- Email: [email protected]
Nonfluent aphasia in a patient with Waldenstrom’s macroglobulinemia
Case reports / Journal of Clinical Neuroscience 14 (2007) 601–603
601
Nonfluent aphasia in a patient with Waldenstrom’s macroglobulinemia Markus Donix a
a,*
, Bettina Beuthien-Baumann b, Ru¨diger von Kummer c, Georg Gahn d, Fatima Thomas a, Vjera Holthoff a
Department of Psychiatry and Psychotherapy, University of Technology, Fetscherstrasse 74, 01307 Dresden, Germany b Department of Nuclear Medicine, University of Technology Dresden, Germany c Department of Neuroradiology, University of Technology Dresden, Germany d Department of Neurology, University of Technology Dresden, Germany Received 7 February 2006; accepted 16 March 2006
Abstract Waldenstrom’s macroglobulinemia (WM) is an uncommon low-grade lymphoma. Cognitive impairment due to central nervous system infiltration by lymphoplasmocytoid cells (Bing-Neel syndrome) has been rarely reported. We describe a 54-year-old man who was referred to a memory disorder clinic with a 9-month history of clinically obvious nonfluent aphasia and WM. He underwent extensive neuropsychological testing, clinical examination and structural and functional brain imaging. The diagnosis of the diffuse form of the Bing-Neel syndrome was supported by abnormal lymphoid cells found in the cerebrospinal fluid. Structural and functional brain imaging revealed impairment of brain areas due to white matter changes and subsequent functional deficits mimicking the neuropsychological syndrome encountered in progressive nonfluent aphasia. The diffuse form of Bing-Neel syndrome and neurological deficits are assumed to be the result of leptomeningeal infiltration by malignant cells and/or neoplastic vascular obstruction. 2006 Elsevier Ltd. All rights reserved. Keywords: Waldenstrom’s macroglobulinemia; Bing-Neel syndrome; Neuropsychology
1. Introduction Waldenstrom’s macroglobulinemia (WM), a lymphoplasmacytic lymphoma, is characterized by neoplastic proliferation of B lymphocytes and excessive production of monoclonal immunoglobulin M (IgM). The leading clinical features are lymphadenopathy and/or splenomegaly, anemia and hyperviscosity syndrome.1 2. Case report We report a 54-year-old man with a 9-month history of clinically obvious nonfluent aphasia with nonfluent spontaneous speech, agrammatism and phonemic paraphasias. The symptoms developed after the patient was diagnosed with WM but prior to completion of the treatment, including plasmaphereses and chemotherapy. The deficits showed an insidious onset, progressing over several weeks to a clinical syndrome that remained stable thereafter. Upon presentation in our memory disorder clinic he underwent extensive neuropsychological testing, clinical examination and structural imaging with MRI and functional brain imaging with 2-[18F]fluorodeoxy-2-glucose positron emission tomography (FDG-PET). He scored 26 points on the Mini-Mental State Examination2 as a global measure *
Corresponding author. Tel.: +49 351 458 2376; fax: +49 351 458 4324. E-mail address: [email protected] (M. Donix).
of cognitive status. The neuropsychological test battery included tests for different aspects of memory (California Verbal Learning Test [CVLT],3 delayed recall of the ReyOsterrieth-Figure,4 digit span forward and reverse5) as well as for speed of information processing and executive functioning (Trail Making Test A and B6), visuo-constructive abilities (copying the Rey-Osterrieth-figure), word fluency and language (semantic fluency task ‘animals’,4 parts of the Aachen Aphasia Test7). Testing identified severe impairment in both initial letter and category-based verbal fluency and mild impairment in memory (for example, digit span forward score: 7/12, [normative data (mean/SD): 8.0/ 1.73]; reverse score: 6/12, [7.06/1.88]), attention and visuoconstructive abilities (Rey-Osterrieth-figure copying: 34/36. [35.6/0.76]; Rey-Osterrieth-figure recall: 17/36 [18.8/7.37]). Physical and neurological examination was unrevealing. Neither laboratory values nor clinical symptoms supported a hyperviscosity syndrome. Hematologic laboratory values revealed a monoclonal IgM-j-gammopathy, mild anemia, a normal white-cell count with normal differential count, and normal platelets. Analysis of CSF demonstrated a dysfunction of the blood-brain barrier, elevated protein level (457 mg/L; albumin 338 mg/L; IgM: 33.9 mg/L) without additional abnormalities, specifically no signs of cerebral infection. CSF cytology revealed lymphocytosis with abnormal lymphocytoid cells, showing multiple mitoses. There was no past or present history of other vascular risk factors. Color-duplex sonography of the cervical arter-
602
Case reports / Journal of Clinical Neuroscience 14 (2007) 601–603
Fig. 1. Regional glucose metabolism by 2-[18] fluorodeoxy-2-glucose positron emission tomography (lmol/100 g/min). Note significant decrease in left frontal and temporal cortex and left striatal, thalamic and right caudate metabolism as well as crossed cerebellar diaschisis.
