Importance of Early Diagnosis
In summary, this study highlights the detailed caregiver language used to describe “red flags” suggestive of the early clinical picture of MLD— specifically the lack of notable prior history plus most commonly reported early symptoms (coordination difficulties, clonus, comprehension challenges). This study provides detailed insights into the initial signs and symptoms of MLD in the words of the caregiver. There are few studies that focus specifically on the language used by caregivers of children with MLD—a key information source and important clue for clinicians to address individuals’ symptoms in a timely manner [12, 13, 14]. The first signs and symptoms of MLD are an often missed opportunity during the critical window for early therapeutic intervention. Across all MLD individuals in this study’s sample, time to diagnosis took an average of 13.7 months, which meant that in many cases individuals were too far progressed to be suitable candidates for interventional therapies, leaving palliative and supportive care as their only options. As the European Group for Blood and Marrow Transplantation Guidelines suggests, in individuals with MLD, HSCT is “recommended in presymptomatic individuals or while neuropsychologic function and independence in activities of daily living remain good.” [15]. This urgency to treat is exemplified by the short window of opportunity before rapid and devastating disease progression occurs. In Kehrer et al. (2011) the time from first motor symptoms to loss of walking without support, the point after which individuals experienced rapid disease progression, was only 8 to 27 months for those with late infantile and juvenile onset MLD respectively [16]. Our study’s findings also illuminate the detriments of the rapid disease progression in MLD— 34.4% (11/32) of the MLD individuals were considered to have developmental regression at the same time the first symptoms were noticed. Similarly, close to half of individuals (14/30, 46.7%) were reported to have experienced developmental regression within 6 months or less from onset of initial symptoms.
There is reasonable opportunity for disease stabilization post-transplant if the individual is presymptomatic or at an early enough stage in their symptom progression particularly in the juvenile form of MLD. The studies conducted by Beschle, et al. (2020), Groeschel, et al. (2016), and van Rappard et al. (2016) emphasize certain prognostic factors attributing to disease stability post-transplant. Baseline characteristics of those who underwent a successful transplant included: presymptomatic individuals, acceptable gross motor function levels, low MRI severity scores, among others [8, 17, 18]. Beschle’s recent study also explores the short-term effects in an HSCT cohort that did not meet these positive prognostic factors, leading to rapid progression of symptoms at an even faster rate than non-transplanted individuals [8]. In our sample, only 5 MLD individuals (15.6%) were not too far progressed at diagnosis to be able to receive transplant. This rapid progression further underscores the short window for therapeutic intervention which is often missed due to delays in diagnosis. Those who were eligible for transplant were either diagnosed through early genetic testing based on a sibling’s diagnosis (2/5, 40%) or had a slower progressing juvenile onset type that allowed for some passing of time to recognize the constellation of symptoms forming (3/5, 60%). Similarly, Fumagalli et al. demonstrates how treatment effects of HSC gene therapy were found to be durable and clinically relevant even in early-symptomatic early juvenile individuals who were treated prior to moving into the rapidly progressive phase of the disease [19]. The factors associated with an effective and durable response to gene therapy also highlight the need for early disease identification and intervention to give individuals the best chance for disease stabilization. Even for individuals who are eligible for HSCT, there is a clear need for more effective options given the variability in response. In a single institution cohort of 40 MLD individuals who had undergone HSCT, the estimated 6-year survival was 50% for late infantile and 59% for juvenile forms of MLD [9]. Since the late infantile and juvenile forms of MLD account for close to 80% of all MLD individuals, there is a clear underserved population with an urgent need for both earlier recognition and intervention as well as alternatives to HSCT [20].
Symptom Onset
When referring to “first signs and symptoms”, caregivers of late infantile MLD individuals often report signs of development delays and stagnation—as in, slowing and stagnation of their child meeting milestones. This finding is supported by the Kehrer, et al. (2014), retrospective study on early symptoms of late infantile and juvenile MLD, which reports that about half of the late infantile individuals never learned to speak in complete sentences after having acquired one- and two-word sentences within the normal time range, indicating stagnation in language development. Consequently, Kehrer, et al. recommends further investigation if absence of acquisition of complete sentences after initial normal language acquisition is noted [21]. Development delays and stagnation are not well circumscribed symptoms, but rather indicate a lack of developmental progress or gaining milestones. Throughout this study, we see this theme of the “persistent toddler” – part of the challenge here is to highlight the lack of developmental progress, with the history of previously normal development as raising a “red flag” and prompting further investigation. Further, the nature of developmental issues makes it challenging to pinpoint the exact onset of first signs and symptoms. The insidious nature here is worth noting— onset may be a period of concern that develops over time as the delays reveal themselves and persist rather than a discrete time point. This subtlety is further confounded by the lack of perinatal injury or other clear cause.
