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Prion-Associated Dilated Cardiomyopathy

Prion-Associated Dilated Cardiomyopathy Creutzfeldt-Jakob disease is a spongiform encephalopathy affecting 1 individual per million population per year. We report on a previously healthy 43-year-old patient who presented with the simultaneous onset of a movement disorder, encephalopathy, cognitive decline, and dilated cardiomyopathy, and was found to have spongiform encephalopathy on brain biopsy. Although her neurological features could be explained by Creutzfeldt-Jakob disease, the etiology of the dilated cardiomyopathy could not be established. Finally, special staining of the endomyocardial biopsy specimen revealed the presence of abnormal prion, possibly infectious scrapie prion. As an exhaustive search for familial, ischemic, infectious, autoimmune, toxic, and metabolic causes of dilated cardiomyopathy was unrevealing, the presence of abnormal prion in the cardiac muscle suggested the possibility of prion-induced dilated cardiomyopathy in our patient.Creutzfeldt-Jakob disease (CJD) is a spongiform encephalopathy affecting 1 individual per million population per year. We report on a patient with CJD who had dilated cardiomyopathy associated with an accumulation of abnormally folded prion protein in the heart muscle. To our knowledge, this is the first reported case of this association.REPORT OF A CASEA 43-year-old female dance instructor with no significant medical history presented with symptoms of ataxia, impaired mentation, myoclonic jerks, dyspnea, and a 13.5-kg weight gain, all of which started simultaneously and gradually worsened over 6 months. There was no family history of similar problems, sudden death, or dilated cardiomyopathy (DCM). On examination she was confused and had difficulty with short-term memory and episodic athetotic movements of the hands and legs. Laboratory test results showed serum levels of lactate dehydrogenase of 526 U/L (normal range, 97-190 U/L), aspartate aminotransferase of 269 U/L (normal range, 15-38 U/L), alanine aminotransferase of 307 U/L (normal range, 5-37 U/L), and total bilirubin of 1.5 mg/dL (26 mmol/L) (normal range, 0.2-1.3 mg/dL [3-22 μmol/L]). Complete blood cell count, serum electrolyte and creatinine levels, erythrocyte sedimentation rate, and serum urea nitrogen levels were within normal limits. Human immunodeficiency virus serologic results, along with serologic results for hepatitis A, B, and C, were negative. Results of cerebrospinal fluid studies were normal. A chest radiograph revealed cardiomegaly and a right-sided pleural effusion. An echocardiogram showed severe left ventricular dilation with markedly diminished systolic function and a mildly dilated right ventricle. Cardiac catheterization revealed normal coronary arteries with diffuse hypokinesis and an ejection fraction of 20% to 25%. At 1352 pg/mL (998 pmol/L), the serum level of vitamin B12 was elevated (normal range, 180-914 pg/mL [133-674 pmol/L]). Imaging studies of the brain and an electroencephalogram were read as normal. Serum levels of ceruloplasmin, thyroid-stimulating hormone, angiotensin converting enzyme, antinuclear antibodies, antistreptolysin antibodies, and vitamin E were normal, as well as blood levels of lactate, pyruvate, and carnitine. The results of a heavy metal screen and a 24-hour urine copper test were also normal. A search for known causes of DCM was unrevealing. Because of the patient’s progressive cardiac and neurologic deterioration, an endomyocardial biopsy was performed. It showed subendocardial fibrosis but was nondiagnostic. Special stainings for amyloid and iron deposition were negative. Findings of repeated imaging studies of the brain and electroencephalograms were normal. A brain biopsy revealed diffuse vacuolar change in the gray matter neurophils but not in the white matter neurophils as well as spongiform cortical changes consistent with CJD. Findings of subsequent cerebrospinal studies were positive for protein 14-3-3, which has been suggested to be specific for CJD.The patient’s poor condition was discussed with her family and she was transferred to a hospice facility.Unstained tissue sections of the endomyocardial biopsy specimen were sent to an outside neuropathology laboratory to test for abnormal prion protein (PrP) accumulation. Normal cellular PrPs (PrPc) have the same amino acid building blocks as the abnormal scrapie PrPs (PrPSc) but the amino acids in PrPScare folded differently, into looser β-sheets instead of tight α-helicoidal structures. Immunohistochemistry studies were performed using the PrP-specific 