X-linked adrenoleukodystrophy (ALD) is a metabolic disorder caused by a pathogenic variant in the ABCD1
gene that results in a broad phenotype, including adrenal insufficiency and cerebral demyelination, leading to neurological deficits and progressive paralysis [1
]. Patients with ALD are asymptomatic at birth; however, approximately 80% of males with ALD will develop adrenal insufficiency during their life, usually before adulthood. It is estimated that all males and many females with ALD will develop progressive myelopathy. This may present as spastic gait, spastic paraparesis, and sensory ataxia [2
]. The most severe form of-ALD is cerebral ALD (cALD), which affects approximately 38% of males with the ABCD1
gene variant [3
]. Symptoms usually appear between 5–10 years of age followed by death or severe disability within several years. When cerebral manifestations appear in childhood, the earliest symptoms are typically related to cognitive dysfunction such as declining school performance and behavioral issues. Other symptoms may follow, including visual and sensory agnosia, decline in motor skills, and epileptic seizures [2
]. It is estimated that more than 80% of females with the ABCD1
gene variant may develop symptoms of myelopathy or neuropathy by age 60. Females are usually not impacted by adrenal insufficiency or cALD [3
Hematopoietic stem cell transplantation (HSCT) is a well-established treatment proven to halt cerebral demyelination for boys with early-stage cALD [1
]. Periodic brain MRI’s can determine whether a boy at risk for cALD is an appropriate candidate for HSCT by utilizing an MRI severity scale known as the “Loes scale” (range, 0 to 34) [4
]. A score of ≥1 is considered abnormal and treatment success is highest in patients with scores ≤9 [4
]. Transplant-related mortality is less than 5%; however, there are significant morbidity concerns including graft rejection, graft-vs-host disease, and associated long-term immunosuppression [3
Given the potential benefits of early diagnosis in boys at risk for ALD, New York was the first state to add ALD to their newborn screening (NBS) panel in 2013, followed by Connecticut, California, Minnesota, and Pennsylvania. At least 14 states now screen for ALD, and many others are mobilizing to begin screening in the near future [7
To date, evaluations of NBS programs have focused primarily on the statistical outcomes of the screening program but have failed to include longer-term clinical outcomes of children identified through ALD NBS or on the impact that positive screening results have on families. Thus, this study explores family perspectives on California’s ALD NBS program to identify areas of concern and to offer health care providers (HCPs) recommendations that go beyond treating only the medical expressions of this condition.
Ten mothers were interviewed about their experience with California’s NBS program for ALD. No fathers volunteered to be interviewed for this study. Demographic information is summarized in Table 1
. The majority of mothers had sons (6/10) originally identified on NBS, as compared to daughters (4/10). Notably, five children were found to have a variant of uncertain significance (VUS); four were found to have a known pathogenic variant; and one had no variant identified but presented with elevated very long chain fatty acids (VLCFAs) only. As per the parent’s reports, none of the children exhibited symptoms of ALD at this time.
3.1. Communication of Positive NBS Results
All mothers received an initial phone call regarding the NBS screening result. Six received the results from a non-genetics provider, usually a pediatrician and in one case a nurse, while three families received the news from a geneticist. One family was unsure of the role of the individual who conveyed the initial results over the phone. Regarding prior knowledge of ALD, only one family was aware of the condition due to a previously diagnosed family memberand thus prepared for possible results found on NBS. The remaining nine families had no prior knowledge of ALD. Seven mothers reported a lack of understanding or familiarity with ALD by the HCP conveying the results.
“I was shocked. I was in tears. She [pediatrician] didn’t seem like she knew anything. So it wasn’t like I could ask her any questions.”
Given the limited information some HCPs provided over the phone, many mothers left the initial phone call with fear and confusion regarding if and how their child was affected.
“I was a mess. I had no idea what was going on. All I knew was my daughter has this thing and she’s gonna die.”
Eight mothers responded negatively to hearing this news, describing feeling “shock”, “fear”, “anxiety”, and “confusion”. The majority of mothers (80%) reported searching the internet for ALD after learning the results. This search yielded overwhelmingly disturbing results, which often catapulted families into further distress.
