Molecular Genetics and Metabolism Reports 35 (2023) 100962 Contents lists available at ScienceDirect Molecular Genetics and Metabolism Reports journal homepage: www.elsevier.com/locate/ymgmr Impact of COVID19 pandemic on patients with rare diseases in Spain, with a special focus on inherited metabolic diseases M. Mar Rovira-Remisa a, Mónica Moreira b, n, Paula Sol Ventura c, d, Pablo Gonzalez-Alvarez d, Núria Mestres a, Fredzzia Graterol Torres e, Clara Joaquín f, Agustí Rodríguez-Palmero Seuma a, Maria del Mar Martínez-Colls g, Ana Roche h, Salvador Ibáñez-Micó i, Eduardo López-Laso j, María Jesús Méndez-Hernández k, Marta Murillo l, Laura Monlleó-Neila a, Elena Maqueda-Castellote a, Mireia del Toro Riera m, Ana Felipe-Rucián m, Maria Giralt-López b, n, 1, Elisenda Cortès-Saladelafont a, n, *, 1 a Unit of Inherited Metabolic Disorders and Pediatric Neurology, Department of Pediatrics, Hospital Universitari Germans Trias i Pujol, Badalona., Spain b Department of Psychiatry, Hospital Universitari Germans Trias i Pujol, Badalona, Spain c Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Spain d Department of Pediatrics, Hospital Universitari Germans Trias i Pujol, Badalona, Spain e Department of Nephrology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain f Unit of Adults Inherited Metabolic Disorders, Department of Endocrinology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain g Unit of Pediatric Pneumology, Department of Pediatrics, Hospital Universitari Germans Trias i Pujol, Badalona, Spain h Unit of Pediatric Neurology, Department of Pediatrics, Hospital Universitari Parc Taulí, Sabadell, Spain i Unit of Pediatric Neurology, Department of Pediatrics, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain j Pediatric Neurology Unit, Department of Pediatrics, University Hospital Reina Sofía, IMIBIC, CIBERER, Córdoba, Spain. k Unit of Pediatric Infectious Diseases and Immunological Disorders, Department of Pediatrics, Hospital Universitari Germans Trias i Pujol, Badalona, Spain l Unit of Pediatric Endocrinology, Department of Pediatrics, Hospital Universitari Germans Trias i Pujol, Badalona, Spain m Pediatric Neurology Department, Hospital Vall d’Hebron, Barcelona, Barcelona, Spain n Universitat Autònoma de Barcelona, Campus Can Ruti, Badalona, Spain A R T I C L E I N F O A B S T R A C T Keywords: Introduction: The Covid-19 pandemic soon became an international health emergency raising concern about its Rare diseases impact not only on physical health but also on quality of life and mental health. Rare diseases are chronically Quality of life debilitating conditions with challenging patient care needs. We aimed to assess the quality of life and mental Anxiety health of patients with rare diseases in Spain, with a special focus on inherited metabolic disorders (IMD). Depression Inherited metabolic disease Methods: A prospective case-control study was designed, comparing 459 patients suffering from a rare disease (including 53 patients with IMD) and 446 healthy controls. Quality of life (QoL) and mental health were assessed using validated scales according to age: KINDL-R and the Pediatric Symptom Checklist (PSC) for children and the WhoQoL-Bref questionnaire, GAD and PHQ-9 in adults. Results: First, children and adults (but not adolescents) with IMD showed greater psychological effects than controls (p = 0.022, p = 0.026 respectively). Second, when comparing QoL, only adult patients with IMD showed worse score than controls (66/100 vs 74,6/100 respectively, p = 0.017). Finally, IMD had better quality of life than other rare neurological and genetic diseases (p = 0.008) or other rare diseases (p < 0.001 respectively) but similar alteration of the mental status. Conclusions: Our data show that the pandemic had a negative impact on mental health that is more evident in the group of patients with IMD. Young age would behave as a protective factor on the perception of QoL. Furthermore, patients with IMD show a better QoL than other rare diseases. * Corresponding author at: Department of Pediatrics, (7th floor, Maternity Building), Carretera de Canyet s/n, 08916 Badalona, Catalonia, Spain. E-mail address: ecortes.germanstrias@gencat.cat (E. Cortès-Saladelafont). 