When a Heel-Prick Test Finds Something Your Baby Doesn't Have Yet

What an Italian screening programme, a new way of reading uncertain genetic results, and a Dutch cost study tell families about adrenoleukodystrophy found at birth

Newborn screening can now find X-linked adrenoleukodystrophy — a rare inherited condition that can damage the adrenal glands and the brain — in babies who look completely healthy. Three studies published in 2025 and 2026 show what happens after such a result: what screening programmes in Italy and the Netherlands actually found, and how doctors are learning to tell which children truly need years of monitoring.

What this condition is, and why finding it early matters

Every baby born in a country with a newborn screening programme has a few drops of blood taken from the heel in the first days of life. That card of dried blood is tested for a short list of rare conditions that are treatable if caught before symptoms start. X-linked adrenoleukodystrophy — usually shortened to ALD — has been added to that list in a growing number of places over the past decade.

ALD is caused by a change in a gene called ABCD1, which sits on the X chromosome. The gene normally makes a protein that moves a particular type of fat, called very-long-chain fatty acids, into small compartments inside cells where they are broken down. When the gene doesn't work properly, those fats build up — particularly in the adrenal glands, which sit above the kidneys and make essential hormones, and in the white matter of the brain [1].

Because the gene is on the X chromosome, boys are affected more severely than girls. Two problems matter most in childhood. The first is adrenal insufficiency, sometimes called Addison's disease: the adrenal glands stop making enough cortisol, a hormone the body needs to handle stress and illness. More than eight in ten affected boys develop this at some point, and about half of those do so before the age of ten [2]. Untreated, it can cause a sudden, dangerous collapse during an ordinary childhood illness. Treated, it is managed with a daily hormone tablet or granules. The second problem is a form of brain damage called cerebral ALD, in which the protective coating around nerve fibres breaks down. It can be stopped by a bone-marrow (stem-cell) transplant — but only if the transplant is done after the very first changes appear on a brain scan and before the child shows any neurological symptoms. Once symptoms begin, the transplant no longer works [3].

That narrow window is the entire reason for screening. It is also why ALD is such an unusual entry on a newborn screening panel.

How families used to find out, and why that had to change

Before screening existed, there were three ways a family learned their son had ALD, and none of them was good. Some boys were diagnosed after an adrenal crisis — a sudden collapse during a stomach bug or a chest infection — because the earlier signs, tiredness, poor appetite, feeling sick, look like a hundred ordinary things. Some were diagnosed only when a previously healthy schoolboy began losing skills or struggling with vision and hearing, by which point the brain damage was too far along for treatment to help. And some were diagnosed because an older brother or cousin had already been through one of the first two routes. That last path, family testing, has been known for decades to find relatives who carry the gene change but have no symptoms yet [4] — which is what screening now does for everyone, without needing a tragedy first.

Screening became possible when researchers showed that a specific fatty substance, C26:0-lysophosphatidylcholine, could be measured reliably in the dried blood spot and was raised in babies with ALD. New York State became the first place in the world to screen newborns for ALD, in 2013 [5]. Expert groups later agreed what should happen to a child once ALD is confirmed: regular blood tests to check adrenal hormones, and regular brain scans — roughly every six months through early childhood — to catch the first signs of cerebral disease [6], [7]. For young children, those scans usually require sedation or a general anaesthetic.

What happened in Italy over four years

Between September 2021 and June 2025, a pilot programme in the Lombardy region of northern Italy, run across 33 newborn units and coordinated from Vittore Buzzi Children's Hospital in Milan, screened 138,116 babies — about 58 out of every 100 eligible newborns, because families had to opt in [8].

Eleven children — six boys and five girls — were found to carry a disease-causing change in the ABCD1 gene. In every case, the change had been inherited from the mother, who had not known she carried it.

By the time the programme reported, three of the six boys had developed adrenal insufficiency. All three began hormone replacement between one and two years of age. The most important detail for families is this: none of them had any symptoms at the time it was diagnosed. The blood tests picked up the problem months before the child would have looked unwell, which is precisely what the monitoring is for. Every family was also given a written emergency letter explaining what to do, and what a hospital should do, if their child became seriously ill — a simple safeguard in a condition most emergency doctors will never have seen.

