The importance of early diagnosis and views on newborn screening in metachromatic leukodystrophy: results of a Caregiver Survey in the UK and Republic of Ireland

Patient demographics

A total of 24 patients were included in the study, representing 20 families. This represents around half of all patients known to the patient organisations. Respondents were mostly parents of patients that were alive at the time of the survey (n = 21), with the remaining comprising bereaved parents (n = 2) and bereaved carergivers (n = 1). The median age of patients was 7.3 years, and three patients were deceased. One third (n = 8) of patients had a sibling with a confirmed diagnosis of MLD. Of the patients in the study, thirteen had late infantile MLD, six had early juvenile MLD, two had late juvenile MLD and three had adult onset MLD. In total, 58% (n = 14) were female and 88% (n = 21) were from England, with the remaining patients from Republic of Ireland (8%, n = 2) and Northern Ireland (4%, n = 1).

Diagnostic delay and disease progression

Diagnostic delay was defined as time from the first symptom to diagnosis of MLD. This was a qualitative measure reported by the parent or caregiver. Six patients were excluded from the analysis of diagnostic delay, of these, four patients were diagnosed before symptoms due to the diagnosis of an older sibling and two patients failed to provide the age at which first symptoms appeared. The median age of patients when symptoms first appeared was 2.8 years, and the median age of patients when diagnosed was 4.3 years (Table 1). Diagnostic delay was between 0 and 3 years, with a median of 1 year (n = 18), during this time deterioration was rapid, especially in earlier onset MLD (Table 2).

Table 1 Patient characteristics Table 2 First symptoms and symptoms at diagnosis (mobility, speech, swallow, and continence) Late infantile MLD

Three patients with late infantile MLD were diagnosed before symptoms appeared due to diagnosis of an older sibling, and inconsistent answers regarding age at symptom onset and diagnosis were reported for one patient. These four patients were therefore excluded from the analysis of diagnostic delay. The median age of patients when symptoms first appeared was 1.3 years (n = 9). The median age of patients when diagnosed was 2.5 years (n = 9, Table 1). Diagnostic delay was between 0 and 2.3 years, with a median of 0.8 years (n = 9, Table 1), and deterioration was rapid (Table 3, Late infantile).

Table 3 Case studies: pathways to diagnosis

While most children had met their early developmental milestones for speech and learning around two thirds had not achieved their walking milestones. The most common first symptoms included issues with walking (n = 9, Table 2), difficulty swallowing (n = 4, Table 2), hypotonia (n = 5, Table 4), and hypertonia (n = 4, Table 4). One parent described the many issues that were present from an early age:

Table 4 Other first symptoms and symptoms present before diagnosis (including first symptoms)

As a baby [Name] was floppy, breathing was a concern and had a poor suck and swallow making feeding hard. This was suggested to be due to an asymmetric jaw. He had a small fontanelle, which is what got us the initial appointment with the paediatrician. His head size was a concern and his fingers didn’t always open. As time went on [Name] had pronated feet, making it difficult to stand and this opened up the door to physiotherapy, before he was two. [Name] struggled to eat food, this was a long journey right from the beginning and alongside this speech was delayed.

Another parent described how issues with walking had been one of the first signs that something was wrong:

She’d started to walk, but she wouldn’t progress from walking holding onto things to walking independently. So, when she got to two years old, that’s when we first went to the doctors, thinking that maybe something wasn’t quite right, because she just wasn’t going past that next stage.

Rapid disease progression was seen in the time taken to reach diagnosis. By the time of diagnosis, 50% (5/10) were wheelchair dependent, 30% were unable to speak, and 50% were tube fed (Table 2). One parent describes how their child went from crawling up and down stairs to being completely bedbound over a period of six months from diagnosis:

…we noticed that her walking even when holding onto things was then becoming more difficult for her. [By the time of diagnosis] she had deteriorated more. Her speech had slurred quite significantly, and she was dribbling excessively. And her sleep was really disturbed as well. She would take a long time to fall asleep and she would cry a lot as well. She was in pain, but it wasn’t obvious where she might be in pain.…it wasn’t long after her diagnosis that she had her first seizure and we had the ambulance out.

Mobility issues were followed by a rapid decline in speech and cognition for another child in a 9–12-month period, between the age of 2–3 years. As physical decline occurred before cognitive decline, the rapid loss of skills was particularly distressing for the child and parents. The child had deteriorated from being able to eat and drink independently, to total dependence on their parents. By the time of diagnosis, he was being fed by a naso-gastric tube and needed a gastrostomy at age 3 years.

…he was speaking very well compared to others his age. He was very talkative and fine at two. At that age then he began to slow down speaking and slowly but surely losing all his ability. He was really quite well developed at two years of age as a little boy but over the course of about nine months all that disappeared on him. From that age of two to three where he lost his physical ability before his mental faculties was very traumatic for him and for us and physically painful and emotionally upsetting and confusing and distressing for [Name] and for us. It was terrible to watch him.

