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Detection of 14-3-3 protein in the cerebrospinal fluid in mitochondrial encephalopathy with lactic acidosis and stroke-like episodes
Journal of the Neurological Sciences 239 (2005) 115 – 118 www.elsevier.com/locate/jns
Short communication
Detection of 14-3-3 protein in the cerebrospinal fluid in mitochondrial encephalopathy with lactic acidosis and stroke-like episodes Katsunori Fujii a,*, Yuzo Tanabe b, Kazuhiko Kobayashi b, Hideki Uchikawa a, Yoichi Kohno a a
Department of Pediatrics, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8670, Japan b Division of Neurology, Chiba Children’s Hospital, Chiba, Japan Received 23 May 2005; received in revised form 15 July 2005; accepted 15 August 2005 Available online 5 October 2005
Abstract We describe a 13-year-old boy with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) who experienced a stroke-like episode resulting in severe mental regression and quadriplegia. We tested 14-3-3 protein in the cerebrospinal fluid (CSF) of the patient four times around a stroke-like episode in a magnetic resonance imaging (MRI) study. Detection of the protein in the CSF was well correlated with the clinical course and range of damage of the brain lesion on MRI. Interestingly, 14-3-3 CSF protein was detected at the beginning of mitochondrial encephalopathy without new MRI abnormalities, suggesting that it is a sensitive brain marker. We conclude that 14-3-3 CSF protein is a useful biological marker of brain disruption in MELAS as well as other neurological disorders. D 2005 Elsevier B.V. All rights reserved. Keywords: 14-3-3 protein; CSF; MELAS; MR study; Immunoblotting; Isoforms
1. Introduction Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) is characterized by strokelike episodes, seizures, subacute dementia, and lactic acidosis due to mitochondrial DNA mutation [1,2]. Stroke-like episodes in MELAS frequently cause focal brain injury leading to neurological sequelaes such as hemiparesis, hemianopia, and focal seizures. Although many drugs have been applied to prevent disease progression, no successful therapy has been established [3]. 14-3-3 protein is abundantly expressed in the brain, and its presence in the cerebrospinal fluid (CSF) reflects brain destruction in underlying diseases [4]. Indeed, Creutzfeldt – Jakob disease, multiple sclerosis, Alzheimer disease, transverse myelitis and other neurological diseases are accompanied by 14-3-3 protein in the CSF [5]. So far, there has been only one report about 14-3-3 protein detection in MELAS, but its details remain unknown [6]. * Corresponding author. Tel.: +81 43 226 2144; fax: +81 43 226 2145. E-mail address: [email protected] (K. Fujii). 0022-510X/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2005.08.007
Since the chance for CSF examination in a patient is limited, there have only been a few reports about the time course detection of 14-3-3 protein [7,8]. Here, we tested 143-3 CSF protein four times around a stroke-like episode in a MELAS patient to determine whether 14-3-3 CSF protein reflects brain disruption in MELAS together with a magnetic resonance imaging (MRI) study which confirmed the damaged lesion in the brain.
2. Case report The patient was normal at birth and had normal motor developmental milestones. When he was 5 years old, he presented with edema in his lower extremities, leading to the diagnosis of heart failure caused by hypertrophic cardiomyopathy. He also had sensory deafness, muscle atrophy and weakness in the lower extremities. Blood examinations showed high lactate (8.03 mmol/L), high pyruvate (0.32 mmol/L), and hyper-CKemia (758 U/L), and there were scattered ragged red fibers seen by muscle biopsy. With a mitochondrial DNA mutation of A3243G,
116
K. Fujii et al. / Journal of the Neurological Sciences 239 (2005) 115 – 118
acute encephalopathy a stroke-like episode
day 1
day 111
day 135
day 204
14-3-3 protein MRI
MRI
Fig. 1. 14-3-3 protein detection during the progression of MELAS. 14-3-3 CSF protein was detected by immunoblotting using anti-14-3-3 pan antibodies. The first specimen obtained at the first admission (Day 1) showed a weak 14-3-3 protein band, but the second specimen obtained at the beginning of a stroke-like episode (Day 111) was negative. The third specimen obtained in the stroke-like episode (Day 135) showed a very strong 14-3-3 protein band, and the fourth specimen obtained in the stable condition (Day 204) was negative. All results were independently judged by two doctors (KF and HU). The days were counted from the day when the patient was obtunded and admitted to our hospital.
