Korean Journal of Cerebrovascular Surgery 2005;7(4):329-332.
Published online December 1, 2005.
MELAS Syndrome Presenting as Occipital Brain Infarct: Case Report.
Han, In Bo , Ahn, Jung Yong , Kim, Hyun Sook , Kim, Ok Jun
1Department of Neurosurgery, Pundang CHA Hospital, College of Medicine, Pochon CHA University, Seongnam, Korea. jyahn@cha.ac.kr
2Department of Neurology, Pundang CHA Hospital, College of Medicine, Pochon CHA University, Seongnam, Korea.
Abstract
MELAS syndrome is characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. A 14-year-old male presented with symptoms that resemble stroke including headache, seizure, visual disturbance and slight left hemiparesis. Laboratory investigation showed elevated lactate level in the blood. Brain computed tomography and magnetic resonance image revealed acute infarction in the right occipitoparietal lobe, which was not restricted to a specific vascular territory. Magnetic resonance spectroscopy showed decreased N-acetyl aspartate and increased lactate level in the affected lobe. A molecular genetic analysis identified A3243G point mutation in the peripheral blood leukocytes and confirmed MELAS syndrome. We describe clinical, radiological and molecular genetic findings in the patient with MELAS syndrome presenting occipital brain infarct.
Key Words: MELAS syndrome, A3243G, Mitochondrial DNA mutation

Introduction


  
Stroke is rare in young patients and its etiology is different from that of adult patients. In the patients younger than 30 years of age, thrombus and cardiogenic embolus comprise about 40 to 50% of all etiologies and the frequency of other etiologies is higher and mitochondrial disorders approximately comprise about 2% of stroke.2)9)
   Stroke-like episodes in MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) resemble acute stroke and have a propensity for the occipital lobe.1) The frequency of a mitochondrial disorder in patients with occipital brain infarct before the age of 45 years is 10%, although it is uncommon in oriental persons including Korean.9) The patient with MELAS may be misdiagnosed as stroke. Clinical, radiological and molecular genetic analysis can confirm MELAS syndrome presenting as occipital infarct.
   We report one patient with clinical features that resemble stroke and describe radiological and molecular genetic findings.

Case Report

   This male patient was born after a normal pregnancy and delivery. There was no family history of neurological diseases and the parents were not related. Motor and intellectual development was normally attained during the infancy. At 14 months, the patient underwent balloon valvuloplasty due to pulmonary artery stenosis. Although the patient had begun to show delayed motor and intellectual development since the age of 10 years, the patient was not carried to hospital and was not evaluated.
   At the age of 14 years, the patient was carried to pediatric outpatient department with severe headache, vomiting and visual disturbance. The patient was referred to our neurosurgical department because of suspecting of brain lesion. On examination, the patient showed intellectual delay, inattention and incoherent speech. The patient was suspected of having left homonymous hemianopsia. The patient was short (143 cm:less than 3 percentile) and thin (36 kg:less than 10 percentile). Brain computed tomography (CT) scan revealed acute infarction in right occipital lobe (Fig. 1). Electrocardiogram revealed the normal sinus rhythm. Echocardiography was performed to identify the cardiac origin of ischemic stroke and showed only mild pulmonary artery stenosis with-out cardiomyopathy. Although we recommended admission, the patient was not hospitalized. The patient began to take an aspirin 100 mg per day for the treatment of stroke.
   Ten days later, the patient was carried to the emergency department with left motor seizure. Occasional dystonic flexor postures of left extremities were seen. The patient also had slight left hemiparesis. Brain MRI T2 scan revealed high signal intensities in the right occipital and parietal lobe (Fig. 2A). Diffusion weighted image (DWI) also demonstrated high signal intensity in the same area (Fig. 2B). MR angiography showed no vascular abnormality. These clinical and radiological findings suggested MELAS syndrome. Thus, we performed laboratory investigations including blood lactate and urine organic acid, electroencephalography (EEG), magnetic resonance spectroscopy(MRS) and genetic analysis.
   The serum and urine lactate levels were significantly elevated to 41.9 mg/dL (normal range 4.5-19.8 mg/dL) and 194.2 mmol/mol creatine (normal:2.7-23.7 mmol/mol creatine) respectively. Blood pyruvate was 1.0 mg/dL (normal range 0.3-0.7 mg/dL). The serum glucose level was slightly increased to 151 mg/dL (normal range 70-110 mg/dL). Thyroid function was also measured. The levels of T3 and free T4 were 1.30 ng/mL (normal range 0.60-1.81 ng/mL) and 1.38 ng/dL (normal range 0.89-1.76 ng/dL) respectively. The level of anti-nuclear antibody was measured to rule out con-nective tissue disorder and it was normal.
   EEG demonstrated diffuse slow background activities, poorly regulated posterior dominant rhythm and focal slowing on the right posterior head quadrant region. Such findings suggested moderate diffuse cerebral dysfunction and structural lesion in the right posterior head quadrant region. MR spectroscopy showed decreased N-acetyl aspartate (NAA) and increased lactate level in the right occipitoparietal lobe (Fig. 3).
   The DNA was extracted from peripheral blood leukocytes. Mutant DNA was detected by Hae III digestion of the polymerase chain reaction (PCR) products. Adenine to guanine transition at nucleotide position 3243 in transfer ribonucleic acid (tRNA) leucine (Leu)(UUR) gene in comparison with reference sequence was confirmed (Fig. 4).
   The patient was apparently diagnosed as MELAS syndrome based on the clinical findings and genetic study, although muscle biopsy was not examined. The patient was discharged with the oral medications including coenzyme Q10, vitamins B1, B2 and anticonvulsant.

