POLG1 mutations and stroke like episodes: a distinct clinical entity rather than an atypical MELAS syndrome

Abstract

Background: POLG1 mutations have been associated with MELAS-like phenotypes. However given several clinical differences it is unknown whether POLG1 mutations are possible causes of MELAS or give raise to a distinct clinical and genetic entity, named POLG1-associated encephalopathy.

Case presentation: We describe a 74 years old man carrying POLG1 mutations presenting with strokes, myopathy and ragged red fibers with 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.

Conclusion: The lack of available data hampers a definite diagnosis in our patient as well as makes it 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. However, 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.

Figure 1

A-D: Skeletal muscle biopsy showing one ragged red fiber with histological methods (A-B: H&E, 10X ; B: GT, 40X). Histochemical reactions for COX (C, 10X) and COX-SDH (D, 10X) in cross serial sections show lack of COX activity in several skeletal muscle fibers (C), many of which also show increased SDH activity (D).E-H: Axial T2-weighted cerebral MRI sequences showing a cortico-subcortical fronto-parietal hyperintensity with restricted diffusion (not shown) consistent with acute ischaemic lesion and bilateral old ischaemic lesions in the right occipital and left temporal lobe.

Figure 2

Molecular analysis of muscle-derived mitochondrial DNA. Southern blot (A) and PCR assay (B) showing the accumulation of multiple deletions in patient’s tissue.