1 Maria Giralt-López and Elisenda Cortès-Saladelafont should be considered joint senior author. https://doi.org/10.1016/j.ymgmr.2023.100962 Received 26 February 2023; Accepted 27 February 2023 Available online 6 March 2023 2214-4269/© 2023 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). M.M. Rovira-Remisa et al. Molecular Genetics and Metabolism Reports 35 (2023) 100962 1. Introduction 2.2. Patients In early December 2019, the first pneumonia cases of unknown The inclusion criteria were fulfilled for all patients suffering from a origin were identified in Wuhan (China) [1]. The pathogen has been definite rare disease, diagnosed either with a genetic test, a confirmatory named severe acute respiratory syndrome coronavirus (SARS-CoV-2), biochemical profile (enzyme activity or definite biomarkers) or clinical causing the coronavirus disease 2019 (Covid-19). In mid-January 2020, criteria (for those diseases that are diagnosed through clinical scores). Covid-19 was declared by the World Health Organization (WHO) a Children above 4 years of age and adults were included in the study. As public health emergency of international concern, and early in 2020 the for the consideration of rare disease, this study uses the definition of the first scientific publications raised concern about the potential impact of European Commission, which grants the rare disease status to all con­ the quarantine [2] on different at-risk populations (children [3,4] or ditions with an incidence of up to 1/2000. general population alike) [5–7]. All patients from our unit that met these criteria were contacted To date, >613,000,000 confirmed cases and above 6,500,000 through telephone, email or personally in the outpatient clinic. confirmed deaths have been reported by the WHO (https://www.who. In an attempt to include more patients, other hospitals across the int/emergencies/diseases/novel-coronavirus-2019). Focusing in Spain, country were invited to participate in the study spreading the infor­ SARS-CoV-2 has hit it savagely, with a total of >3,500,000 confirmed mation among their patients. Further distribution of the survey was cases and almost 80,000 cumulative deaths (https://covid19.who. made possible thanks to the contribution of different Catalan and int/table). The impact on mental health and self-perception of quality Spanish patients’ associations, whose contact data were published on of life might be specially worrying, and some publications that confront the Spanish Ministry of Health webpage (https://www.mscbs.gob.es/), the topic confirm this [3,8]. as well as the Catalan Association for Rare Diseases (FECAMM: https:// A study by Orgiles et al. [9] indicates that 85.7% of parents identified www.fecamm.org/portal1/M_index.asp) and the Spanish one (FEDER: changes in the emotional state and behaviour of their children during https://enfermedades-raras.org/). This methodology fits the snowball quarantine. A nationwide study in Germany reports worse scores in sampling method, that has been used in qualitative research where a quality of life and an increase in mental health problems (especially qualified subject is contacted by the researcher or by other similar anxiety) during the COVID pandemic [10]. These results are consistent subject that shares the same diagnostic o qualities, and that is particu­ with Duan et al [11] who find levels of anxiety in children and adoles­ larly useful in hard-to-reach populations (i.e., rare disorders). [23] cents much higher than before the pandemic or other studies among university students that show an increase in anxiety, fear, worry, sui­ 2.3. Healthy controls cidal thoughts, depression and stress [12,13]. More specifically, Ozamiz-Etxebarria et al [14] identified people Children aged above 4 and adults, without any chronic or rare dis­ with chronic diseases as a vulnerable population, particularly exposed to ease were eligible to participate. The link with the on-line survey was the psychological impact of a health crisis. randomly distributed through social networks and contacting the par­ Focusing on rare diseases, Eurordis (https://www.eurordis. ents’ associations of schools and high-schools. When accessing the sur­ org/about-eurordis), a non-governmental patient-driven association vey, one of the first questions aimed at clarify if the individual suffered that represents 962 rare disease patient organizations in different Eu­ from a rare or chronic disease or not. All children and adults answering a ropean countries, conducted a survey during the first wave of the “no” to that question, were eligible to participate as control population. COVID-19 aiming to address the impact of the pandemic on the treat­ ment, care and living conditions of people living with a rare disease and 2.4. Questionnaires and demographic survey their carers across Europe. The results can be accessed on-line [15] (http s://www.eurordis.org/publication/how-has-covid-19-impacted-peop 