he was diagnosed as having mitochondrial cardiomyopathy with sensory deafness. Multiple drugs such as co-enzyme Q10, diuretics, digoxin, vitamins, and sodium dichloroacetate were prescribed. When the patient was 13 years old, he was admitted to our hospital because he was obtunded and unable to walk. Laboratory examinations revealed high titers of lactate in the serum (5.23 mmol/L) and CSF (4.65 mmol/ L). 14-3-3 protein in the CSF was weakly positive (first sampling on Day 1; Fig. 1). The method used for detecting 14-3-3 protein in the CSF was previously described [9,10]. We have used rabbit anti-h (pan) 143-3 antibodies (sc-629; Santa Cruz Biotechnology, Santa Cruz, CA) for detection of 14-3-3 protein in the cerebrospinal fluid, which have been widely used for this purpose. Two doctors (KF and HU) independently judged
the results, and 14-3-3 protein was tested by at least two independent experiments. An MRI showed remarkable brain atrophy with T1 and T2 high intensities in the bilateral corpus striatum (Fig. 2), suggesting calcification under chronic disease progression. Compared with his previous MRI studies, no new lesions were detected. Electroencephalography showed theta waves as a basic activity without apparent paroxysms. Taken together, we diagnosed him as having mitochondrial encephalopathy. After receiving daily intravenous infusion, he gradually recovered and was discharged from the hospital, although he remained unable to walk. Three months later, he was admitted to our hospital again because of poor oral intake. On the day of admission, he also presented with a stroke-like episode including seizure, eye deviation, myoclonus and loss of consciousness.
day 1
A
B
C
D
E
F
day 135
Fig. 2. Brain MRI studies during the disease progression. MRI studies were demonstrated on Day 1 (A – C) and Day 135 (D – F). (A) T1-weighted MRI of the brain on Day 1 in a patient with MELAS showing diffuse brain atrophy with bilateral high intensity in the corpus striatum. (B) T2 fluid attenuated inversion recovery (FLAIR)-weighted MRI on Day 1 showing slight high intensity and a cavity in the corpus striatum. (C) Diffusion-weighted MRI on Day 1 showing no significant brain lesions. (D) T1-weighted MRI of the brain on Day 135 showing bilateral high intensity in the corpus striatum. (E) T2 FLAIR-weighted MRI on Day 135 showing prominent high intensity mainly in the left occipital and bilateral temporal lobes. (F) Diffusion-weighted MRI on Day 135 showing high intensity mainly in the left occipital and right temporal lobes.
K. Fujii et al. / Journal of the Neurological Sciences 239 (2005) 115 – 118
Laboratory examination revealed high titers of lactate in the CSF (9.78 mmol/l) and the serum (5.53 mmol/l). 14-3-3 CSF protein was tested again, but found to be negative (second sampling on Day 111; Fig. 1). He had intermittent seizures, but treatment with diazepam was successful. Three weeks later, MRI showed T2 high intensity on the right temporal lobe and left occipital lobe (Fig. 2). Diffusion weighted imaging also revealed high signal intensity on the same lesion, suggesting that severe cellular damage had occurred during this period. On the same day, 14-3-3 CSF protein was found to be positive (third sampling on Day 135; Fig. 1). The isoforms of 14-3-3 protein were also identified as beta, theta and gamma using isoform-specific antibodies (data not shown). After a stroke-like episode, he became severely handicapped but could sit on a wheel chair without respiratory disturbance. Two months later, the CSF study was performed again and 14-3-3 CSF protein was not detected (fourth sampling on Day 204; Fig. 1).
