The in cis T251I and P587L POLG1 base changes: Description of a new family and literature review

•We report a family that carried the T251I+P587L and the new P116Q mutation in POLG1 gene.•We describe a particular spectrum of clinical signs associated with these three mutations.•We do an extensive revision of literature data about the T251I+P587L mutations.

Mutations in the polymerase gamma-1 (POLG1) gene, encoding the catalytic subunit of the mtDNA-specific polymerase-γ, compromise the stability of mitochondrial DNA (mtDNA) and are responsible for numerous clinical presentations as autosomal dominant or recessive progressive external ophthalmoplegia (PEO), sensory ataxia, neuropathy, dysarthria and ophthalmoparesis (SANDO), spinocerebellar ataxia with epilepsy (SCAE) and Alpers syndrome.POLG1 mutations result in extremely heterogeneous phenotypes which often have overlapping clinical findings, making it difficult to categorize patients into syndromes, and genotype-phenotype correlations are still unclear.We describe a new family with a particular spectrum of clinical signs, that carried the c.752C>T mutation in exon 3 (T251I) and the c.1760C>T in exon 10 (P587L) in cis. These mutations were associated in the proband and in her brother with the new probably pathogenic mutation c.347C>A in exon 2 (P116Q).The proband presented a progressive cognitive impairment, mild myopathy, dilated cardiac right atrium and posterior white matter mild signal alteration, while her brother had migraine, mild myopathy, palpebral ptosis and posterior white matter mild signal alteration. Their mother and their sister carried the in cis T251I and the P587L mutations. The first presented neurosensorial hypoacusia, fatigue, heart block and a cerebral arteriovenous malformation nidus, while the latter had borderline intellectual functioning and signs of muscular involvement. Their father, with the P116Q mutation, had diabetes and myopathy.The complexity of the genotype-phenotype correlations associated with POLG1 mutations is reinforced in this work as evidenced by the presence of different clinic features in patients carrying the same mutations.