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<p>Mitochondrial DNA (mtDNA) maintenance defects (specifically mtDNA depletion syndromes, MDS) are autosomal recessive disorders caused by a severe reduction in mtDNA content, leading to impaired oxidative phosphorylation and energy deficiency in affected tissues. The clinical heterogeneity of mtDNA maintenance defects correlates with specific gene mutations, with <i>POLG</i> being one of the most frequently implicated genes in mitochondrial dysfunction. We report a novel case of mtDNA maintenance defects manifesting with progressive ocular symptoms, including blepharoptosis, blurred vision, and diplopia, associated with a rare homozygous <i>POLG</i> mutation (c.924G &gt; T, p.Gln308His), which is the second reported homozygous variant at this nucleotide site. Among five previously reported <i>POLG</i> c.924G &gt; T-associated MDS cases, 4 are heterozygous (compound heterozygous or combined with other mitochondrial gene variants). POLG encodes DNA polymerase γ, essential for mtDNA replication; mutations impair mitochondrial function, reducing respiratory chain activity and ATP production. This case adds to the existing literature on the phenotypic variability of <i>POLG</i>-related disorders and expands the known spectrum of pathogenic <i>POLG</i> variants. Despite the rarity of this mutation, its clinical presentation is consistent with classic progressive external ophthalmoplegia (PEO), underscoring the importance of genetic testing in diagnosing mtDNA maintenance defects. Further studies are needed to clarify genotype-phenotype correlations and develop targeted therapeutic strategies for <i>POLG</i>-associated mitochondrial dysfunction.</p>

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A case of POLG-related mitochondrial DNA maintenance defect

  • 期刊论文

  • 发表日期：

    2025年10月31日

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  • Junyi Wang,
  • Changhong Tan,
  • Fen Deng,
  • Xi Liu,
  • Lifen Chen

摘要

Mitochondrial DNA (mtDNA) maintenance defects (specifically mtDNA depletion syndromes, MDS) are autosomal recessive disorders caused by a severe reduction in mtDNA content, leading to impaired oxidative phosphorylation and energy deficiency in affected tissues. The clinical heterogeneity of mtDNA maintenance defects correlates with specific gene mutations, with POLG being one of the most frequently implicated genes in mitochondrial dysfunction. We report a novel case of mtDNA maintenance defects manifesting with progressive ocular symptoms, including blepharoptosis, blurred vision, and diplopia, associated with a rare homozygous POLG mutation (c.924G > T, p.Gln308His), which is the second reported homozygous variant at this nucleotide site. Among five previously reported POLG c.924G > T-associated MDS cases, 4 are heterozygous (compound heterozygous or combined with other mitochondrial gene variants). POLG encodes DNA polymerase γ, essential for mtDNA replication; mutations impair mitochondrial function, reducing respiratory chain activity and ATP production. This case adds to the existing literature on the phenotypic variability of POLG-related disorders and expands the known spectrum of pathogenic POLG variants. Despite the rarity of this mutation, its clinical presentation is consistent with classic progressive external ophthalmoplegia (PEO), underscoring the importance of genetic testing in diagnosing mtDNA maintenance defects. Further studies are needed to clarify genotype-phenotype correlations and develop targeted therapeutic strategies for POLG-associated mitochondrial dysfunction.