Data collected from a global patient registry for individuals with Leigh syndrome is presented. The authors did not find prior studies on Leigh syndrome reporting outcomes described above such as loss of milestones, specialists seen, disease management, or healthcare utilization, making this the first publication of such results.
Although the registry and Cure Mito Foundation are US-based, nearly 70% of participants reside outside of the US, spanning 8 geographic regions, and 25 countries. Of note, this geographical diversity likely represents the first truly global registry for any mitochondrial disease, a product of the broad-reaching recruitment effort through social media platforms and directly via international Cure Mito partner families. Cure Mito builds connections with patient families from around the world by empowering patients to unite (regardless of language and cultural barriers) to advance research in the Leigh syndrome community. This was initially accomplished with the assistance of international partner families translating the surveys into their own language, being mindful of cultural sensitivity for participants. Subsequent registry enrollment included surveys that were already translated into various languages (Spanish, Portuguese).
Time to diagnosis of Leigh syndrome reported by the participants in the current study is significantly shorter than previously reported in other research on mitochondrial disease overall. A study analyzing data from 210 Rare Diseases Clinical Research Network Contact Registry participants, with self-reported diagnosis of mitochondrial disease found participants saw an average of 8.1 clinicians and over half received 1 or more non-mitochondrial diagnoses before their final mitochondrial diagnosis. [10] Another study, conducted in the Department of Neurogenetics, Royal North Shore Hospital, UK, on 68 participants, found that the mean time to diagnosis was 6.2 years. [11] However, our study focuses on Leigh syndrome specifically, rather than on all mitochondrial disorders. Furthermore, a study of 130 patients with Leigh syndrome by Sofou and colleagues demonstrated a median elapsed time from disease onset to diagnostic testing was 0.9 years (interquartile range Q25-Q75: 0.2-3.1 years). [12] This is similar to our results, and underscores the fact that findings for mitochondrial disorders as a group may not necessarily be generalized for individual mitochondrial diseases. Possibly, as Leigh syndrome is a very severe disease and is much harder to overlook or misdiagnose compared to more mild types of mitochondrial disease, the time to diagnosis is shorter.
Twenty-four (24) distinct genetic loci are represented by the patients in this registry to date, though currently there is a significantly higher number of patients carrying mutations in SURF1. This is likely the result of a significant number of participants being recruited from the Cure Mito Foundation, which originally began as the Cure SURF1 Foundation. While there would undoubtedly be some distortion of normal distribution of clinical data of Leigh syndrome populations due to the higher number of SURF-1 related Leigh syndrome entries, this is expected to diminish as the size and genetic diversity of the registry increases. When the registry size allows, further analyses based on genetic loci, and eventually specific genetic lesions, is likely to offer additional insights into the clinical presentation of Leigh syndrome.
Leigh syndrome is typically described as a severe neurological disorder, which is reflected in the high number of registry participants who see neurologists (78%) and therapists for neurodevelopmental disorders. However, the wide variety and quantity (1-30) of specialists seen by participants reflects the severity and multi-system nature of Leigh syndrome. A lot can be learned from the list of other specialists reported by participants including pulmonologists, cardiologists, and gastroenterologists (among others). It is important for general practice clinicians to look beyond neurodevelopmental concerns and consider referrals to other specialists if appropriate. These percentages also underscore the healthcare burden, financial impact, and imposition on quality of life that multiple specialty visits may have on the individual with Leigh syndrome and their caregiver.
It is important to underscore that the number of specialists seen is significantly affected by the country where the participant lives and the healthcare system as well as standard of living in that country. For example, one of the international participants shared with the Cure Mito Foundation, that their child is bed-bound and unable to ever leave their house due to not having any means of transportation with a wheelchair. The child is occasionally visited at home by their primary care provider. The neurologist sometimes adjusts seizure medications over the phone. Therefore, the child sees only one specialist, but that speaks to the family’s living situation, rather than the child's health.
The first concerns expressed by participants varied but were overwhelmingly connected to developmental delay or regression (68%). A majority, 56%, of participants have never achieved at least one milestone (40% of participants never walked). This again highlights the importance of specialist referral and testing by pediatricians for children losing milestones or experiencing developmental delays.
However, only 16% of participants reported that their child’s health care provider raised a concern. This discordance underscores the importance of swift referral to appropriate specialists and genetic testing to confirm the diagnosis. This is also evidenced by the fact that most of the participants see neurologists and a variety of therapists.
