Newborn screening for tyrosinaemia – are we making headway?

On 2 February UK National Screening Committee (UK NSC) announced the recommendation that tyrosinaemia type 1 should be screened for at birth in the UK. This is welcome news for future babies born with tyrosinaemia type 1 and their families. Genetic Alliance UK has been critical of the UK NSC's decision-making process for rare diseases (see BioNews 1023), so we were keen to see this first addition since 2015 as a turning point, and perhaps an indication that UK NSC is beginning to recognise and adapt to the challenges of making decisions about rare genetic conditions.

Tyrosinaemia type 1 is a rare genetic condition that can damage the liver, kidneys and the nervous system if it is not identified and treated quickly. Support for tyrosinaemia type 1 is provided by Metabolic Support UK which is among the group of advocates in the Newborn Screening Collaborative who should be congratulated on their work to advocate for this screening process. It's been a long slog.

As the recommendation notes, the condition was considered for addition in 2017 and again in 2022. There was also a review in 2014 and the first rejection of a proposal to consider this condition was in 2005. Having started the review cycles so long ago, the UK now follows 16 EU member states and Norway in this decision. In 2011 there were six EU member states (not counting half of Belgium) who were screening for the condition. Medicinal treatment for the condition was launched in 2005. These are dates to worry rare condition communities.

The first breakthrough drug for spinal muscular atrophy (SMA) became available on the NHS in 2019 one year after the UK NSC first rejected a proposal to add the condition to the heel prick test. There have been two more NHS-funded treatments since. SMA is a rare genetic condition that causes progressive muscle weakness and loss of movement due to muscle wasting. Without newborn screening (or an affected elder sibling) irreversible progression of the condition must occur before diagnosis can be made and treatment can be delivered.

This delay leaves children with permanent loss of muscle function despite the delivery of the treatment. The UK NSC announced a new review of SMA in 2022 following their three-year review cycle, and there is also a study currently running in the Thames Valley. Perhaps the 2019 treatment funding decision should have triggered an earlier review? The UK SMA Newborn Screening Alliance would estimate that more than 250 children have been born with SMA since that first drug became available in England.

Adrenoleukodystrophy (ALD) was first successfully treated in 1990. ALD is a rare genetic condition that causes a progressive loss of physical and mental skills in boys. Alex TLC holds a database on the diagnosis of ALD and its treatment with haematopoietic stem cell (bone marrow) transplantation in the UK. Since the start of the database in 2004, 115 boys have been diagnosed with ALD, yet only 17 have been treated successfully – mostly due to an elder brother who was also diagnosed with ALD, but too late for treatment – showing how important early diagnosis is.

Since the first review of ALD as a candidate for the newborn screening programme in 2017, the Alex TLC database holds records for 29 boys diagnosed with untreatable cerebral ALD, nine of whom have since died. ALD has now been reviewed twice and Alex TLC has spent £80,000 on staff time on the application process and commissioning research to satisfy the UK NSC's evidential requirements.

Could the tyrosinaemia announcement be a positive sign for those working to get SMA and ALD approved for screening? A fortnight later, the UK NSC published a blog, which helps put the tyrosinaemia announcement into context.

The committee recognises that '[m]aking recommendations on rare diseases is particularly difficult because their very rarity means there is often a lack of high-quality evidence from the usual research methods such as randomised controlled trials.' We would go further and say it is by definition very difficult to have this quality of evidence about rare conditions, and to gather it takes disproportionate amounts of time and money.

This recognition is a great sign, as the UK NSC is a delivery partner for Action 1 of the England Rare Diseases Action Plan 2022 which commits the Department of Health and Social Care 'to improving how decisions are made across the UK on newborn screening for rare diseases.'

Then: '[s]everal reports have highlighted differences between countries in their approaches to screening for these conditions.' Genetic Alliance UK is among the organisations that regularly communicate that there are more than 20 European countries screening for more conditions than the UK with most of those screening for 20 conditions or more. We believe there might be a consensus outside of the UK that we could learn from. Tyrosinaemia type 1 brought the UK's total to ten conditions.

Other UK health decision-makers have taken the rare disease challenge recognised by UK NSC and adapted it. The Scottish Medicines Consortium has its ultra-orphan pathway and NHS England has its highly specialised services based on advice from its Rare Disease Advisory Group. This kind of adaptation may be an element within other nations' screening approval processes.

Instead, the UK NSC blog explains that the UK is an outlier as 'one of only two countries to state in its evidence review criteria that "clinical management of the condition [being screened for] and patient outcomes should be optimised in all health care providers prior to participation in a screening programme"'. For many rare diseases, it is hard to see how that would be feasible when the consequences of late diagnosis are so severe.

Finally, under the title 'UK NSC's rigorous approach', the blog commits that: '[t]he committee will continue to set the evidential bar for screening deliberately high because the harms of screening, including false positive and false negative results, overtreatment, treatment risks and anxiety, can outweigh the benefits.' Rigorous processes need not have high evidence thresholds.

From this inflexible position, it might not be possible to improve how decisions are made across the UK on newborn screening for rare diseases. We need to lower that bar to account for the fundamental challenges inherent in decisions about rare conditions. We can do it with a robust, evidence-based process and with academic rigour. But if we don't lower it, we will continue to have a process that makes us wait years to catch up with other nations' decisions, requiring charities to spend tens of thousands, while babies get treated too late.