117
reason why 14-3-3 CSF protein was not detected at the beginning of the stroke-like episode may have been due to too early examination of the stroke-like episode. There has been only one report about 14-3-3 protein detection in a patient with MELAS [6]. There, 14-3-3 CSF protein was detected with progressive dementia. Since there was no description of when 14-3-3 CSF protein was tested and how it was correlated with the distribution of the damaged brain areas on MRI, our report is of importance regarding the significance of 14-3-3 protein detection in this disorder. In conclusion, we showed that 14-3-3 CSF protein reflects brain destruction in MELAS as well as other neurological disorders. 14-3-3 protein was detected at the beginning of mitochondrial encephalopathy, so that it may be a sensitive biological marker for brain destruction in MELAS.
Acknowledgement 3. Discussion Biological CSF markers such as neuron-specific enolase (NSE), myelin basic protein (MBP), S100, and tau protein are useful for studying underlying diseases. Although the specific significance such as MBP for multiple sclerosis, tau protein for Alzheimer’s disease, and S100 for Creutzfeldt – Jakob disease has been reported, no definite general marker for brain damage has been established [11]. 14-3-3 protein, a well-conserved family of acidic 30-kDa protein, constitutes a new member of biological markers for brain destruction. Originally, 14-3-3 CSF protein was confirmed to be useful for the diagnosis of Creutzfeldt – Jakob disease with high sensitivity and specificity [12]. However, other neurological disorders such as multiple sclerosis [13], vascular dementia [14], paraneoplastic diseases [15] and transverse myelitis [16] are also accompanied by 14-3-3 protein in the CSF. Thus, a role of 14-3-3 CSF protein as a biological marker for brain destruction has been suggested. In our study, 14-3-3 protein was twice detected in the CSF of the MELAS patient, once when he was obtunded and unable to walk, suggesting that he was affected by mitochondrial encephalopathy. MRI study did not show any new brain lesions. However, 14-3-3 protein was detected in the CSF. Since there exists no diagnostic marker for mitochondrial encephalopathy, the detection of 14-3-3 CSF protein may be a useful and sensitive marker for the diagnosis of mitochondrial encephalopathy. The other time for 14-3-3 CSF protein detection was when the patient was in the stroke-like episode, but not at the beginning of the episode. A 14-3-3 protein band was most remarkable in this series of the investigation, suggesting that severe damage had occurred in the brain during this period. In fact, MRI study confirmed broad affected lesions in the brain such as in the occipital and temporal lobes. The
This study was supported by grants from the Ministry of Health and Welfare, Japan (No. 15591085).
References [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. [2] Goto Y, Nonaka I, Horai S. A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 1990;348:651 – 3. [3] Schmiedel J, Jackson S, Schafer J, Reichmann H. Mitochondrial cytopathies. J Neurol 2003;250:267 – 77. [4] Burkhard PR, Sanchez JC, Landis T, Hochstrasser DF. CSF detection of the 14-3-3 protein in unselected patients with dementia. Neurology 2001;56:1528 – 33. [5] Berg D, Holzmann C, Riess O. 14-3-3 proteins in the nervous system. Nat Rev Neurosci 2003;4:752 – 62. [6] Satoh J, Kurohara K, Yukitake M, Kuroda Y. The 14-3-3 protein detectable in the cerebrospinal fluid of patients with prion-unrelated neurological diseases is expressed constitutively in neurons and glial cells in culture. Eur Neurol 1999;41:216 – 25. [7] Giraud P, Biacabe AG, Chazot G, Later R, Joyeux O, Moene Y, et al. Increased detection of 14-3-3 protein in cerebrospinal fluid in sporadic Creutzfeldt – Jakob disease during the disease course. Eur Neurol 2002;48:218 – 21. [8] Brandel JP, Peoc’h K, Beaudry P, Welaratne A, Bottos C, Agid Y, et al. 14-3-3 protein cerebrospinal fluid detection in human growth hormone-treated Creutzfeldt – Jakob disease patients. Ann Neurol 2001;49:257 – 60. [9] Lemstra AW, van Meegen MT, Vreyling JP, Meijerink PH, Jansen GH, Bulk S, et al. 14-3-3 testing in diagnosing Creutzfeldt – Jakob disease: a prospective study in 112 patients. Neurology 2000;55:514 – 6. [10] Zerr I, Bodemer M, Gefeller O, Otto M, Poser S, Wiltfang J, et al. Detection of 14-3-3 protein in the cerebrospinal fluid supports the diagnosis of Creutzfeldt – Jakob disease. Ann Neurol 1998;43: 32 – 40. [11] Otto M, Wiltfang J, Cepek L, Neumann M, Mollenhauer B, Steinacker P, et al. Tau protein and 14-3-3 protein in the differential diagnosis of Creutzfeldt – Jakob disease. Neurology 2002;58:192 – 7.
