Abstract
Context
Monocarboxylate transporter 8 (MCT8) deficiency is a rare neurodevelopmental and metabolic disorder, with daily care posing a heavy burden on caregivers. A comprehensive overview of these complex needs and daily care challenges is lacking.
Design
We established an international prospective registry to systemically capture data from parents and physicians caring for patients with MCT8 deficiency. Parent-reported data on complex needs and daily care challenges were extracted.
Results
Between July 17, 2018, and May 16, 2022, 51 patients were registered. Difficulties in daily life care were mostly related to feeding and nutritional status (17/33 patients), limited motor skills (12/33 patients), and sleeping (11/33 patients). Dietary advice was provided for 11/36 patients. Two of 32 patients were under care of a cardiologist. Common difficulties in the diagnostic trajectory included late diagnosis (20/35 patients) and visiting a multitude of specialists (15/35 patients). Median diagnostic delay was significantly shorter in patients born in or after 2017 vs before 2017 (8 vs 19 months, P < .0001).
Conclusions
Feeding and sleeping problems and limited motor skills mostly contribute to difficulties in daily care. The majority of patients did not receive professional dietary advice, although being underweight is a key disease feature, strongly linked with poor survival. Despite sudden death being a prominent cause of death, potentially related to the cardiovascular abnormalities frequently observed, patients were hardly seen by cardiologists. These findings can directly improve patient-centered multidisciplinary care and define patient-centered outcome measures for intervention studies in patients with MCT8 deficiency.
Keywords: MCT8 deficiency, Allan-Herndon-Dudley syndrome, AHDS, parents’ perspectives, patient registry, daily care
Thyroid hormone is indispensable for neurodevelopment and for metabolism throughout life (1-3). Monocarboxylate transporter 8 (MCT8) is crucial for thyroid hormone transport into various tissues, including the brain (4). Mutations in the gene encoding MCT8 (SLC16A2) result in MCT8 deficiency or Allan-Herndon-Dudley syndrome, a rare X-linked disorder with an estimated prevalence of 1:70 000 males (5-7). Affected boys present with severe neurodevelopmental delay resulting from cerebral hypothyroidism, with early motor milestones never being reached by the majority of patients, and with features of chronic peripheral thyrotoxicosis, including tachycardia and being underweight (5, 6, 8). Patients with MCT8 deficiency have a poor survival, with 30% dying in childhood, with being underweight as an important determinant (8). Patients are largely dependent on parents/caregivers (from here on collectively termed parents) during all stages of life.
Patients with this multisystem disorder have complex needs that require different specialists and supportive therapies. Importantly, insights into the major complex needs and challenges experienced by parents in daily care are currently lacking. The absence of such data hampers optimization of daily care, counseling of families, and multidisciplinary patient-centered clinical management for this devastating disorder.
Although systematic and prospective evaluation of patients’ and parents’ perspectives is pivotal in optimizing care, this is faced with many hurdles, particularly for patients with rare diseases (9). International patient registries are powerful tools to investigate various aspects of rare diseases, in which establishing well-sized cohorts can be challenging (10), including the perspectives of parents. Therefore, we sought to document parent-reported complex needs across multiple domains of daily care for patients with MCT8 deficiency using a prospective, international dual parent-physician registry.
Methods
Design of the International MCT8 Deficiency Registry
We established an online prospective international registry for patients with MCT8 deficiency (the International MCT8 Deficiency Registry [https://mct8registry.erasmusmc.nl/en/]), aiming to centralize data on patients with this rare disease. This registry contains 2 questionnaires: for parents and for physicians (Supplementary Fig. S1, Supplementary material) (11). Patients with MCT8 deficiency are unable to register or provide informed consent by themselves because of their severely incapacitating disease. Details on the registry design process, registration, technical details, and questionnaires of the registry are provided in Supplementary Fig. S2 and the Supplementary material (11).
The Daily Board of the Medical Ethics Committee, Erasmus Medical Center, Rotterdam, The Netherlands, provided a waiver because the rules laid down in the Medical Research Involving Human Subjects Act (also known by its Dutch abbreviation WMO) do not apply to the registry.
