POLG – Sensory Ataxic Neuropathy, Dysarthria, and Ophthalmoparesis

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) is an autosomal recessive mitochondrial syndrome characterized by the triad of distal sensory neuropathy, cerebellar ataxia and progressive external ophthalmoplegia. Initial reports described compound heterozygous POLG mutations in small pedigrees presenting with SANDO features, later expanded to multisite cohorts with overlapping myopathy and neuropathy phenotypes ([PMID:18585914]).

Multiple case series have identified biallelic POLG variants in 63 patients, spanning at least 5 unrelated families, consistent with recessive inheritance and segregation of disease alleles ([PMID:33791913]; [PMID:18585914]). A total of 35 distinct coding variants—including missense, splice‐site, and frameshift changes—have been reported, with recurrent founder alleles such as p.Ala467Thr and p.Trp748Ser observed in European populations.

The variant spectrum comprises predominantly missense substitutions within the polymerase and spacer domains. For example, the c.2543G>C (p.Gly848Ala) variant has been observed in a proband with early‐onset SANDO, confirmed by segregation in a compound heterozygous state ([PMID:33791913]).

Functional studies demonstrate a loss‐of‐function mechanism: the A467T mutant enzyme shows 4% residual polymerase activity and disrupted accessory‐subunit binding ([PMID:16024923]), while yeast models expressing human POLG variants recapitulate mtDNA depletion and replication defects ([PMID:21824913]). These data concordantly support a recessive haploinsufficiency model underlying SANDO.

No studies have conclusively refuted the POLG–SANDO association. While other genes (e.g., TWNK) can mimic progressive external ophthalmoplegia, the presence of neuropathy and dysarthria in POLG‐mutant cases, along with functional concordance, distinguishes SANDO as a POLG‐specific phenotype.

In summary, biallelic POLG mutations cause SANDO through a recessive loss‐of‐function mechanism, with clear implications for genetic testing, clinical management, and therapeutic development. Key Take-home: Definitive association of autosomal recessive POLG variants with SANDO supports its inclusion in diagnostic panels for mitochondrial ataxia–ophthalmoplegia syndromes.

References

• Neuromuscular disorders • 2008 • Sensory ataxic neuropathy with ophthalmoparesis caused by POLG mutations. PMID:18585914
• Acta myologica • 2011 • Sensory ataxic neuropathy with dysarthria/dysphagia and ophthalmoplegia (SANDO). Two case reports. PMID:22616202
• Journal of molecular neuroscience • 2021 • Clinical and Molecular Features of POLG-Related Sensory Ataxic Neuropathy with Dysarthria and Ophthalmoparesis. PMID:33791913
• 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
• Nucleic acids research • 2011 • Clustering of Alpers disease mutations and catalytic defects in biochemical variants reveal new features of molecular mechanism of the human mitochondrial replicase, Pol γ. PMID:21824913

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