Discussion

   MELAS is one of the most common mitochondrial disorders, inherited maternally and frequently associated with mutations of mitochondrial DNA (mtDNA). The patients with MELAS syndrome present with various clinical features including headache, vomiting, short stature, dementia, muscle weakness, deafness, stroke-like episodes, endocrine system dysfunction and cardiomyopathy.3)5)6)7)12)
   Among these, stroke-like episode resembles acute ischemic stroke at onset and in symptoms and MELAS may be misdiagnosed as stroke. The infarct-like lesions in MELAS have a propensity for the occipital area. The lesion seen in CT and MRI is not clearly correlated with vascular territories.1)8)9)12) Stroke-like episodes play an important role in the neurological prognosis of MELAS. Thus, mitochondrial disorders including MELAS syndrome should be suspected in young patients with occipital infarct for early detection.
   The pathology of the stroke-like episode in MELAS is unclear. So far it has been supposed that infarct-like lesions might result from a focal, transient impairment of oxidative metabolism in the parenchyma or from large vessels and/or arterioles occlusion.12) Single photon emission CT (SPECT) shows global reduction of cerebral blood flow and positron emission tomography (PET) demonstrates reduction of oxidative metabolism.4) These features suggest that mismatches of metabolism and cerebral blood flow (CBF) might be involved in the genesis of cerebral focal lesions in MELAS. Defective vascularization and depressed oxidative metabolism might precipitate an increased metabolic demand, causing anaerobic metabolism activation, parenchyma lactate accumulation and tissue damage.8)12)
   Our patient presented with clinical features of MELAS such as developmental delay, short stature, visual disturbance and left motor seizure. Laboratory investigation showed an elevated concentration of lactate in blood. The lesion seen in CT or MRI resembles that of an ischemic stroke. However, MR angiography revealed no vascular abnormalities. MR spectroscopy of affected right occipital lobe showed lower NAA and higher lactate level. Although muscle biopsy was not performed, a molecular genetic analysis identified A3243G point mutation in the peripheral blood leukocytes. Thus, the patient could be diagnosed as MELAS syndrome, harboring the adenine to guanine transition at mtDNA position 3243.
  
The substitution of adenine (A) to guanine (G) at the nucleotide position 3243 in the mitochondrial tRNA leucine (UUR) gene is the most common cause of MELAS, being responsible for about 80% of the cases.7)10)11) Recently, a variety of minor mutations, occurring at nucleotide position 3271, 3252, 3291, have been reported in the patients with MELAS syndrome.5) Because of the considerable overlap and wide range of clinical features, clinical diagnosis and classification are difficult.
   Most of the pathogenic mtDNA mutations are hetroplasmic, i.e. mtDNA molecules coexist with a residual number of wild-type mtDNA molecules. The heteroplasmy of mtDNA mutations and proportion of mutated genes are responsible for the diversity of the symptoms, the severity and progression of the disease.13)
   MELAS syndrome remains largely untreatable, however, we may prevent the progression of symptoms by reduction of metabolic demand. Thus, complete prevention and control of infection, seizure and metabolic acidosis are very important. Therapeutic regimens have included cytochrome c, coenzyme Q10, dichloroacetic acid, and vitamins B1, B2, and B6.4)
   Although stroke is rare in young patients, MELAS may be one of the etiologies of the stroke. In young patients with stroke-like episodes and occipital infarct, we should investigate the blood and cerebrospinal fluid (CSF) lactate and/or muscle biopsy sample and identify transfer gene mutation for early MELAS detection.

Conclusions

   Clinical and molecular analysis of young patient with occipital brain infarct suggests that mitochondrial disorder may be one of the rare etiologies of stroke. The patients with MELAS syndrome and occipital stroke can probably be detected on a clinical basis and blood lactate determination. When the patients have the occipital stroke with serum lactate elevation, a mitochondrial cause of the disease should be considered, especially in young patients.


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