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To describe 2 unrelated patients with novel variations in the POLG1 gene and features undistinguishable from multiple sclerosis, ie, optic neuritis, brain white matter hyperintense areas, and unmatched cerebrospinal fluid oligoclonal bands.
Both patients subsequently developed bilateral ophthalmoplegia, ptosis, myopathy, cardiomyopathy, ataxia, dysphagia, and hearing and cognitive impairment.
Main Outcome Measures
Detailed clinical and laboratory examinations including brain magnetic resonance imaging, morphological analysis of a muscle biopsy, characterization of mitochondrial DNA integrity, sequencing of the POLG1 gene, and screening of control subjects for POLG1 sequence variants.
Ragged red fibers and multiple deletions of mitochondrial DNA were detected in the skeletal muscle. Four compound heterozygous variations, including 3 previously unreported, were identified in POLG1.
Clinicians should be aware of the existence of POLG1-related multiple sclerosis–like illness, as it has important implications for management, treatment, and genetic counseling.
Variations in the POLG1 gene, which encodes the catalytic subunit of the mitochondrial DNA (mtDNA) polymerase γ (pol γ), are associated with an expanding phenotypic spectrum ranging from severe encephalopathy and liver failure in childhood to late-onset external ophthalmoplegia, ataxia, myopathy, and isolated muscle pain or epilepsy.1-3 We describe 2 patients with novel recessive POLG1 variations initially presenting with features undistinguishable from multiple sclerosis (MS), ie, optic neuritis, brain white matter abnormalities, and oligoclonal bands in the cerebrospinal fluid (CSF).
Report of cases
A 37-year-old woman presented with blurred vision in the left eye. T2-weighted brain magnetic resonance imaging demonstrated unilateral periventricular white matter hyperintense areas (Figure 1), and visual evoked-response studies showed bilateral increased P100 latency. The CSF was crystal clear and contained 1.00 g/L of protein (reference value, <0.50 g/L) and a lymphocyte count of 2/mm3. Serological tests for neurotropic viruses and syphilis in the CSF were negative, and the search for unmatched oligoclonal bands was positive. The patient was diagnosed with optic neuritis, ie, a clinically isolated syndrome suggestive of MS.4 Corticosteroid treatment was started but no improvement was observed. In the following 19 years, she successively developed various neurological signs, ie, bilateral external ophthalmoplegia, ataxia, hearing impairment, and severe depression, which were attributed to progressive MS. Corticosteroid and interferon beta treatments were ineffective. Progressively, she also developed ptosis, myopathy, cardiomyopathy, and dysphagia, and a diagnosis of mitochondrial disease was considered. Muscle biopsy performed at 56 years of age showed numerous ragged-red fibers with abnormal mitochondria, and long-range polymerase chain reaction analysis of the muscle revealed multiple mtDNA deletions (Figure 1). The 2 novel p.Tyr452Cys and p.Thr914Ala variations in POLG1 gene were identified as compound heterozygous (Figure 2).
A and B, Transverse view of patients 1 (A) and 2 (B) T2-weighted brain magnetic resonance imaging demonstrating areas of hyperintense signal in the periventricular white matter. C, Muscle biopsy specimen from patient 1 showing numerous ragged-red fibers (Gomori trichrome, original magnification ×250). D, Long-range polymerase chain reaction analysis of muscle DNA from patient 1 revealing multiple mitochondrial DNA (mtDNA) deletions. In lanes 1 through 7, primer pairs were used for the detection of mtDNA deletions. In lane 8, a primer pair was used as an internal control to amplify wild-type mtDNA in a region not usually deleted. Examples of amplified fragments from wild-type mtDNA are indicated by arrows. M indicates a 1-kilobase marker.
Sequence analysis of the DNA regions encompassing the 4 POLG1 variations identified in patients 1 and 2. Variations are indicated with arrows.
A 30-year-old man presented with blurred vision in his left eye. T2-weighted brain magnetic resonance imaging demonstrated bilateral periventricular white matter hyperintense areas (Figure 1), and visual evoked-response studies showed bilateral increased P100 latency. The CSF was crystal clear and contained 0.80 g/L of protein (reference value, <0.50 g/L) and a lymphocyte count of 1/mm3. Serological tests for neurotropic viruses and syphilis in the CSF were negative, and the search for unmatched oligoclonal bands was positive. The patient was diagnosed with optic neuritis, ie, a clinically isolated syndrome suggestive of MS.4 Corticosteroid treatment was introduced, leading to gradual improvement. In the following 33 years, the patient successively developed various neurological signs including bilateral ophthalmoplegia, ataxia, and hearing and cognitive impairment, which were attributed to progressive MS. Corticosteroid and interferon beta treatments were ineffective. Progressively, he also developed ptosis, myopathy, and dysphagia, and mitochondrial disease was suspected. Muscle biopsy performed at 63 years of age showed numerous ragged-red fibers and multiple mtDNA deletions. This patient was compound heterozygous for the common p.Ala467Thr and the novel p.Arg275Gln POLG1 variations (Figure 2).
We describe 2 unrelated patients with a multisystem disorder whose initial features, including optic neuritis, brain white matter abnormalities, and oligoclonal bands in the CSF, mimicked MS and led to corticosteroid and interferon beta treatment.