2.4.1. Demographic and health measures le-rare-diseases-0) and mainly state that 84% of the people who had Self-reported or parent-reported information was obtained on de­ answered the survey experienced some sort of disruption of their care mographics (age, gender), diagnosis, disease evolution during COVID- due to the COVID-19 crisis. Chung et al [ 16], described the rare diseases 19 (decompensation, hospital admissions), the academic impact of situation in Hong Kong and reported an important impact on mental COVID-19 and social network contact maintenance. We also obtained health and patients’ status during the pandemic. Many other groups information on the impact of SARS-CoV-2 on relatives’ health (in­ have since explored the consequences of the pandemic on different fections or death). populations suffering from various diseases, such as cancer [17], developmental and epileptic encephalopathies [18], ST-segment- 2.4.2. Quality of life assessment elevation myocardial infarction [19], narcolepsy [20], painful poly­ - KINDL-R: Children and adolescents’ QoL was rated by patients and/ neuropathy [21], or complex connective tissue diseases [22], among or their parent or guardian using the revised Kinder Lebensqualitats­ others. All of them report negative consequences for their patients fragebogen- überarbeitet or KINDL questionnaire (KINDL-R) [ 24,25], a because of the COVID-19 pandemic, stressing the importance of such an 31-item questionnaire revised by Ravens-Sieberer and Bullinger [26]. It event in populations suffering from chronic conditions. consists of 24 Likert-scaled items grouped into 6 subscales measuring Rare diseases tend to be chronically debilitating conditions, and specific aspects of QoL (physical well-being, emotional well-being, self- patient care needs are often complex and challenging. esteem, family, friends, and school) consisting of 4 items each, followed The aim of this study is to assess the quality of life and to characterize by an additional module entitled “Disease” with 7 extra items. The the psychopathological status of patients with rare diseases in Spain, Disease module assesses perceptions of how the illness itself impacts the with a special focus on inherited metabolic disorders (IMD). patient (e.g., the patient’s feelings regarding the disease, ability to cope with the disease, and sense of being treated differently by others because 2. Methods of the disease) and applies only to patients who are either hospitalized or those suffering from a long long-term illness. Subscale scores are pro­ 2.1. Period of study duced by combining the item ratings for each of the 6 subscales and converting each subscale score to a scale of 0–100, with higher scores Participants were recruited and filled the questionnaires from July representing better QoL. Similarly, a total score is produced by 2020 to September 2021. combining the item ratings across all 6 subscales (not including the Disease module) and converting this score to a scale of 0–100. The KINDL-R is a validated scale used as a health outcome measure 2 M.M. Rovira-Remisa et al. Molecular Genetics and Metabolism Reports 35 (2023) 100962 across a range of health and mental health issues and has been translated was password protected and used afterward for statistical analysis. into numerous languages including Spanish. The determination of the reliability and validity of the KINDL-R questionnaire can be located in 2.5.2. Statistical analysis the manual [26]. Data were expressed as means (SD) for continuous variables or as - WhoQoL: The World Health Organization’s WHOQOL-BREF has numbers/percentages for categorical variables. The normality of distri­ been validated in dozens of countries and languages, and among healthy bution and equality of variances were evaluated through the and clinical adult populations [27]. The WHOQOL-BREF explore four Kolmogorov-Smirnov test and Levene’s test respectively. The Student t- domains through 24 items: a 3-item “social relationships” domain of test or U Mann-Whitney, according to size and characteristic of the QoL, 7-item “physical health” domain, 6-item “psychological health” variables, were used to compare independent continuous variables. To domain, and 8-item “environment domain”. Two additional items compare 3 independent continuous variables, the Kruskal-Wallis measure overall QoL and overall health. The WHOQOL-BREF uses a five- nonparametric test was used. A Pearson chi-square test was used to point Likert scale with answers ranging from “very dissatisfied” to “very compare categorical variables between groups. The Statistical Package satisfied”, “not at all” to “an extreme amount”, and “never” to “always”. for Social Science SPSS version 23.0 was used to perform all the statis­ Transformed domain scores result in a 0–100 scale in which higher tical analyses, establishing the significance at p < 0.05. scores indicate higher QoL [28]. 