Many mutations in POLG, the gene that encodes pol γ, have been associated with mitochondrial diseases such as myocerebrohepatopathy spectrum (MCHS) disorders, Alpers-Huttenlocher syndrome, myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS), and progressive external ophthalmoplegia (PEO).
To investigate the phenotypic-genotypic correlations in Alpers syndrome and to identify potential differences among patients with Alpers syndrome with or without pathogenic POLG1 mutations.
Our cases underscore several important findings: POLG mutations have been observed in every ethnic group studied to date; early predominance of epileptiform discharges over the occipital region is common in POLG-induced epilepsy; the EEG and MRI findings varying between patients and stages of the disease; and VPA dosing at any stage of Alpers-Huttenlocher syndrome can precipitate liver failure.
The heterozygous presence of the novel p.P1073L mutation in trans with another recessive POLG mutation causes a hepatocerebral disorder identical or very similar to Alpers syndrome.
This series of patients illustrates the large array of clinical presentations associated with mtDNA stability defects, ranging from isolated benign PEO to fatal Alpers syndrome.
As a member of the mt-aaRS family, PARS2 encoding prolyl-tRNA synthetase 2 was recently shown to be associated with Alpers syndrome and certain infantile-onset neurodegenerative disorders in four patients.
Biallelic PARS2 or NARS2 mutations are reported to cause Alpers' syndrome, which is an autosomal recessive neurodegenerative disorder characterized by psychomotor regression and epilepsy with variable degree of liver involvement.