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Table of Contents    
Year : 2012  |  Volume : 60  |  Issue : 1  |  Page : 86-89

A study of familial MELAS: Evaluation of A3243G mutation, clinical phenotype, and magnetic resonance spectroscopy-monitored progression

1 Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
2 Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Department of Psychiatry, Harvard Medical School, Division of Alcohol and Drug Abuse, and Mailman Research Center, McLean Hospital, Belmont, MA, U.S.A.
3 Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
4 Department of Neurology, Renmin Hospital of Wuhan University, China

Date of Submission09-Nov-2011
Date of Decision16-Nov-2011
Date of Acceptance05-Dec-2011
Date of Web Publication7-Mar-2012

Correspondence Address:
Tao Wang
Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Road, Wuhan 430022, Hubei, China

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Source of Support: Grants 30870866, 31171211 and 81071021 from the National Natural Science Foundation of China (to TW), grant 81100958 from the National Natural Science Foundation of China (to ZTZ) and grant 20066002100 from the Wuhan Science and Technology Bureau, China (to TW), Conflict of Interest: None

DOI: 10.4103/0028-3886.93609

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 » Abstract 

The clinical manifestations of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS syndrome) are nonspecific and can easily be misdiagnosed. Magnetic resonance spectroscopy (MRS)-based detection of lactate in the brain has been found to be of diagnostic help in MELAS syndrome, however, the issue of whether MRS features vary by stage remains unresolved. We assessed the causative mutation and radiological features of a family of MELAS. Four of the family members harbored the A3243G mutation, probably of maternal inheritance. However, the clinical phenotypic expression was different in these patients. MRS showed a lactate peak, decreased N-acetylaspartate, choline, and creatine, which became more pronounced with progression of the disease, demonstrating that brain-MRS-based detection of lactate may be a suitable way to monitor the progression and treatment of MELAS.

Keywords: Magnetic resonance imaging, magnetic resonance spectroscopy, mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes syndrome, mitochondrial disease, mutation

How to cite this article:
Chen C, Xiong N, Wang Y, Xiong J, Huang J, Zhang Z, Wang T. A study of familial MELAS: Evaluation of A3243G mutation, clinical phenotype, and magnetic resonance spectroscopy-monitored progression. Neurol India 2012;60:86-9

How to cite this URL:
Chen C, Xiong N, Wang Y, Xiong J, Huang J, Zhang Z, Wang T. A study of familial MELAS: Evaluation of A3243G mutation, clinical phenotype, and magnetic resonance spectroscopy-monitored progression. Neurol India [serial online] 2012 [cited 2023 Dec 1];60:86-9. Available from:

Chunnuan Chen and Nian Xiong: These authors equally contributed to the work

 » Introduction Top

Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes syndrome (MELAS) is one of the maternally inherited mitochondrial encephalomyopathies, first described by Pavlakis in 1984. [1] The early clinical manifestations of MELAS are varied and nonspecific, this often results in misdiagnosis. Early diagnosis and timely treatment can slow the progression of the disease and may improve the quality of life. In this study, we discuss the clinical features and magnetic resonance spectroscopy (MRS) features in a MELAS family with A3243G mutation.

 » Case Report Top

The family was from Hubei, China and informed consent was obtained from all participants. Affected members were treated with ATP, CoQ 10 , and vitamins which resulted in reductions in the symptoms and improvements in the quality of life.

Genetic features

Subjects I: 1, II: 1, II: 4, III: 1, III: 2, and III: 3 were asymptomatic, and I: 2, II: 2, II: 3, III: 4, and III: 5 were symptomatic carriers [Figure 1]. II: 2 (the affected father) did not deliver the trait to his offspring, while II: 3 (the affected mother) transmitted the trait to her offspring (III: 4 and III: 5), suggesting maternal inheritance.
Figure 1: Family pedigree of the proband with MELAS syndrome. Solid symbols represent the patients with A3243G mutation and open symbols represent healthy relatives. The proband is indicated by an arrow

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A3243G mutation

An assessment of common point mutations known to cause mitochondrial disease (sites 3243, 3271, 8344, and 8993) showed that several members of the family harbored the A3243G mutation. Sequence analysis indicated that the polymerase chain reaction (PCR)-amplified mitochondrial DNA (mtDNA) fragment contained the A3243G point mutation, which was consistent with the results of PCR-restriction fragment length polymorphism (RFLP) analysis [Figure 2] and [Figure 3]. Patients harboring the A3243G showed three bands on the agarose gel with the length of 553 bp, 424 bp, and 129 bp respectively [Figure 3]. The proportion of mutant mtDNA in the peripheral blood of the patients is shown in [Table 1].
Figure 2: Identification of the A3243G mutation in the MELAS family. Arrowheads indicate the patients' transition sites (II: 2, III: 4, II: 3, and III: 5). The sequence of one unaffected family member is shown at the top