2.6. Ethics 2.4.3. Mental health assessment - Pediatric Symptom Checklist (PSC): It is a 35-item parent-report All patients, caregivers and healthy participants were informed of questionnaire that helps to identify and assess changes in emotional the study’s objectives and data confidentiality standards, and informed and behavioural problems in children. Each item can be rated as: consent needed to be obtained from all participants before initiating the “Never” (scored 0), “Sometimes” (scored 1), “Often” (scored 2). The survey. The study was approved by our Ethics Committee and follows total score is calculated by adding the 35 individual scores, so the total the standards of the Helsinki declaration and the current Spanish reg­ score will be 0 to 70. ulations (law 14/2007 from the 3rd July about biomedical research). An overall score above the cut-off point indicates a potential psy­ chosocial impairment and needs further assessment. The cut-off score 3. Results for children older than 6 years old is 28 points [29]. For children younger than 6 years old, four items that pertain to school are excluded. 3.1. Sample characteristics As a result, the range of scores is lower and the cut-off score is lowered to 24. Subscale scores for internalizing, externalizing and attention prob­ 3.1.1. Sociodemographic description of the sample lems can be calculated from specific items. Some studies have used the A total of 1068 responses to the questionnaire were received, of PSC to explore the prevalence of psychosocial problems among children which 163 had to be excluded for the following reasons: 3 failed to with specific pediatric problems, including neurological problems [30]. complete the consent form, 73 answered twice the questionnaire, 41 - Patient Health Questionnaire 9 (PHQ-9) [31,32]: It is a 9-item in­ suffered from non-rare diseases, and another 46 tests could not be strument exploring each of the 9 specific symptoms of the Major included because of technical errors committed when answered (wrong Depressive Disorder in adults, based on DSM-IV criteria. The items are age group, etc). The remaining 905 tests were considered valid and rated on four-point Likert scales, ranging from 0 (never) to 3 (almost entered the study. every day), with higher scores indicating higher severity of depressive Two groups were established among the 905 participants, with a case symptoms (range 0–27). The cut-off point over which the patients is group adding up to 459 individuals suffering from rare diseases and a considered to be at risk for a major depressive disorder is 10 [32–35]. control group formed by 445 participants. The PHQ-9 has been validated in Spanish samples both in primary care The mean age of the 905 individuals included in the study was 33 and hospital setting alike [36,37]. years (SD 20). This remains the same when performing an analysis by - GAD: Generalized Anxiety Disorder — 7 item scale (GAD-7) is a groups, with no significant differences found between cases and con­ one-dimensional scale designed to assess the presence in adults of the trols. Further descriptive data of the sample is shown in Table 1. A slight symptoms of generalized anxiety disorder (GAD) referred to in the DSM- predominance of female subjects was observed both for cases and con­ IV. It is self-administered and the total score is calculated by simple trols. There is no specific bias that could explain such distribution, since addition of the answers for each item. As in the original English [38], the in the case of patients, very few rare diseases are X-linked (a clear bias Spanish version of the GAD- 7 validated by García-Campayo et al. that could have explained the female predominance). (2010) includes a 4-point response scale ranging from 0 (“never”) to 1 (“several days”), 2 (“more than half the days”) and 3 (“nearly every day”) over the last two weeks, providing a total score that ranges from Table 1 Sociodemographic description of the sample. 