Typically, once a family was notified of the NBS result, they were referred to a specialist, usually a geneticist, for confirmatory testing. The amount of time between receiving the phone call and seeing a specialist varied significantly. Four families were seen by a specialist within 1–2 days, two within two weeks, and four families had to wait a month or more before seeing a geneticist. Typically, males identified on NBS were seen more quickly than females, unless females had older brothers. In one circumstance, a family moved homes during this time period, which may have led to the long wait time. Other factors that may have led to longer than expected wait times were limited genetics providers in the area and insurance issues. Regardless of time spent waiting, mothers reported feeling “panicked”, “stressed”, and “concerned”.
Unlike the initial phone call, the majority of mothers (70%) reported that the information provided by the geneticist was “sufficient”. The three mothers who reported that the information provided was “not sufficient” expressed frustration that the geneticist had limited first-hand experience with ALD and thus was unable to offer more nuanced information.
“Essentially he and the counselor just gave us a print-out of adrenoleukodystrophy. The specialist didn’t know what adrenoleukodystrophy was before Jeremy. We were the first.”
Three mothers reported feeling most reassured after meeting with the neurologist involved in the ongoing care of patients with ALD. Five mothers expressed a desire for the initial in-person consultation to include the geneticist and genetic counselor, as well as the neurologist and endocrinologist.
“If my kids are going to be seeing neurology and endocrinology for the rest of their lives, I want one of those team members in that room with genetics. You shouldn’t have let me walk out with so much fear.”
3.2. Emotional Progression and Coping with the NBS Result
Interviews took place between 4 and 26 months after receiving the initial phone call. By this time, 60% of mothers reported feeling moderately or very hopeful about their child’s future, and 70% reported a positive progression in their emotions about their child’s diagnosis, even though much sadness and uncertainty remained. Differences in emotional progression were noted in mothers of sons versus daughters, with the former generally reporting more hopefulness and acceptance of their son’s result and possible ALD diagnosis when compared to mothers of daughters. This discrepancy may be explained by mothers’ misunderstanding of their daughter’s NBS result. Two of the three mothers with daughters expressed concern that their child may become severely disabled or die in childhood, even though females generally develop only the milder symptoms of myelopathy in adulthood.
Mothers who experienced a positive emotional progression regarding their child’s NBS result utilized varied coping approaches, including relying on faith, seeking information, and maintaining hope. Half of the mothers mentioned the importance of religion in their ability to adjust to their child’s diagnosis.
“Religiously, I don’t believe that just because you die it’s the end of that life, so it’s not as much of a loss.”
Information seeking was reported by 7/10 mothers as a major coping strategy. This included going back to school, actively engaging with the ALD community, attending conferences, researching and participating in clinical trials, and gaining an in-depth understanding of the condition, possible progression, and outcomes.
Mothers of both boys and girls struggled with a lack of concrete answers regarding their child’s NBS result and possible disease progression.
“I think that’s the worst part, because you don’t know. They told me they expect her to have a normal childhood, but then what if she doesn’t? And if she goes all her life and she has normal childhood and then what if it hits in her adult years and she can’t live the way that she wants to live. As a parent, you already have a lifetime responsibility. But, now, I’ve created a long-term responsibility for myself.”
One mother reported denial of potential future health impacts on affected sons to better manage the painful emotions associated with this train of thought.
“I try not to think about the future too much because it freaks me out. I try to envision positive things, but if I think too far in the future sometimes my mind goes: What if he’s in a wheelchair? What if he’s dead? So I really don’t think about it very often. I guess that’s the way that I deal with it.”
At the time of these interviews, none of the children identified on NBS were symptomatic. Thus, although uncertainty was often mentioned as a major source of stress, it also offered mothers hope: hope that their child may never develop the fatal form of ALD, as well as hope that, given their young age, better treatments and potential cures would become available.
“In 10, 20 years there may be a medication. Or the gene therapy is going to be the gold standard and we’re good. I do feel lucky that he is so young and we have time on our side.”