3F4 monoclonal antibody.No immunostaining of cardiac muscle or peripheral nerve occurred (Figure 1), suggesting an absence of PrPc. Pretreatment of the section with formic acid was then performed, followed by autoclaving in a citrate buffer to expose the 3F4 epitope and look for PrPSc. After pretreatment a weak, diffuse staining and a more intense punctate staining of cardiac muscle fibers were noticed (Figure 2), which was consistent with the presence of abnormally folded prion proteins—possibly PrPSc—in the cardiac tissue. In addition, strong linear immunostaining, which appeared to be adjacent to some of the muscle fibers, suggested immunostaining of peripheral nerve twigs.Figure 1.Endomyocardial biopsy specimen before pretreatment, showing an absence of normal prion protein.Figure 2.Endomyocardial biopsy specimen after pretreatment with formic acid followed by autoclaving, showing diffuse and punctate staining of abnormal prion proteins. Linear staining adjacent to the fibers may represent immunostaining of peripheral nerves (arrow).As an exhaustive search for familial ischemic, infectious, autoimmune, toxic, and metabolic causes of DCM was unrevealing, the presence of abnormal PrPs in the cardiac muscle suggested the possibility of prion-induced DCM in our patient.COMMENTCreutzfeldt-Jakob disease was first described by H. G. Creutzfeldtand A. M. Jakobin 1920 and 1921, respectively. It can be classic CJD, which can be sporadic, familial, iatrogenic, or variant CJD (vCJD), the latter being associated with the bovine spongiform encephalopathy epidemic in Great Britain and Europe.Our patient presented with the clinical triad of dementia, akinetic mutism, and myoclonus, which is considered typical of classic CJD.Typical signs begin with loss of memory or confusion, behavioral aberrations, and gait instability.At autopsy, microscopic sections exhibit widespread spongiform changes accompanied by gliosis and neuronal loss, while immunochemical staining reveals numerous protease-resistant PrPs.The definitive diagnosis is usually made by cerebral biopsy,as in our patient. The presentation of vCJD differs from that of classic CJD with younger age of onset, psychiatric symptoms, and different neuropathologic changes.The disease in our patient was most likely sporadic, as she had no history of using pituitary hormones and no family history of CJD, and her presentation was not suggestive of vCJD.High concentrations of infectious PrPSchave been reported in certain skeletal muscle groups after injecting infective material from hamsters into miceand also in skeletal muscles and spleen at autopsy in patients with established CJD.Mutant PrP in intermediate concentrations has been reported in the skeletal muscles, heart, testes, and, in low concentrations, in the kidneys, lungs, spleen, intestines, and stomach of transgenic mice expressing the mouse PrP homologue of the CJD mutation.Western blot analysis did not detect PrPScin the cardiac muscle of 3 patients with vCJDand there have been no reports of cardiac muscle involvement in classic CJD or scrapie. Our patient had a simultaneous onset of a movement disorder, encephalopathy, cognitive decline, and dilated cardiomyopathy. Although all the other features could be explained by CJD, the etiology of the DCM could not be established. The finding of abnormal PrPs, possibly infectious PrPSc, in the endomyocardial biopsy specimen suggests that the DCM in our patient could have been secondary to infection by the prion causing CJD.CONCLUSIONSIn conclusion, the simultaneous and rapid cardiac and neurologic decline over a few months in a patient with CJD, combined with the presence of abnormally folded PrPs in the cardiac tissue, suggests an association between PrPScand DCM. The presence of abnormal PrP in the cardiac muscle raises important questions. First, was this PrP infectious PrPSc, and, if so, can endocardial biopsy be a way of diagnosing CJD instead of carrying out the much more invasive brain biopsy? Second, until further confirmatory studies are available, because of a possible cardiac muscle infection in patients with CJD, safe handling of cardiac muscle in these patients should probably be recommended. Finally, could CJD be a multisystem disease?Correspondence:Mahi Lakshmi Ashwath, MD, 11477 Mayfield Rd, Apt 318, Cleveland, OH 44106.Accepted for Publication:August 17, 2004.Previous Presentation:This study was presented as a clinical vignette at the American College of Physicians–American Society of Internal Medicine (Georgia chapter); March 26-28, 2004; Savannah, Ga.REFERENCESDAMillerRAVittiMMMaslackThe role of 99m-Tc