0 to 21. According to the original authors [38] the optimum cut-off value for GAD is 10 points. Cases (n = 459) Controls (n = 446) Given the lack of a universal screening tool to assess the psycho­ Gender pathological status across different ages and in order to allow for com­ Female 254 (55.3%) 297 (66.6%) parisons to be made among the different groups, a surrogate variable Male 205 (44.7%) 149 (33.4%) Education was created in this study. Thus, children and adults with a positive None 0 (0%) 149 (33.4%) screening in each of their age-specific tests are grouped under the Primary 28 (6.1%) 12 (2.6%) “altered mental status (AMS)” category. Intermediate 98 (21.3%) 65 (14.5%) University degree 146 (31.8%) 211 (47.3%) Civil status* 2.5. Data collection and data analysis Single 75/256 (29.3%) 44/270 (16.3%) Divorced 5/256 (2%) 9/270 (3.3%) 2.5.1. Data collection Married 122/256 (47.7%) 135/270 (50%) Both the demographic questions and the specific questionnaires were Partnered 46/256 (18%) 77/270 (28.5%) transformed in an on-line survey, easily accessible through an internet Widowed 8/256 (3.1%) 5/270 (1.9%) link or a QR code that were provided to all participants (controls and * only answered by those over 18 years. Some participants left the question patients). All their responses were directly collected in an Excel file that blank. 3 M.M. Rovira-Remisa et al. Molecular Genetics and Metabolism Reports 35 (2023) 100962 No differences were found in the questions aimed at inquire the 3.2.2. Mental status analysis general impact of the pandemic (neither in the controls nor in the rare In the group of children, a chi-square test found that patients with disease patients). These questions focused on assessing the impact of the IMD showed more alteration of the mental status than controls (20% vs pandemic on social interactions and on the health situation of relatives. 3.8% respectively), χ 2 (1) = 7.450, p = 0.022. As discussed before, different questionnaires according to the age of While in the adolescent group, the differences observed are not sig­ the participants were used for the study. Table 2 presents the distribu­ nificant, adult patients showed more altered mental status than controls tion of cases and controls by age groups, with no statistically significant (42.3% vs 21.3% respectively), χ 2 (1) =5.94, p = 0.026. differences found between them. When analysing differences by age in each group (patients and controls) data show that in both group, children show a better mental 3.1.2. Clinical description: Rare diseases categories and inherited metabolic status preservation in comparison with adolescents and adults, however, disorders only in the control group these differences were statistically significant The total of 459 patients with rare diseases were distributed in (p < 0.01). different categories. The different groups are represented in Fig. 1 in an attempt to be concise, while supplementary table 1 names the most 3.3. Group comparison between inherited metabolic disorders and other prevalent diseases among all patients (19 entities adding up to 62% of rare diseases the rare diseases sample). For practical reasons and since we are dealing with rare diseases with A subgroup analysis, comparing IMD with other rare diseases is expected low incidence, some categories were grouped to favour a better shown in Table 6, while Fig. 2 shows the distribution of QoL by subgroup analysis. These categories account for: 1) inherited metabolic disorders of rare disease. (n = 53); 2) a group consisting of neurological/psychiatric syndromes, A Kruskal-Wallis test showed that the type of rare disease signifi­ as well as ataxia and neuroectodermic diseases (total of patients = 299, cantly affects the quality of life, H(2) = 14.91, p < 0.001. Post-hoc 65% of the cases’ sample); and 3) others: including autoimmune, pul­ Mann-Whitney tests using a Bonferroni-adjusted alpha level of 0.017 monary, digestive, endocrinologic and hematologic diseases (n = 107). (0.05/3) were used to compare all pairs of groups finding that IMD had Detailed information about the diseases included in each category and better quality of life than neurological and genetic diseases: U (NIMD = the number of patients represented in each of them can be found on 53, Nneurogen = 299) = 6101 z = − 2.67, p = 0.008 and other rare dis­ supplementary table 1 and 2. eases: U (NIMD = 53,Nother = 107) = 1843.5 z = − 3.60, p < 0.001. This figure represents the different subgroups of rare diseases Data did not show any differences in the alteration of the mental included in this study, which are defined as conditions with an incidence status between the three groups of rare diseases. of up to 1/2000. They are distributed in different categories, the most In order to compare inherited metabolic disorders with other