bims-tyki2d 2026-06-07 papers

Issue of 2026–06–07
three papers selected by
Zoya Panahloo, UCB

Cell Metab. 2026 Jun 02. pii: S1550-4131(26)00152-X. [Epub ahead of print]38(6): 1079-1080

Is an emerging pharmacotherapeutic era for rare mitochondrial diseases here?

After decades without approved pharmacotherapies, mitochondrial disease care is shifting. Two FDA approvals emerged in 1 year, elamipretide (Forzinity) for Barth syndrome and deoxynucleoside therapy (Kygevvi) for TK2 deficiency, with another under review. Zink et al.1 suggest sildenafil (Viagra) could treat Leigh syndrome, highlighting drug repurposing for severe pediatric mitochondrial disease.

DOI: https://doi.org/10.1016/j.cmet.2026.04.014

Eur J Med Genet. 2026 Jun 02. pii: S1769-7212(26)00020-0. [Epub ahead of print]82 105086

Genotype before phenotype? Reversing the diagnostic odyssey in genomic medicine.

Alain Chebly, Said El Shamieh.

For decades, the diagnosis of rare genetic disorders has relied on a phenotype-driven approach, often resulting in a prolonged "diagnostic odyssey." The widespread use of whole-exome and whole-genome sequencing has transformed this paradigm, increasingly enabling genotype-first diagnoses before a clear clinical phenotype is recognized. This shift may contribute to a reversal of the diagnostic odyssey, in which genetic findings guide subsequent clinical evaluation through reverse phenotyping. Large-scale biobank studies and newborn genomic screening programs are further accelerating this paradigm shift. Although this approach has improved diagnostic yield, it also introduces interpretative challenges, including the risk of phenotype reinterpretation bias and the persistent burden of variants of uncertain significance (VUS), particularly when genetic variants only partially explain the clinical presentation. This article discusses the emergence of genotype-driven diagnosis and emphasizes the need for balanced integration of genomic and clinical data in modern precision medicine.

Keywords: Diagnostic odyssey; Genomic medicine; Genomic sequencing; Genotype-first approach; Newborn genomic screening; Precision medicine; Rare diseases; Reverse phenotyping; Variant interpretation

DOI: https://doi.org/10.1016/j.ejmg.2026.105086

Cell Rep Med. 2026 Jun 02. pii: S2666-3791(26)00258-2. [Epub ahead of print] 102841

Emerging therapeutic strategies for mitochondrial DNA-related diseases.

Rubing Shi, Micol Falabella, Jana Aref, Michael G Hanna, Michal Minczuk, Carlo Viscomi, Robert D S Pitceathly.

Primary mitochondrial diseases (PMDs) are among the most common inherited metabolic disorders, affecting approximately 1 in 4,300 individuals. They result from pathogenic variants in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) that disrupt oxidative phosphorylation and lead to multisystem disease. Although advances in genomic testing have significantly improved diagnostic rates in PMDs, effective disease-modifying therapies remain limited. Therapeutic development increasingly focuses on mtDNA-targeted approaches because mtDNA variants are a major cause of disease and may offer opportunities for targeted intervention. Current strategies include allotopic expression, mitochondria-targeted nucleases, and next-generation base editors, which reduce or correct pathogenic mtDNA variants. Other emerging approaches include pharmacological modulation of heteroplasmy, reproductive techniques such as mitochondrial donation, and therapeutic strategies based on mitochondrial transplantation. This review summarizes advances in gene editing, pharmacological approaches, and reproductive and mitochondrial transplantation strategies for mtDNA-related PMDs, highlighting progress toward more targeted interventions.

Keywords: gene therapy; mitochondrial DNA; mitochondrial replacement therapy; primary mitochondrial diseases

DOI: https://doi.org/10.1016/j.xcrm.2026.102841