HMPAO SPECT in the diagnosis of Creutzfeldt-Jacob disease.AJNR Am J Neuroradiol1998194544559541298GHsichKKenneyCJGibbsThe 14-3-3 brain protein in cerebrospinal fluid as a marker for transmissible spongiform encephalopathies.N Engl J Med19963359249308782499IZerrMBodemerOGefellerDetection of 14-3-3 in the cerebrospinal fluid supports the diagnosis of Creutzfeldt-Jakob disease.Ann Neurol19984332409450766RJKascsakRRubensteinPAMerzMouse polyclonal and monoclonal antibody to scrapie-associated fibril proteins.J Virol198761368836932446004HGCreutzfeldtÜber eine eigenartige herdförmige Erkrankung des Zentralnervensystems.In: Nissl F, Alzheimer A, eds. Histologische und Histopathologische Arbeiten über die Grosshirnrinde. Jena, Germany: Gustav Fischer; 1921:1-48AJakobÜber eigenartige Erkrankungen des Zentralnervensystems mit bemerkenwerten anatomischem Befunde (spastische Pseudosklerose Encephalo-myelopathie mit disseminierten Degenerationsherden).Dtsch Z Nervenheilkd192170132146NPedersenESmithPrion diseases: epidemiology in man.APMIS2002110142212064251RDAdamsMVictorPrinciples of Neurology.2nd ed. New York, NY: McGraw-Hill Books Co; 1981LFishbeinTransmissible spongiform encephalopathies, hypotheses and food safety: an overview.Sci Total Environ199821771829695172HAKretzschmarJWIronsideSJDeArmondJTateishiDiagnostic criteria for sporadic Creutzfeldt-Jakob disease.Arch Neurol1996539139208815857PBosqueCRyouGTellingPrions in skeletal muscle.Proc Natl Acad Sci U S A2002993812381711904434MGlatzelEAbelaMMaissenAAguzziExtraneural pathologic prion protein in sporadic Creutzfeldt-Jakob disease.N Engl J Med20033491812182014602879RChiesaAPestronkRESchmidtPrimary myopathy and accumulation of PrPSc-like molecules in peripheral tissues of transgenic mice expressing a prion protein insertional mutation.Neurobiol Dis2001827928811300723JDWadsworthSJoinerAFHillTissue distribution of protease resistant prion protein in variant Creutzfeldt-Jakob disease using a highly sensitive immunoblotting assay.Lancet200135817118011476832 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Internal Medicine American Medical Association

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American Medical Association
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Copyright 2005 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
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2168-6106
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2168-6114
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10.1001/archinte.165.3.338
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15710800
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Abstract

Creutzfeldt-Jakob disease is a spongiform encephalopathy affecting 1 individual per million population per year. We report on a previously healthy 43-year-old patient who presented with the simultaneous onset of a movement disorder, encephalopathy, cognitive decline, and dilated cardiomyopathy, and was found to have spongiform encephalopathy on brain biopsy. Although her neurological features could be explained by Creutzfeldt-Jakob disease, the etiology of the dilated cardiomyopathy could not be established. Finally, special staining of the endomyocardial biopsy specimen revealed the presence of abnormal prion, possibly infectious scrapie prion. As an exhaustive search for familial, ischemic, infectious, autoimmune, toxic, and metabolic causes of dilated cardiomyopathy was unrevealing, the presence of abnormal prion in the cardiac muscle suggested the possibility of prion-induced dilated cardiomyopathy in our patient.Creutzfeldt-Jakob disease (CJD) is a spongiform encephalopathy affecting 1 individual per million population per year. We report on a patient with CJD who had dilated cardiomyopathy associated with an accumulation of abnormally folded prion protein in the heart muscle. To our knowledge, this is the first reported case of this association.REPORT OF A CASEA 43-year-old female dance instructor with no significant medical history presented with symptoms of ataxia, impaired mentation, myoclonic jerks, dyspnea, and a 13.5-kg weight gain, all of which started simultaneously and gradually worsened over 6 months. There was no family history of similar problems, sudden death, or dilated cardiomyopathy (DCM). On examination she was confused and had difficulty with short-term memory and episodic athetotic movements of the hands and legs. Laboratory test results showed serum levels of lactate dehydrogenase of 526 U/L (normal range, 97-190 U/L), aspartate aminotransferase of 269 U/L (normal range, 15-38 U/L), alanine aminotransferase of 307 U/L (normal