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Clinical/Scientific Notes
May 14, 2007
Letter to the Editor

MELAS ASSOCIATED WITH MUTATIONS IN THE POLG1 GENE

May 15, 2007 issue
68 (20) 1741-1742
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Letters to the Editor
9 September 2007
Reply from the authors
Robert W. Taylor, Mitochondrial Research Group, Newcastle University
Marcus Deschauer, Douglass M. Turnbull, Robert W. Taylor

We thank Drs. Tzoulis and Bindoff for their helpful comments on our recent article and would agree and disagree with their remarks. Mitochondrial disease is increasingly pervading many different domains within clinical neurology and it is important that we and others highlight clinical scenarios in which mitochondrial involvement is likely.

Establishing a robust clinical and genetic diagnosis in these difficult cases is helpful in terms of patient management and providing appropriate genetic counseling to patients and their families.

In the case we described with a stroke-like episode [1], our intention was to highlight the similarity in the clinical presentation between this patient with recessive POLG1 mutations and patients with MELAS due to the maternally-inherited m.3243A>G mutation of mitochondrial DNA (mtDNA). This is important because there are many patients who are screened for the m.3243A>G mutation on clinical grounds who turn out to be negative.

While further mtDNA testing may be indicated in certain patients on the basis of biochemical investigations [5,6], under these circumstances clinicians should be aware that further genetic tests including POLG1 analysis may be warranted, even in the absence of histochemical and secondary mtDNA changes such as multiple mtDNA deletions.

Both the MELAS syndrome and POLG1 gene defects highlight the complexity of the genotype-phenotype relationship in mitochondrial disorders. MELAS was defined as a clinical syndrome in 1984 [7] and subsequently many different mtDNA point mutations have been identified in patients with MELAS.

On the other hand, it has recently become clear that POLG1 mutations are not associated with a distinct, clinical picture but instead demonstrate an enormous phenotypic spectrum ranging from severe childhood encephalopathy and hepatopathy to late-onset ophthalmoplegia. [8]

We would agree with Tzoulis and Bindoff that confusion can be created by the use of acronyms - perhaps devised to make mitochondrial disease as obscure as possible for the clinical neurologist. However, it is now difficult to piece together the clinical, biochemical and genetic diagnosis of this complex group of disorders and a rational clinical classification is needed.

References

5. Pulkes T, Eunson L, Patterson V, et al. The mitochondrial DNA G13513A transition in ND5 is associated with a LHON/MELAS overlap syndrome and may be a frequent cause of MELAS. Ann. Neurol 1999;46:916-919.

6. Kirby DM, McFarland R, Ohtake A, et al. Mutations of the mitochondrial ND1 gene as a cause of MELAS. J Med Genet 2004;41:784-789.

7. Pavlakis SG, Phillips PC, DiMauro S, De Vivo DC, Rowland LP. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. Ann Neurol 1984;16:481-488.

8. Horvath R, Hudson G, Ferrari G, et al. Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. Brain 2006;129:1674-1684.

The Editorialist was also given the opportunity to respond but declined.

Disclosure: The authors report no conflicts of interest.

9 September 2007
MELAS ASSOCIATED WITH MUTATIONS IN THE POLG1 GENE
Charalampos Tzoulis, Department of Neurology, Haukeland University Hospital
Laurence A. Bindoff

Deschauer et al describe a patient carrying the POLG1 mutations R627Q and G848S in trans who presented with a stroke-like episode (SLE). [1] Visual phenomena and headache preceded the development of focal seizures. Occipital focus was demonstrated on MRI and EEG, and COX-negative fibers (CNF) were found in skeletal muscle. The authors concluded that the case fulfills the diagnostic criteria for MELAS. [1]

This interesting case exposes a problem faced in medicine, specifically the use of abbreviations to make clinical statements. The case does fulfill the traditional, diagnostic criteria for MELAS. However, the phenotype is also typical for the A467T or W748S POLG1 mutations.

We reported a large number of patients with these mutations who presented in their teens or early twenties with migraine-like headaches, visual disturbances, encephalopathy, epilepsy and occipital foci both on EEG and MRI. [2,3]. Whether or not these events should be called SLEs is more a matter of definition and nomenclature and less of substance. We have chosen not to do so, in order to avoid confusion with MELAS, which is a genetically and clinically distinct entity.

