bims-tyki2d 2026-09-20 papers

Issue of 2026–09–20
six papers selected by
Zoya Panahloo, UCB

J Genet Couns. 2026 Oct;35(5): e70284

Caring for Rare Genetic Disease: A Vision for the Future.

Ruth Horn, Sarah L Wynn, Sofia Douzgou Houge.

The United Nations, 2021 resolution to promote and protect the human rights of the estimated 300 million People Living with a Rare Disease and their families, set a milestone worldwide. At the same time, the successful diagnostic results of large genomic initiatives are reshaping rare disease healthcare in many countries. However, increasing diagnostic capability does not necessarily translate into improved care. Patients, families, and healthcare professionals navigate challenges in variant interpretation and prognosis, uneven access to specialist expertise and follow-up, limited natural history information and therapeutic options, and the wider familial and reproductive implications of genomic findings. Healthcare systems also face challenges related to workforce and service capacity, data governance, equity, research sustainability, and the integration of genomic technologies into longitudinal care. Drawing on published evidence, patient-organization experience and illustrative clinical scenarios, we argue that the value of genomic medicine for rare disease should be assessed beyond diagnostic yield alone and across individual, clinical and societal levels. Our vision for the future includes accessible education for families and professionals, multidisciplinary and longitudinal rare disease services embedded within publicly funded healthcare, sustainable research and data-sharing frameworks, partnership with patient advocacy organizations, and meaningful representation of people living with rare disease in governance, research, and innovation.

Keywords: advocacy; diagnosis; education; engagement; genomic medicine; healthcare; people living with a rare disease

DOI: https://doi.org/10.1002/jgc4.70284

J Cachexia Sarcopenia Muscle. 2026 Oct;17(5): e70380

Quantitative Muscle MRI Fat Fraction as a Biomarker of Disease Severity in Mitochondrial Myopathies.

Ana Bermejo-Moriñigo, Paloma Martín-Jiménez, Violeta González-Méndez, Laura Bermejo-Guerrero, Luz Edith Ochoa, Cristina Martín-Arriscado, Andrea Alcalá-Galiano, Cristina Casado-Pérez, María Navarro-Riquelme, Rocío Garrido-Moraga, Adrián González Quintana, Alberto Blázquez, Cristina Domínguez-González.

BACKGROUND: Quantitative muscle MRI is increasingly used to assess structural muscle damage in inherited myopathies, but its application in primary mitochondrial myopathies (PMM) has not been systematically evaluated in large cohorts. Because PMM are clinically and genetically heterogeneous, objective imaging biomarkers are needed to quantify skeletal-muscle involvement and define meaningful subgroups. We assessed whether MRI-derived proton density fat fraction (PDFF) captures genotype- and phenotype-specific patterns of fatty replacement and reflects disease severity using motor function outcomes and circulating biomarkers.
METHODS: We performed a cross-sectional analysis of 49 adults with genetically confirmed PMM enrolled in a prospective natural history study. Participants underwent standardised lower-limb MRI, including T1-weighted sequences and mDIXON-QUANT fat fraction imaging. Muscle involvement was assessed semi-quantitatively with the modified Mercuri scale and quantitatively by PDFF measurement in selected pelvic girdle and thigh muscles. A total fat fraction score (FF sum) was calculated. PDFF was compared across genotypes and phenotypes and against MRC score, NSAA, 6-min walk test, 100-m run test, CK, serum creatinine, GDF15 and disease duration.
RESULTS: Mean age at onset was 26.3 ± 15.1 years, mean age at MRI was 50.0 ± 12.3 years, and median disease duration was 23 years (IQR 15-31). Genetic diagnoses included mtDNA variants in 29 patients (59.1%; single large-scale deletions, n = 19; point mutations, n = 10), nuclear variants in POLG (n = 8), TK2 (n = 8) and TWNK (n = 4). Phenotypes were exercise intolerance without overt weakness (n = 7), isolated progressive external ophthalmoplegia (PEO; n = 16), PEO-plus (n = 16) and progressive myopathy (n = 8). Highest median PDFF values were observed in tensor fasciae latae (31%), gluteus maximus (30%), sartorius (25%) and gracilis (20%). FF sum correlated with MRC score (r = -0.567, p < 0.0001), NSAA (r = -0.731, p < 0.0001), 100-m run test time (r = 0.629, p < 0.0001), 6-min walk distance (r = -0.311, p = 0.0476) and serum creatinine (r = -0.715, p < 0.0001), but not with CK or GDF15. TK2 deficiency showed the highest fat replacement, particularly in gluteus maximus and gracilis (p < 0.001). Progressive myopathy showed greater fatty replacement than other phenotypes (p < 0.001), while exercise intolerance showed higher fat fraction than isolated PEO (p = 0.033).
CONCLUSIONS: Quantitative muscle MRI provides objective and clinically meaningful measures of muscle involvement in PMM. MRI-derived fat fraction reflects disease severity, discriminates between genotypes and phenotypes, and detects subclinical muscle damage. These cross-sectional findings support PDFF as a candidate imaging biomarker for patient stratification and disease characterisation; prospective longitudinal studies will be required to establish its sensitivity to change and its validity as an outcome measure for therapeutic trials.

