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Biomedical subjects

Jerry Vockley

Publications and source records attributed to Jerry Vockley.

4 recordsLinked to original sources
PubMed2026

Comprehensive functional testing in fibroblasts has strong utility to diagnose mitochondrial disease.

Genome sequencing is the first-line diagnostic method for primary mitochondrial diseases (PMDs), yet its effectiveness is limited by variants of uncertain significance or unresolved genetic findings. We systematically evaluated the clinical performance of fibroblast-based functional testing, comprised of respiratory chain enzyme assays, blue native polyacrylamide gel electrophoresis with in-gel activity staining (BN-PAGE), complex I assembly assay, and targeted protein abundance assessments, in a cohort of 204 genetically confirmed PMD patients, 51 healthy controls, and 53 patients with differential diagnoses. Individually, enzyme assays, BN-PAGE, and complex I assembly assay showed sensitivities of 46%, 40%, and 49%, with specificities of 93%, 98%, and 99%, respectively. Combined, the assays achieved an overall sensitivity of 76%, a specificity 93%, a positive predictive value 96%, and a negative predictive value of 67%. Sensitivity was highest for isolated respiratory chain deficiencies, nuclear DNA-encoded mitochondrial translation defects, cofactor deficiencies, and mitochondrial aminoacyl-tRNA synthetase disorders, whereas mitochondrial DNA variants and maintenance defects remained challenging. Secondary mitochondrial dysfunction was rare. The strong clinical utility of comprehensive fibroblast functional testing improves PMD diagnosis when used complementary to genomic sequencing.

Journal Article↗
PubMed2026

Effect of long-term sepiapterin treatment on dietary phenylalanine tolerance in patients with phenylketonuria: Interim results from the phase 3 APHENITY Extension Study.

PURPOSE: To report interim results from the ongoing, open-label, phase 3 APHENITY Extension Study (NCT05166161), evaluating long-term treatment with sepiapterin in patients with phenylketonuria. METHODS: Participants received an age-based dose of oral sepiapterin daily; those with mean blood phenylalanine (Phe) levels <360 &#x3bc;mol/L (<5.95 mg/dL) after 2 weeks underwent a 26-week dietary Phe tolerance assessment, wherein dietary Phe intake was adjusted and blood Phe levels monitored. Other participants continued treatment with optional diet liberalization. Primary endpoints included change from baseline to week 26 in dietary Phe intake and treatment-emergent adverse events (TEAEs). RESULTS: As of September 2, 2024, 169 participants received sepiapterin (median [minimum, maximum] age: 14.0 [0.2, 55.0] years, median exposure: 72.9 weeks); 102 participants underwent dietary Phe tolerance assessments. Mean (SD) dietary Phe intake increased from 27.6 (18.0) mg/kg/day at baseline to 62.5 (41.5) mg/kg/day at week 26 (least-squares mean change [SE]: 36.4 [2.8] mg/kg/day from baseline) (P < .0001 from post hoc analysis). The incidence of treatment-related TEAEs was 29.0%; 3 participants (1.8%) discontinued treatment owing to treatment-related TEAEs. There were no treatment-related serious TEAEs or deaths. CONCLUSION: Interim results support the long-term safety of sepiapterin and demonstrate the potential for diet liberalization in adults and children with phenylketonuria. GOV IDENTIFIER: NCT05166161 (https://www. CLINICALTRIALS: gov/study/NCT05166161; date of registration, December 8, 2021).

Humans↗
PubMed2024

Inactivation of the SLC25A1 gene during embryogenesis induces a unique senescence program controlled by p53.

Germline inactivating mutations of the SLC25A1 gene contribute to various human disorders, including Velocardiofacial (VCFS), DiGeorge (DGS) syndromes and combined D/L-2-hydroxyglutaric aciduria (D/L-2HGA), a severe systemic disease characterized by the accumulation of 2-hydroxyglutaric acid (2HG). The mechanisms by which SLC25A1 loss leads to these syndromes remain largely unclear. Here, we describe a mouse model of SLC25A1 deficiency that mimics human VCFS/DGS and D/L-2HGA. Surprisingly, inactivation of both Slc25a1 alleles results in alterations in the development of multiple organs, and in&#xa0;a severe proliferation defect by activating two senescence programs, oncogene-induced senescence (OIS) and mitochondrial dysfunction-induced senescence (MiDAS), which converge upon the induction of the p53 tumor suppressor. Mechanistically, cells and tissues with dysfunctional SLC25A1 protein undergo metabolic and transcriptional rewiring leading to the accumulation of 2HG via a non-canonical pathway and to the depletion of nicotinamide adenine dinucleotide, NAD+, which trigger senescence. Replenishing the pool of NAD+ or promoting the clearance of 2HG rescues the proliferation defect of cells with dysfunctional SLC25A1 in a cooperative fashion. Further, removal of p53 activity via RNA interference restores proliferation, indicating that p53 acts as a critical barrier to the expansion of cells lacking functional SLC25A1. These findings reveal unexpected pathogenic roles of senescence and of p53 in D/L-2HGA and identify potential therapeutic strategies to correct salient molecular alterations driving this disease.

Animals↗