Four POLG1 heterozygous variants were identified, the common pathogenic p.Ala467Thr mutation and the 3 unreported mutations, p.Arg275Gln, p.Tyr452Cys, and p.Thr914Ala.5 To date, these 3 last variants have not been found in 200 control alleles from the same ethnic background. Furthermore, they were not reported in the Human Polymerase γ Mutation Database (http://tools.niehs.nih.gov/polg/). To evaluate the functional effect of these variants, we used the decision-support software application ALAMUT (Interactive Biosoftware, Rouen, France). We observed that the new variants and the known p.Ala467Thr variant change highly conserved amino acids in the exonuclease (p.Arg275Gln) or polymerase (p.Tyr452Cys, p.Ala467Thr, and p.Thr914Ala) domains of mtDNA pol γ.5 As a result, they most likely significantly reduce polymerase and/or proofreading exonuclease activity of the pol γ holoenzyme. We also used the recent report of the crystal structure of human pol γ to accurately situate the variations in the subdomains of the protein and to analyze the effects of these new variations on the various activities of pol γ.5 It appears that the 4 recessive variations are expected to be pathogenic, and each combination, p.[Tyr452Cys]+[Thr914Ala] and p.[Arg275Gln]+[Ala467Thr], could be responsible for the progressive and complex illness described in our patients.
Our patients initially presented with features that have never been described until now in persons with POLG1 variations, ie, optic neuropathy and oligoclonal bands in the CSF. Although the existence of an independent condition affecting the central nervous system cannot be strictly ruled out, this study suggests that the POLG1 variations are most likely responsible for the ophthalmological and CSF abnormalities observed in both cases. Ocular involvement is a prominent feature of mitochondrial disorders, as observed in Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy, the 2 most common inherited optic neuropathies.6 Numerous families with dominant optic atrophy harbor pathogenic variations in the OPA1 nuclear gene, which encodes for optic atrophy 1, an important profusion mitochondrial protein that works in tandem with other members of the dynamin-related mitofusin family, mfn-1 and mfn-2.6 In contrast, LHON is the result of mtDNA primary mutations, the most frequent being m.3460G>A, m.11778G>A, and m.14484T>C.6 Interestingly, a significant minority of white patients with LHON, predominantly women with the homoplasmic m.11778G>A mutation, develop clinical and neuroimaging features indistinguishable from MS including unmatched oligoclonal bands in the CSF (Harding disease).7 The patients with POLG1 mutation with multiple mtDNA deletions described here show an intriguing degree of clinical overlap with Harding disease, with both disorders causing eye, brain, and CSF abnormalities that potentially mimic MS.7
These observations prompt speculation about the role of immunological factors in the pathogenesis of POLG1 mitochondrial disease and of mitochondrial genes in MS. Interestingly, clinical and experimental observations lead to the hypothesis that visual failure in LHON may be produced by abnormal immune responses directed against the optic nerves, arising directly or indirectly from mutations in mtDNA.7 This process may involve other myelinated axons in the central nervous system, producing a disorder undistinguishable from MS.7 Whether such phenomena are also present in patients with POLG1 variations and disrupted mtDNA integrity remains to be elucidated.
Although the initial clinical presentation was atypical, our patients later presented with clinical features typically associated with POLG1 variations including ophthalmoplegia, ptosis, myopathy, ataxia, dysphagia, hearing and cognitive impairment, cardiomyopathy, and depression.1-3 Both patients had a stereotypical clinical course, suggesting that the POLG1-linked mitochondrial disorder they presented with is progressive in postmitotic tissues, thus corroborating previous clinical studies of POLG1 mutations.1-3
Our study demonstrates that POLG1 variations may induce optic neuropathy, as observed in LHON and dominant optic atrophy, and may present with clinical, neuroimaging, and CSF abnormalities that mimic MS. Clinicians should be aware of the existence of POLG1-related MS-like illness, as it has important implications for management, treatment, and genetic counseling. From the clinical point of view, our observations indicate that POLG1 variations should be checked for in patients who present with optic neuritis, brain white matter abnormalities, and unmatched oligoclonal bands in the CSF and do not respond to corticosteroid and/or interferon beta treatment.
Correspondence: Andoni Echaniz-Laguna, MD, PhD, Département de Neurologie, Hôpital Civil, BP 426, 67091 Strasbourg, France (email@example.com).
Accepted for Publication: April 29, 2010.
Author Contributions:Study concept and design: Echaniz-Laguna, Chassagne, Mohr, and Mousson de Camaret. Acquisition of data: Echaniz-Laguna, Chassagne, Mohr, Clerc-Renaud, Tranchant, and Mousson de Camaret. Analysis and interpretation of data: Echaniz-Laguna, de Sèze, Mohr, and Clerc-Renaud. Drafting of the manuscript: Echaniz-Laguna, Chassagne, Mohr, and Clerc-Renaud. Critical revision of the manuscript for important intellectual content: Echaniz-Laguna, Chassagne, de Sèze, Mohr, Clerc-Renaud, Tranchant, and Mousson de Camaret. Statistical analysis: Echaniz-Laguna, Chassagne, Mohr, and Mousson de Camaret. Obtained funding: Echaniz-Laguna, Chassagne, Mohr, and Mousson de Camaret. Administrative, technical, and material support: Echaniz-Laguna, Chassagne, Mohr, and Mousson de Camaret. Study supervision: Echaniz-Laguna, de Sèze, Mohr, and Clerc-Renaud.
Financial Disclosure: None reported.
Echaniz-Laguna A, Chassagne M, de Sèze J, et al. POLG1 Variations Presenting as Multiple Sclerosis. Arch Neurol. 2010;67(9):1140–1143. doi:10.1001/archneurol.2010.219
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