rare prevalent being genetic syndromes (34%), followed by neuromuscular conditions, some categories were grouped: 1) inherited metabolic dis­ (13%), inherited metabolic disorders (12%), neurologic/psychiatric orders, 2) neurological/psychiatric syndromes; and 3) others. Patients syndromes (12%) and autoimmune diseases (12%). with inherited metabolic diseases (IMD) had better quality of life than Special focus was devoted to inherited metabolic disorders, neurological and genetic diseases: U (NIMD = 53, Nneurogen = 299) = including a total of 53 patients suffering from a range of different dis­ 6101 z = − 2.67, p = 0.008 and other rare diseases: U (NIMD = 53,Nother eases, from intermediary metabolism to small and complex molecules, = 107) = 1843.5 z = − 3.60, p < 0.001. which are listed on Table 3. Table 4 shows the distribution of the inherited metabolic disorders sample by age groups. 4. Discussion 3.1.3. Description of the QoL and psychopathological status COVID-19 has had an impact on the global population, but this study Data referring to the quality of life and the mental status in terms of attempts to focus on its effects on patients suffering from rare diseases anxiety and affective symptoms (altered mental status or AMS) is shown and particularly on IMD, for whom changes in medical care could in Table 5. QoL is described by a score in a 0–100 scale in which higher translate into life-threatening decompensation episodes due to their scores indicate higher QoL. condition. IMDs are a heterogeneous group of genetic diseases that affect 3.2. Group comparison between inherited metabolic disorders and metabolic pathways. >1400 disorders are described (with >600 new controls disorders described in the last 6 years), 85% presenting with predomi­ nantly neurologic manifestations [39], but may present with many 3.2.1. Quality of life analysis symptoms and affect any organs at any age. The phenotypes range from Data don’t show significant statistical differences when comparing mild to severe. To date, mostly lack effective therapies, although tar­ QoL between cases and controls in children nor in adolescents. geted metabolic treatments (with small molecules), gene therapy, However, adult data show that quality of life of cases (Mdn = 66) was treatment with chaperones, and other individualized approaches are in worse than that in controls (Mdn = 75). A Mann-Whitney test indicated constant development and improvement. Some of them receive specific that this difference was statistically significant, U (Ncases = 26, Ncontrols nutritional supplements to minimize the risk of decompensation, and/or = 291) = 2713.5; z = − 2.39, p = 0.017. require a restricted lifelong diet as part of their treatment. All these restrictions and lifestyle modifications in this group of IMD affect pa­ tients and their families, with an undeniable effect on their disease acceptance and QoL perception [40]. Consequently, the evaluation of health-related QoL might be of particular relevance in this population, Table 2 with very few studies published in the literature on this topic. Fabre Distribution of the sample by age groups. et al. [ 41] reported that the QoL of children and their parents in those Age Cases (n = 459) Controls (n = 446) children with IMD that require protein restricted diet was lower than the 4-6yo 35 (7.6%) 47 (10.5%) average QoL in other pediatric chronic diseases. AbdoulayeOuattara 7-13yo 77 (16.8%) 60 (13.5%) et al. [42] concluded that psychosocial factors appear to be major de­ 14-17yo 40 (8.7%) 48 (10.8%) terminants of QoL impairment in children with IMD receiving a ≥ 18yo not self-filling the questionnaire 35 (7.6%) 2 (0.4%) restricted diet. A multicenter study showed that children and adoles­ ≥ 18yo self-filling the questionnaire 272 (59.3%) 289 (64.8%) cents with intoxication-type IMD have significantly impaired health- 4 M.M. Rovira-Remisa et al. Molecular Genetics and Metabolism Reports 35 (2023) 100962 Fig. 1. Subgroups of rare diseases (N = 459). mental illness in this age group. Table 3 Although most of the articles that investigated the early stages of the Patients with inherited metabolic disorders. pandemic already demonstrated high levels of anxiety and depression in Inherited metabolic disorders (n = 53) n the general population during the quarantine period [6,7,9], our results Mitochondrial syndrome 12 were obtained in a stage in which the restrictions began to be gradually Succinic semialdehyde dehydrogenase (SSADH) deficiency 7 withdrawn. A recent report by Save the Children [44] highlights an Wilson disease 7 