All six boys were neurologically well, with normal brain scans where scans were done. Their growth was mostly normal, but one finding is worth knowing about. The children were offered a special diet low in very-long-chain fatty acids, along with a supplement known as Lorenzo's Oil. Over two years their height gradually slipped below average, and the two children drifting furthest were among those whose families had found the diet hardest to follow — while the diet did not bring the fatty acid levels in their blood back to normal. The diet is demanding, its benefit is still unproven, and it needs careful growth monitoring if it is used at all.

The hardest result to receive: "we're not sure"

Not every positive screen leads to a clear answer. Sometimes genetic testing finds a change in the gene that nobody has seen cause illness before. Doctors call this a "variant of uncertain significance". It is roughly three times more common in newborn screening than in testing done because a child is already unwell [9], and it leaves parents in an exhausting position: a healthy baby, a worrying letter, and years of scans under anaesthetic with no way to know whether any of it is necessary.

A second study published in 2026 offers a way out. The Grey Zone Project — run by the patient organisation ALD Connect, with testing carried out at a specialist laboratory in Amsterdam and partner centres in Germany and the United States — collected careful measurements from 1,627 people without ALD and 196 men and boys known to have it [10]. By comparing them, the researchers worked out three bands. Below a certain level, the child does not have ALD at all. In a middle band, the risk of childhood adrenal or brain disease is low. Above the upper level, the risk is real and monitoring is needed.

When they applied these bands to 108 samples from children with uncertain results, half of the gene changes turned out to fall in the "no ALD" band, and most of the rest in the lower-risk band. One important practical point: the confirming blood sample has to be taken after about three months of age, because newborn blood naturally contains more red blood cells and that pushes the reading up artificially.

The researchers are careful to say this is not a replacement for standard genetic testing, and that it needs to be tested in more children and more laboratories before it is used to stop a child's scans. But it is the first serious attempt to answer the question parents actually ask, which is not "is this variant pathogenic?" but "does my son need this?" The same difficulty — sequencing finding more than it can explain — runs through newborn screening generally, and is explored in a companion In[Neo]Sight article on genomic newborn screening.

Is screening worth what it costs?

The third study asked a question health systems have to answer: does adding ALD to newborn screening represent good value [11]? Dutch researchers modelled the programme their country added in October 2023. The test itself is inexpensive — about EUR 2.21 per baby — but because the condition is rare, finding one affected child costs roughly EUR 40,630, and the years of monitoring that follow add considerably more. Balanced against the healthy years gained by preventing adrenal crises and catching brain disease in time, the result came out at about EUR 34,084 for each additional year of good-quality life, which falls within the range the Netherlands considers worthwhile.

The researchers were honest about the uncertainty. They did not include children with uncertain results in the model at all — and, as they point out, monitoring children who were never going to become ill is money and worry spent for nothing. That is the gap the risk bands are designed to close, which is why these two studies belong together.

What this means for your family, and what comes next

If your son has been identified through newborn screening, the most likely path is years of feeling entirely well while being checked regularly. The checks are not a sign that something is wrong; they are the thing that keeps treatment available. Adrenal problems, if they come, are treatable with daily hormone replacement, and knowing about them in advance turns a potential emergency into a routine prescription. Ask your team for a written emergency plan, and make sure everyone who cares for your child knows where it is.

If your son's result was uncertain, it is reasonable to ask whether a confirmatory measurement after three months of age could clarify how much monitoring he really needs. And because the gene is nearly always inherited from the mother, a positive result usually means other relatives should be offered testing and counselling too — including women, who rarely develop the childhood forms but can develop mobility problems in adult life [12].

Researchers are now working on three things: following screened children long enough to confirm that brain disease is caught in time, testing the risk bands in more laboratories so they can be used with confidence, and improving treatments — including gene therapy, which has stabilised early brain disease in boys without a matched bone-marrow donor [13]. Early evidence already shows that screened children reach an adrenal diagnosis far earlier than those found only when they fall ill [14]. The remaining work is about making that benefit reach every child who needs it, and sparing the monitoring for those who don't.

References

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