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K. Fujii et al. / Journal of the Neurological Sciences 239 (2005) 115 – 118
[12] Hsich G, Kenney K, Gibbs CJ, Lee KH, Harrington MG. The 14-3-3 brain protein in cerebrospinal fluid as a marker for transmissible spongiform encephalopathies. N Engl J Med 1996;335:924 – 30. [13] Martinez-Yelamos A, Saiz A, Sanchez-Valle R, Casado V, Ramon JM, Graus F, et al. 14-3-3 protein in the CSF as prognostic marker in early multiple sclerosis. Neurology 2001;57:722 – 4. [14] Lemstra AW, van Meegen MT, Vreyling JP, Meijerink PH, Jansen GH, Bulk S, et al. 14-3-3 testing in diagnosing Creutzfeldt – Jakob disease: a prospective study in 112 patients. Neurology 2000;55:514 – 6.
[15] Saiz A, Graus F, Dalmau J, Pifarre A, Marin C, Tolosa E. Detection of 14-3-3 brain protein in the cerebrospinal fluid of patients with paraneoplastic neurological disorders. Ann Neurol 1999;46:774 – 7. [16] Irani DN, Kerr DA. 14-3-3 protein in the cerebrospinal fluid of patients with acute transverse myelitis. Lancet 2000;355:901.
Short communication
Detection of 14-3-3 protein in the cerebrospinal fluid in mitochondrial encephalopathy with lactic acidosis and stroke-like episodes Katsunori Fujii a,*, Yuzo Tanabe b, Kazuhiko Kobayashi b, Hideki Uchikawa a, Yoichi Kohno a a
Department of Pediatrics, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8670, Japan b Division of Neurology, Chiba Children’s Hospital, Chiba, Japan Received 23 May 2005; received in revised form 15 July 2005; accepted 15 August 2005 Available online 5 October 2005
Abstract We describe a 13-year-old boy with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) who experienced a stroke-like episode resulting in severe mental regression and quadriplegia. We tested 14-3-3 protein in the cerebrospinal fluid (CSF) of the patient four times around a stroke-like episode in a magnetic resonance imaging (MRI) study. Detection of the protein in the CSF was well correlated with the clinical course and range of damage of the brain lesion on MRI. Interestingly, 14-3-3 CSF protein was detected at the beginning of mitochondrial encephalopathy without new MRI abnormalities, suggesting that it is a sensitive brain marker. We conclude that 14-3-3 CSF protein is a useful biological marker of brain disruption in MELAS as well as other neurological disorders. D 2005 Elsevier B.V. All rights reserved. Keywords: 14-3-3 protein; CSF; MELAS; MR study; Immunoblotting; Isoforms
1. Introduction Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) is characterized by strokelike episodes, seizures, subacute dementia, and lactic acidosis due to mitochondrial DNA mutation [1,2]. Stroke-like episodes in MELAS frequently cause focal brain injury leading to neurological sequelaes such as hemiparesis, hemianopia, and focal seizures. Although many drugs have been applied to prevent disease progression, no successful therapy has been established [3]. 14-3-3 protein is abundantly expressed in the brain, and its presence in the cerebrospinal fluid (CSF) reflects brain destruction in underlying diseases [4]. Indeed, Creutzfeldt – Jakob disease, multiple sclerosis, Alzheimer disease, transverse myelitis and other neurological diseases are accompanied by 14-3-3 protein in the CSF [5]. So far, there has been only one report about 14-3-3 protein detection in MELAS, but its details remain unknown [6]. * Corresponding author. Tel.: +81 43 226 2144; fax: +81 43 226 2145. E-mail address: [email protected] (K. Fujii). 0022-510X/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2005.08.007
Since the chance for CSF examination in a patient is limited, there have only been a few reports about the time course detection of 14-3-3 protein [7,8]. Here, we tested 143-3 CSF protein four times around a stroke-like episode in a MELAS patient to determine whether 14-3-3 CSF protein reflects brain disruption in MELAS together with a magnetic resonance imaging (MRI) study which confirmed the damaged lesion in the brain.