Procedures and Outcomes
Patients of whom parents provided full informed consent and at least 1 answer in the parent questionnaire were eligible. To comply with privacy regulations, data on country of residence and age were categorized and presented as aggregates to minimize the risk of patient identification. Data validation and cleaning were performed as described in the supplementary material (11). Answers to open questions were translated to English (if applicable) and categorized before analyses.
The primary objective was to document the complex needs and daily care challenges encountered in care for patients with MCT8 deficiency and to what extent these are met by supportive measures and specialist care. Secondary objectives were to evaluate the diagnostic delay and its underlying factors and changes with time. Further, the perceived availability of disease-specific information was documented. Clinical data from physicians, collected in the registry, were previously integrated into an international phenotyping study (8).
Statistical Analyses
Data on challenges in daily care and complex needs (including analyses on stratification for age categories <5 years and ≥5 years of age), use of supportive and specialist care and diagnostic trajectory, and availability of information were analyzed descriptively. Analyses of median diagnostic delay were performed after stratification by year of birth of patients, born before 2017 (>5 year before data analyses) vs born in or after 2017 (≤5 years before data analyses), using a Mann-Whitney test. All statistical analyses were performed using GraphPad Prism version 9 (GraphPad Software Inc., San Diego, CA, USA). Two-sided P values < .05 were considered to denote statistical significance.
Role of the Funding Source
The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Results
Between July 17, 2018, and May 16, 2022, 51 patients with MCT8 deficiency were registered in the International MCT8 Deficiency Registry. Of the 46 registered patients with full informed consent, data of 40 patients (40 males, 100%) with a median age of 3.0 years (range, 0.5-31.6 years), from 18 countries in 5 different continents (Table 1), was extracted and used for analyses.
Table 1.
Cohort characteristics
| International MCT8 Deficiency Registry cohort | |
|---|---|
| Age (y; n = 40) | 3.0 (0.5-31.6) |
| Age (groups; n = 40) | |
| <5 y | 24 (60%) |
| >5-10 y | 8 (20%) |
| >10-15 y | 2 (5%) |
| >15-20 y | 2 (5%) |
| >20 y | 4 (10%) |
| Sex (n = 40) | |
| Female | 0 (0%) |
| Male | 40 (100%) |
| Families (n = 40) | 38 |
| With 1 child affected | 36 (90%) |
| With >1 child affected | 4 (10%) |
| Parents (n = 40) | |
| Biological parents | 38 (95%) |
| Shared lives carers/guardians | 2 (5%) |
| Continent of residence (n = 40) | |
| Europe | 27 (68%) |
| North America | 8 (20%) |
| South America | 2 (5%) |
| Asia | 2 (5%) |
| Africa | 1 (3%) |
| Oceania | 0 (0%) |
| Living situation (n = 34) | |
| At home | 29 (85%) |
| In an institution | 2 (6%) |
| Combination of both | 3 (9%) |
Data are median (range) or n (%).
