bims-curels 2023-04-30 papers

J Cardiovasc Dev Dis. 2023 Apr 01. pii: 154. [Epub ahead of print]10(4):

Why Don't More Mitochondrial Diseases Exhibit Cardiomyopathy?

Nina Singh, Mindong Ren, Colin K L Phoon.

BACKGROUND: Although the heart requires abundant energy, only 20-40% of children with mitochondrial diseases have cardiomyopathies.METHODS: We looked for differences in genes underlying mitochondrial diseases that do versus do not cause cardiomyopathy using the comprehensive Mitochondrial Disease Genes Compendium. Mining additional online resources, we further investigated possible energy deficits caused by non-oxidative phosphorylation (OXPHOS) genes associated with cardiomyopathy, probed the number of amino acids and protein interactors as surrogates for OXPHOS protein cardiac "importance", and identified mouse models for mitochondrial genes.
RESULTS: A total of 107/241 (44%) mitochondrial genes was associated with cardiomyopathy; the highest proportion were OXPHOS genes (46%). OXPHOS (p = 0.001) and fatty acid oxidation (p = 0.009) defects were significantly associated with cardiomyopathy. Notably, 39/58 (67%) non-OXPHOS genes associated with cardiomyopathy were linked to defects in aerobic respiration. Larger OXPHOS proteins were associated with cardiomyopathy (p < 0.05). Mouse models exhibiting cardiomyopathy were found for 52/241 mitochondrial genes, shedding additional insights into biological mechanisms.
CONCLUSIONS: While energy generation is strongly associated with cardiomyopathy in mitochondrial diseases, many energy generation defects are not linked to cardiomyopathy. The inconsistent link between mitochondrial disease and cardiomyopathy is likely to be multifactorial and includes tissue-specific expression, incomplete clinical data, and genetic background differences.

Keywords: cardiomyopathy; mitochondrial disease; mouse models; oxidative phosphorylation

DOI: https://doi.org/10.3390/jcdd10040154

Clin Chem. 2023 Apr 26. pii: hvad037. [Epub ahead of print]

Methodologies in Mitochondrial Testing: Diagnosing a Primary Mitochondrial Respiratory Chain Disorder.

Emily L Gill, Jing Wang, Angela N Viaene, Stephen R Master, Rebecca D Ganetzky.

BACKGROUND: Mitochondria are cytosolic organelles within most eukaryotic cells. Mitochondria generate the majority of cellular energy in the form of adenosine triphosphate (ATP) through oxidative phosphorylation (OxPhos). Pathogenic variants in mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) lead to defects in OxPhos and physiological malfunctions (Nat Rev Dis Primer 2016;2:16080.). Patients with primary mitochondrial disorders (PMD) experience heterogeneous symptoms, typically in multiple organ systems, depending on the tissues affected by mitochondrial dysfunction. Because of this heterogeneity, clinical diagnosis is challenging (Annu Rev Genomics Hum Genet 2017;18:257-75.). Laboratory diagnosis of mitochondrial disease depends on a multipronged analysis that can include biochemical, histopathologic, and genetic testing. Each of these modalities has complementary strengths and limitations in diagnostic utility.CONTENT: The primary focus of this review is on diagnosis and testing strategies for primary mitochondrial diseases. We review tissue samples utilized for testing, metabolic signatures, histologic findings, and molecular testing approaches. We conclude with future perspectives on mitochondrial testing.
SUMMARY: This review offers an overview of the current biochemical, histologic, and genetic approaches available for mitochondrial testing. For each we review their diagnostic utility including complementary strengths and weaknesses. We identify gaps in current testing and possible future avenues for test development.

DOI: https://doi.org/10.1093/clinchem/hvad037

Nat Rev Drug Discov. 2023 Apr 27.

Opportunities for mitochondrial disease gene therapy.

Carlo Viscomi, Jelle van den Ameele, Kathrin C Meyer, Patrick F Chinnery.

DOI: https://doi.org/10.1038/d41573-023-00067-z

J Patient Cent Res Rev. 2023 ;10(2): 68-76

Attitudes Toward Personal Health Data Sharing Among People Living With Sickle Cell Disorder, Exemplar for Study of Rare Disease Populations.

Rebecca Baines, Sebastian Stevens, Zainab Garba-Sani, Arunangsu Chatterjee, Daniela Austin, Simon Leigh.