ies and transcranial Doppler sonography was unrevealing. Brain MRI showed numerous hyperintense lesions in the centrum semiovale on T2-weighted and FLAIR sequences, left more than right, without signal loss on T1-weighted sequences or signs of general atrophy. FDG-PET demonstrated bilateral and widespread decreases in temporal and frontal metabolism with a significant asymmetry affecting the left more than the right hemisphere. Left subcortical regions including caudate nucleus, putamen and thalamus revealed a significant decrease in metabolism. There was evidence of additionally remote effects in the cerebellum (crossed cerebellar diaschisis), a phenomenon known to occur as a consequence of acute functional interruptions in the contralateral cerebral hemisphere as previously described in stroke (Fig. 1).8
viscosity. CSF analysis excluded infectious diseases of the brain, including meningitis or encephalitis. Structural images showed multiple small microvascular lesions in the centrum semiovale and functional brain imaging revealed large areas of hypometabolism in cortical and subcortical areas. The patient showed no history or presence of vascular risk factors for chronic vascular brain disease, such as hypertension or metabolic diseases and we attributed the patient’s history of alterations in his cognitive abilities to microvascular neoplastic obstructive brain lesions on the basis of Bing-Neel syndrome. Our diagnosis is strengthened by the occurrence of malignant cells in the patient’s CSF. After the diagnosis was made, he was admitted to the Department of Hematology for his next course of chemotherapy.
3. Discussion References The patient presented here is remarkable as he suffered from WM and offered a complex clinical syndrome mimicking progressive nonfluent aphasia.9 Based on clinical evaluation including brain imaging and supported by CSF cytology, cerebral infiltration by malignant cells is the most likely explanation and is known as Bing-Neel syndrome.10 There is a tumoral form with lymphoplasmacytic cells forming a brain lymphoma, usually characterized by focal neurologic defects11 and a diffuse form that is associated with leptomeningeal infiltration12 and or cerebral infarcts due to neoplastic vascular obstruction presenting with nonfocal dysfunctions, such as personality changes or dementia.13 Whereas the tumoral form of Bing-Neel syndrome can be confirmed by stereotactic biopsy, diagnosis of the diffuse form is more difficult. Leptomeningeal infiltration can be undetectable in structural brain imaging (presenting with meningeal gadolinium enhancement)14 and necessitates CSF cytology for malignant lymphoid cells for the diagnosis, that is additionally strengthened by clinical symptoms of behavioral change and/or cognitive decline. The patient presented had no clinical history of a hyperviscosity syndrome, which would present with symptoms of dizziness, fatigue, blurred vision or easy bleeding of mucous membranes and regular laboratory evaluation, since the diagnosis of WM, revealed no changes of blood hyper-
1. Dimopoulos MA, Alexanian R. Waldenstrom’s macroglobulinemia. Blood 1993;83:1452–9. 2. Folstein MF, Folstein SE, McHugh PR. ‘‘Mini-mental state’’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–98. 3. Delis DC, Kramer JH, Kaplan E, et al. California Verbal Learning Test, Adult Version. San Antonio: The Psychological Corporation; 1987. 4. Spreen O, Strauss E. A Compendium of Neuropsychological Tests: Administration, Norms, and Commentary. New York: Oxford University Press; 1998. 5. Wechsler D. Wechsler Memory Scale. 3rd ed. San Antonio: The Psychological Corporation; 1997. 