Symptom Constellation
Eichler, et al. (2016) underscores the complex nature of MLD and how initial symptomatology can vary between and within patient types [12]. Our caregiver reports highlight that it is often a constellation of symptoms, rather than an individual symptom, that ultimately leads to diagnosis. These manifestations are a key characteristic of white matter disorders that affect the connecting fibers and thus multiple functions [22]. In our study, 56.3% of MLD individuals (18/32) were recalled by their caregivers with a constellation of symptoms developing prior to diagnosis. Trends start to emerge from this study in terms of the more common combinations of symptoms recalled by caregivers. Some offer greater distinction and specificity that could prove useful if incorporating into a diagnostic algorithm (see Fig. 4 for example starting point for a diagnostic algorithm), though most common early symptom constellations include a non-specific mix of physical symptoms (i.e., coordination difficulties plus clonus). Fumagalli, et al. (2021) also underlined the sequence of symptoms that develop at disease onset. For instance, in early juvenile individuals, they found that even those who first presented with isolated behavioral or cognitive impairment, motor symptoms occurred within the next few months [3]. While a focus upon multiple symptoms rather than individual ones may unfortunately warrant passing of time as further symptoms present, it is an important characteristic of the disease. A confounding factor is the variability and non-specific nature of these earliest signs and symptoms that can add to the challenge of connecting these constellations of symptoms to MLD specifically. Nonetheless, recognizing the common language used by caregivers to describe the early constellation of symptoms can be another step towards earlier diagnosis.
Late Infantile versus Juvenile MLD
Kehrer et al. (2020) found that all individuals with late infantile and early juvenile onset MLD presented with motor symptoms (with or without additional cognitive symptoms). This study of 97 individuals with MLD highlights that a small subset (3/35, 9%) of late infantile individuals will present with both motor and cognitive symptoms, while most do present with motor symptoms only. Isolated cognitive symptoms were found to occur only in older children and adults— 39% of early-juvenile individuals presented with both motor and cognitive symptoms as opposed to 61% of the late-juvenile cohort who exhibited isolated cognitive symptoms at disease onset [23]. Similarly, our study found that a majority of late infantile individuals present with physical symptoms and directionally less recognition of cognitive changes compared to juvenile cases. These distinctions may be more dependent on where these children are on the curve of motor and intellectual developmental milestones at the time of disease progression rather than any fundamental differences in the pathology of the disease. Changes in personality or behavior, for instance, are more noticeable in an older child at that stage of development as opposed to an infant where these cognitive signs may be less apparent. In juvenile cases, this clearer behavioral symptomology that can be distinguished from their normal behaviors and performance provides a more concrete picture in terms of identifying early signs of regression. Conversely in late infantile cases, the developmental issues often reported can lack specificity and be more difficult to translate into a definitive sign of MLD.
Absence of Notable Prior History
Confounding diagnosis is the lack of predicated indications of concerning signs in these MLD individuals. All the above points gain further importance in light of normal pregnancy and birth history, creating a discrepancy and lack of explanation for the initial presenting symptoms. The absence of notable prior history becomes an important clue to diagnosis and a vital part of the full picture in assessing the first signs and symptoms of MLD.
Call to Action
The findings supported by this research provide a clear call to action for clinicians across specialties to support broader awareness of MLD and its early indicators as described by caregivers. It is important for the medical community to recognize caregiver-reported symptoms consistent with MLD to direct individuals to immediate appropriate testing [24, 25]. Understanding the language used can be educational for caregivers, clinicians, and patient advocacy communities to keep an open and understanding dialogue around this condition and its related early manifestations. Increasingly critical assessments of these early signs can facilitate more rapid referral to proper specialists and streamline the referral pathway [19]. There is a recognizable opportunity for success that comes from providers taking “ownership” of the case as well. A challenge in rare diseases is that due to their specialized nature referrals are often thought to be the necessary and limiting factor. However, “referral” does not exclude taking “ownership”— the non-specialized nurse, for example, can refer while also pushing the PCP to initiate brain imaging.
It is also possible that other non-clinical persons, such as teachers and school behavioral specialists, pick up on these signs and escalate concerns as necessary to parents or clinicians. Those involved in the social sphere of interactions with these families may be well suited to connect individuals with the medical community, should their awareness of the neurological signs and symptoms be improved.
While this study does support means by which to help clinicians observe and therefore diagnose MLD earlier, we acknowledge that MLD is a rare condition with symptoms that are difficult to identify. It is unlikely, even with concrete anecdotes and language to listen for, that every general practitioner will be able to discern these subtle signs and make the connection to a leukodystrophy. Ultimately, newborn screening (NBS) will be crucial to diagnosing MLD as early as possible. NBS has precedent in other lysosomal storage disorders, such as MPS-1 where windows of therapeutic intervention are also best when performed before significant disease progression [26]. The development of MLD treatments recently approved, and on the horizon, also further highlights the need for NBS to ensure early patient identification and optimal therapeutic benefit.
Limitations
It is important to note the potential limitations of the data as they are presented here. The respondents participating in this study are restricted to members of a convenience sample, such that their experiences and perspectives may differ from those of the real-world population of interest. These respondents were also asked to use their recollection rather than medical records for open-ended questions. This may have resulted in variability, recall bias, and inaccuracy of certain data. Given the small sample size, geographical generalizability and comparison across counties can be limited. However, relevance to caregivers and clinicians as a whole is not expected to be limited. However, due to the rarity of the disease this study highlights the importance of the caregiver experience that will enhance the body of literature for MLD recognition and treatment.