Raphaela Muri and Roman Trepp join the JIMD Podcast to explore what happens to the adult brain in phenylketonuria. We discuss the effects of phenylalanine exposure on brain structure, what MRI studies reveal about potentially reversible changes, how these findings relate to cognition, and whether the latest evidence really suggests altered brain ageing in early-treated PKU.

Papers discussed and related work

Brain Age in Adult Patients With Early-Treated Phenylketonuria

Winiger et al.

https://doi.org/10.1002/jimd.70158

Neural Correlates of Working Memory and Its Association With Metabolic Parameters in Early-Treated Adults With Phenylketonuria

Abgottspon et al.

https://doi.org/10.1016/j.nicl.2022.102974

Cortical Thickness and Its Relationship to Cognitive Performance and Metabolic Control in Adults With Phenylketonuria

Muri et al.

https://doi.org/10.1002/jimd.12561

Do Early-Treated Adults With Phenylketonuria Sense High Phenylalanine Levels?

Hauri et al.

https://doi.org/10.1002/jmd2.12446

Cerebral Blood Flow and White Matter Alterations in Adults With Phenylketonuria

Steiner et al.

https://doi.org/10.1016/j.nicl.2023.103550

Reversible White Matter Changes Following a 4-Week High Phenylalanine Exposure in Adults With Phenylketonuria

Muri et al.

https://doi.org/10.1002/jimd.12823

Transient Brain Structure Changes After High Phenylalanine Exposure in Adults With Phenylketonuria

Muri et al.

https://doi.org/10.1093/brain/awae139

Cognition After a 4-Week High Phenylalanine Intake in Adults With Phenylketonuria – A Randomized Controlled Trial

Trepp et al.

https://doi.org/10.1016/j.ajcnut.2023.11.007

Are Functional Brain Networks Sensitive to High Phenylalanine in Adults With Phenylketonuria?

Vallesi et al.

https://doi.org/10.1002/jmd2.70108

Research Round-Up: Sterols and Bile Acids by Journal of Inherited Metabolic Disease

Júlio César Rocha, Anne Daly and Anita MacDonald discuss how nutritional management can move beyond metabolic control towards better lifelong health. From protein substitutes and point-of-care monitoring to new therapies and AI, what might the future look like?

From Control to Optimisation: Evolving Strategies in the Nutritional Management of Inborn Errors of Protein Metabolism

Júlio César Rocha, Anne Daly, Anita MacDonald

https://doi.org/10.1002/jimd.70123

Sarah Firman explores how dietary management can rapidly reduce phytanic acid levels in adult Refsum disease. This case series shows why adequate energy and carbohydrate intake, and avoiding weight loss and catabolism, matter alongside phytanic acid restriction.

Adult Refsum Disease: Case Series of Reducing Circulating Phytanic Acid Levels With Dietary Interventions

Sarah J. Firman, et al

https://doi.org/10.1002/jmd2.70048

Are inherited metabolic disorders more common, and less predictable, than we previously thought?

Large-scale genomic studies are identifying adults with disease-associated variants who have escaped diagnosis, sometimes despite lifelong symptoms. At the same time, expanding genomic newborn screening risks identifying children who may remain well for decades or never develop clinically significant disease at all.

In this episode Dr Nina Gold, Dr Jessica Gold, and Professor Mirjam Langeveld, explore the tension between missed diagnosis and overdiagnosis and ask, when does knowing more genuinely help?

Are Inherited Metabolic Disorders More Common and Less Predictable Than We Thought?

N Gold et al

https://doi.org/10.1002/jimd.70094

Screening for Life: Perspectives From Adult Metabolic Specialists on Newborn Screening for Inherited Metabolic Diseases.

M Langeveld, et al.

https://doi.org/10.1002/jimd.70057

Exclusion-based exome sequencing in critically ill adults 18–40 years old has a 24% diagnostic rate and finds racial disparities in access to genetic testing.

American Journal of Human Genetics

J Gold et al

https://www.cell.com/ajhg/fulltext/S0002-9297(25)00238-1

Long-term Penetrance of Disease Variants in Genes Prioritized for Genomic Newborn Screening.

Gold NB, et al.

https://www.medrxiv.org/content/10.64898/2026.06.10.26355380v1 - pre-print not peer reviewed

Phenylketonuria (PKU) was one of the first inherited metabolic disorders to be recognised, but there is still plenty to discover. Silvia Radenkovic and Rodrigo Starosta are joined by Dr Cary Harding and Dr Wendy Smith to discuss evolving treatments, updated management guidelines and where PKU research is heading next.

The views and opinions expressed in this podcast are those of the speakers and do not necessarily reflect those of their institutions or organisations.

A study of rapamycin in Niemann-Pick C raises an important question: what if the success of a treatment depends on a patient's wider genetic background? Dr Andrés Klein discusses pharmacogenomics, modifier genes and why precision medicine may need to go far beyond making the diagnosis.

A Rapamycin Pharmacogenomic Approach for the Childhood Dementia Niemann-Pick C

Benjamín Szenfeld, et al

https://doi.org/10.1002/jimd.70214

In this JIMD Shortcast, first author Arty Selvanathan discusses their study exploring how clinical outcomes relate to biochemical findings in cobalamin C (cblC) disease. What can biochemical markers really tell us about disease severity, and where do their limitations lie?

Clinical Outcomes and Correlation With Biochemical Control in Hydroxocobalamin-Treated Patients With Early-Onset Cobalamin C Disease

Arthavan Selvanathan, et al

https://doi.org/10.1002/jmd2.70091

How much of metabolic control in methylmalonic acidemia is determined by diet, and how much by the microbiome? In this episode, Engin Köse discusses a prospective longitudinal study exploring protein composition, gut microbial changes, and the impact of metronidazole on biochemical control in MMA.

Dietary Protein Modulation, Gut Microbiota, and Metabolic Control in Methylmalonic Acidemia: A Prospective Longitudinal Study

Engin Köse, et al

https://doi.org/10.1002/jimd.70172

In this Shortcast Dr Mark Wijnen presents two cases where Teriparatide was used to treat bone complications in MPD IVB but explains how temporally associated cardiac disease compels his groups to advise caution in its use.

Teriparatide in Two Patients With Mucopolysaccharidosis Type IVB

Mark Wijnen, Evert F. S. van Velsen, J. Gert-Jan Milhous, Esmee Oussoren, Bram C. J. van der Eerden, Margreet A. E. M. Wagenmakers

First published: 13 April 2026 https://doi.org/10.1002/jmd2.70088