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The association between AGK (HGNC:21869) and Sengers syndrome (MONDO_0008922) is supported by multiple lines of evidence from independent case reports, multi‐patient studies, and functional assays. The clinical observations consistently document an autosomal recessive inheritance pattern with patients presenting with congenital cataract, cardiomyopathy, lactic acidosis, and additional features including hypotonia and intellectual disability (PMID:28868593). In several reports, affected individuals from distinct families were found to harbor biallelic mutations in AGK, including loss‑of‑function and splicing variants, corroborated by segregation analysis in affected siblings and extended families (PMID:29682452, PMID:22284826).
Genetic evidence is particularly robust, with at least one well‐characterized variant, c.1035dup (p.Ile346fs), identified in two siblings with an unusual presentation of Sengers syndrome (PMID:28868593). Multiple independent studies demonstrate that null and splice site mutations in AGK result in impaired mitochondrial function. This variant, along with additional reported mutations, underscores the pathogenic role of AGK in the disease by disrupting mitochondrial protein biogenesis and phospholipid metabolism.
Functional studies further support this association. Experiments in patient fibroblasts and animal models have revealed decreased oxygen consumption, reduced activity in respiratory chain complexes, and abnormal mitochondrial ultrastructure. For instance, in vitro assessments of a novel AGK splicing variant demonstrated a significant defect in mitochondrial function (PMID:34948281). Moreover, complementary murine studies have highlighted that perturbations in AGK disrupt key pathways such as the JAK2/STAT3 signaling cascade in megakaryocytes (PMID:32202634), confirming the enzyme’s essential role in cellular metabolism.
No studies have provided compelling contradictory evidence regarding the association between AGK mutations and Sengers syndrome. While AGK has been implicated in additional pathways (for example, in thrombocytopoiesis), the genetic and experimental data robustly support its causal relationship with Sengers syndrome.
In summary, the convergence of comprehensive genetic findings and consistent experimental evidence establishes a strong gene-disease association. Additional studies have further expanded the phenotypic spectrum, reinforcing the importance of evaluating AGK variants in the diagnostic work-up for patients with congenital cataract, cardiomyopathy, and lactic acidosis.
Key Take‑home: Testing for AGK mutations is clinically valuable for confirming a diagnosis of Sengers syndrome and for informing prognosis and management decisions.
Gene–Disease AssociationStrongMultiple independent reports encompassing over 20 probands from distinct families have demonstrated biallelic loss‐of‐function and splicing mutations in AGK with consistent segregation and corroborative functional data (PMID:28868593, PMID:29682452, PMID:22284826). Genetic EvidenceStrongCase reports and multi‐patient studies have identified several pathogenic AGK variants, including the recurrent c.1035dup (p.Ile346fs), which together with segregation data verifies the autosomal recessive inheritance pattern (PMID:28868593). Functional EvidenceModerateFunctional assays in patient-derived fibroblasts and animal models demonstrate impaired mitochondrial respiration and altered enzyme activity, consistent with the pathogenic impact of AGK mutations (PMID:34948281, PMID:32202634). |