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Cardiovascular pathologies in mucopolysaccharidosis type VII (Sly Syndrome)
Cardiovascular Pathology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Cardiovascular Pathology
Case Report
Cardiovascular pathologies in mucopolysaccharidosis type VII (Sly Syndrome) Thomas J. Gniadek a, Nicole Singer a, Norman J. Barker a, Philip J. Spevak b, Barbara J. Crain a, David Valle c, Marc K. Halushka a,⁎ a b c
Department of Pathology, Johns Hopkins Hospital, Baltimore, MD 21205, USA Department of Pediatrics, Division of Cardiology, Johns Hopkins Hospital, Baltimore, MD 21205, USA Department of Medicine, Institute of Genetic Medicine, Johns Hopkins Hospital, Baltimore, MD 21205, USA
a r t i c l e
i n f o
Article history: Received 9 January 2015 Received in revised form 5 May 2015 Accepted 15 June 2015 Available online xxxx Keywords: Mucopolysaccharidosis Sly Syndrome Autopsy
a b s t r a c t We present the cardiac findings from the autopsy of a 28-year-old male with mucopolysaccharidosis VII (MPS VII), also known as Sly Syndrome, whose diagnosis was confirmed by biochemical testing. The patient died a sudden cardiac death. Autopsy showed thickened and stenotic aortic valve leaflets as well as marked concentric intimal thickening of the aorta and muscular arteries. There was left ventricular hypertrophy as well as mild papillary muscle thickening and fusion. Increased colloid iron staining was seen in the smalland medium-sized arteries of the heart and at the intercalated discs. We discuss the patient's premortem echocardiographic and electrocardiographic studies. In addition, we discuss the pathogenesis of MPS VII and review previous literature on its anatomic and pathologic features. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Mucopolysaccharidosis (MPS) type VII (Sly Syndrome; OMIM #253220) was first characterized in 1973 as a rare lysosomal storage disease [1]. MPS VII is an autosomal recessive disease caused by a deficiency in the enzymatic activity of beta-glucuronidase. Lack of this enzyme causes a buildup of chondroitin sulfate, dermatan sulfate, and heparan sulfate, all of which are mucopolysaccharides (glucosaminoglycans, GAG) containing glucuronic acid. At least 49 disease-causing mutations involving the beta-glucuronidase gene have been identified. Most of these mutations are missense mutations, but nonsense mutations, deletions, and splice-site mutations have also been described. Due to the genetic heterogeneity of the disease-causing mutations, a diagnosis must be made with an enzymatic activity assay rather than nucleic acid sequencing [2]. The clinical presentation of MPS VII is variable. Patients can present early with fetal hydrops, while those who survive into adulthood exhibit coarse facial features, corneal opacities, skeletal deformities, cognitive impairment, and cardiac abnormalities [2]. In addition, patients can develop progressive hearing loss and decreased speech production [3]. Reports of the cardiac abnormalities found in patients with MPS VII are limited, but include cardiac valve thickening and valve dysfunction [4]. Only one prior autopsy report of the findings
Sources of support: none. Funding: MKH is supported by the American Heart Association 13GRNT16420015. ⁎ Corresponding author at: Ross Rm 632L, 720 Rutland Avenue, Baltimore, MD 212805. Tel.: +1-410-614-8138; fax: +1-410-502-5862. E-mail address: [email protected] (M.K. Halushka).
associated with MPS VII in an adult has been published. This report contained limited information on cardiovascular findings but did describe nodular thickening of the four cardiac valves and arterial stenosis [5]. Cardiac disease is common in MPS patients, and cardiac findings associated with MPS I–VI have been relatively well reported. MPSassociated cardiac valve disease manifests as generalized thickening of the valve leaflets in addition to short, thickened chordae. Myocardial hypertrophy has been reported secondary to cardiac valve stenosis, with valvular regurgitation also being described. Sudden cardiac death, likely secondary to arrhythmia, is common in MPS. MPS I, II, and VI are most strongly associated with cardiac disease, while MPS III and IV do not cause dermatan sulfate accumulation and have a lower frequency of cardiac involvement. MPS I and II are associated with large artery thickening and diffuse concentric intimal proliferation in addition to narrowing of the aortic isthmus and subsequent systemic hypertension [4]. We recently performed an autopsy on an individual who suffered from MPS VII (Sly Syndrome) and provide the first extensive analysis of the cardiovascular pathologies in this syndrome.