Keywords: MRI‐derived fat fraction; biomarkers; mitochondrial myopathies; quantitative muscle MRI

DOI: https://doi.org/10.1002/jcsm.70380

J Community Genet. 2026 Sep 15. pii: 107. [Epub ahead of print]17(5):

Rare diseases in Brazil: a nationwide analysis of the diagnostic odyssey.

Raras Network Group

BACKGROUND: The diagnostic odyssey of individuals with rare diseases is prolonged and associated with clinical, emotional, and financial burden. In Brazil, data on diagnostic delays and their determinants remain scarce.
OBJECTIVE: This study aims to characterize the diagnostic odyssey of individuals with rare diseases using data from the Brazilian Rare Diseases Network (RARAS).
METHODS: This descriptive cross-sectional study analyzed ambispective data collected from 2018-2025 across RARAS centers nationwide. Diagnostic odyssey was defined as the time between symptom onset and definitive diagnosis. Prenatal and newborn screening diagnoses were excluded. Sociodemographic, clinical and etiological data were collected through a standardized REDCap-based instrument.
RESULTS: Among 18,625 unique participants, 12,048 had confirmed diagnoses and 5,984 met criteria for diagnostic odyssey analysis. The mean diagnostic interval was 6.21 years (± 8.41; median 2.94, IQR 0.80-8.13), indicating substantial heterogeneity. Longer delays were observed in individuals with symptom onset during adolescence. Patients referred during hospital admission experienced shorter diagnostic intervals. Regional differences were significant (p <0.001), with longer intervals in the Southeast region. Mean time to diagnosis ranged from 2.01 (± 2.89) years (achondroplasia) to 16.40 (± 12.59) years (hereditary angioedema). Patients consulted a mean of 5.32 (± 9.63) physicians and accessed 3.15 (± 4.96) healthcare services before diagnosis. Diagnostic intervals varied by race/ethnicity and etiological category, with longer delays among those with molecular diagnoses, while no association was observed with socioeconomic class.
CONCLUSION: The diagnostic odyssey for rare diseases in Brazil remains prolonged and heterogeneous, reflecting structural disparities, healthcare fragmentation, and diagnostic complexity. These findings suggest that delays are not driven solely by limited access to advanced diagnostics, but also by barriers in early recognition, referral pathways, and care coordination, underscoring the need for integrated strategies across the health system.

Keywords: Brazil; Brazilian rare diseases network; Diagnostic odyssey; Public health; Rare diseases

DOI: https://doi.org/10.1007/s12687-026-00939-y

Mamm Genome. 2026 Sep 18. pii: 108. [Epub ahead of print]37(1):

The role of impaired mitochondrial function in neurological manifestations of mitochondrial diseases.

Danielle Brister, Mariana Zarate-Mendez, Denisa Hathazi, Rita Horvath.

