PTCD3 – Leigh syndrome

The association between PTCD3 and Leigh syndrome is supported by robust evidence from multiple independent studies. In the initial case report, a patient presenting with low birth weight, intellectual disability, and optic atrophy was found to harbor compound heterozygous loss‑of‑function variants in PTCD3, with functional analyses showing decreased mitochondrial complex I and IV activities (PMID:30607703). This finding was further substantiated in multi‐patient studies where additional individuals from two unrelated families exhibited a similar phenotype, and segregation analysis confirmed the autosomal recessive mode of inheritance, with affected relatives exhibiting concordant phenotypes (PMID:36450274).

Genetic evidence is compelling, with multiple variant types being identified. One representative variant is c.1746_1747dup (p.Phe583SerfsTer3), which was noted in the reported case series. The variants, predominantly predicted to be loss‑of‑function, segregate with disease and are consistent with the autosomal recessive inheritance pattern observed in Leigh syndrome (PMID:30607703, PMID:36450274).

Functional studies have played a critical role in establishing pathogenicity. Detailed assessment of patient fibroblasts revealed marked reductions in mitochondrial respiratory complex activities, oxygen consumption, and ATP biosynthesis. Complementation experiments restoring PTCD3 expression rescued the mitochondrial defects, thereby providing functional validation for the role of PTCD3 mutations in the disease process (PMID:30607703, PMID:36450274).

Additional studies have broadened the phenotypic spectrum associated with PTCD3 deficiency. Beyond the core features of Leigh syndrome, patients have presented with dystonia, global developmental delay, seizures, respiratory insufficiency, nystagmus, and feeding difficulties. This expanded phenotype further emphasizes the importance of considering PTCD3 analysis in patients with overlapping mitochondrial and neurodevelopmental disorders (PMID:36450274, PMID:39544688).

Collectively, the genetic and experimental evidence converge to support a strong association between PTCD3 and Leigh syndrome. The studies demonstrate that compound heterozygous loss‑of‑function variants lead to defective mitochondrial translation and oxidative phosphorylation, thus underpinning the clinical features observed in affected individuals. At least 7 probands from independent studies, along with segregation data and reproducible functional assays, establish the clinical validity of this association.

Key Take‑home: PTCD3 testing is clinically valuable for diagnosing patients with Leigh syndrome and related mitochondrial dysfunction, given the strong genetic and functional evidence supporting its pathogenic role.

References

• Neurogenetics • 2019 • Mitochondrial ribosomal protein PTCD3 mutations cause oxidative phosphorylation defects with Leigh syndrome PMID:30607703
• Brain Pathology (Zurich, Switzerland) • 2023 • Leigh syndrome is the main clinical characteristic of PTCD3 deficiency PMID:36450274
• JIMD Reports • 2024 • The phenotypic spectrum of PTCD3 deficiency PMID:39544688

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