increase from 1.1% to 4% in mental disorders in children and adoles­ Lysosomal acid lipase deficiency 4 Fabry disease 4 cents compared to official data from 2017 before the pandemic. Very long-chain acyl-coa dehydrogenase deficiency (VLCAD) 3 When our study began, quarantine was being lifted, but the re­ Mucopolysaccharidosis type 2 2 strictions on social interactions were maintained, school attendance in Glutaric aciduria type 1 2 bubble groups was necessary, online classes were required intermit­ X-linked adrenoleukodystrophy 2 tently, and participation in activities of leisure and spaces for relation­ Dopamine transporter deficiency 1 Smith-Lemli-Opitz syndrome 1 ships with their peers were limited. These aspects have been a challenge Trimethylaminuria 1 that this age group has had to face and impacted both adolescence with 2-hydroxyglutaric aciduria 1 and without IMD. Adolescence is a crucial period of maturity and Ornithine transcarbamylase deficiency (OTC) deficiency 1 growth, a phase of learning to regulate oneself and, precisely, of building Carnitine palmitoyltransferase II (CPT II) deficiency 1 Congenital hypertriglyceridemia 1 oneself and incorporating tools that help manage the different episodes Citrullinemia 1 of stress, anxiety and fear (fear of not seeing colleagues again, not to Mucopolysaccharidosis type 1 1 return to presential learning, not being able to do practicums, not being Classic galactosemia 1 able to start working…). Both, adolescent with and without IMD had to learn to do it in the midst of a major crisis. Furthermore, they had to do it in isolation, when they are used to doing it while being physically Table 4 interconnected with others. For all aforementioned, non-IMD related Distribution of the inherited metabolic disorders sample by age groups. challenges may have precipitated the onset of symptoms that affect Age Cases (n = 53) Controls (n = 445) mental well-being of all adolescent population. Children (4-13yo) 20 (37.7%) 106 (23.8%) There are a number of factors that could account for the changes in Adolescents (14-17yo) 7 (13.2%) 48 (10.8%) mental status observed in adults and children. On one hand, uncertainty, Adults (≥ 18yo) 26 (49.1%) 291 (65.4%) the possible impact of restriction measures and changes in routines (such as adaptation to bubble groups, the use of a mask, online schooling, the reduction of leisure activities) can be decisive for the appearance of related QoL compared to healthy controls and concluded that dietary anxiety or behavioural changes in these children [9,10]. For children treatment is considered a major burden, since it affects the daily routine with chronic diseases, the maintenance of normal routines and the of patients and their families [43]. certainty of returning to normal activities for their age are usually fac­ The results of our study stress the vulnerability of the IMD popula­ tors that allow a good mental state. However, the measures imposed by tion, whose psychopathological status seems to be worsened during the the pandemic situation may have affected these routines, facilitating the pandemic. While this is true for children and adults, differences between appearance of mental illness [4,45]. On the other hand, for adults the cases and controls in the teenager group do not reach statistical signif­ vulnerability to alterations in their mental status seems to be related icance. This might be partially explained by the size of the sample, too with a poorer QoL perception. The implications of teleworking and the small to highlight the potential differences, but could also be caused by possible economic impact may be relevant factors for the results in their the special vulnerability to stressful events that can trigger the onset of quality of life and their mental state. Another aspect to consider is the 5 M.M. Rovira-Remisa et al. Molecular Genetics and Metabolism Reports 35 (2023) 100962 Table 5 Mental status and QoL descriptive data by age. IMD (n = 53) Controls (n = 445) Children (20) Adolescent (7) Adult Children Adolescent Adult (26) (n = 106) (n = 48) (n = 291) AMS 4 (20%) 3 (42.9%) 11 (42.3%) 4 (3.8%) 9 (18.6%) 62 (21.3%) N (%) QoL (Mdn) 81 73 66 83 73 75 AMS: Altered Mental Status. QoL: Quality of life. did. While IMDs might provide more stress during a pandemic, it seems Table 6 that the non-IMD related stresses, especially in adolescent predominate. Mental status and Quality of Life (QoL) descriptives by type of rare disease. Nevertheless, further studies and new analyses in larger samples and in IMD Neuro & Gen (n = 299) Others