Maria-Rita Moio, et al

https://doi.org/10.1002/jimd.70038

With Rodrigo off caring for sick children, James Nurse joins Silvia Radenkovic to speak with Dr Judith Jans and Dr Devin Oglesbee about the emerging field of untargeted metabolomics.

Authors’ opinions are their own and do not represent their institutions.

Referenced papers include:

Miller MJ, et al

The emerging role of metabolomics analysis in genetic and genomic testing: A points to consider statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2025 Jul 17:101493. doi: 10.1016/j.gim.2025.101493. Epub ahead of print.

Evans AM, et al

Dissemination and analysis of the quality assurance (QA) and quality control (QC) practices of LC-MS based untargeted metabolomics practitioners. Metabolomics. 2020 Oct 12;16(10):113. doi: 10.1007/s11306-020-01728-5.

Wurth R, et al.

An evaluation of untargeted metabolomics methods to characterize inborn errors of metabolism. Mol Genet Metab. 2024 Jan;141(1):108115. doi: 10.1016/j.ymgme.2023.108115. Epub 2023 Dec 15.

Haijes HA, et al.

Direct Infusion Based Metabolomics Identifies Metabolic Disease in Patients' Dried Blood Spots and Plasma. Metabolites. 2019 Jan 11;9(1):12. doi: 10.3390/metabo9010012.

Willems AP, et al

A one-year pilot study comparing direct-infusion high resolution mass spectrometry based untargeted metabolomics to targeted diagnostic screening for inherited metabolic diseases. Front Mol Biosci. 2023 Nov 2;10:1283083. doi: 10.3389/fmolb.2023.1283083.

Haijes HA, et al.

Aspartylglycosamine is a biomarker for NGLY1-CDDG, a congenital disorder of deglycosylation. Mol Genet Metab. 2019 Aug;127(4):368-372. doi: 10.1016/j.ymgme.2019.07.001. Epub 2019 Jul 9. PMID: 31311714.

Hoegen B, et al

Application of metabolite set enrichment analysis on untargeted metabolomics data prioritises relevant pathways and detects novel biomarkers for inherited metabolic disorders. J Inherit Metab Dis. 2022 Jul;45(4):682-695. doi: 10.1002/jimd.12522. Epub 2022 May 22. PMID: 35546254; PMCID: PMC9544878.

Gao Q, et al

A diagnostic algorithm for inherited metabolic disorders using untargeted metabolomics. Metabolomics. 2025 Jul 27;21(4):101. doi: 10.1007/s11306-025-02302-7. PMID: 40715884; PMCID: PMC12301266.

Kerkhofs MHPM, et al.

Cross-Omics: Integrating Genomics with Metabolomics in Clinical Diagnostics. Metabolites. 2020 May 18;10(5):206. doi: 10.3390/metabo10050206.

Ashenden AJ, et al.

The Multi-Omic Approach to Newborn Screening: Opportunities and Challenges. Int J Neonatal Screen. 2024 Jun 21;10(3):42. doi: 10.3390/ijns10030042.

Liu N, et al.

Comparison of Untargeted Metabolomic Profiling vs Traditional Metabolic Screening to Identify Inborn Errors of Metabolism. JAMA Netw Open. 2021 Jul 1;4(7):e2114155. doi: 10.1001/jamanetworkopen.2021.14155.

Can small molecules stabilise OTC enzyme activity and change the outlook for urea cycle disorders? Dr Alexander Laemmle (University Hospital Bern) discusses pharmacological chaperones, a novel approach that strengthens enzyme stability in patient-derived liver models and offers new hope for female OTC carriers.

Novel Treatment Strategy for Patients With Urea Cycle Disorders: Pharmacological Chaperones Enhance Enzyme Stability and Activity in Patient-Derived Liver Disease Models

Adhuresa Ramosaj, et al

https://doi.org/10.1002/jimd.70043

Induced pluripotent stem cell technology as diagnostic tool in patients with suspected ornithine transcarbamylase deficiency lacking genetic confirmation

Adhuresa Ramosaj et al

https://doi.org/10.1016/j.ymgmr.2023.101007