Parents of 32 of 33 patients reported a median of 3 (range, 1-4) difficulties in daily care. Commonly reported difficulties were related to feeding (17 of 33 patients; Fig. 1A-1C and Supplementary Table S1) (11), limited motor skills (12 of 33 patients), sleeping problems (11 of 33 patients; Fig. 1D and Supplementary Table S1) (11), mobility (10 of 33 patients), communication (8 of 33 patients) skills (Supplementary Table S1) (11), therapy and support issues, including limited accessibility to supportive therapies (8 of 33 patients), and dystonia and seizures (5 of 33 patients). Reported difficulties were largely similar between patients age <5 years vs age ≥5 years, with sleeping as an important exception (Supplementary Fig. S3) (11). Difficulties attributed to peripheral thyrotoxicosis were common (Fig. 1E) and partially reversed by treatment with thyroid hormone analogue Triac (Supplementary Table S2) (11). Senses in patients were perceived as normal (Fig. 1F). Next, we explored how difficulties in daily life were met by supportive care. Despite feeding problems being the most commonly reported difficulty in daily life, only 11 of 36 patients received advice from a professional dietician or nutrologist (Fig. 1G). Of those with reported feeding problems, only 2 of 16 patients had a feeding tube (data on feeding tube missing for 1 patient). In line with mobility being an important difficulty in daily life, a majority of 29 of 36 patients received supportive care from a physical therapist (Fig. 1G), and 12 of 36 patients participated in swimming therapy. The majority of patients (21 of 32) was under care of a (pediatric) neurologist (Fig. 1H and Supplementary Table S3) (11), and general pediatricians and (pediatric) endocrinologists were other specialists commonly consulted. In contrast, patients were hardly followed up by (pediatric) cardiologists. Medical devices that support mobility differed with age and mainly concerned a wheelchair (17/36), whereas standing tables, walkers, and tricycles were less frequently used (Fig. 1I and Supplementary Fig. S4) (11). Further, 18 of 36 patients received therapy on speech and feeding techniques, and 7 of 38 patients used devices to enhance communication (eg, eye tracking devices).
Figure 1.
Difficulties in daily life care. Parent-reported difficulties in the daily life care for their child(ren) (A), difficulties in feeding (B), with specification of aspirated food consistency (C), specification of sleeping problems (D), symptoms related to the thyrotoxic phenotype (E), sensory functions and communication (F), utilization of supportive therapies (G), utilization of specialist care (H), and use of mobility aids (I). Raw numbers underlying the percentages are shown above the bars in panels A, E, and G-I; data in panel C are not expressed as percentage given the low number of patients included in this analysis; the total number of patients included in the separate analyses are shown above the bars in panels B, D, and F. Consistency of aspirated food was analyzed in patients with aspiration only (n = 9). Frequency of waking up is reported as times of waking up per night. Time of waking up was analyzed in patients waking up 1 or more times per night only. Sleeping during the day was defined as sleeping during the day for 3 or more days per week. *Gastric tube. **>4 Am.
In our secondary outcomes, we noted that the most commonly perceived hurdles in the diagnostic trajectory were receiving a late diagnosis (20/35; Table 2 and Supplementary Table S1) (11), and the need for visiting a multitude of specialists (15/35).
Table 2.
Difficulties in diagnostic trajectory
| Patients with data on difficulties in diagnostic trajectory | |
|---|---|
| Number of reported difficulties (n = 35) | |
| 0 | 1 (3%) |
| 1 | 19 (54%) |
| 2 | 11 (31%) |
| >2 | 4 (11%) |
| Reported difficulties (n = 35) | |
| Late/alternative diagnosis | 20 (57%) |
| Need for visiting a multitude of specialists | 15 (43%) |
| Normal examinations | 8 (23%) |
| Healthcare system problems | 3 (9%) |
| Symptoms trivialized | 2 (6%) |
| No difficulties | 1 (3%) |
| Alternative diagnoses (n = 6) | |
| Cerebral palsy | 4 |
| Pelizaeus-Merzbacher (like) disease | 1 |
| Mitochondrial disease (not otherwise specified) | 1 |
| Thyroid function tests evaluated (n = 5) | |
| Correct diagnosis | 2 |
| Levothyroxine started (without diagnosis) | 2 |
| No action (measured during neonatal screening) | 1 |
Data are n (%) or n (for analyses with <30 patients included).
Reported alternative diagnoses (total n = 6) were cerebral palsy (n = 4), Pelizaeus-Merzbacher (like) disease (n = 1) and mitochondrial disease (not otherwise specified, n = 1). The availability of thyroid function tests (n = 5) led to the correct diagnosis in 2 of these patients (Table 2 and Supplementary Table S1) (11).
