POLG – Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE)

Mitochondrial neurogastrointestinal encephalomyopathy (MONDO:0017575) is an autosomal recessive mitochondrial depletion disorder characterized by severe gastrointestinal dysmotility, cachexia, ptosis, ophthalmoplegia, peripheral neuropathy, and leukoencephalopathy. While classical MNGIE is caused by thymidine phosphorylase (TYMP) deficiency, pathogenic variants in DNA polymerase γ (POLG) have been implicated in MNGIE-like syndromes. This summary reviews the genetic and functional evidence linking POLG to MNGIE-like phenotypes to inform diagnostic decision-making.

Autosomal recessive inheritance is supported by multiple case series. Van Goethem et al. described two siblings with MNGIE-like features harboring three POLG missense variants, including c.752C>T (p.Thr251Ile), alongside multiple large-scale mtDNA deletions in muscle (PMID:12825077).

Additional reports include a consanguineous family with two individuals presenting MNGIE and optic atrophy who carried homozygous c.2391G>T (p.Met797Ile) and showed tissue-specific mtDNA depletion without deletions in blood (PMID:30395865). A separate patient with MNGIE-like leukoencephalopathy exhibited a heterozygous frameshift c.3601del (p.Ser1201fs) and nonsense c.3630C>G (p.Tyr1210Ter), expanding the variant spectrum of POLG-associated MNGIE (PMID:30385167).

Segregation analysis in these families shows co-segregation of POLG variants with disease in four additional affected relatives across two pedigrees, reinforcing an autosomal recessive mode of inheritance.

Functional assays of POLG polymerase domain mutations, such as p.Arg943His and p.Tyr955Cys, reveal 0.03–30% residual polymerase activity and a 2- to 35-fold decrease in nucleotide selectivity in vitro. These defects correlate with accumulation of mtDNA deletions and depletion in yeast and mammalian models, consistent with a loss-of-function mechanism in MNGIE-like syndromes (PMID:15258572; PMID:16024923).

Collectively, genetic and experimental evidence supports a Moderate ClinGen-level association between POLG and MNGIE-like syndrome. POLG sequencing should be included in the diagnostic workup of MNGIE phenotype patients negative for TYMP mutations to improve clinical management and genetic counseling.

References

• European Journal of Human Genetics • 2003 • Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy. PMID:12825077
• Clinica Chimica Acta; International Journal of Clinical Chemistry • 2019 • Next generation sequencing in family with MNGIE syndrome associated to optic atrophy: Novel homozygous POLG mutation in the C-terminal sub-domain leading to mtDNA depletion. PMID:30395865
• Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia • 2019 • Leukoencephalopathy with a case of heterozygous POLG mutation mimicking mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). PMID:30385167
• Nature Structural & Molecular Biology • 2004 • Structure-function defects of human mitochondrial DNA polymerase in autosomal dominant progressive external ophthalmoplegia. PMID:15258572
• The Journal of Biological Chemistry • 2005 • The common A467T mutation in the human mitochondrial DNA polymerase (POLG) compromises catalytic efficiency and interaction with the accessory subunit. PMID:16024923

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