2. Case report The patient was normal at birth and had normal motor developmental milestones. When he was 5 years old, he presented with edema in his lower extremities, leading to the diagnosis of heart failure caused by hypertrophic cardiomyopathy. He also had sensory deafness, muscle atrophy and weakness in the lower extremities. Blood examinations showed high lactate (8.03 mmol/L), high pyruvate (0.32 mmol/L), and hyper-CKemia (758 U/L), and there were scattered ragged red fibers seen by muscle biopsy. With a mitochondrial DNA mutation of A3243G,
116
K. Fujii et al. / Journal of the Neurological Sciences 239 (2005) 115 – 118
acute encephalopathy a stroke-like episode
day 1
day 111
day 135
day 204
14-3-3 protein MRI
MRI
Fig. 1. 14-3-3 protein detection during the progression of MELAS. 14-3-3 CSF protein was detected by immunoblotting using anti-14-3-3 pan antibodies. The first specimen obtained at the first admission (Day 1) showed a weak 14-3-3 protein band, but the second specimen obtained at the beginning of a stroke-like episode (Day 111) was negative. The third specimen obtained in the stroke-like episode (Day 135) showed a very strong 14-3-3 protein band, and the fourth specimen obtained in the stable condition (Day 204) was negative. All results were independently judged by two doctors (KF and HU). The days were counted from the day when the patient was obtunded and admitted to our hospital.
he was diagnosed as having mitochondrial cardiomyopathy with sensory deafness. Multiple drugs such as co-enzyme Q10, diuretics, digoxin, vitamins, and sodium dichloroacetate were prescribed. When the patient was 13 years old, he was admitted to our hospital because he was obtunded and unable to walk. Laboratory examinations revealed high titers of lactate in the serum (5.23 mmol/L) and CSF (4.65 mmol/ L). 14-3-3 protein in the CSF was weakly positive (first sampling on Day 1; Fig. 1). The method used for detecting 14-3-3 protein in the CSF was previously described [9,10]. We have used rabbit anti-h (pan) 143-3 antibodies (sc-629; Santa Cruz Biotechnology, Santa Cruz, CA) for detection of 14-3-3 protein in the cerebrospinal fluid, which have been widely used for this purpose. Two doctors (KF and HU) independently judged
the results, and 14-3-3 protein was tested by at least two independent experiments. An MRI showed remarkable brain atrophy with T1 and T2 high intensities in the bilateral corpus striatum (Fig. 2), suggesting calcification under chronic disease progression. Compared with his previous MRI studies, no new lesions were detected. Electroencephalography showed theta waves as a basic activity without apparent paroxysms. Taken together, we diagnosed him as having mitochondrial encephalopathy. After receiving daily intravenous infusion, he gradually recovered and was discharged from the hospital, although he remained unable to walk. Three months later, he was admitted to our hospital again because of poor oral intake. On the day of admission, he also presented with a stroke-like episode including seizure, eye deviation, myoclonus and loss of consciousness.