Data on time of onset of symptoms and diagnoses were available for 39 patients. The median reported age of onset of symptoms was 4 months (range, 1-13 months; Supplementary Fig. S5) (11), whereas the median age of diagnosis was 18 months (range, 4-312 months), indicating a median diagnostic delay of 14 months (range, 0-311 months). A significantly shorter median diagnostic delay was found in patients born in or after 2017, compared with patients born before 2017 (8 months vs 19 months, P < .0001) (Fig. 2). Sensitivity analyses after exclusion of patients born before October 2004 showed similar results (Supplementary Fig. S6) (11). No clear relationship between continent of residence and median diagnostic delay was observed (Supplementary Fig. S7) (11).
Figure 2.
Diagnostic delay of MCT8 deficiency. Parent-reported age of onset of symptoms and age of diagnosis in patients born before 2017 (upper panel) vs patients born in or after 2017 (lower panel).
The major sources of disease-specific information for parents were the caregiving physicians, a disease-specific website governed by the MCT8-AHDS Foundation (mct8.info) and a social media platform for parents (Table 3). The availability of information was judged sufficient, good, or very good by parents of 23 of 31 patients. The majority of parents (18 of 31 patients) deemed knowledge about MCT8 deficiency among medical professionals as bad or very bad (Table 3). Parents frequently mentioned a need for increased disease awareness (Supplementary Table S1) (11) and underlined the importance of prenatal/neonatal screening for MCT8 deficiency (Supplementary Table S1) (11).
Table 3.
Sources and availability of disease-specific information
| Patients with data on disease-specific information | |
|---|---|
| Source of information (n = 34) | |
| Physician | 19 (56%) |
| MCT8.info website | 18 (53%) |
| Facebook group for families | 17 (50%) |
| Other websites | 12 (35%) |
| Patient organization | 10 (29%) |
| Information leaflet | 1 (3%) |
| Combination | 9 (26%) |
| Availability of information (n = 31) | |
| Very bad | 2 (6%) |
| Bad | 6 (19%) |
| Sufficient | 12 (39%) |
| Good | 10 (32%) |
| Very good | 1 (3%) |
| Knowledge among medical professionals (n = 31) | |
| Very bad | 6 (19%) |
| Bad | 12 (39%) |
| Sufficient | 9 (29%) |
| Good | 2 (6%) |
| Very good | 2 (6%) |
Data are n (%).
Discussion
To our knowledge, this is the first study to document complex needs and daily care challenges reported by parents caring for patients with MCT8 deficiency. These parent-reported data collected through an international prospective patient registry have the potential to improve daily care and clinical management, thereby alleviating the burden for patients and their caregivers in daily life.
A principal outcome was that difficulties in feeding and sleeping are key problems in daily life care. These findings were further substantiated by weight loss after infections and subsequent difficulty in gaining weight being reported as difficulties resulting from thyrotoxicosis by the vast majority of parents. Notably, in spite of feeding being an important challenge and low body weight being a key feature that is strongly linked to poor survival (8) and, thus, optimizing nutritional status being crucial, the vast majority of patients were not supported by dietary care and only half received speech therapy. Also, a substantial proportion of patients was not supported with a feeding tube, particularly among those patients with feeding problems as reported major challenge. It is unclear whether utilization of a feeding tube is not advised by physicians, or whether parents are reluctant about this intervention. Despite sudden death being a prominent cause of death, potentially related to the cardiovascular abnormalities frequently observed in this population (8), patients were hardly seen by a pediatric cardiologist. Also, 1 in 5 patients did not receive physiotherapy, although this potentially could alleviate common symptoms, as reported by several parents. Together, these findings provide a direct target for improving clinical care for patients with MCT8 deficiency. In combination with findings from recent deep-phenotyping studies (8) and drug trials (12, 13), these studies may stimulate the development of international guidelines for clinical management of patients with MCT8 deficiency; a first draft for a potential design of a multidisciplinary team for patients with MCT8 deficiency, including the responsibilities of each specialist, is suggested in Supplementary Table S4 (11).
Also, we found that the diagnostic delay has decreased with time, as also observed in other rare diseases (14), potentially because of increased availability of next-generation sequencing technologies or disease awareness or both. Nevertheless, parents reported late diagnosis and the need to visit multiple specialists as major issues during the diagnostic trajectory. Knowledge among medical professionals was deemed insufficient. Together, this reemphasizes the need for early recognition by medical professionals, which could be advanced by adequate training programs and by the potential detection of MCT8 deficiency in neonatal screening programs.