range, 5-37 U/L), and total bilirubin of 1.5 mg/dL (26 mmol/L) (normal range, 0.2-1.3 mg/dL [3-22 μmol/L]). Complete blood cell count, serum electrolyte and creatinine levels, erythrocyte sedimentation rate, and serum urea nitrogen levels were within normal limits. Human immunodeficiency virus serologic results, along with serologic results for hepatitis A, B, and C, were negative. Results of cerebrospinal fluid studies were normal. A chest radiograph revealed cardiomegaly and a right-sided pleural effusion. An echocardiogram showed severe left ventricular dilation with markedly diminished systolic function and a mildly dilated right ventricle. Cardiac catheterization revealed normal coronary arteries with diffuse hypokinesis and an ejection fraction of 20% to 25%. At 1352 pg/mL (998 pmol/L), the serum level of vitamin B12 was elevated (normal range, 180-914 pg/mL [133-674 pmol/L]). Imaging studies of the brain and an electroencephalogram were read as normal. Serum levels of ceruloplasmin, thyroid-stimulating hormone, angiotensin converting enzyme, antinuclear antibodies, antistreptolysin antibodies, and vitamin E were normal, as well as blood levels of lactate, pyruvate, and carnitine. The results of a heavy metal screen and a 24-hour urine copper test were also normal. A search for known causes of DCM was unrevealing. Because of the patient’s progressive cardiac and neurologic deterioration, an endomyocardial biopsy was performed. It showed subendocardial fibrosis but was nondiagnostic. Special stainings for amyloid and iron deposition were negative. Findings of repeated imaging studies of the brain and electroencephalograms were normal. A brain biopsy revealed diffuse vacuolar change in the gray matter neurophils but not in the white matter neurophils as well as spongiform cortical changes consistent with CJD. Findings of subsequent cerebrospinal studies were positive for protein 14-3-3, which has been suggested to be specific for CJD.The patient’s poor condition was discussed with her family and she was transferred to a hospice facility.Unstained tissue sections of the endomyocardial biopsy specimen were sent to an outside neuropathology laboratory to test for abnormal prion protein (PrP) accumulation. Normal cellular PrPs (PrPc) have the same amino acid building blocks as the abnormal scrapie PrPs (PrPSc) but the amino acids in PrPScare folded differently, into looser β-sheets instead of tight α-helicoidal structures. Immunohistochemistry studies were performed using the PrP-specific 3F4 monoclonal antibody.No immunostaining of cardiac muscle or peripheral nerve occurred (Figure 1), suggesting an absence of PrPc. Pretreatment of the section with formic acid was then performed, followed by autoclaving in a citrate buffer to expose the 3F4 epitope and look for PrPSc. After pretreatment a weak, diffuse staining and a more intense punctate staining of cardiac muscle fibers were noticed (Figure 2), which was consistent with the presence of abnormally folded prion proteins—possibly PrPSc—in the cardiac tissue. In addition, strong linear immunostaining, which appeared to be adjacent to some of the muscle fibers, suggested immunostaining of peripheral nerve twigs.Figure 1.Endomyocardial biopsy specimen before pretreatment, showing an absence of normal prion protein.Figure 2.Endomyocardial biopsy specimen after pretreatment with formic acid followed by autoclaving, showing diffuse and punctate staining of abnormal prion proteins. Linear staining adjacent to the fibers may represent immunostaining of peripheral nerves (arrow).As an exhaustive search for familial ischemic, infectious, autoimmune, toxic, and metabolic causes of DCM was unrevealing, the presence of abnormal PrPs in the cardiac muscle suggested the possibility of prion-induced DCM in our patient.COMMENTCreutzfeldt-Jakob disease was first described by H. G. Creutzfeldtand A. M. Jakobin 1920 and 1921, respectively. It can be classic CJD, which can be sporadic, familial, iatrogenic, or variant CJD (vCJD), the latter being associated with the bovine spongiform encephalopathy epidemic in Great Britain and Europe.Our patient presented with the clinical triad of dementia, akinetic mutism, and myoclonus, which is considered typical of classic CJD.Typical signs begin with loss of memory or confusion, behavioral aberrations, and gait instability.At autopsy, microscopic sections exhibit widespread spongiform changes accompanied by gliosis and neuronal loss, while immunochemical staining reveals numerous protease-resistant PrPs.The definitive diagnosis is usually made by cerebral biopsy,as in our patient. The presentation