Int J Mol Sci. 2023 Jan 15;24(2):1709. doi: 10.3390/ijms24021709.

ABSTRACT

Even though the application of Next-Generation Sequencing (NGS) has significantly facilitated the identification of disease-associated mutations, the diagnostic rate of rare diseases is still below 50%. This causes a diagnostic odyssey and prevents specific treatment, as well as genetic counseling for further family planning. Increasing the diagnostic rate and reducing the time to diagnosis in children with unclear disease are crucial for a better patient outcome and improvement of quality of life. In many cases, NGS reveals variants of unknown significance (VUS) that need further investigations. The delineation of novel (lipid) biomarkers is not only crucial to prove the pathogenicity of VUS, but provides surrogate parameters for the monitoring of disease progression and therapeutic interventions. Lipids are essential organic compounds in living organisms, serving as building blocks for cellular membranes, energy storage and signaling molecules. Among other disorders, an imbalance in lipid homeostasis can lead to chronic inflammation, vascular dysfunction and neurodegenerative diseases. Therefore, analyzing lipids in biological samples provides great insight into the underlying functional role of lipids in healthy and disease statuses. The method of choice for lipid analysis and/or huge assemblies of lipids (=lipidome) is mass spectrometry due to its high sensitivity and specificity. Due to the inherent chemical complexity of the lipidome and the consequent challenges associated with analyzing it, progress in the field of lipidomics has lagged behind other omics disciplines. However, compared to the previous decade, the output of publications on lipidomics has increased more than 17-fold within the last decade and has, therefore, become one of the fastest-growing research fields. Combining multiple omics approaches will provide a unique and efficient tool for determining pathogenicity of VUS at the functional level, and thereby identifying rare, as well as novel, genetic disorders by molecular techniques and biochemical analyses.

PMID:36675224 | PMC:PMC9866746 | DOI:10.3390/ijms24021709

Int J Mol Sci. 2023 Jan 14;24(2):1661. doi: 10.3390/ijms24021661.

ABSTRACT

Screening for pathogenic variants in the diagnosis of rare genetic diseases can now be performed on all genes thanks to the application of whole exome and genome sequencing (WES, WGS). Yet the repertoire of gene-disease associations is not complete. Several computer-based algorithms and databases integrate distinct gene-gene functional networks to accelerate the discovery of gene-disease associations. We hypothesize that the ability of every type of information to extract relevant insights is disease-dependent. We compiled 33 functional networks classified into 13 knowledge categories (KCs) and observed large variability in their ability to recover genes associated with 91 genetic diseases, as measured using efficiency and exclusivity. We developed GLOWgenes, a network-based algorithm that applies random walk with restart to evaluate KCs' ability to recover genes from a given list associated with a phenotype and modulates the prediction of new candidates accordingly. Comparison with other integration strategies and tools shows that our disease-aware approach can boost the discovery of new gene-disease associations, especially for the less obvious ones. KC contribution also varies if obtained using recently discovered genes. Applied to 15 unsolved WES, GLOWgenes proposed three new genes to be involved in the phenotypes of patients with syndromic inherited retinal dystrophies.

PMID:36675175 | PMC:PMC9864172 | DOI:10.3390/ijms24021661

Int J Mol Sci. 2023 Jan 4;24(2):930. doi: 10.3390/ijms24020930.

ABSTRACT

This review describes, from a chemical point of view, the top "blockbuster" small molecule orphan drugs according to their forecasted sales in 2026. Orphan drugs are intended for the treatment, prevention, or diagnosis of a rare disease or condition. These molecules are mostly addressed to the treatment of rare forms of cancer. The respiratory and central nervous systems represent other common therapeutic subcategories. This work will show how the orphan drugs market has significantly grown and will account for a consistent part of prescriptions by 2026.

PMID:36674441 | PMC:PMC9864910 | DOI:10.3390/ijms24020930

Int J Environ Res Public Health. 2023 Jan 5;20(2):968. doi: 10.3390/ijerph20020968.