6. Reitan R, Wolfson D. The Halstead-Reitan Neuropsychological Test Battery: Theory and Clinical Interpretation. Tucson: Neuropsychology Press; 1993. 7. Huber W, Poeck K, Willmes K. The Aachen Aphasia Test. Adv Neurol 1984;42:291–303. 8. Baron JC, Bousser MG, Comar D, et al. Noninvasive tomographic study of cerebral blood flow and oxygen metabolism in vivo. Potentials, limitations, and clinical applications in cerebral ischemic disorders. Eur Neurol 1981;20:273–84. 9. Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurol 1998;51:1546–54. 10. Bing J, Neel A. Two cases of hyperglobulinaemia with affection of the central nervous system on a toxi-infection basis. Acta Med Scand 1936;88:492–506. 11. Delgado J, Canales MA, Garcia B, et al. Radiation therapy and combination of cladribine, cyclophosphamide, and prednisone as
Case reports / Journal of Clinical Neuroscience 14 (2007) 603–607 treatment of Bing-Neel syndrome: Case report and review of the literature. Am J Neurol 2002;69:127–31. 12. Bhatti MT, Yuan C, Winter W, et al. Bilateral sixth nerve paresis in the Bing-Neel syndrome. Neurol 2005;64:576–7. 13. Arias M, Pereiro ZI, Requena CI, et al. Rapidly progressing dementia as the presenting symtpom of Waldenstrom’s macroglobulinemia:
603
findings from magnetic resonance imaging of the brain in Bing-Neel syndrome. Rev Neurol 2004;38:640–2. 14. Hug A, Haas J, Storch-Hagenlocher B, et al. Leptomeningeal tumor cell infiltration as first manifestation of an immunocytoma (Waldenstro¨m’s macroglobulinemia). Nervenarzt 2004;75: 1012–5.
doi:10.1016/j.jocn.2006.03.025
Immunohistochemical and ultrastructural abnormalities in muscle from a patient with sensorineural hearing loss related to a 1555 A-to-G mitochondrial mutation Hideaki Kouzaki *, Mikio Suzuki, Takeshi Shimizu Department of Otolaryngology, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu 520 2192, Japan Received 1 February 2005; accepted 14 October 2005
Abstract Genetic studies indicate that hereditary susceptibility of the inner ear to aminoglycoside antibiotic toxicity is caused by a nucleotide 1555 A-to-G mutation in the mitochondrial 12S rRNA gene. Although the phenotype associated with this mutation is nonsyndromic hearing loss, the possibility remains that there could be effects on other tissues that, like the inner ear, contain numerous mitochondria, particularly muscle. We obtained a temporalis muscle specimen from a deaf patient with the A1555G mutation and found informative pathologic features, including mosaic activity of cytochrome c oxidase immunoreactivity and mitochondrial ultrastructure. These findings suggest that mitochondrial dysfunction from the A1555G mutation extends beyond the inner ear. 2006 Elsevier Ltd. All rights reserved. Keywords: Hearing loss; Cytochrome c oxidase; Ragged-red fibre; Mitochondria; Point mutation
1. Introduction Mitochondrial mutations have been reported in association with a variety of multisystem disorders.1 As the primary adenosine 5’-triphosphate (ATP)-generating organelles in mammalian cells, mitochondria produce ATP via oxidative phosphorylation in five respiratory complexes located within the inner mitochondrial membrane.2 Cytochrome c oxidase (COX), complex IV of the respiratory chain, catalyzes transfer of reducing equivalents from cytochrome c to molecular oxygen. Enzyme histochemistry to detect COX activity has proven to be the most reliable light microscopic method for visualization of normal mitochondria and for the diagnosis and interpretation of certain mitochondrial disorders affecting skeletal muscle.3,4 Genetic defects affecting the
*
Corresponding author. Tel.: +81 77 548 2261; fax: +81 77 548 2783. E-mail address: [email protected] (H. Kouzaki).