of vCJD differs from that of classic CJD with younger age of onset, psychiatric symptoms, and different neuropathologic changes.The disease in our patient was most likely sporadic, as she had no history of using pituitary hormones and no family history of CJD, and her presentation was not suggestive of vCJD.High concentrations of infectious PrPSchave been reported in certain skeletal muscle groups after injecting infective material from hamsters into miceand also in skeletal muscles and spleen at autopsy in patients with established CJD.Mutant PrP in intermediate concentrations has been reported in the skeletal muscles, heart, testes, and, in low concentrations, in the kidneys, lungs, spleen, intestines, and stomach of transgenic mice expressing the mouse PrP homologue of the CJD mutation.Western blot analysis did not detect PrPScin the cardiac muscle of 3 patients with vCJDand there have been no reports of cardiac muscle involvement in classic CJD or scrapie. Our patient had a simultaneous onset of a movement disorder, encephalopathy, cognitive decline, and dilated cardiomyopathy. Although all the other features could be explained by CJD, the etiology of the DCM could not be established. The finding of abnormal PrPs, possibly infectious PrPSc, in the endomyocardial biopsy specimen suggests that the DCM in our patient could have been secondary to infection by the prion causing CJD.CONCLUSIONSIn conclusion, the simultaneous and rapid cardiac and neurologic decline over a few months in a patient with CJD, combined with the presence of abnormally folded PrPs in the cardiac tissue, suggests an association between PrPScand DCM. The presence of abnormal PrP in the cardiac muscle raises important questions. First, was this PrP infectious PrPSc, and, if so, can endocardial biopsy be a way of diagnosing CJD instead of carrying out the much more invasive brain biopsy? Second, until further confirmatory studies are available, because of a possible cardiac muscle infection in patients with CJD, safe handling of cardiac muscle in these patients should probably be recommended. Finally, could CJD be a multisystem disease?Correspondence:Mahi Lakshmi Ashwath, MD, 11477 Mayfield Rd, Apt 318, Cleveland, OH 44106.Accepted for Publication:August 17, 2004.Previous Presentation:This study was presented as a clinical vignette at the American College of Physicians–American Society of Internal Medicine (Georgia chapter); March 26-28, 2004; Savannah, Ga.REFERENCESDAMillerRAVittiMMMaslackThe role of 99m-Tc HMPAO SPECT in the diagnosis of Creutzfeldt-Jacob disease.AJNR Am J Neuroradiol1998194544559541298GHsichKKenneyCJGibbsThe 14-3-3 brain protein in cerebrospinal fluid as a marker for transmissible spongiform encephalopathies.N Engl J Med19963359249308782499IZerrMBodemerOGefellerDetection of 14-3-3 in the cerebrospinal fluid supports the diagnosis of Creutzfeldt-Jakob disease.Ann Neurol19984332409450766RJKascsakRRubensteinPAMerzMouse polyclonal and monoclonal antibody to scrapie-associated fibril proteins.J Virol198761368836932446004HGCreutzfeldtÜber eine eigenartige herdförmige Erkrankung des Zentralnervensystems.In: Nissl F, Alzheimer A, eds. Histologische und Histopathologische Arbeiten über die Grosshirnrinde. Jena, Germany: Gustav Fischer; 1921:1-48AJakobÜber eigenartige Erkrankungen des Zentralnervensystems mit bemerkenwerten anatomischem Befunde (spastische Pseudosklerose Encephalo-myelopathie mit disseminierten Degenerationsherden).Dtsch Z Nervenheilkd192170132146NPedersenESmithPrion diseases: epidemiology in man.APMIS2002110142212064251RDAdamsMVictorPrinciples of Neurology.2nd ed. New York, NY: McGraw-Hill Books Co; 1981LFishbeinTransmissible spongiform encephalopathies, hypotheses and food safety: an overview.Sci Total Environ199821771829695172HAKretzschmarJWIronsideSJDeArmondJTateishiDiagnostic criteria for sporadic Creutzfeldt-Jakob disease.Arch Neurol1996539139208815857PBosqueCRyouGTellingPrions in skeletal muscle.Proc Natl Acad Sci U S A2002993812381711904434MGlatzelEAbelaMMaissenAAguzziExtraneural pathologic prion protein in sporadic Creutzfeldt-Jakob disease.N Engl J Med20033491812182014602879RChiesaAPestronkRESchmidtPrimary myopathy and accumulation of PrPSc-like molecules in peripheral tissues of transgenic mice expressing a prion protein insertional mutation.Neurobiol Dis2001827928811300723JDWadsworthSJoinerAFHillTissue distribution of protease resistant prion protein in variant Creutzfeldt-Jakob disease using a highly sensitive immunoblotting assay.Lancet200135817118011476832

Journal

JAMA Internal MedicineAmerican Medical Association

Published: Feb 14, 2005

References