ABSTRACT

At least 50% of chronic disease patients don't follow their care plans, leading to lower health outcomes and higher medical costs. Providing Patient Education Materials (PEMs) to individuals living with a disease can help to overcome these problems. PEMs are especially beneficial for people suffering from multisystemic and underrecognized diseases, such as rare diseases. Congenital disorders of glycosylation (CDG) are ultra-rare diseases, where a need was identified for PEMs in plain language that can clearly explain complex information. Community involvement in the design of PEMs is extremely important for diseases whose needs are underserved, such as rare diseases; however, attempts to involve lay and professional stakeholders are lacking. This paper presents a community-based participatory framework to co-create PEMs for CDG, that is transferable to other diseases. A literature review and questionnaire were performed, and only four articles describing the development of PEMS for rare diseases have been found, which demonstrates a lack of standardized approaches. The framework and PEMs were co-developed with CDG families and will be crucial in increasing health literacy and empowering families. We will close a gap in the creation of PEMs for CDG by delivering these resources in lay language in several languages.

PMID:36673723 | PMC:PMC9859511 | DOI:10.3390/ijerph20020968

Int J Environ Res Public Health. 2023 Jan 4;20(2):937. doi: 10.3390/ijerph20020937.

ABSTRACT

Patients with rare diseases (RDs) generally have delayed diagnosis and misdiagnosis, which lead to inappropriate care or the need to modify treatment during the course of the disease. The medical care of RD patients can be further complicated by the presence of comorbidities. In this population-based study, we evaluated the prevalence, intensity of use, and consumption of drugs prescribed to RD patients residing in Tuscany (Italy) in the years 2008-2018. Data from the Registry of Rare Diseases of Tuscany were integrated with information retrieved from regional pharmaceutical prescription databases. The overall prevalence of drug use in the RD patients was 85.4%. Drugs for the alimentary tract and metabolism and antiinfectives for systemic use showed the highest prevalence of use, while drugs for the nervous system had the highest intensity of use only in the pediatric patients. The adults exhibited a female preponderance in terms of the prevalence of use and drug consumption in almost all the age groups and therapeutic categories. Conversely, a higher prevalence of use was observed in the male children. These results provide relevant insights into drug profiles in RD patients, representing a first step for future analyses to monitor changes in drug utilization in patients with RDs over time.

PMID:36673691 | PMC:PMC9858964 | DOI:10.3390/ijerph20020937

Int J Environ Res Public Health. 2023 Jan 4;20(2):933. doi: 10.3390/ijerph20020933.

ABSTRACT

This study explores the perception of social and educational quality of life in minors with rare diseases (RDs). Two meta-analyses were performed, applying the random effects model. Results: Regarding the social Quality of Life, the meta-sample consisted of k = 40 samples, with a total population of 1943 children (mean age = 9.42 years), of whom 687 (35.3%) were girls, 615 (31.4%) were boys and 641 (33%) did not report their sex. The effect size was large (mean size = 7.68; p < 0.000; 99% Confidence Interval; lower limit = 7.22; upper limit = 8.14). The results of the meta-regression and model analysis showed the importance of the measurement instrument (Paediatric Quality-of-Life Inventory and Prototypes of the Quality of life) and the dissimilarity of perception among caregivers. The nationality and the type of RD were not relevant. With respect to the educational Quality of Life, the meta-sample consisted of k = 19 samples, with 699 minors (mean age = 10.3 years), of whom 266 (38%) were girls, 242 (34.6%) were boys and 191 (27.4%) did not report their sex. The effect size was large (mean size = 7.15; p < 0.000; 99% CI; lower limit = 6.35; upper limit = 7.94). The meta-regression and comparison of models showed that the type of RD was essential. The measurement instrument was a moderating variable, especially the Parent version Paediatric Quality-of-Life Inventory. This study reveals the need for further research on RDs and their social-educational effects.

PMID:36673688 | PMC:PMC9859107 | DOI:10.3390/ijerph20020933

Genes (Basel). 2023 Jan 12;14(1):196. doi: 10.3390/genes14010196.

ABSTRACT

Complex genetic disease mechanisms, such as structural or non-coding variants, currently pose a substantial difficulty in frontline diagnostic tests. They thus may account for most unsolved rare disease patients regardless of the clinical phenotype. However, the clinical diagnosis can narrow the genetic focus to just a couple of genes for patients with well-established syndromes defined by prominent physical and/or unique biochemical phenotypes, allowing deeper analyses to consider complex genetic origin. Then, clinical-diagnosis-driven genome sequencing strategies may expedite the development of testing and analytical methods to account for complex disease mechanisms as well as to advance functional assays for the confirmation of complex variants, clinical management, and the development of new therapies.