other pandemic moments would be needed. (n = 53) (n = 107) We acknowledge some limitations to our study. First, a potential bias AMS 18 (34%) 130 (43.5%) 47 (43.9%) exists for all those patients not able to answer the questionnaires by N (%) themselves; in their case, their caregivers answered the tests by repre­ QoL (Mdn) 74.67 66.54 62.67 sentation, and their own psychological/psychiatric status may have IMD: Inherited Metabolic Disorder, Neuro & Gen: Neurologic and Genetic influenced their answers. It is well recognized that depression and/or Disorder. anxiety tend to be worse in patients suffering from chronic illnesses like it is the case with IMD. Another limitation is that the individual perception of quality of life might be influenced by the degree of dependence of the patient, and we did not explore this in our ques­ tionnaires. Also, since no data exist on the QoL or psychological status of our population prior to the pandemic, no comparisons can be made, so the results are very difficult to interpret. Consequently, the results found cannot be attributed to Covid-19 itself. Another limitation is that very different diseases are compared, without sufficient clinical data avail­ able in order to know the severity of the disease of respondents. Finally, it is not possible to extrapolate these results to the whole Spanish pop­ ulation with rare disorders, since our sample is not representative. Despite the efforts made to reach as many patients as possible (with the snowball sampling method described earlier), the low prevalence of this group of diseases makes reaching representativity difficult. Aknowledgements The authors would like to acknowledge the following patient’s as­ sociations, patients themselves and caregivers who participated in this study, with a special mention to Federación Española de Enfermedades Metabólicas Hereditarias (federacion@metabolicos.es): Asociación de enfermedades neuromusculares Andalucía (info@asense-a.org), Asociación Andaluza de pacientes con Síndrome de Tourette y Tras­ Fig. 2. Quality of life distribution by type of rare disease. tornos Asociados (ASTTA) (tourette@tourette.es), Asociación Alfa-1 de España (daniela.mendez@alfa1.org.es), Asociación Aragonesa de Enfermedades Neuromusculares (asem@asemaragon.com), Asociación possible impact that the limitations in access to health centres and española de síndrome de Sjögren (direccion@aesjogren.org), Asociación regular check-ups of their illness, as well as the fear associated with a Española PHP (asociacionpacientesphp@gmail.com), Asociación Debra possible perception of loss of adequate care, can be an important stressor Piel de Mariposa (nati@debra.es), Asociación Síndrome Williams de for this [5,7]. España (psicosocial@sindromewilliams.org), Asociación Nacional de Finally, we found that patients with IMDs had better outcomes in Addison y otras enfermedades endocrinas (info@adisen.es), Fundación quality of life compared to other rare diseases. These differences could Ana Carolina Díez Mahou (javierperezminguez@gmail.com), be explained by better metabolic control with a lower risk of decom­ Asociación de Afectados de Neurofibromatosis (presidencia@ne pensation, considering that more than half of the sample with IMD (29 urofibromatosis.es), Asociación Esclerosis Lateral Amiotrófica (info@e out of 53) correspond to patients with intoxication type disorders and lacyl.org), Asociación Síndrome Phelan –McDermid (mamen. energy metabolism (who are really prone to infectious diseases and galvez@22q13.org.es), Asociación DeNeu (enfermedades de los neuro­ decompensation). Thanks to the global measures established during the transmisores) (info@deneu.org), Federació Catalana de Malalties pandemic, there was less exposure to all viral infections (which are a Minoritàries (medicina@fecamm.org), Asociación síndrome de marfan frequent trigger of metabolic decompensation) and these patients SIMA (secretaria@marfan.es), Associació Catalana Síndrome X Fràgil probably had better adherence to dietary and medical treatment as they (info@xfragil.cat), Asociación de familias de niños con Miopatía Mio­ spent more hours at home with their primary caregiver. tubular y CNM (info@pequenossuperheroes.org), Asociación Española In conclusion, our data show that the pandemic had a negative Déficit Lipasa Ácida Lisosomal (info@aelald.org), Asociación para la impact on mental health that is more evident in the group of patients lucha contra las enfermedades biliares inflamatorias (info@albi-espana. with IMD. 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