Given the involvement of multiple systems in the disease profile, management of Leigh syndrome requires multimodal therapies to achieve patient outcomes and improve quality of life. Although no curative treatment exists, therapies and devices that target neurological symptoms are commonly used for symptomatic care. Interventions such as mobility devices, feeding tubes including nasogastric, gastro-jejunal, and gastric tubes, orthotics, tracheotomy, communication devices, and secretion management were ranked highly utilized by registry participants. The reported number of medical interventions used ranged from a minimum of no devices up to seven devices. Although not captured in the initial results from the Cure Mito registry, pharmacotherapies have been proposed to be integral for managing Leigh syndrome. Medications, specifically, nutraceuticals with antioxidant properties or that function in the biochemical pathways that result in Leigh syndrome are frequently suggested as possible therapies, although clinical evidence is controversial. Examples of nutraceuticals include Coenzyme Q10, L-carnitine, α-lipoic acid, creatine-monohydrate, biotin, thiamine, and riboflavin. [13-15]
The most common symptoms first reported within the first year are in line with previously reported data. [16] Our data demonstrates that there is a correlation with symptoms of failure to thrive, gastric reflux, seizures and hypotonia, more commonly reported earlier in life and increasing child age. These suggest that Leigh syndrome presents with early onset of disease in infancy and emphasis on resolving feeding issues, providing nutritional alternatives and seizure management are important. In addition, recognition of these early clinical features may aid earlier diagnosis and disease management. Interestingly, the higher prevalence of dystonia and movement disorders is observed above the age of 1 year and remains relatively consistent with age suggesting brain stem and basal ganglia involvement and supports the assessment of early identification by MRI. Of the patients who reported a history of regression or loss of acquired skills, the majority had common symptoms of abnormal development, including verbal delay (2 word speech), gross motor delay (sitting, crawling, walking) and social delay (toilet training). This data correlates with our findings of disease management and the early requirement for devices to assist daily living. The commonly reported first symptoms of failure to thrive and gastric reflux in infancy correlates with the reported use of a feeding tube in patients less than 1 year old. As the child's age increases, the need for assisted motor and speech devices correlates with reported data of gross motor and verbal delays.
Healthcare system utilization is significant but varies widely across the respondents, as measured by number of ER visits, admissions, and days spent in inpatient care. The majority of patients did not visit the ER. However, among those who did, the number of visits ranged from 1 to 45 over the previous twelve months. The average number of hospital admissions roughly tripled between the 3-month and 12-month observation windows, and nearly half (48.4%) of all respondents were admitted at least once. Further, 20% of those admitted were admitted 4 or more times in the past year. Among non-zero responders, the mean number of days in the hospital were 12.5 and 26.8 for 3 months and 12 months, respectively. Notably, one respondent indicated 150 days of inpatient care. Overall, the data suggest that for patients whose Leigh syndrome is well managed and stable, healthcare utilization is relatively low. However, when patients do experience symptoms they require significantly more medical care.
The Everylife Foundation completed a study of the economic burden of rare diseases in the US in 2019. [17] This study concluded that the total excess direct medical cost associated with the 379 diseases studied is $418 billion, which translates to $26,887 excess direct medical costs per person with a rare disease. In fact, the costs are even higher for children, averaging $32,037 excess medical costs per child.
According to the study, the estimated total indirect and non-medical cost of rare disease is $64 billion for children (age less than 18 years). For many Leigh syndrome families, one of the spouses must give up their employment to take care of the affected child. In addition, the costs of absenteeism for the caregivers surpass those for people with the rare disease.
Leigh syndrome was not represented in the 379 rare diseases surveyed in the Everylife study. It is also difficult to extrapolate these cost estimates to the 25 countries represented in the Leigh syndrome global registry due to differing healthcare systems and medical practice. However, the low median age of patients in the registry suggests that the per person cost of healthcare utilization for Leigh syndrome is likely to be higher than for diseases in older populations.
It is interesting to note that despite reported limitations related to pain and energy, the majority responded that participants rated their own health as good, and the majority never or rarely feel depressed. Although this finding may seem counterintuitive, it is supported by other research. A study of 115 children with severe disabilities and their parents, found that parents describe their children's health related quality of life (HRQoL) significantly higher than physicians do and express more optimism regarding their child’s future compared to physicians. [18]
One way of bridging the disparity between physician and patient/family is for physicians to go beyond solely having a medical outlook and proactively engage patients in discussions about their QofL. Authors of the article, “Asset-Based Health Care for Children With Severe Neurologic Impairment” explain that parents of children with severe neurological impairments want their clinical team to see their child as they do, including knowing what brings the child and the family joy, hope, and meaning. [19] They suggest that clinicians have conversations with the family that go beyond the medical diagnosis and proactively ask about the child’s QofL as well as what are the hopes of the parents for their child’s future.
As illustrated by the current study, the majority of caregivers feel stressed when it comes to providing care to the person with the illness. A significant percentage (over a third) at least sometimes feel drained by their responsibilities as a caregiver. However, the majority reported never or rarely feeling burdened with the responsibility of caring for the person with the illness. In our opinion, this could be explained by the continuum of hope and love parents feel for their children. During the shared journey, parents provide care for their children out of love and do not view them as a burden. A cross-sectional study on 249 caregivers of children with chronic diseases revealed that “those caregivers who were responsible for caregiving for a longer period, experienced lower caregiving burden in isolation and disappointment sub-scales. It seems that they have found approaches to coping with their responsibilities and caregiving-induced limitations over time.” [20]
Although our study showed that caregivers are resilient and those living with Leigh syndrome have a positive attitude, we know that Leigh syndrome is a severe progressive disease, and it is important to have support resources available. It is also possible that those families who are coping better have joined our registry. While for those having a harder time, it may have been too difficult or time-consuming, and we didn’t capture their responses.