Another parent described the loss of skills that occurred before her child was diagnosed with MLD. The child had been pulling themselves up to stand, was crawling, and was quick at going upstairs. By the age of 2, the parent started to notice a decline and the child started using a walker. In less than a year, the child had stopped crawling, walking, speaking and eating.

Like he didn’t go up the stairs as quick as he did. He wasn’t pulling himself to stand as much. He was sitting more. And if he did there was a bit more reluctance there.” The child had an MRI and was diagnosed with MLD 6 months later. “He started showing less interest in doing things. And then by the time we came round to the MRI scan, he’d already not been going up the stairs. He’d already not been pulling himself up to stand. He was still crawling, and he crawled most of that year.…and then by the Christmas he wasn’t doing any of it. So no crawling, no talking, no walking, no eating. We had three months and it all just went really quickly.

In most cases, the diagnostic journey was long, with multiple referrals, doctors, and specialists required to eventually confirm MLD disease, often referred to as “diagnostic odyssey”. In two patients, the deterioration between the first symptoms and diagnosis was extremely apparent (Table 3, Late infantile: case study 1 and 2). In the case of one child, first symptoms were observed at 3 months old, and the parents were concerned that the child had a degenerative condition from an early age. The child was seen multiple times by the GP with feeding issues, chest infections and concerns over breathing at night. The child was referred to a paediatrician who according to the parents, ultimately disregarded their concerns. Subsequent visits to the GP and hospitalisation led to a second paediatrician referral:

We got rushed into the hospital and that’s where I met the second consultant, where I just broke down and said, I know he’s got a chest infection, but I think there’s more than this. I think there’s more to it than this and I feel like nobody’s listening to me. Like the doctor’s not listened to me, the other paediatrician didn’t listen to me. And I feel like we just need some help.

The child was seen by a physiotherapist and then a midwife, who referred the child to a community paediatrician. Assessments were carried out and the parents were told that the child was just delayed. The mother persevered, and the child was referred to a neurologist. Finally, late infantile MLD was diagnosed at 2 years and 6 months (Table 3 Late infantile: case study 3).

Early juvenile MLD

One child with early juvenile MLD was diagnosed before symptoms appeared due to diagnosis of an older sibling and were excluded from the analysis of diagnostic delay leaving a total of five children who were symptomatic before diagnosis. The median age of patients when symptoms first appeared was 5.0 years (n = 5), and the median age of patients when diagnosed was 6.0 years (n = 5, Table 1). Diagnostic delay was between 0 and 3 years, with a median of 1.2 years (n = 5) and during this time deterioration was rapid (Table 3, Early juvenile).

All children had met their early developmental milestones for speech, learning, and walking. Initial symptoms included issues with walking, toileting, and learning/behavioural problems (Tables 2 and 4). At diagnosis, 60% (n = 3) were starting to use a wheelchair, 60% (n = 3) had difficulty speaking (Table 2), and 60% (n = 4) had uncontrollable crying (Table 4). One parent described the rapid progression from first symptoms that were noticed when the child started pre-school to diagnosis six months later:

Yes, certainly she started becoming more clumsy, I would say. But even up until the MRI, which happened about two weeks after the computerized tomography (CT) scan, she was still walking normally. Although maybe slightly heavier on her feet, almost like a flat-footed type sound she was making. But then after she’d had the MRI, she almost… She just deteriorated quite rapidly after the MRI. But I would say maybe a week to two weeks after the MRI, you could really see that she was struggling with overall walking. She was still walking, but she was leaning forward for balance reasons, I guess. And she couldn’t run for any length of time either. It was very quick, within a couple of months. Certainly, within three months of having a CT scan, she’d stopped walking.

In one case, the first symptoms appeared at 5 years old. The child had previously been bright but had lost interest in reading, become clumsy, and had wet themselves a few times. The school had also reported behaviour issues. The mother of the child recounted how she felt:

I was quite often just shrugged off as a neurotic mother, I think. There was various things that just weren’t adding up to me. Just little things. And our initial thoughts were that she wasn’t settling in very well for school. She’d just started reception. And I had approached the school for help many times weekly. And probably on a weekly basis, I was in asking for her to be referred somewhere. And I was just constantly met with… Just made to be obviously neurotic, really. And she was just a naughty, difficult child.

After the child’s nursery teacher spoke to the doctor, the child had a CT scan, and a brain degenerative condition was confirmed. The child had an MRI in July and by September was unable to walk. Early juvenile MLD was diagnosed at 5 years and 6 months old (Table 3, Early juvenile: case study 1). In another case, the first symptoms appeared at 3 years old when the child began to fall over. A decline in motor function and issues with behaviour followed and after much perseverance from the parents to achieve a diagnosis, early juvenile MLD was finally diagnosed 3 years later (Table 3, Early juvenile: case study 2).