synthesis of mitochondrial enzymes and proteins can explain how mitochondrial diseases affect multiple organ systems.5 Sensorineural hearing loss (SNHL) in association with a genetic mutation can be classified into syndromic and nonsyndromic deafness, based on whether additional organs are involved. SNHL sometimes appears as one of several symptoms of a mitochondrial disease. For example, approximately half of patients with Kearns-Sayre syndrome (KSS), myoclonus epilepsy associated with ragged-red fibres (MERRF), or mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) have SNHL.6 An A-to-G point mutation at position 1555 in the mitochondrial 12S rRNA gene causes hereditary susceptibility to aminoglycoside antibiotic ototoxicity. Characteristically, this mutation produces nonsyndromic hearing loss.7 Cortopassi and Hutchin8 suspected that sensorineural hearing loss associated with this mutation results from inhibited mitochondrial function within the stria vascularis, compromising the function of Na+/K+ ATPase and disrupting the ion
601
Nonfluent aphasia in a patient with Waldenstrom’s macroglobulinemia Markus Donix a
a,*
, Bettina Beuthien-Baumann b, Ru¨diger von Kummer c, Georg Gahn d, Fatima Thomas a, Vjera Holthoff a
Department of Psychiatry and Psychotherapy, University of Technology, Fetscherstrasse 74, 01307 Dresden, Germany b Department of Nuclear Medicine, University of Technology Dresden, Germany c Department of Neuroradiology, University of Technology Dresden, Germany d Department of Neurology, University of Technology Dresden, Germany Received 7 February 2006; accepted 16 March 2006
Abstract Waldenstrom’s macroglobulinemia (WM) is an uncommon low-grade lymphoma. Cognitive impairment due to central nervous system infiltration by lymphoplasmocytoid cells (Bing-Neel syndrome) has been rarely reported. We describe a 54-year-old man who was referred to a memory disorder clinic with a 9-month history of clinically obvious nonfluent aphasia and WM. He underwent extensive neuropsychological testing, clinical examination and structural and functional brain imaging. The diagnosis of the diffuse form of the Bing-Neel syndrome was supported by abnormal lymphoid cells found in the cerebrospinal fluid. Structural and functional brain imaging revealed impairment of brain areas due to white matter changes and subsequent functional deficits mimicking the neuropsychological syndrome encountered in progressive nonfluent aphasia. The diffuse form of Bing-Neel syndrome and neurological deficits are assumed to be the result of leptomeningeal infiltration by malignant cells and/or neoplastic vascular obstruction. 2006 Elsevier Ltd. All rights reserved. Keywords: Waldenstrom’s macroglobulinemia; Bing-Neel syndrome; Neuropsychology
1. Introduction Waldenstrom’s macroglobulinemia (WM), a lymphoplasmacytic lymphoma, is characterized by neoplastic proliferation of B lymphocytes and excessive production of monoclonal immunoglobulin M (IgM). The leading clinical features are lymphadenopathy and/or splenomegaly, anemia and hyperviscosity syndrome.1 2. Case report We report a 54-year-old man with a 9-month history of clinically obvious nonfluent aphasia with nonfluent spontaneous speech, agrammatism and phonemic paraphasias. The symptoms developed after the patient was diagnosed with WM but prior to completion of the treatment, including plasmaphereses and chemotherapy. The deficits showed an insidious onset, progressing over several weeks to a clinical syndrome that remained stable thereafter. Upon presentation in our memory disorder clinic he underwent extensive neuropsychological testing, clinical examination and structural imaging with MRI and functional brain imaging with 2-[18F]fluorodeoxy-2-glucose positron emission tomography (FDG-PET). He scored 26 points on the Mini-Mental State Examination2 as a global measure *
Corresponding author. Tel.: +49 351 458 2376; fax: +49 351 458 4324. E-mail address: [email protected] (M. Donix).
of cognitive status. The neuropsychological test battery included tests for different aspects of memory (California Verbal Learning Test [CVLT],3 delayed recall of the ReyOsterrieth-Figure,4 digit span forward and reverse5) as well as for speed of information processing and executive functioning (Trail Making Test A and B6), visuo-constructive abilities (copying the Rey-Osterrieth-figure), word fluency and language (semantic fluency task ‘animals’,4 parts of the Aachen Aphasia Test7). Testing identified severe impairment in both initial letter and category-based verbal fluency and mild impairment in memory (for example, digit span forward score: 7/12, [normative data (mean/SD): 8.0/ 1.73]; reverse score: 6/12, [7.06/1.88]), attention and visuoconstructive abilities (Rey-Osterrieth-figure copying: 34/36. [35.6/0.76]; Rey-Osterrieth-figure recall: 17/36 [18.8/7.37]). Physical and neurological examination was unrevealing. Neither laboratory values nor clinical symptoms supported a hyperviscosity syndrome. Hematologic laboratory values revealed a monoclonal IgM-j-gammopathy, mild anemia, a normal white-cell count with normal differential count, and normal platelets. Analysis of CSF demonstrated a dysfunction of the blood-brain barrier, elevated protein level (457 mg/L; albumin 338 mg/L; IgM: 33.9 mg/L) without additional abnormalities, specifically no signs of cerebral infection. CSF cytology revealed lymphocytosis with abnormal lymphocytoid cells, showing multiple mitoses. There was no past or present history of other vascular risk factors. Color-duplex sonography of the cervical arter-
602
Case reports / Journal of Clinical Neuroscience 14 (2007) 601–603
Fig. 1. Regional glucose metabolism by 2-[18] fluorodeoxy-2-glucose positron emission tomography (lmol/100 g/min). Note significant decrease in left frontal and temporal cortex and left striatal, thalamic and right caudate metabolism as well as crossed cerebellar diaschisis.