day 1
A
B
C
D
E
F
day 135
Fig. 2. Brain MRI studies during the disease progression. MRI studies were demonstrated on Day 1 (A – C) and Day 135 (D – F). (A) T1-weighted MRI of the brain on Day 1 in a patient with MELAS showing diffuse brain atrophy with bilateral high intensity in the corpus striatum. (B) T2 fluid attenuated inversion recovery (FLAIR)-weighted MRI on Day 1 showing slight high intensity and a cavity in the corpus striatum. (C) Diffusion-weighted MRI on Day 1 showing no significant brain lesions. (D) T1-weighted MRI of the brain on Day 135 showing bilateral high intensity in the corpus striatum. (E) T2 FLAIR-weighted MRI on Day 135 showing prominent high intensity mainly in the left occipital and bilateral temporal lobes. (F) Diffusion-weighted MRI on Day 135 showing high intensity mainly in the left occipital and right temporal lobes.
K. Fujii et al. / Journal of the Neurological Sciences 239 (2005) 115 – 118
Laboratory examination revealed high titers of lactate in the CSF (9.78 mmol/l) and the serum (5.53 mmol/l). 14-3-3 CSF protein was tested again, but found to be negative (second sampling on Day 111; Fig. 1). He had intermittent seizures, but treatment with diazepam was successful. Three weeks later, MRI showed T2 high intensity on the right temporal lobe and left occipital lobe (Fig. 2). Diffusion weighted imaging also revealed high signal intensity on the same lesion, suggesting that severe cellular damage had occurred during this period. On the same day, 14-3-3 CSF protein was found to be positive (third sampling on Day 135; Fig. 1). The isoforms of 14-3-3 protein were also identified as beta, theta and gamma using isoform-specific antibodies (data not shown). After a stroke-like episode, he became severely handicapped but could sit on a wheel chair without respiratory disturbance. Two months later, the CSF study was performed again and 14-3-3 CSF protein was not detected (fourth sampling on Day 204; Fig. 1).
117
reason why 14-3-3 CSF protein was not detected at the beginning of the stroke-like episode may have been due to too early examination of the stroke-like episode. There has been only one report about 14-3-3 protein detection in a patient with MELAS [6]. There, 14-3-3 CSF protein was detected with progressive dementia. Since there was no description of when 14-3-3 CSF protein was tested and how it was correlated with the distribution of the damaged brain areas on MRI, our report is of importance regarding the significance of 14-3-3 protein detection in this disorder. In conclusion, we showed that 14-3-3 CSF protein reflects brain destruction in MELAS as well as other neurological disorders. 14-3-3 protein was detected at the beginning of mitochondrial encephalopathy, so that it may be a sensitive biological marker for brain destruction in MELAS.
Acknowledgement 3. Discussion Biological CSF markers such as neuron-specific enolase (NSE), myelin basic protein (MBP), S100, and tau protein are useful for studying underlying diseases. Although the specific significance such as MBP for multiple sclerosis, tau protein for Alzheimer’s disease, and S100 for Creutzfeldt – Jakob disease has been reported, no definite general marker for brain damage has been established [11]. 14-3-3 protein, a well-conserved family of acidic 30-kDa protein, constitutes a new member of biological markers for brain destruction. Originally, 14-3-3 CSF protein was confirmed to be useful for the diagnosis of Creutzfeldt – Jakob disease with high sensitivity and specificity [12]. However, other neurological disorders such as multiple sclerosis [13], vascular dementia [14], paraneoplastic diseases [15] and transverse myelitis [16] are also accompanied by 14-3-3 protein in the CSF. Thus, a role of 14-3-3 CSF protein as a biological marker for brain destruction has been suggested. In our study, 14-3-3 protein was twice detected in the CSF of the MELAS patient, once when he was obtunded and unable to walk, suggesting that he was affected by mitochondrial encephalopathy. MRI study did not show any new brain lesions. However, 14-3-3 protein was detected in the CSF. Since there exists no diagnostic marker for mitochondrial encephalopathy, the detection of 14-3-3 CSF protein may be a useful and sensitive marker for the diagnosis of mitochondrial encephalopathy. The other time for 14-3-3 CSF protein detection was when the patient was in the stroke-like episode, but not at the beginning of the episode. A 14-3-3 protein band was most remarkable in this series of the investigation, suggesting that severe damage had occurred in the brain during this period. In fact, MRI study confirmed broad affected lesions in the brain such as in the occipital and temporal lobes. The
This study was supported by grants from the Ministry of Health and Welfare, Japan (No. 15591085).
