Mutations in the POLG gene have emerged as one of the most common causes of 
inherited mitochondrial disease in children and adults. They are responsible for 
a heterogeneous group of at least 6 major phenotypes of neurodegenerative 
disease that include: 1) childhood Myocerebrohepatopathy Spectrum disorders 
(MCHS), 2) Alpers syndrome, 3) Ataxia Neuropathy Spectrum (ANS) disorders, 4) 
Myoclonus Epilepsy Myopathy Sensory Ataxia (MEMSA), 5) autosomal recessive 
Progressive External Ophthalmoplegia (arPEO), and 6) autosomal dominant 
Progressive External Ophthalmoplegia (adPEO). Due to the clinical heterogeneity, 
time-dependent evolution of symptoms, overlapping phenotypes, and 
inconsistencies in muscle pathology findings, definitive diagnosis relies on the 
molecular finding of deleterious mutations. We sequenced the exons and flanking 
intron region from approximately 350 patients displaying a phenotype consistent 
with POLG related mitochondrial disease and found informative mutations in 61 
(17%). Two mutant alleles were identified in 31 unrelated index patients with 
autosomal recessive POLG-related disorders. Among them, 20 (67%) had Alpers 
syndrome, 4 (13%) had arPEO, and 3 (10%) had ANS. In addition, 30 patients 
carrying one altered POLG allele were found. A total of 25 novel alterations 
were identified, including 6 null mutations. We describe the predicted 
structural/functional and clinical importance of the previously unreported 
missense variants and discuss their likelihood of being pathogenic. In 
conclusion, sequence analysis allows the identification of mutations responsible 
for POLG-related disorders and, in most of the autosomal recessive cases where 
two mutant alleles are found in trans, finding deleterious mutations can provide 
an unequivocal diagnosis of the disease.