ies and transcranial Doppler sonography was unrevealing. Brain MRI showed numerous hyperintense lesions in the centrum semiovale on T2-weighted and FLAIR sequences, left more than right, without signal loss on T1-weighted sequences or signs of general atrophy. FDG-PET demonstrated bilateral and widespread decreases in temporal and frontal metabolism with a significant asymmetry affecting the left more than the right hemisphere. Left subcortical regions including caudate nucleus, putamen and thalamus revealed a significant decrease in metabolism. There was evidence of additionally remote effects in the cerebellum (crossed cerebellar diaschisis), a phenomenon known to occur as a consequence of acute functional interruptions in the contralateral cerebral hemisphere as previously described in stroke (Fig. 1).8
viscosity. CSF analysis excluded infectious diseases of the brain, including meningitis or encephalitis. Structural images showed multiple small microvascular lesions in the centrum semiovale and functional brain imaging revealed large areas of hypometabolism in cortical and subcortical areas. The patient showed no history or presence of vascular risk factors for chronic vascular brain disease, such as hypertension or metabolic diseases and we attributed the patient’s history of alterations in his cognitive abilities to microvascular neoplastic obstructive brain lesions on the basis of Bing-Neel syndrome. Our diagnosis is strengthened by the occurrence of malignant cells in the patient’s CSF. After the diagnosis was made, he was admitted to the Department of Hematology for his next course of chemotherapy.
3. Discussion References The patient presented here is remarkable as he suffered from WM and offered a complex clinical syndrome mimicking progressive nonfluent aphasia.9 Based on clinical evaluation including brain imaging and supported by CSF cytology, cerebral infiltration by malignant cells is the most likely explanation and is known as Bing-Neel syndrome.10 There is a tumoral form with lymphoplasmacytic cells forming a brain lymphoma, usually characterized by focal neurologic defects11 and a diffuse form that is associated with leptomeningeal infiltration12 and or cerebral infarcts due to neoplastic vascular obstruction presenting with nonfocal dysfunctions, such as personality changes or dementia.13 Whereas the tumoral form of Bing-Neel syndrome can be confirmed by stereotactic biopsy, diagnosis of the diffuse form is more difficult. Leptomeningeal infiltration can be undetectable in structural brain imaging (presenting with meningeal gadolinium enhancement)14 and necessitates CSF cytology for malignant lymphoid cells for the diagnosis, that is additionally strengthened by clinical symptoms of behavioral change and/or cognitive decline. The patient presented had no clinical history of a hyperviscosity syndrome, which would present with symptoms of dizziness, fatigue, blurred vision or easy bleeding of mucous membranes and regular laboratory evaluation, since the diagnosis of WM, revealed no changes of blood hyper-
1. Dimopoulos MA, Alexanian R. Waldenstrom’s macroglobulinemia. Blood 1993;83:1452–9. 2. Folstein MF, Folstein SE, McHugh PR. ‘‘Mini-mental state’’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–98. 3. Delis DC, Kramer JH, Kaplan E, et al. California Verbal Learning Test, Adult Version. San Antonio: The Psychological Corporation; 1987. 4. Spreen O, Strauss E. A Compendium of Neuropsychological Tests: Administration, Norms, and Commentary. New York: Oxford University Press; 1998. 5. Wechsler D. Wechsler Memory Scale. 3rd ed. San Antonio: The Psychological Corporation; 1997. 6. Reitan R, Wolfson D. The Halstead-Reitan Neuropsychological Test Battery: Theory and Clinical Interpretation. Tucson: Neuropsychology Press; 1993. 7. Huber W, Poeck K, Willmes K. The Aachen Aphasia Test. Adv Neurol 1984;42:291–303. 8. Baron JC, Bousser MG, Comar D, et al. Noninvasive tomographic study of cerebral blood flow and oxygen metabolism in vivo. Potentials, limitations, and clinical applications in cerebral ischemic disorders. Eur Neurol 1981;20:273–84. 9. Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurol 1998;51:1546–54. 10. Bing J, Neel A. Two cases of hyperglobulinaemia with affection of the central nervous system on a toxi-infection basis. Acta Med Scand 1936;88:492–506. 11. Delgado J, Canales MA, Garcia B, et al. Radiation therapy and combination of cladribine, cyclophosphamide, and prednisone as