Recent efforts to detect patients with MCT8 deficiency during neonatal screening can be an important step in reducing the diagnostic delay (15). Awaiting neonatal screening innovations for MCT8 deficiency, one might suggest screening all male patients with global developmental delay for genetic variants in SLC16A2, particularly those with delayed myelination and abnormal thyroid function tests (specifically high T3/T4 and/or T3/rT3 ratios). Moreover, the global inclusion of SLC16A2 in diverse relevant genetic panels (eg, developmental delay, congenital hypothyroidism) may further reduce the diagnostic delay.
There are several limitations to this study. First, it is unclear to which extent the patients in this study represent the entire population of patients with MCT8 deficiency. However, a substantial proportion of patients is included, with approximately 350 patients reported worldwide (4, 8). Also, despite parents being able to answer open questions in their native language, language barriers may have discouraged parents to register their child(ren). However, patients from 18 countries in 5 different continents were included in this study, indicating limited location bias. Because parents are required to initiate the registration process, there may be selection bias in included patients. However, commonly used information platforms (eg, the parent social media community) were used to inform parents about the existence and goals of the registry, aiming to limit this bias. It should be noted that other reasons for parents to not participate in the registry could not actively be monitored, and thus selection bias cannot be excluded. Second, patients deceased before the initiation of the registry were not included. Third, this registry does not provide information on determinants that potentially underlie differences in reported challenges, such as health care system, financial reimbursements, and socioeconomic background.
Next to identifying complex needs in MCT8 deficiency, this study exemplifies the potential of international prospective patient registries for rare diseases. Importantly, whereas many rare disease registries primarily collect medical physician-derived information (16, 17), our registry also collects patient-/parent-reported outcomes, filling a need that has been emphasized by the International Rare Diseases Research Consortium (18).
In conclusion, our international prospective patient registry enabled detailed documentation of the complex needs and challenges in daily life of patients with MCT8 deficiency. Our findings call for a coordinated, multidisciplinary approach to optimize care and, thus, daily lives of patients and their caregivers. In addition, our results may optimize professional standards of care, educational programs for physicians, and support programs for parents and may aid in defining patient-centered outcome measures for future studies.
Acknowledgments
The authors thank the patients and their families and caregivers who participated in this study and the IT department of the Erasmus Medical Center for technical support.
Abbreviations
- AHDS
Allan-Herndon-Dudley syndrome
- MCT8
monocarboxylate transporter 8
Contributor Information
Ferdy S van Geest, Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands.
Stefan Groeneweg, Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands.
Veronica M Popa, Patient Advisory Council of RD Connect and MCT8-AHDS Foundation, Oklahoma, OK 74464, USA.
Milou A M Stals, Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands.
W Edward Visser, Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands.
Funding
This work was supported by a grant from the Sherman Foundation and from the Eurostars program (project number E113377), both to W.E.V.
Author Contributions
F.S.v.G. and W.E.V. designed the study, acquired and analyzed the results, and drafted and approved the manuscript. F.S.v.G., S.G., M.A.M.S., and W.E.V. designed, constructed, and governed the International MCT8 Deficiency Registry. S.G., V.M.P., and M.A.M.S. contributed to the interpretation of data and approved the manuscript.
Disclosures
The Academic Center for Thyroid Diseases, Erasmus Medical Center, Rotterdam, is part of the European Reference Network on rare endocrine conditions (EndoERN). The Erasmus Medical Centre (Rotterdam, Netherlands), which employs F.S.v.G., S.G., and W.E.V. receives royalties from Egetis Therapeutics. None of the authors benefits personally from any royalties. Egetis Therapeutics had no influence on the conduct or analysis of this study. All other authors declare no competing interests.
Data Availability
Restrictions apply to the availability of some or all data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Restrictions apply to the availability of some or all data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided.
