Rare Metabolic Diseases: Advancing Understanding, Improving Outcomes

The latest event organised by PET (the Progress Educational Trust) brought together clinicians, researchers and patient advocates to discuss the challenges faced by people with inherited metabolic diseases (IMDs). The presentations covered diagnosis, treatment, support and broader public understanding and awareness of IMDs.

Event chair and PET director Sarah Norcross started by explaining that a vast range of diseases involve disruption of human metabolism, and thousands of these conditions can be inherited. These IMDs are rare, in that the precise cause and consequence of each disease occurs in a relatively small number of people. Collectively, however, IMDs are common. Many IMDs affect the central nervous system, but any organ system can be affected, with potentially devastating consequences for patients and families.

The first speaker was Jonathan Gibson, lead for campaigns and communications at Metabolic Support UK, who provided an overview of the charity's work. Metabolic Support UK provides multidisciplinary support, advocacy, and policy engagement, working both nationally and internationally. Gibson highlighted the challenges faced by affected families, which can include lack of awareness, difficulties accessing benefits, employment barriers, and the practicalities of accessing healthcare for rare conditions. For example, patients with IMDs living in Cornwall may need to travel to London for treatment.

Gibson explained that there are just under 2000 IMDs, of which seven are currently included in the newborn screening panel for England – the 'heel prick test', carried out when a baby is around five days old (see BioNews 1120, 1123, 1180 and 1294). Adults affected by IMDs can struggle to maintain employment due to symptoms such as fatigue and pain, and often require advocacy to access reasonable adjustments in the workplace. Navigating healthcare can be particularly challenging, as this may require coordination across multiple services. Gibson highlighted the charity's targeted campaigns, such as those addressing hyperammonaemia, and broader initiatives like the 'Living Well' movement.

Metabolic Support UK carries out research into quality of life for patients with IMDs, and plays a key role in influencing policy – for example, participating in discussions to expand the number of IMDs included in the newborn screening panel. The charity also supports research, including patient engagement strategies for clinical trials, and works to ensure that patient-reported outcomes reflect the needs of the community.

The next speaker – Dr Srividya Sreekantam, consultant in paediatric inherited metabolic disorders at Birmingham Women's and Children's Hospital NHS Trust – provided a clinical overview of IMDs, demonstrating the diversity of symptoms and the critical importance of early diagnosis. She explained how rare genetic mutations can cause enzyme deficiencies that disrupt metabolism, leading to the accumulation of toxic substances and a wide range of clinical presentations, from infancy through adulthood.

Dr Sreekantam described a wide range of clinical 'red flags' that can indicate a metabolic disease including developmental delay, organ enlargement and unexplained neurological symptoms. She emphasised that timely diagnosis is essential, as early intervention can dramatically improve outcomes.

Biochemical, enzyme, and genetic testing can all be used to help diagnose IMDs, and treatments include dietary restrictions, enzyme replacement therapy, substrate reduction therapy (thereby reducing the harmful substances that accumulate in cells), and gene therapy.

Dr Sreekantam described the case of a child with metachromatic leukodystrophy, who received enzyme replacement therapy as her symptoms were too advanced to receive gene therapy. This highlights the need for early diagnosis of IMDs, both to ensure effective treatments for affected individuals, and to enable genetic testing of pre-symptomatic siblings. She also stressed the importance of genetic counselling to support families planning future pregnancies.

Professor Evangeline Wassmer, consultant in paediatric neurology at Birmingham Women's and Children's Hospital NHS Trust, spoke about IMDs that cause neurological symptoms. She highlighted the limited evidence base for many interventions, noting that while some medications and therapies are standard practice, robust data on efficacy and safety are often lacking. Professor Wassmer described the broad range of symptoms that can affect patients including movement difficulties, epilepsy, behavioural issues, and sleep disturbances.

Professor Wassmer explained that motor symptoms can range from unsteady gait to severe stiffness and movement disorders. Treatments can include medication, physiotherapy, and – in some cases – surgical procedures. Epilepsy management requires careful selection of drugs, as some are not suitable for treating specific metabolic disorders. Behavioural and mental health challenges are common, but access to appropriate services is often limited.

Professor Wassmer called for more research to guide treatment decisions, particularly regarding when and how to intervene, and stressed the need for better data to inform clinical practice.

Next, Frances Platt – professor of biochemistry and pharmacology at the University of Oxford – described recent progress in the treatment of lysosomal storage disorders, particularly for Niemann-Pick disease Type C (NPC). This rare inherited neurogenerative disease involves accumulation of lipids in the liver, brain and spleen, causing a wide range of symptoms.

Professor Platt described the evolution of available treatments, from enzyme replacement therapy – which requires invasive intravenous administration – to the newer small-molecule drugs, that work by reducing enzyme substrate or enhancing enzyme activity. Importantly, approved small-molecule drugs for NPC may have the potential to treat other disorders, since they target downstream effects of the disease. They may also have synergistic effects, providing more effective symptomatic control if used in combination.

Professor Platt highlighted the importance of real-world data collection and the contribution of the International Niemann-Pick Disease Registry. This international, patient-held registry of clinical outcomes in NPC can help to guide the use of combination therapies, and thus optimise patient outcomes.

The final speaker was Dr Julien Baruteau, consultant in paediatric metabolic medicine at Great Ormond Street Hospital for Children and the UK principal investigator for OTC-HOPE (see BioNews 1272). This clinical trial is for a novel gene therapy to treat ornithine transcarbamylase (OTC) deficiency, a serious genetic condition in which ammonia is not broken down by the liver and instead accumulates in the blood. Early diagnosis and treatment are essential; otherwise, the brain can be affected. Currently available treatments for OTC deficiency are a low-protein diet, ammonia-lowering drugs, and liver transplantation.

Dr Baruteau explained that in the OTC-HOPE trial, a gene 'knock-in' approach is used to insert a working copy of the OTC gene into a precise location in the genome of the liver cells, via genome editing. This one-time treatment ensures that the therapeutic gene is copied every time cells divide, making it effective for babies and children as their livers are growing rapidly. One of the first patients treated was Tomas, who received a single two-hour infusion of the gene therapy when he was six months old.

Dr Baruteau emphasised the many different hospital teams required to coordinate and deliver the treatment. He finished with a quote from Tomas' parents, who described the hope the gene therapy trial gave them following his initial diagnosis, when they were told the only option would be a liver transplant. 'Thanks to this treatment, he no longer needs a transplant. His ammonia levels are now stable, and he can eat normally again – still with a cautious diet but without the strict limitations we once faced. For us, this is already a huge step and something we are deeply grateful for.'

A wide-ranging discussion sparked by audience questions followed the presentations, covering aspects including diagnostic challenges, access to treatment and support, costs of 'one-off' gene therapy compared to lifetime treatment with other therapies, and the long-term safety monitoring of patients treated with gene therapies.

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PET is grateful to Amicus Therapeutics for supporting this event.