Late juvenile MLD

The two patients were symptomatic before diagnosis and some disease progression was observed in this period. The median age of patients when symptoms first appeared was 10.5 years and the median age of patients when diagnosed was 11.5 years, with a median diagnostic delay of 1 year (n = 2, Table 1). In late juvenile MLD, both patients had met all their early developmental milestones. Initially, 50% (n = 1) reported issues with walking (Table 2), 50% (n = 1) presented with hypertonia, and 50% (n = 1) had learning difficulties (Table 4). At diagnosis, both patients had started to lose the ability to walk and had learning issues. One patient had hypertonia, and one patient had memory and concentration issues (Tables 2 and 4).

Adult onset MLD

All three patients were symptomatic before diagnosis, however, age at first symptoms, diagnosis, and subsequent delay in diagnosis were only recorded for two patients. The median age of patients when symptoms first appeared was 22.5 years, and the median age of patients when diagnosed was 24.5 years, with a median diagnostic delay of 2 years (Table 1).

One patient had not met their early developmental milestones, initial symptoms were a change in behaviour and cognitive deterioration (Table 4). In the case of one patient with adult onset MLD, the first symptoms were observed at 20–21 years old. The parent described how the first symptoms were appearing while their child was at university. Doctors initially thought the problem was psychiatric and it was not until the patient lost the ability to tell the time that further tests were done.

I think the difficulty we had; he was away at university. And he was able to mask a lot of the symptoms. So, I suspect the symptoms had actually started a lot earlier. But we first really noticed when [patient] was about 20, 21 that he was becoming forgetful and that. And that’s really when we took him to the doctors, and we finally, finally got a diagnosis when he was 23 after being lumped into psychiatry. No, what really led to [diagnosis] was when he suddenly stopped being able to tell the time. I finally managed to get him out of the hands of the psychiatrist and get an MRI scan done.

The parents strongly believed that an earlier diagnosis would have led to a far brighter future for their son:

If we’d got the diagnosis a year earlier, he would probably have been living independent life still, albeit supported. Because it was that last year, was really when the symptoms started to manifest. And it was obvious we couldn’t leave him alone for any length of time. We had to monitor what was happening. He’d put a meal in the oven to cook and then go out.

Adult onset MLD was diagnosed at 23 years old.

NBS: family views

Responses were received from all 20 families taking part in the survey. In one family, both the father and mother replied, giving 21 responses in total. The questions and responses are summarised in Fig. 1.

Fig. 1figure 1

Family views on NBS: results from the online survey

Information about NBS and the heel prick test

The majority (79%) of parents received information from healthcare professionals about the purpose of NBS. Only 2 parents (10%) were not able to recall their child’s NBS heel prick test.

Interpretation of screening results

Approximately half of respondents were informed of the meaning of positive and negative results (53%), and just under half understood the possibility of obtaining a “false positive” result (47%).

Outcome of NBS results and effect upon reproductive choices

Most respondents (80%) considered an undetected case of MLD at birth as more harmful than a false positive screening result. When respondents were asked if NBS for MLD would have helped to inform their reproductive choices, 86% said that it would have helped to make an educated decision, whilst the remaining respondents said that it would not have affected their reproductive choices or they were too old by the time of diagnosis. The majority of respondents (86%) believed detection at birth would have changed their child’s future. One parent described the torment of realising they were too late for medical intervention:

Yes, [child] had no symptoms pre diagnosis. She did have dyslexia but so do I and her sister and cousin. [She] woke up one morning saying she could not walk. She had a scan 2hrs later then a blood test to confirm scan diagnosis. We was shell shocked and at the time not very good at researching. The doctors did not tell us about trials. We have to live with knowing we was too late. A test at birth could of changed that.

Another respondent expressed their gratitude for an early diagnosis as a result of familial MLD screening offered at birth and how it had changed their child’s future:

It did and it absolutely has I will be forever grateful for his early diagnosis thanks to his older sister.

Three respondents with offspring who were diagnosed with adult onset MLD thought that detecting MLD at birth would not have changed their child’s future. One respondent said:

No because they lived a good life, went to school, got jobs, married and had families.

One parent felt that NBS for MLD would not have influenced their child’s future as treatments were not yet available:

Probably not as treatments to delay or prevent symptoms were not available until after his condition was already significantly degenerated.

Support for NBS

Overall, there was a high degree of support for NBS among caregivers, with 95% describing it as very or extremely important and 5% describing it as not at all important. Twenty out of 21 respondents were willing to support an application for MLD to be added to the UK NBS programme.

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