In a family with 3 affected sibs with autosomal recessive PEO (PEOB1; 258450), Van Goethem et al. (2001) identified compound heterozygosity for 2 missense mutations in the POLG gene: a 1399G-A transition, resulting in an ala467-to-thr (A467T) substitution, and a 911T-G transversion, resulting in a leu304-to-arg substitution (L304R; 174763.0003). In 2 affected individuals in another family, Van Goethem et al. (2001) identified the A467T mutation in compound heterozygous state with an 8G-C transversion, resulting in an arg3-to-pro substitution (R3P; 174763.0004). Three of 229 control individuals were heterozygous for A467T (allele T frequency of 0.6%). The R3P mutation was not observed in any of the control individuals. The A467T mutation occurs in the linker region of the protein (Stewart et al., 2009).
Van Goethem et al. (2003) stated that the A467T mutation has a frequency of 0.6% in the Belgian population and that sensory neuropathy is the initial feature in Belgian compound heterozygous autosomal recessive progressive external ophthalmoplegia patients, all carrying the POLG A467T mutation in combination with another mutation.
Van Goethem et al. (2003) reported a patient who was homozygous for the A467T mutation, which they incorrectly reported as ALA476THR. (Van Broeckhoven (2004) reported the correct mutation as A467T.) At age 15 years, the patient experienced mild ataxia, and later developed myoclonus, seizures, and sensory neuropathy. External ophthalmoplegia was absent on repeated examinations. Muscle biopsy did not show any abnormalities, including no ragged-red fibers, but long-range PCR detected a low proportion of mtDNA deletions in the patient's muscle. Van Goethem et al. (2003) noted that the clinical features in this patient were unique and suggested that some features overlapped with the syndrome of myoclonus, epilepsy, and ragged-red fibers (MERRF; 545000).
In 3 sibs with sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (607459) originally reported by Rantamaki et al. (2001), Van Goethem et al. (2004) identified homozygosity for the A467T mutation. An unrelated British patient was compound heterozygous for the A467T mutation and W748S (174763.0013). An unrelated Belgian patient with a variant form of SANDO without ophthalmoparesis was also homozygous for the A467T mutation. That patient had psychiatric symptoms, severe gastroparesis, and dilated cardiomyopathy, illustrating the variable clinical phenotype that can result from recessive POLG mutations.
In 2 affected patients from a family with mitochondrial DNA depletion syndrome-4A (MTDPS4A; 203700), manifest as Alpers syndrome, Naviaux and Nguyen (2005) identified compound heterozygosity for 2 mutations in the POLG gene: A467T and E873X (174763.0008). An earlier report on these patients by Naviaux and Nguyen (2004) had incorrectly stated that they were homozygous for the E873X mutation.
In 2 sisters with mtDNA depletion syndrome manifest as Alpers syndrome, Nguyen et al. (2005) identified compound heterozygosity for 2 mutations in the POLG gene: a A467T and W1020X (174763.0017). Two affected sibs from another family with Alpers syndrome were compound heterozygous for A467T and G848S (174763.0006). Another child with Alpers syndrome from an unrelated family who was homozygous for the A467T mutation showed late-onset at age 8.5 years and death by age 9 years.
Winterthun et al. (2005) identified homozygosity for the A467T mutation in affected members from 2 families with a form of SANDO characterized by early onset of migraine headaches and/or seizures, and the later development of myoclonus (see SCAE; 607459).
Hakonen et al. (2007) demonstrated that the A467T disease chromosomes of patients from Australia, New Zealand, and the United States shared a common haplotype with European patients, indicating that they all derived from a common European founder. Further analysis indicated that the Norwegian A467T disease haplotype diverged from the European founder earlier than the other haplotypes. Hakonen et al. (2007) estimated that the common ancestor for A467T lived more than 15 to 30 generations ago, before 1700 to 1400 A.D.
By reevaluation of 2 sibs reported by Bird and Shaw (1978), who were classified as having progressive myoclonic epilepsy-5 (EPM5; see 607459), Sandford et al. (2016) identified compound heterozygous mutations in the POLG gene (A467T on 1 allele and W748S, 174763.0013 and G497H, 174763.0016 in cis on the other allele). In these sibs, Tao et al. (2011) had previously identified 2 heterozygous missense variants in the PRICKLE2 gene (608501.0001) that occurred on the same allele. Furthermore, Sandford et al. (2016) showed that the 2 heterozygous missense variants in the PRICKLE2 gene identified by Tao et al. (2011) occurred on opposite chromosomes, which would be more consistent with recessive inheritance. Sandford et al. (2016) concluded that the phenotype in these patients resulted from the POLG mutations and not from the PRICKLE2 variants. In a response, Mahajan and Bassuk (2016) maintained that the PRICKLE2 variants identified by Tao et al. (2011) contributed to the phenotype in their patients.