PMID:36672937 | PMC:PMC9858967 | DOI:10.3390/genes14010196

Genes (Basel). 2023 Jan 7;14(1):169. doi: 10.3390/genes14010169.

ABSTRACT

BACKGROUND: Research participant feedback is rarely collected; therefore, investigators have limited understanding regarding stakeholders' (affected individuals/caregivers) motivation to participate. Members of the Genes to Mental Health Network (G2MH) surveyed stakeholders affected by copy number variants (CNVs) regarding perceived incentives for study participation, opinions concerning research priorities, and the necessity for future funding. Respondents were also asked about feelings of preparedness, research burden, and satisfaction with research study participation.

METHODS: Modified validated surveys were used to assess stakeholders´ views across three domains: (1) Research Study Enrollment, Retainment, Withdrawal, and Future Participation; (2) Overall Research Experience, Burden, and Preparedness; (3) Research Priorities and Obstacles. Top box score analyses were performed.

RESULTS: A total of 704 stakeholders´ responded from 29 countries representing 55 CNVs. The top reasons for initial participation in the research included reasons related to education and altruism. The top reasons for leaving a research study included treatment risks and side effects. The importance of sharing research findings and laboratory results with stakeholders was underscored by participants. Most stakeholders reported positive research experiences.

CONCLUSIONS: This study provides important insight into how individuals and families affected with a rare CNV feel toward research participation and their overall experience in rare disease research. There are clear targets for areas of improvement for study teams, although many stakeholders reported positive research experiences. Key findings from this international survey may help advance collaborative research and improve the experience of participants, investigators, and other stakeholders moving forward.

PMID:36672911 | PMC:PMC9859499 | DOI:10.3390/genes14010169

Genes (Basel). 2022 Dec 22;14(1):30. doi: 10.3390/genes14010030.

ABSTRACT

The re-analysis of nondiagnostic exome sequencing (ES) has the potential to increase diagnostic yields in individuals with rare diseases, but its implementation in the daily routines of laboratories is limited due to restricted capacities. Here, we describe a systematic approach to re-analyse the ES data of a cohort consisting of 1040 diagnostic and nondiagnostic samples. We applied a strict filter cascade to reveal the most promising single-nucleotide variants (SNVs) of the whole cohort, which led to an average of 0.77 variants per individual that had to be manually evaluated. This variant set revealed seven novel diagnoses (0.8% of all nondiagnostic cases) and two secondary findings. Thirteen additional variants were identified by a scientific approach prior to this re-analysis and were also present in this variant set. This resulted in a total increase in the diagnostic yield of 2.3%. The filter cascade was optimised during the course of the study and finally resulted in sensitivity of 85%. After applying the filter cascade, our re-analysis took 20 h and enabled a workflow that can be used repeatedly. This work is intended to provide a practical recommendation for other laboratories wishing to introduce a resource-efficient re-analysis strategy into their clinical routine.

PMID:36672771 | PMC:PMC9858523 | DOI:10.3390/genes14010030

Biomolecules. 2023 Jan 9;13(1):133. doi: 10.3390/biom13010133.

ABSTRACT

Several studies have identified rare and common genetic variants associated with severe COVID-19, but no study has reported genetic determinants as predisposition factors for neurological complications. In this report, we identified rare/unique structural variants (SVs) implicated in neurological functions in two individuals with neurological manifestations of COVID-19. This report highlights the possible genetic link to the neurological symptoms with COVID-19 and calls for a collective effort to study these cohorts for a possible genetic linkage.

PMID:36671517 | DOI:10.3390/biom13010133

Proc Natl Acad Sci U S A. 2023 Jan 24;120(4):e2209964120. doi: 10.1073/pnas.2209964120. Epub 2023 Jan 20.

ABSTRACT

Sonic hedgehog signaling regulates processes of embryonic development across multiple tissues, yet factors regulating context-specific Shh signaling remain poorly understood. Exome sequencing of families with polymicrogyria (disordered cortical folding) revealed multiple individuals with biallelic deleterious variants in TMEM161B, which encodes a multi-pass transmembrane protein of unknown function. Tmem161b null mice demonstrated holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes consistent with impaired Shh signaling, but were without limb defects, suggesting a CNS-specific role of Tmem161b. Tmem161b depletion impaired the response to Smoothened activation in vitro and disrupted cortical histogenesis in vivo in both mouse and ferret models, including leading to abnormal gyration in the ferret model. Tmem161b localizes non-exclusively to the primary cilium, and scanning electron microscopy revealed shortened, dysmorphic, and ballooned ventricular zone cilia in the Tmem161b null mouse, suggesting that the Shh-related phenotypes may reflect ciliary dysfunction. Our data identify TMEM161B as a regulator of cerebral cortical gyration, as involved in primary ciliary structure, as a regulator of Shh signaling, and further implicate Shh signaling in human gyral development.

