POLG - Related diseases

POLG (DNA Polymerase Gamma, Catalytic subunit) is a protein coding gene. The proteins are involved in nucleotide metabolism and cell cycle control of chromosomal replication. Disorders related to POLG comprise a continuum of overlapping phenotypes that have an onset from infancy to late adulthood.

• Alpers-Huttenlocher syndrome (AHS), one of the most severe phenotypes, is characterized by childhood-onset progressive and ultimately severe encephalopathy with intractable epilepsy and hepatic failure.
• Childhood myocerebrohepatopathy spectrum (MCHS) presents between the first few months of life and about age three years with developmental delay or dementia, lactic acidosis, and a myopathy with failure to thrive. Other findings can include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss.
• Myoclonic epilepsy myopathy sensory ataxia (MEMSA) describes the spectrum of disorders with epilepsy, myopathy, and ataxia without ophthalmoplegia. MEMSA now includes the disorders previously described as spinocerebellar ataxia with epilepsy (SCAE).
• The ataxia neuropathy spectrum (ANS) includes the phenotypes previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO). About 90% of persons in the ANS have ataxia and neuropathy as core features. Approximately two thirds develop seizures and almost one half develop ophthalmoplegia; clinical myopathy is rare.
• Autosomal recessive progressive external ophthalmoplegia (arPEO) is characterized by progressive weakness of the extraocular eye muscles resulting in ptosis and ophthalmoparesis (or paresis of the extraocular muscles) without associated systemic involvement. The neuropathy commonly precedes the onset of PEO by years to decades.
• Autosomal dominant progressive external ophthalmoplegia (adPEO) typically includes a generalized myopathy and often variable degrees of sensorineural hearing loss, axonal neuropathy, ataxia, depression, parkinsonism, hypogonadism, and cataracts (in what has been called "chronic progressive external ophthalmoplegia plus," or "CPEO+").

Imaging

Patients may present with progressive ataxia. Imaging may show vermian and cerebellar hemisphere atrophy. Patients may have asymmetic FLAIR hyperintensities of the cerebellar cortex. Increased T2 signal may be seen in the cerebellar white matter, dorsal thalami/pulvinar, and inferior olivary nuclei. Supratentorially patients may have atrophy of the occipital lobes with increased T2 signal of the cortex and juxtacortical white matter reflecting stroke like episodes.

Patients with liver disease may have MRI features of chronic hepatic encephalopathy manifesting increased T1 signal in the globus pallidi and subthalamic regions related to manganese deposition.

References

POLG-Related Disorders, Cohen BH, Chinnery PF, Copeland WC, Gene Reviews [Internt], https://www.ncbi.nlm.nih.gov/books/NBK26471/

Characteristic brain MRI findings in ataxia-neuropathy spectrum related to POLG mutation. Henao AI, Pira S, Herrera DA, Vargas SA, Montoya J, Castillo M. Neuroradiol J. 2016 Feb; 29(1): 46-48