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Figure 3: Co-segregation of A3243G mutation in this family. RFLP analysis showed the presence of both normal (553 bp) and mutant mtDNA (424 bp and 129 bp) in affected individuals (II: 2, III: 4, II: 3, and III: 5)

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Table 1: Clinical manifestations and laboratory findings of the patients

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MELAS-related mutations and clinical phenotype

Different phenotypic expressions of this heteroplasmic mitochondrial mutation (A3243G mutation) are given in [Table 1]. Not all individuals with the mutation developed full MELAS syndrome. I: 2, presumed to harbor this mutation, presented with serious diabetes mellitus and died at a young age. II: 2 (son of I: 2) suffered from mild MELAS syndrome and a hearing loss with late onset, while II: 3 (daughter of I: 2) with the lowest mutation load was asymptomatic. III: 5 showed muscular weakness and short stature without obvious encephalopathy, though she harbored the highest proportion of mutant mtDNA. However, the age of onset of III: 5 was earlier than that of III: 4 (the proband). The proband with a lower mutation load manifested typical MELAS symptoms.

Although the patients harboring the A3243G mutation presented with different phenotypic expressions, all had elevated blood lactic acid and pyruvic acid levels above the normal controls at rest and the levels further elevated with exercise, suggesting lactic acidosis in all affected family members.

Computed tomography and magnetic resonance imaging features

The proband suffered from recurrent stroke-like episodes during the follow-up period. Brain computed tomography (CT) and magnetic resonance imaging (MRI) showed infarct-like lesions in posterior temporo-occipital regions, bilateral basal ganglia calcification and mild cerebral and cerebellar atrophy. First brain CT revealed a low-density lesion in the left temporo-occipital regions and bilateral basal ganglia calcification [Figure 4]a. Two years later, a fresh lesion was found in right temporo-occipital regions [Figure 4]b. Gyral swelling with mass effect on the adjacent ventricular system was observed in the fresh right temporo-occipital lesion. MRI showed hyperintense lesions in right temporo-occipital regions and left occipital lobe. These were more pronounced in the right temporo-occipital regions at the intermission of this disease [Figure 4]c. An MRI study of II: 2 (proband's uncle) performed at onset, showed mild cerebral atrophy, which was disproportionate to his age [Figure 4]d. MRI features indicated that lesions which did not conform to large vessel territories, involved predominantly the cortex.
Figure 4: Cerebral CT and MR images of two affected patients. (a) and (b) Brain CT of the index case. (a) Bilateral basal ganglia calcification and low density in the left temporo-occipital regions. (b) Migration of lesions involving right temporo-occipital regions. (c) MRI of residual lesions, which were more pronounced in right temporo-occipital regions, involving both the right and left posterior lobes. (d) MRI of II: 2 revealed a left temporo-occipital hyperintense signal involving both the gray and white matter and mild cerebral atrophy

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Magnetic resonance spectroscopy manifestation over the clinical course of MELAS

Proton MRS of the proband was monitored during onset of MELAS and through the intermission that followed treatment. Proton MRS of the lesion showed a lactate peak, N-acetylaspartate level decrease, and slight reduction in choline level. MRS image of the proband during his intermission showed a small lactate peak [Figure 5]a. MRS of the index case obtained when seizures recrudesced displayed a bigger inverted peak (Lac/Cr) [Figure 5]b. However, images of III: 5 (the proband's sister), who did not manifest obviously symptomatic encephalopathy, indicated the smallest lactate peak of any of the volunteers [Figure 5]c, suggesting that MRS might be sensitive enough to detect preclinical abnormalities. The MRS of II: 2 showed the biggest peak (Lac/Cr) during the period of first onset [Figure 5]d. MRS images of II: 3 (the proband's mother) were normal without any abnormal lactate peaks (data not shown).
Figure 5: Proton MRS of the proband, III: 5 (the proband's sister), and II: 2 (the proband's uncle). The MRS of the proband, III: 5 and II: 2 showed a decrease in NAA (NAA/Cr) and an inverted double peak in lactate. (a) The proband indicated an inverted lactate peak. (b) The proband showed a lactate peak (Lac/Cr) bigger than (a) when seizures recrudesced. (c) Proband's sister, who lacked obvious symptomatic encephalopathy, manifested the smallest peak in lactate (Lac/Cr). (d) The proband's uncle showed the biggest lactate peak (Lac/Cr) at onset

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 » Discussion Top

In our study, we found that the family members harboring A3243G mutation showed various phenotypes and that MRS could be a potential means of diagnosing MELAS syndrome and monitoring progression of the disease. These data provided a theoretical basis for better understanding, early detection and diagnosis of this syndrome. Genetic screening of mitochondrial diseases should include the most common mutations: A3243G (MELAS-related), T3271C (MELAS-related), A8344G (mostly MERRF-related), and T8993G/C (Leigh syndrome-related). This study detected these four mutations and revealed the causative mutation at the 3243 site of the mtDNA. We found the transition G peak in the sequencing electropherogram to partially indicate the relative mutation load, which was consistent with the results of RFLP [Figure 2].