PMID:36669111 | DOI:10.1073/pnas.2209964120

Ital J Pediatr. 2023 Jan 19;49(1):11. doi: 10.1186/s13052-023-01413-y.

ABSTRACT

BACKGROUND: Schimke immunoosseous dysplasia (SIOD) is an ultra-rare inherited disease affecting many organ systems. Spondyloepiphyseal dysplasia, T-cell immunodeficiency and steroid resistant nephrotic syndrome are the main symptoms of this disease.

CASE PRESENTATION: We aimed to characterize the clinical, pathological and genetic features of SIOD patients received at tertiary Pediatric Nephrology Center, University Hospital Motol, Prague, Czech Republic during the period 2001-2021. The mean age at diagnosis was 21 months (range 18-48 months). All patients presented with growth failure, nephropathy and immunodeficiency. Infections and neurologic complications were present in most of the affected children during the course of the disease.

CONCLUSIONS: Although SIOD is a disease characterized by specific features, the individual phenotype may differ. Neurologic signs can severely affect the quality of life; the view on the management of SIOD is not uniform. Currently, new therapeutic methods are required.

PMID:36658659 | PMC:PMC9850320 | DOI:10.1186/s13052-023-01413-y

Orphanet J Rare Dis. 2023 Jan 19;18(1):14. doi: 10.1186/s13023-022-02557-6.

ABSTRACT

300 million people live with at least one of 6,000 rare diseases worldwide. However, rare disease research is not always reviewed with scrutiny, making it susceptible to what the author refers to as nontransparent science. Nontransparent science can obscure animal model flaws, misguide medicine regulators and drug developers, delay or frustrate orphan drug development, or waste limited resources for rare disease research. Flawed animal models not only lack pharmacologic relevance, but also give rise to issue of clinical translatability. Sadly, these consequences and risks are grossly overlooked. Nontransparency in science can take many forms, such as premature publication of animal models without clinically significant data, not providing corrections when flaws to the model are discovered, lack of warning of critical study limitations, missing critical control data, questionable data quality, surprising results without a sound explanation, failure to rule out potential factors which may affect study conclusions, lack of sufficient detail for others to replicate the study, dubious authorship and study accountability. Science has no boarders, neither does nontransparent science. Nontransparent science can happen irrespective of the researcher's senority, institutional affiliation or country. As a patient-turned researcher suffering from Bietti crystalline dystrophy (BCD), I use BCD as an example to analyze various forms of nontransparent science in rare disease research. This article analyzes three papers published by different research groups on Cyp4v3-/-, high-fat diet (HFD)-Cyp4v3-/-, and Exon1-Cyp4v3-/- mouse models of BCD. As the discussion probes various forms of nontransparent science, the flaws of these knockout mouse models are uncovered. These mouse models do not mimic BCD in humans nor do they address the lack of Cyp4v3 (murine ortholog of human CYP4V2) expression in wild type (WT) mouse retina which is markedly different from CYP4V2 expression in human retina. Further, this article discusses the impact of nontransparent science on drug development which can lead to significant delays ultimately affecting the patients. Lessons from BCD research can be helpful to all those suffering from rare diseases. As a patient, I call for transparent science in rare disease research.

PMID:36658594 | PMC:PMC9854194 | DOI:10.1186/s13023-022-02557-6

Tidsskr Nor Laegeforen. 2023 Jan 13;143(1). doi: 10.4045/tidsskr.22.0488. Print 2023 Jan 17.

NO ABSTRACT

PMID:36655957 | DOI:10.4045/tidsskr.22.0488

AAPS J. 2023 Jan 18;25(1):16. doi: 10.1208/s12248-023-00784-8.

