The human mitochondrial genome is replicated by the DNA polymerase γ, pol γ, which is encoded by POLG1, which is a 23 exons nuclear gene located on chromosome 15q25. Heterozygous and homozygous POLG1 mutations have been typically associated with heterogeneous and severe clinical phenotypes of PEO, both in autosomal dominant or recessive form. They can also result in adult onset cerebellar ataxia with mtDNA multiple deletions and Alpers syndrome, an autosomal recessive hepatocerebral disease characterized by severe developmental delay, intractable seizures, liver failure and death in childhood. Moreover, throughout the years a wide spectrum of clinical findings including parkinsonism, neuropathy, optic neuritis, psychiatric disorders has been described in POLG1 mutations carriers [12, 14–19]. Deschauer et al. 2007 described a patient presenting with occipital seizures and residual homonymous hemianopsia, headache and ataxia and carrying two heterozygous POLG1 mutations . The presence of occipital symptoms and lesions, interpreted as stroke-like episodes, together with elevated CSF lactate and ragged red fibers, posed the suspicion of MELAS, raising the question whether POLG1 mutations could be associated with a MELAS like phenotype [7, 20]. However, given several clinical differences between POLG1 patient characteristics and MELAS, it has been supposed that, despite some overlapping symptoms, POLG1 represent a distinct clinical and genetic entity. POLG-associated encephalopathy has been postulated to give rise to a distinct phenotype, including variable age at onset, either recessive or dominant inheritance pattern and peculiar neuroimaging findings characterized by predominant posterior ischemic lesions and lack of cerebral calcification .
Our case had some atypical aspects for MELAS such as late onset, lack of cerebral calcification and presence of frontal and occipital MRI lesions better consistent with the POLG associated-encephalopathy spectrum. However, it is difficult to assess with certainty whether our patient could be classified as MELAS-like or POLG-associated encephalopathy. Moreover, although the patient did not present any vascular risk factor, given the elderly age a co-incidence between a POLG myopathy and a cerebrovascular disease can not be excluded at all.
However, it is difficult to compare MELAS, which is a clearly defined clinical syndrome, with POLG1-associated encephalopathy, which is so far a purely molecularly defined syndrome with a quite heterogeneous clinical picture. In addition, although 140 POLG mutations have been described in patients with symptoms that suggest mitochondrial disease, most of mutations are reported in heterozygous in whom each POLG allele can be one or more different mutations and only few of these has been replicated in not related families. This makes difficult a clear definition of phenotype and in providing evidence of the disease causing nature of these mutations .
Our patient harboured the haplotype p.[T251I P587L] in combination with D1186H located in polymerase domain. The haplotype T251I and P587L has been already described but it is currently not possible to know whether T251I or P587L is the primary pathogenic allele or whether both mutations are necessary to cause disease. Nevertheless both variants have also been reported in trans one each other in affected subjects. Notably both P587 and D1186 residues are located in the DNA binding channel of POLG enzyme. Thus, the substitutions found in our patient could be consistent with a reduced DNA binding capacity.
However, given the lack of available data, the implementation of existing databases (http://tools.niehs.nih.gov/polg/) including single unpublished observations from clinicians, is necessary to determine allelic frequencies of the myriad of POLG1 mutations [22, 23]. Ongoing studies on biochemical measurements of polymerase activity and in vivo measurement of mitochondrial dysfunction will provide further issue on their pathogenic role.
The present report contributes to expand the phenotypic spectrum of POLG1 mutations underlining the importance of searching POLG1 mutations in patients with mitochondrial signs and MELAS like phenotypes but negative for common mtDNA mutations.