Typical MELAS include stroke-like episodes, encephalopathy, seizures, migraine headache, mental retardation, muscular weakness, and short stature. Some patients may develop hearing loss, hemiparesis, hemianopia, diabetes mellitus, cardiomyopathy, progressive external ophthalmoplegia and others. [2] Harrison-Gomez et al., reported a case in which A3243G mutation was connected to the neurologic, cardiovascular, and endocrine systems. [3] In our study, the affected patients who had A3243G mutation, showed different phenotype, such as diabetes, MELAS syndrome with or without hearing defect, and myopathy. The proband, who initially diagnosed as a case of encephalitis, presented with fever, headache, and vomiting. He recovered after a one-week treatment. Two years later, patient showed full MELAS syndrome and brain CT demonstrated migration of lesions. MELAS syndrome was considered as a diagnosis. The proband had a higher mutation load than his uncle, and he manifested with a more serious MELAS phenotype at the early stage. We suggest that there may be a connection between the severity of clinical symptoms and the proportion of mutant mtDNA, but the phenotypes are not significantly correlated to the mutation load.

Brain CTs and MRIs of the patient showed typical radiological changes of MELAS: Bilateral basal ganglia calcification and infarct-like lesions, which did not conform to large-vessel territories. [4],[5],[6] In agreement with a previous report, MRI of our cases showed: Migration of lesions, disappearance of lesions, and appearance of new lesion. [6] During the early stage, infarct-like lesions might show swelling and mass effects. Contrast enhancement was seldom noted on MRI images or CT scans. However, MRI is more sensitive than CT in demonstrating the number and extent of the lesions. MRS can be of help for early diagnosis of MELAS. In a patient 48 hours after a stroke-like episode, a lactate peak in MRS could be seen much before the changes in DWI sequence. Two weeks later, a high signal was observed on MRI sequence where MRS had shown a lactate peak. [7] In our study MRS of III: 5 detected an abnormal lactate peak without MRI findings or obvious clinical encephalopathy. That proton MRS showed lactate regardless of MR findings in patients, indicates that proton MRS may be more sensitive for detecting MELAS-associated preclinical abnormalities compared to MRI, [8] as all patients with MELAS have lactic acidosis. Moreover, the lactate peak varies at different stages of the disease, which could be a marker of the severity and progression of the MELAS syndrome. MR-angiography revealed no vascular stenosis but proliferation of small vessels, which was distinguishable from cerebral vascular diseases.

The members of this family displayed different phenotypes even when they had the same mutation. Radiological study, especially MRS, may be an appropriate way to diagnose the MELAS syndrome early and monitor progression and treatment. Improving the recognition of the MELAS syndrome would benefit all familial patients of MELAS.

 » Acknowledgments Top

This work was supported by grants 30870866, 31171211 and 81071021 from the National Natural Science Foundation of China (to TW), grant 81100958 from the National Natural Science Foundation of China (to ZTZ) and grant 20066002100 from the Wuhan Science and Technology Bureau, China (to TW). We are grateful to Dr. Xiukun Cui for assisting with experimental instructions.

 » References Top

1.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;16:481-8.  Back to cited text no. 1
2.Thambisetty M, Newman NJ. Diagnosis and management of MELAS. Expert Rev Mol Diagn 2004;4:631-44.  Back to cited text no. 2
3.Harrison-Gomez C, Harrison-Ragle A, Macias-Hernandez A, Guerrero-Sanchez V. [A3243G mitochondrial DNA mutation and heterogeneous phenotypic expression]. Rev Med Inst Mex Seguro Soc 2009;47:219-25.  Back to cited text no. 3
4.Clark JM, Marks MP, Adalsteinsson E, Spielman DM, Shuster D, Horoupian D, et al. MELAS: Clinical and pathologic correlations with MRI, xenon/CT, and MR spectroscopy. Neurology 1996;46:223-7.  Back to cited text no. 4
5.Ito H, Mori K, Harada M, Minato M, Naito E, Takeuchi M, et al. Serial brain imaging analysis of stroke-like episodes in MELAS. Brain Dev 2008;30:483-8.  Back to cited text no. 5
6.Kim IO, Kim JH, Kim WS, Hwang YS, Yeon KM, Han MC. Mitochondrial myopathy-encephalopathy-lactic acidosis-and strokelike episodes (MELAS) syndrome: CT and MR findings in seven children. AJR Am J Roentgenol 1996;166:641-5.  Back to cited text no. 6
7.Abe K, Yoshimura H, Tanaka H, Fujita N, Hikita T, Sakoda S. Comparison of conventional and diffusion-weighted MRI and proton MR spectroscopy in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like events. Neuroradiology 2004;46:113-7.  Back to cited text no. 7
8.Castillo M, Kwock L, Green C. MELAS syndrome: Imaging and proton MR spectroscopic findings. AJNR Am J Neuroradiol 1995;16:233-9.  Back to cited text no. 8


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

  [Table 1]

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