All patients (age range = 16-78 years; 31 men; 58 progressive external ophthalmoplegia [PEO], 12 myoclonic epilepsy with ragged red fibres [MERRF], eight mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes [MELAS], two mitochondrial neurogastrointestinal encephalomyopathy [MNGIE] and 13 other MDs) underwent a structured diagnostic headache interview using an operational diagnostic tool following the IHS criteria.
Mutations in POLGA, affecting the stability of mtDNA, have been identified in several human pathologies such as progressive external ophthalmoplegia and Alpers' syndrome.
Cellular alterations identified in pluripotent stem cell-derived midbrain spheroids generated from a female patient with progressive external ophthalmoplegia and parkinsonism who carries a novel variation (p.Q811R) in the POLG1 gene.
The six leading disorders caused by POLG mutations are Alpers-Huttenlocher syndrome, which is one of the most severe phenotypes; childhood myocerebrohepatopathy spectrum, which presents within the first 3 years of life; myoclonic epilepsy myopathy sensory ataxia; ataxia neuropathy spectrum; autosomal recessive progressive external ophthalmoplegia; and autosomal dominant progressive external ophthalmoplegia.
Only patients presenting PEO as part of their clinical phenotype had POLG mutations, in seven of them together with myopathic signs and in one with a sensori-motor peripheral neuropathy.
We present the case of a male patient with a mitochondriopathy with phenotype of chronic progressive external ophthalmoplegia (PEO), due to an autosomal dominant mutation in nDNA, in the DNA polymerase subunit gamma (POLG) gene, the pathogenic variant c.2864A>G (p.Tyr955Cys), morphologically investigated and diagnosed using a skeletal muscle biopsy.
Finally, this study expands the spectrum of POLG mutations and highlights the need to sequence the whole set of nuclear genes associated with PEO and multiple mtDNA deletions.
Two homozygous POLG1 mutations, within the exonuclease domain, were able to induce an increased mutational burden also in fibroblasts from patients with PEO.
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.
One sibling presented with sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO), a phenotype previously associated with the POLG1 gene, highlighting the clinical overlap in autosomal PEO.
Sequencing of other nuclear genes that are associated with CPEO and multiple mtDNA deletions, such as; POLG1, POLG2, TK2, ANT1, DGUOK, MPV17 and RRM2B did not reveal any pathogenic mutation in patients with C10orf2 mutation.
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).
Progressive external ophthalmoplegia (PEO) is a mitochondrial disorder associated with mutations in the POLG gene encoding the mitochondrial DNA polymerase (pol gamma).
Nineteen exhibited a cluster of three or more predefined clinical manifestations suggestive of POLG-related disease: progressive external ophthalmoplegia, seizures and/or an abnormal electroencephalogram, neuropathy, ataxia, liver function abnormalities, migraine or dysphagia/dysarthria.
Here we report two novel mutations in POLG1 in a compound heterozygous patient with autosomal recessive PEO, followed by pseudo-orthostatic tremor evolving into levodopa-responsive parkinsonism.