Case reports / Journal of Clinical Neuroscience 14 (2007) 603–607 treatment of Bing-Neel syndrome: Case report and review of the literature. Am J Neurol 2002;69:127–31. 12. Bhatti MT, Yuan C, Winter W, et al. Bilateral sixth nerve paresis in the Bing-Neel syndrome. Neurol 2005;64:576–7. 13. Arias M, Pereiro ZI, Requena CI, et al. Rapidly progressing dementia as the presenting symtpom of Waldenstrom’s macroglobulinemia:
603
findings from magnetic resonance imaging of the brain in Bing-Neel syndrome. Rev Neurol 2004;38:640–2. 14. Hug A, Haas J, Storch-Hagenlocher B, et al. Leptomeningeal tumor cell infiltration as first manifestation of an immunocytoma (Waldenstro¨m’s macroglobulinemia). Nervenarzt 2004;75: 1012–5.
doi:10.1016/j.jocn.2006.03.025
Immunohistochemical and ultrastructural abnormalities in muscle from a patient with sensorineural hearing loss related to a 1555 A-to-G mitochondrial mutation Hideaki Kouzaki *, Mikio Suzuki, Takeshi Shimizu Department of Otolaryngology, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu 520 2192, Japan Received 1 February 2005; accepted 14 October 2005
Abstract Genetic studies indicate that hereditary susceptibility of the inner ear to aminoglycoside antibiotic toxicity is caused by a nucleotide 1555 A-to-G mutation in the mitochondrial 12S rRNA gene. Although the phenotype associated with this mutation is nonsyndromic hearing loss, the possibility remains that there could be effects on other tissues that, like the inner ear, contain numerous mitochondria, particularly muscle. We obtained a temporalis muscle specimen from a deaf patient with the A1555G mutation and found informative pathologic features, including mosaic activity of cytochrome c oxidase immunoreactivity and mitochondrial ultrastructure. These findings suggest that mitochondrial dysfunction from the A1555G mutation extends beyond the inner ear. 2006 Elsevier Ltd. All rights reserved. Keywords: Hearing loss; Cytochrome c oxidase; Ragged-red fibre; Mitochondria; Point mutation
1. Introduction Mitochondrial mutations have been reported in association with a variety of multisystem disorders.1 As the primary adenosine 5’-triphosphate (ATP)-generating organelles in mammalian cells, mitochondria produce ATP via oxidative phosphorylation in five respiratory complexes located within the inner mitochondrial membrane.2 Cytochrome c oxidase (COX), complex IV of the respiratory chain, catalyzes transfer of reducing equivalents from cytochrome c to molecular oxygen. Enzyme histochemistry to detect COX activity has proven to be the most reliable light microscopic method for visualization of normal mitochondria and for the diagnosis and interpretation of certain mitochondrial disorders affecting skeletal muscle.3,4 Genetic defects affecting the
*
Corresponding author. Tel.: +81 77 548 2261; fax: +81 77 548 2783. E-mail address: [email protected] (H. Kouzaki).
synthesis of mitochondrial enzymes and proteins can explain how mitochondrial diseases affect multiple organ systems.5 Sensorineural hearing loss (SNHL) in association with a genetic mutation can be classified into syndromic and nonsyndromic deafness, based on whether additional organs are involved. SNHL sometimes appears as one of several symptoms of a mitochondrial disease. For example, approximately half of patients with Kearns-Sayre syndrome (KSS), myoclonus epilepsy associated with ragged-red fibres (MERRF), or mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) have SNHL.6 An A-to-G point mutation at position 1555 in the mitochondrial 12S rRNA gene causes hereditary susceptibility to aminoglycoside antibiotic ototoxicity. Characteristically, this mutation produces nonsyndromic hearing loss.7 Cortopassi and Hutchin8 suspected that sensorineural hearing loss associated with this mutation results from inhibited mitochondrial function within the stria vascularis, compromising the function of Na+/K+ ATPase and disrupting the ion