3.3. Impact on Family Dynamics
Four mothers reported that having the ALD diagnosis in the family negatively impacted the relationship with their spouse, three reported a positive impact, and three reported no impact. In two of the families reporting a negative impact, the father was found to carry a pathogenic ABCD1 variant and was diagnosed with ALD. As a result, two mothers found themselves concerned about both their daughter’s and their partner’s health. One mother shared the difficulty her husband was having with his own diagnosis and how it affected their relationship.
“He [husband] went into a depression. We didn’t have any means of communication. I eventually got him to go to therapy, but even during his time in therapy, he wasn’t coming home and talking to me. It’s been a rough almost two years.”
Blaming one another for the diagnosis in the family, the burden of juggling countless medical visits, denial of the diagnosis on behalf of male partners, and deciding to stop trying for more children were also reported as factors that negatively influenced the relationship. One mother pointed out that inequality between her and her partner’s role as health advocates for their child created distance in their marriage.
“I noticed almost immediately that it’s all about the mom. I became my son’s health advocate, a role that I never really anticipated playing. Most of the stress falls on me. I schedule all his appointments. I have all the conversations. I’m a member of the support groups. And he [husband] doesn’t. So that’s a wedge.”
Of the mothers who reported a positive impact, all mentioned that receiving the diagnosis created stronger bonds and appreciation for one another. Mothers who reported a team-based approach to parenting also felt more positive about their relationship.
Most mothers reported that learning the NBS result impacted their parenting style. The eight mothers who adapted their parenting described their style as more protective, loving, indulgent, and attentive. Seemingly minor health concerns were a greater source of anxiety for these mothers, given the potential association with ALD.
“When Justin would get a rash, I would be like, ‘Oh it will go away’, but when Forrest has a fever or anything, it’s really alarming.”
Although mothers did not express favoritism among their children, many did acknowledge that potentially affected children received more attention and were disciplined less harshly than older siblings had been.
3.4. Overall Opinion on the NBS Process and Follow-Up Care
Overwhelmingly, all participants were in favor of including ALD on the NBS panel for both males and females; however, the timing of when testing should be offered varied. Sixty percent of mothers believed that testing for ALD in males should be offered prenatally, and 40% believed it should be offered at birth. For females, 30% believed that testing should be offered prenatally and 70% believed it should be offered at birth.
All affected males were followed by endocrinology and neurology in 6 to 12-month intervals. Of nine families in whom a gene variant was identified in a male, either a son or a father, seven mothers were satisfied with this care plan. Mothers of daughters conceptually understood that their children were not at risk for developing the cerebral form of ALD. However, concern about lack of follow-up care and possible symptoms in childhood were mentioned by two mothers, suggesting additional support and reassurance may be necessary.
“I’m just curious if Clarissa does need to be seen more often. I feel like because she’s female and she’s not presenting right now, they just pushed her to the back burner. I’m left over here wondering, what if she is presenting and I don’t know?”
3.5. Recommendations for Healthcare Providers and Families
The most common advice mothers had was for pediatricians to educate themselves prior to calling families with the NBS results. Alternatively, mothers believed the initial phone call should be made by a specialist with more knowledge of the condition. Three mothers mentioned the need for more mental health resources. Having genetic counselors present for the meeting with the geneticist was appreciated by three mothers. However, an additional two mothers would have preferred to see other specialists at the initial visit as well, in particular the neurologist. Mothers of daughters desired further guidance on how to speak to their children about ALD, in particular on broaching the topic of family planning. Mothers desired more patient-friendly resources on ALD, including information on disease progression, clinical trials, care coordination, and contact lists for specialists with ALD experience. Three mothers asked for information on financial resources for cascade testing and other services not covered by insurance. Lastly, five mothers felt that the time from initial NBS result to official diagnosis was too long. This could potentially be shortened by including ABCD1
sequencing on the NBS. Table 2
summarizes mothers’ recommendations for the HCPs.
Normalization was common advice that mothers offered to other families. They felt it was important to recognize that ALD is a disease like any other, and that parents should appreciate the time they have with their children. One mother expressed concern that learning this diagnosis so early in a child’s life might impact bonding with their newborn and encouraged parents to develop loving relationships with their affected children. Lastly, mothers recommended avoiding the internet to learn more about ALD.