Mitochondria are essential organelles responsible for cellular energy production and the regulation of key metabolic and signalling pathways. Their function depends on the coordinated expression of both mitochondrial and nuclear genomes, and mitochondrial dysfunction leads to a diverse group of mitochondrial diseases. The nervous system is particularly vulnerable to mitochondrial dysfunction due to the high energetic demands and complex morphology of neurons. Neurons rely heavily on mitochondrial ATP production to support processes such as synaptic transmission, axonal transport, and calcium homeostasis, which are tightly regulated by mitochondrial dynamics, intracellular trafficking, and quality control mechanisms. In mitochondrial diseases, impairment of these processes contributes to a range of neurological manifestations, including epilepsy, stroke-like episodes, Leigh syndrome, ataxia, and peripheral neuropathy. Despite the ubiquitous presence of mitochondria, neuronal vulnerability varies between distinct neuronal populations, reflecting differences in neuronal morphology and metabolic demands. This review summarises key mechanisms underlying neuronal susceptibility in mitochondrial disease and highlights how defects in mitochondrial bioenergetics, dynamics, and transport contribute to characteristic neurological phenotypes. Understanding these mechanisms may provide insights into tissue-specific vulnerability and identify potential therapeutic targets to treat mitochondrial diseases and other neurodegenerative disorders associated with mitochondrial mechanisms.

DOI: https://doi.org/10.1007/s00335-026-10278-5

Front Public Health. 2026 ;14 1847004

Research on the innovation of medical expenses protection mechanism for rare disease patients in China.

Meijin Song, Yunhua Li.

Background: As China works to establish a mature medical security system by 2030, the heavy medical expenses faced by patients with rare diseases and the inadequacies in the existing protection mechanisms have become increasingly prominent and problematic, creating an urgent need for further research and policy solutions.
Objectives and methods: This study used an explanatory sequential design. First, a questionnaire survey was conducted to investigate the status of the protection provided to patients by the three major security channels (government, market, and social organizations) and to assess the medical burden on patients. Then, interviews were conducted to identify the shortcomings of the three current major security channels, with the goal of developing an innovative mechanism for addressing the medical expenses of patients with rare diseases.
Results: The results from the 720 questionnaires showed that, among rare disease patients who could be contacted through patient organizations and related networks, the three major protection channels currently available are still insufficient to cover their high medical expenses, resulting in a heavy financial burden. The 14 interviews revealed two types of deficiencies in the three channels. First, each channel demonstrated limited protection effectiveness. Second, coordination among the three protection channels was lacking.
Conclusion: Policy and mechanism innovations are needed at two levels. First, to improve the effectiveness of the three channels, the government should expand the breadth and depth of coverage and gradually equalize protection levels across regions; the market should lower access thresholds for patients, develop a multi-tiered product supply system, and improve operational risk prevention and control mechanisms, while social organizations should strengthen their capacity to raise charitable resources, establish a sustainable project operation model, and build collaborative networks. Second, at the level of cross-channel coordination, the expense-sharing responsibilities of each entity must be clarified, the types of expenses and target patient populations covered by multiple entities should be better defined, and a multi-entity collaborative reimbursement mechanism should be established. Ultimately, a collaborative, multi-entity mechanism for covering the medical expenses of patients with rare diseases should be established.

Keywords: mechanism innovation; medical expenses; medical expenses protection mechanism; multi-entity collaboration; rare diseases

DOI: https://doi.org/10.3389/fpubh.2026.1847004

PLoS Med. 2026 Sep;23(9): e1005253

Living with a rare disease: Why lived experience must shape research.

Gemma Whyatt, Jodi Whitehouse.

Rare diseases are often defined by numbers and clinical perspectives, a narrative that needs re-writing. Drawing on decades of patient advocacy, two women living with the rare condition Congenital Melanocytic Naevus argue that lived experience must shape research from the outset, and discuss how genuine patient-researcher partnership transforms science, care and identity.

DOI: https://doi.org/10.1371/journal.pmed.1005253