References [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. [2] Goto Y, Nonaka I, Horai S. A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 1990;348:651 – 3. [3] Schmiedel J, Jackson S, Schafer J, Reichmann H. Mitochondrial cytopathies. J Neurol 2003;250:267 – 77. [4] Burkhard PR, Sanchez JC, Landis T, Hochstrasser DF. CSF detection of the 14-3-3 protein in unselected patients with dementia. Neurology 2001;56:1528 – 33. [5] Berg D, Holzmann C, Riess O. 14-3-3 proteins in the nervous system. Nat Rev Neurosci 2003;4:752 – 62. [6] Satoh J, Kurohara K, Yukitake M, Kuroda Y. The 14-3-3 protein detectable in the cerebrospinal fluid of patients with prion-unrelated neurological diseases is expressed constitutively in neurons and glial cells in culture. Eur Neurol 1999;41:216 – 25. [7] Giraud P, Biacabe AG, Chazot G, Later R, Joyeux O, Moene Y, et al. Increased detection of 14-3-3 protein in cerebrospinal fluid in sporadic Creutzfeldt – Jakob disease during the disease course. Eur Neurol 2002;48:218 – 21. [8] Brandel JP, Peoc’h K, Beaudry P, Welaratne A, Bottos C, Agid Y, et al. 14-3-3 protein cerebrospinal fluid detection in human growth hormone-treated Creutzfeldt – Jakob disease patients. Ann Neurol 2001;49:257 – 60. [9] Lemstra AW, van Meegen MT, Vreyling JP, Meijerink PH, Jansen GH, Bulk S, et al. 14-3-3 testing in diagnosing Creutzfeldt – Jakob disease: a prospective study in 112 patients. Neurology 2000;55:514 – 6. [10] Zerr I, Bodemer M, Gefeller O, Otto M, Poser S, Wiltfang J, et al. Detection of 14-3-3 protein in the cerebrospinal fluid supports the diagnosis of Creutzfeldt – Jakob disease. Ann Neurol 1998;43: 32 – 40. [11] Otto M, Wiltfang J, Cepek L, Neumann M, Mollenhauer B, Steinacker P, et al. Tau protein and 14-3-3 protein in the differential diagnosis of Creutzfeldt – Jakob disease. Neurology 2002;58:192 – 7.
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K. Fujii et al. / Journal of the Neurological Sciences 239 (2005) 115 – 118
[12] Hsich G, Kenney K, Gibbs CJ, Lee KH, Harrington MG. The 14-3-3 brain protein in cerebrospinal fluid as a marker for transmissible spongiform encephalopathies. N Engl J Med 1996;335:924 – 30. [13] Martinez-Yelamos A, Saiz A, Sanchez-Valle R, Casado V, Ramon JM, Graus F, et al. 14-3-3 protein in the CSF as prognostic marker in early multiple sclerosis. Neurology 2001;57:722 – 4. [14] Lemstra AW, van Meegen MT, Vreyling JP, Meijerink PH, Jansen GH, Bulk S, et al. 14-3-3 testing in diagnosing Creutzfeldt – Jakob disease: a prospective study in 112 patients. Neurology 2000;55:514 – 6.
[15] Saiz A, Graus F, Dalmau J, Pifarre A, Marin C, Tolosa E. Detection of 14-3-3 brain protein in the cerebrospinal fluid of patients with paraneoplastic neurological disorders. Ann Neurol 1999;46:774 – 7. [16] Irani DN, Kerr DA. 14-3-3 protein in the cerebrospinal fluid of patients with acute transverse myelitis. Lancet 2000;355:901.