ABSTRACT

In August 2021, the US Food and Drug Administration approved Nexviazyme (avalglucosidase alfa-ngpt) for intravenous infusion to treat patients 1 year of age and older with late-onset Pompe disease (LOPD). The effectiveness and safety were studied in patients with LOPD and patients with infantile-onset Pompe disease (IOPD). The dosage(s) tested in clinical trials was 20 mg/kg every other week (qow) in patients with LOPD and 20 mg/kg and 40 mg/kg qow in patients with IOPD. While patients 3 years old and greater with LOPD were eligible for participation in the pivotal trial, the youngest patient enrolled was 16 years old. Therefore, pediatric patients with LOPD were not well represented in the clinical trial. The prevalence of LOPD in pediatrics is extremely low. Thus, conducting a clinical trial in pediatric patients with LOPD would be challenging. Given the similar pathophysiology, mechanism of action, and disease manifestations across the age spectrum of patients with LOPD, the approved dosages for pediatric patients younger than 16 years old with LOPD were based on extrapolation of efficacy using a model-informed exposure bridging strategy, leveraging the safety data from pediatric patients with IOPD. Specifically, the exposure associated with 20 mg/kg qow in adult patients with LOPD was the target exposure for bridging of efficacy. The safety data obtained with 40 mg/kg qow in patients with IOPD was leveraged to support approval in pediatric patients with LOPD aged 1 year and older. This article illustrates a regulatory use of model-informed extrapolation approach for dose selection in pediatric patients with a rare disease.

PMID:36653728 | DOI:10.1208/s12248-023-00784-8

Eur Rev Med Pharmacol Sci. 2023 Jan;27(1):426-430. doi: 10.26355/eurrev_202301_30898.

ABSTRACT

OBJECTIVE: In this study, we have evaluated 12 patients with cerebral alveolar echinococcosis (AE). All patients underwent surgery for cerebral AE. We aimed to demonstrate the relationship between the demographic properties of patients and surgical outcomes as well as surgical suggestions about surgical approaches.

PATIENTS AND METHODS: Patients were analyzed according to demographic properties, hepatic/ pulmonary AE lesion existence, symptoms, neurological and radiological examination, histopathological findings, and outcome after treatment.

RESULTS: Preoperative diagnosis based on the history of the patient, neurological examination, serological tests, and radiology. When enhanced radiological imaging like MR-Tractography and intraoperative neuromonitoring is combined with precision surgical methods cerebral AE is treatable. Ten of twelve cerebral AE patients had favorable outcomes after surgery.

CONCLUSIONS: AE of the brain is a rare but life-threatening parasitic disease. Wherever the primary focus is, surgery for cerebral involvement of AE is challenging but safe with appropriate surgical techniques and the help of radiological examination.

PMID:36647892 | DOI:10.26355/eurrev_202301_30898

Int J Equity Health. 2023 Jan 13;22(1):11. doi: 10.1186/s12939-022-01809-y.

ABSTRACT

Early diagnosis of genetic rare diseases is an unmet need in Brazil, where an estimated 10-13 million people live with these conditions. Increased use of chromosome microarray assays, exome sequencing, and whole genome sequencing as first-tier testing techniques in suitable indications can shorten the diagnostic odyssey, eliminate unnecessary tests, procedures, and treatments, and lower healthcare expenditures. A selected panel of Brazilian experts in fields related to rare diseases was provided with a series of relevant questions to address before a multi-day conference. Within this conference, each narrative was discussed and edited through numerous rounds of discussion until agreement was achieved. The widespread adoption of exome sequencing and whole genome sequencing in Brazil is limited by various factors: cost and lack of funding, reimbursement, awareness and education, specialist shortages, and policy issues. To reduce the burden of rare diseases and increase early diagnosis, the Brazilian healthcare authorities/government must address the barriers to equitable access to early diagnostic methods for these conditions. Recommendations are provided, including broadening approved testing indications, increasing awareness and education efforts, increasing specialist training opportunities, and ensuring sufficient funding for genetic testing.

PMID:36639662 | PMC:PMC9837951 | DOI:10.1186/s12939-022-01809-y

WMJ. 2022 Dec;121(4):297-300.

ABSTRACT

INTRODUCTION: Despite universal newborn screening, there is no comprehensive surveillance system to understand the sickle cell disease population in Wisconsin.

METHODS: We initiated the development of a sickle cell disease surveillance system by linking newborn screening data and electronic health records from 2 large tertiary health care institutions in Wisconsin: Children's Wisconsin and Froedtert Hospital.

RESULTS: There were 1478 individuals within the 3 data sources. One hundred thirty-two (82%) of 159 identified by newborn screening from 2013 through 2019 received care at Children's Wisconsin. The majority of individuals with sickle cell disease at Children's Wisconsin and Froedtert Hospital resided in Milwaukee County.