That the occipital lesion in the case reported by Deschauer was larger than those previously described in POLG1 disease does not make it typical of MELAS. MELAS stroke-like lesions are often more extensive and although they may occasionally be limited to the occipital lobe, most usually also extend into the temporal and parietal cortices. [4] The majority of POLG related cerebral cortical lesions thus far described, are confined to the occipital areas. [2,3]

There is significant clinical overlap between syndromes caused by different mtDNA mutations and SLEs have been described in several. That POLG1 mutations can cause similar disorders is expected since genetic defects affect the same system, namely the mitochondrial genome. However, there are clinical differences including the lack of diabetes mellitus and cardiomyopathy.

The clinical spectrum of POLG1 mutations that we and others have described appears to be clinically consistent and we feel that the issue should not be confused by adding terms such as MELAS.

References

1. Deschauer M, Tennant S, Rokicka A, et al. MELAS associated with mutations in the POLG1 gene. Neurology 2007;68:1741-1742.

2. Winterthun S, Ferrari G, He L, et al. Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial polymerase gamma mutations. Neurology 2005;64:1204-1208.

3. Tzoulis C, Engelsen BA, Telstad W, et al. The spectrum of clinical disease caused by the A467T and W748S POLG mutations: a study of 26 cases. Brain 2006;129:1685-1692. [Epub 2006 Apr 25].

4. Iizuka T, Sakai F, Kan S, Suzuki N. Slowly progressive spread of the stroke-like lesions in MELAS. Neurology 2003;61:1238-1244.

Disclosure: The authors report no conflicts of interest.

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Published In

Neurology®
Volume 68Number 20May 15, 2007
Pages: 1741-1742
PubMed: 17502560

Publication History

Published online: May 14, 2007
Published in print: May 15, 2007

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Affiliations & Disclosures

M. Deschauer, MD
From the Department of Neurology (M.D., A.R., T.K., S.Z.), Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany; Northern Regional Genetics Service (S.T.), Institute of Human Genetics, Newcastle upon Tyne, UK; Mitochondrial Research Group (L.H., D.M.T., R.W.T.), School of Neurology, Neurobiology and Psychiatry, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
S. Tennant, DipRCPath
From the Department of Neurology (M.D., A.R., T.K., S.Z.), Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany; Northern Regional Genetics Service (S.T.), Institute of Human Genetics, Newcastle upon Tyne, UK; Mitochondrial Research Group (L.H., D.M.T., R.W.T.), School of Neurology, Neurobiology and Psychiatry, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
A. Rokicka, MD
From the Department of Neurology (M.D., A.R., T.K., S.Z.), Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany; Northern Regional Genetics Service (S.T.), Institute of Human Genetics, Newcastle upon Tyne, UK; Mitochondrial Research Group (L.H., D.M.T., R.W.T.), School of Neurology, Neurobiology and Psychiatry, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
L. He, PhD
From the Department of Neurology (M.D., A.R., T.K., S.Z.), Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany; Northern Regional Genetics Service (S.T.), Institute of Human Genetics, Newcastle upon Tyne, UK; Mitochondrial Research Group (L.H., D.M.T., R.W.T.), School of Neurology, Neurobiology and Psychiatry, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
T. Kraya, MD
From the Department of Neurology (M.D., A.R., T.K., S.Z.), Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany; Northern Regional Genetics Service (S.T.), Institute of Human Genetics, Newcastle upon Tyne, UK; Mitochondrial Research Group (L.H., D.M.T., R.W.T.), School of Neurology, Neurobiology and Psychiatry, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
D. M. Turnbull, FRCP
From the Department of Neurology (M.D., A.R., T.K., S.Z.), Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany; Northern Regional Genetics Service (S.T.), Institute of Human Genetics, Newcastle upon Tyne, UK; Mitochondrial Research Group (L.H., D.M.T., R.W.T.), School of Neurology, Neurobiology and Psychiatry, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
S. Zierz, MD
From the Department of Neurology (M.D., A.R., T.K., S.Z.), Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany; Northern Regional Genetics Service (S.T.), Institute of Human Genetics, Newcastle upon Tyne, UK; Mitochondrial Research Group (L.H., D.M.T., R.W.T.), School of Neurology, Neurobiology and Psychiatry, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
R. W. Taylor, PhD
From the Department of Neurology (M.D., A.R., T.K., S.Z.), Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany; Northern Regional Genetics Service (S.T.), Institute of Human Genetics, Newcastle upon Tyne, UK; Mitochondrial Research Group (L.H., D.M.T., R.W.T.), School of Neurology, Neurobiology and Psychiatry, The Medical School, Newcastle University, Newcastle upon Tyne, UK.

Notes

Address correspondence and reprint requests to Dr. Robert W. Taylor, Mitochondrial Research Group, School of Neurology, Neurobiology and Psychiatry, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK; [email protected]

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