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

Antonella Cheldi,Bianca Bordo,Dario Ronchi,Anna Bersano,Valeria Lucchini,Andreina Bordoni,Silvia Lanfranconi,Pierluigi Baron,Maurizio Moggio,Antonio Colombo,Monica Sciacco,Stefania Corti,Giacomo Pietro Comi,Maria Grazia Bellotti

doi:10.1186/1471-2377-13-8

Abstract

BackgroundPOLG1 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 presentationWe 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.ConclusionThe 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.

Highlights

POLG1 mutations have been associated with MELAS-like phenotypes
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 result in adult onset cerebellar ataxia with mitochondrial DNA (mtDNA) multiple deletions and Alpers syndrome, an autosomal recessive hepatocerebral disease characterized by severe developmental delay, intractable seizures, liver failure and death in childhood

Summary

Conclusion

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. 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 [22].

Background

Findings