DISCUSSION: The new surveillance program will increase our understanding of the sickle cell disease population in Wisconsin and help improve quality of care and health outcomes.

PMID:36637841

Neurobiol Dis. 2023 Jan 10:105996. doi: 10.1016/j.nbd.2023.105996. Online ahead of print.

ABSTRACT

Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin (FXN). Most FRDA patients are homozygous for large expansions of GAA repeats in intron 1 of FXN, while some are compound heterozygotes with an expanded GAA tract in one allele and a missense or nonsense mutation in the other. A missense mutation, changing a glycine to valine at position 130 (G130V), is prevalent among the clinical variants. We and others have demonstrated that levels of mature FXN protein in FRDA G130V samples are reduced below those detected in samples harboring homozygous repeat expansions. Little is known regarding expression and function of endogenous FXN-G130V protein due to lack of reagents and models that can distinguish the mutant FXN protein from the wild-type FXN produced from the GAA-expanded allele. We aimed to determine the effect of the G130V (murine G127V) mutation on Fxn expression and to define its multi-system impact in vivo. We used CRISPR/Cas9 to introduce the G127V missense mutation in the Fxn coding sequence and generated homozygous mice (FxnG127V/G127V). We also introduced the G127V mutation into a GAA repeat expansion FRDA mouse model (FxnGAA230/KO; KIKO) to generate a compound heterozygous strain (FxnG127V/GAA230). We performed neurobehavioral tests on cohorts of WT and Fxn mutant animals at three-month intervals for one year, and collected tissue samples to analyze molecular changes during that time. The endogenous Fxn G127V protein is detected at much lower levels in all tissues analyzed from FxnG127V/G127V mice compared to age and sex-matched WT mice without differences in Fxn transcript levels. FxnG127V/G127V mice are significantly smaller than WT counterparts, but perform similarly in most neurobehavioral tasks. RNA sequencing analysis revealed reduced expression of genes in oxidative phosphorylation and protein synthesis, underscoring the metabolic consequences in our mouse model expressing extremely low levels of Fxn. Results of these studies provide insight into the unique pathogenic mechanism of the FXN G130V mechanism and the tolerable limit of Fxn/FXN expression in vivo.

PMID:36638893 | DOI:10.1016/j.nbd.2023.105996

Orphanet J Rare Dis. 2023 Jan 9;18(1):6. doi: 10.1186/s13023-022-02598-x.

ABSTRACT

The "diagnostic odyssey" describes the process those with undiagnosed conditions undergo to identify a diagnosis. Throughout this process, families of children with undiagnosed conditions have multiple opportunities to decide whether to continue or stop their search for a diagnosis and accept the lack of a diagnostic label. Previous studies identified factors motivating a family to begin searching, but there is limited information about the decision-making process in a prolonged search and how the affected child impacts a family's decision. This study aimed to understand how families of children with undiagnosed diseases decide whether to continue to pursue a diagnosis after standard clinical testing has failed. Parents who applied to the Undiagnosed Disease Network (UDN) at the National Institutes of Health (NIH) were recruited to participate in semi-structured interviews. The 2015 Supportive Care Needs model by Pelenstov, which defines critical needs in families with rare/undiagnosed diseases, provided a framework for interview guide development and transcript analysis (Pelentsov et al in Disabil Health J 8(4):475-491, 2015. https://doi.org/10.1016/J.DHJO.2015.03.009 ). A deductive, iterative coding approach was used to identify common unifying themes. Fourteen parents from 13 families were interviewed. The average child's age was 11 years (range 3-18) and an average 63% of their life had been spent searching for a diagnosis. Our analysis found that alignment or misalignment of parent and child needs impact the trajectory of the diagnostic search. When needs and desires align, reevaluation of a decision to pursue a diagnosis is limited. However, when there is conflict between parent and child desires, there is reevaluation, and often a pause, in the search. This tension is exacerbated when children are adolescents and attempting to balance their dependence on parents for medical care with a natural desire for independence. Our results provide novel insights into the roles of adolescents in the diagnostic odyssey. The tension between desired and realistic developmental outcomes for parents and adolescents impacts if, and how, the search for a diagnosis progresses.

PMID:36624503 | PMC:PMC9830697 | DOI:10.1186/s13023-022-02598-x