Purpose: Rare conditions are often poorly understood, creating barriers in determining the value treatments can provide. This study explored barriers and facilitators to personal health data sharing among those with one particular group of rare hematologic disorders, ie, sickle cell disorder (SCD) and its variants.Methods: A single online focus group among those >18 years of age and living with SCD was conducted. Participants (N=25) were recruited through a United Kingdom-based SCD charity. Discussions were transcribed verbatim, with data therein analyzed using inductive thematic analysis.
Results: Five primary motivators for sharing health data were identified: improving awareness; knowing this would help others; evidencing impact; financial incentives; and being recognized as "experts with lived experience" rather than "specimens to be studied." Barriers included lack of clarity regarding "why" data was sought and "who" benefited. Participants stated that electronic health record (EHR) and genetic data were often "too detailed" and therefore "off limits" for sharing. However, experiences, mindset, and well-being data, often hidden from the EHR, were acceptable to share and considered a better barometer of how rare conditions treat patients day-to-day.
Conclusions: Utilizing patient experience data obtained under real-world conditions is key to painting the most accurate picture of needs and understanding how SCD impacts patients' day-to-day lives. Study findings suggest that patients with SCD are not merely passive providers of health data, but rather experts by experience. To appreciate the value that patient perspectives bring, we must revisit this status quo, amending our approach to patient centricity and reframing patients as high-value managers of their condition and personal health data who crucially decide what, how, and when they share it.

Keywords: data sharing; patient-reported outcomes; qualitative research; rare diseases; real-world data; sickle cell

DOI: https://doi.org/10.17294/2330-0698.2006

Orphanet J Rare Dis. 2023 04 25. 18(1): 93

Transition for adolescents with a rare disease: results of a nationwide German project.

PURPOSE: The transition process from paediatric/adolescent to adult medical care settings is of utmost importance for the future health of adolescents with chronic diseases and poses even more difficulties in the context of rare diseases (RDs). Paediatric care teams are challenged to deliver adolescent-appropriate information and structures. Here we present a structured transition pathway which is patient-focused and adoptable for different RDs.METHODS: The transition pathway for adolescents 16 years and older was developed and implemented as part of a multi-centre study in 10 university hospitals in Germany. Key elements of the pathway included: assessment of patients' disease-related knowledge and needs, training/educational and counselling sessions, a structured epicrisis and a transfer appointment jointly with the paediatric and adult specialist. Specific care coordinators from the participating university hospitals were in charge of organization and coordination of the transition process.
RESULTS: Of a total of 292 patients, 286 completed the pathway. Deficits in disease-specific knowledge were present in more than 90% of participants. A need for genetic or socio-legal counselling was indicated by > 60%. A mean of 2.1 training sessions per patient were provided over a period of almost 1 year, followed by the transfer to adult care in 267 cases. Twelve patients remained in paediatric care as no adult health care specialist could be identified. Targeted training and counselling resulted in improved disease-specific knowledge and contributed to empowering of patients.
CONCLUSION: The described transition pathway succeeds to improve health literacy in adolescents with RDs and can be implemented by paediatric care teams in any RD specialty. Patient empowerment was mainly achieved by individualized training and counselling.

Keywords: Adolescent health; Empowerment; Health literacy; Pathway; Rare disease; Transition

DOI: https://doi.org/10.1186/s13023-023-02698-2

J Pharmacokinet Pharmacodyn. 2023 Apr 24.

External control arms for rare diseases: building a body of supporting evidence.

Artak Khachatryan, Stephanie H Read, Terri Madison.

Comparator arms in randomized clinical trials may be impractical and/or unethical to assemble in rare diseases. In the absence of comparator arms, evidence generated from external control studies has been used to support successful regulatory submissions and health technology assessments (HTA). However, conducting robust and rigorous external control arm studies is challenging and despite all efforts, residual biases may remain. As a result, regulatory and HTA agencies may request additional external control analyses so that decisions may be made based upon a body of supporting evidence.This paper introduces external control studies and provides an overview of the key methodological issues to be considered in the design of these studies. A series of case studies are presented in which evidence derived from one or more external controls was submitted to regulatory and HTA agencies to provide support for the consistency of findings.

Keywords: External control; Historical control; Rare disease; Real-world data; Real-world evidence

DOI: https://doi.org/10.1007/s10928-023-09858-8

BMJ. 2023 Apr 24. 381 p927

Doctors are more extroverted and neurotic than their patients, researchers find.

Abi Rimmer.

DOI: https://doi.org/10.1136/bmj.p927