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Abstract
Mutations in nuclear-encoded genes that are involved in mitochondrial DNA replication and maintenance (e.g., POLG) have been associated with chronic progressive external ophthalmoplegia (CPEO) phenotype. These nuclear genome mutations may lead to multiple mitochondrial DNA deletions or mitochondrial DNA depletion. On the other hand, primary genetic defects of mitochondrial DNA (such as single large-scale deletion or point mutations) have also been associated with the CPEO phenotype. Chronic progressive external ophthalmoplegia (CPEO) may be a manifestation of specific syndromes that, when clinically recognized, prompt clinicians to investigate specific genetic defects. Thus, CPEO, as part of Kearns Sayre syndrome, suggests the presence of a large-scale deletion of mitochondrial DNA. However, in pure CPEO or CPEO plus phenotypes, it is more difficult to know whether causative genetic defects affect the nuclear or mitochondrial DNA. Here, we present a patient with a long-standing history of CPEO plus phenotype, in whom the sequencing of mitochondrial DNA from skeletal muscle was normal, and no other genetic defect was suspected at first. At the time of our evaluation, the presence of polyneuropathy and neuropathic pain prompted us to investigate nuclear genetic defects and, specifically, mutations in the POLG gene. Thus, the sequencing of the POLG gene revealed p.Thr251Ile and p.Pro587Leu mutations in one allele, and p.Ala467Thr mutation in another allele. Although one would expect that mutations in POLG lead to multiple mitochondrial DNA deletions or depletion (loss of copies), the absence of mitochondrial DNA abnormalities in tissue may be explained by heteroplasmy, a lack or no significant involvement of biopsied tissue, or a sampling bias. So, the absence of secondary mitochondrial DNA alterations should not discourage clinicians from further investigating mutations in nuclear-encoded genes. Lastly, mitochondrial point mutations and single mitochondrial DNA deletions very rarely cause CPEO associated with polyneuropathy and neuropathic pain, and POLG-related disease should be considered in this scenario, instead.
Highlights
The human DNA polymerase gamma is formed by a 140 kDa catalytic subunit called POLG and a 55 kDa dimeric accessory subunit called POLG2
chronic progressive external ophthalmoplegia (CPEO) is a characteristic feature of Kearns Sayre syndrome (KSS) that is caused by a large-scale 1.1 to 10 kilobase deletion of mitochondrial DNA (mtDNA), and it can be seen as a clinical manifestation of dominantly or recessively inherited POLG-related disease; mutations in this nuclear gene account for 25% of patients with CPEO phenotype [2–6]
We present a patient with painless, progressive, bilateral, adult-onset ptosis and ophthalmoparesis, who developed symptoms suggestive of peripheral nerve and skeletal muscle involvement
Summary
The human DNA polymerase gamma is formed by a 140 kDa catalytic subunit called POLG and a 55 kDa dimeric accessory subunit called POLG2. A 69-year-old woman was referred to us for paresthesia, neuropathic pain, and cramps in extremities as her main symptoms She was in good health until her early 50s when she first experienced slowly progressive bilateral ptosis that was surgically corrected twice, and restriction of eye movements in all directions that did not bother her much; she never experienced any diplopia. At the age of 59, she underwent a muscle biopsy of left quadriceps muscle that showed mild myopathic and neuropathic features; the former included occasional subsarcolemmal accumulation of mitochondria and scattered COX-negative muscle fibers, while the latter; angulated fibers, nuclear clumps, and mild fiber type grouping that were attributed to her history of lumbosacral radiculopathy (Figure 1) Such mild mitochondrial findings within the sixth decade of life could be a consequence of normal aging, a manifestation of a mitochondrial disorder was plausible. Genetic testing of POLG gene revealed a known compound of heterozygous mutations: one that comprises two single nucleotides in-cis (c.752 C>T and c.1760 C>T, which lead to p.Thr251Ile and p.Pro587Leu, respectively) and another one in-trans (c.1399G>A, p.Ala467Thr); these findings confirmed a POLG-related disease as unifying diagnosis
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