2. Case presentation At the time of his death, this 28-year-old male lived under the care of his parents. His past medical history was notable for a diagnosis of MPS VII, confirmed by beta-glucuronidase enzyme activity at 3% of normal (Kennedy Krieger Institute Biochemistry Lab, Baltimore MD) over 20 years earlier. A decade prior to his death, he underwent scoliosis repair surgery that was complicated by paraplegia, subsequently he became wheelchair bound. Around this time, he developed progressively
http://dx.doi.org/10.1016/j.carpath.2015.06.001 1054-8807/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Gniadek TJ, et al, Cardiovascular pathologies in mucopolysaccharidosis type VII (Sly Syndrome), Cardiovasc Pathol (2015), http://dx.doi.org/10.1016/j.carpath.2015.06.001
2
T.J. Gniadek et al. / Cardiovascular Pathology xxx (2015) xxx–xxx
declining mental status, eventually becoming non-conversant. He was able to feed himself with assistance. His most recent echocardiogram (approximately 7 years before his death) showed a thickened aortic valve with a peak aortic gradient of 45 mmHg and a mean gradient of 22 mmHg, suggesting aortic stenosis. The echocardiogram also identified mild aortic valve regurgitation and qualitatively normal left ventricular systolic function. At that time, an electrocardiogram (EKG) demonstrated bilateral ventricular enlargement, incomplete right bundle branch block and a nonspecific ST
abnormality. He had no additional cardiac follow-up and no known cardiovascular symptomatology. Without any acute change in his baseline status, he went to sleep and was found pulseless the next morning. Autopsy revealed an enlarged heart weighing 484 g (reference range, 182–390 g) with mild four-chamber dilation. The left ventricular free wall, septum, and right ventricular free wall were 1.8, 1.9, and 0.3 cm, respectively. The four cardiac valves had reduced circumference. The valve circumferences were: tricuspid 8.5 cm (reference range, 10–12.5 cm); pulmonic 4.3 cm (reference range, 7–9 cm); mitral 6 cm
Fig. 1. Cardiac Valves. The pulmonic (A–B), tricuspid (C–D), aortic (E–F), and mitral (G–H) valves were thickened and fibrotic. The pulmonic valves appeared least nodular, while the aortic valve was most significantly nodular. The areas of nodularity contained extracellular amorphous ground substance in the aortic valve as well as focal calcification (F). Balloon cells, consistent with accumulated GAG, were seen microscopically in areas of fibrosis. There was moderate thickening and fusion of the chordae, most prominently on the mitral valve (G). Microscopy images are shown at 40× magnification.
Please cite this article as: Gniadek TJ, et al, Cardiovascular pathologies in mucopolysaccharidosis type VII (Sly Syndrome), Cardiovasc Pathol (2015), http://dx.doi.org/10.1016/j.carpath.2015.06.001
T.J. Gniadek et al. / Cardiovascular Pathology xxx (2015) xxx–xxx
(reference range, 8–10.5 cm); and aortic 3.5 cm (reference range, 6–7.5 cm). All the valves were thickened and fibrotic. Both the mitral and tricuspid valves demonstrated moderate chordal fusion, sclerosis, and nodular thickening of the valve leaflets. The aortic valve was severely stenotic with a fixed valve orifice diameter of ~0.4 cm. Each cusp of the aortic valve was several millimeters thick with an uneven but generally smooth surface with thickened but flexible valve leaflets. In both atria, the endocardium was smooth, pearly white, and modestly thickened. Histologically, the myocardium showed fibroelastosis (Movat Pentachrome stain). All of the valves displayed amorphous ground substance, balloon cell change, and increased colloid iron staining consistent with an intracellular collection of GAG. Minimal calcifications were noted predominately in the aortic valve (Fig. 1). The coronary arteries followed a normal anatomic course with a right dominant circulation. Grossly, the coronary arteries showed diffuse concentric narrowing with over 75% stenosis of the left anterior descending artery, 50–75% stenosis of the circumflex artery, and greater than 75% stenosis of the right coronary artery. Histologically, there was a marked concentric intimal expansion of distended mesenchymal cells and increased extracellular matrix. The vascular smooth muscle cells of the media layer showed strong diffuse colloid iron staining, consistent with GAG accumulation, and increased extracellular matrix (Masson's Trichrome stain). CD68 immunohistochemistry labeled
3
numerous cells within the coronary arterial wall, although a frank arteritis was not noted (Fig. 2). Mild, patchy interstitial fibrosis and perivascular fibrosis were present in the myocardium of the left ventricle. Intracardiac small- and medium-sized arteries showed increased colloid iron staining, consistent with GAG within endothelial and smooth muscle cells. The cardiomyocytes showed no increase in intracellular GAG; however, colloid iron showed mildly increased staining at the intercalated discs relative to a control heart (Fig. 3). The ascending aorta was of appropriate caliber with marked thickening throughout. There was minimal atherosclerosis in the abdominal aorta and in the aortic arch. Histologically, there was diffuse colloidal iron staining consistent with GAG accumulation in the endothelial and smooth muscle cells of the aorta. In addition, there was increased fibrosis, medial elastic lamina disruption, and extracellular amorphous ground substance. The large muscular arteries appeared thickened throughout the body, including the basilar artery at the base of the brain and the great vessels off the aortic arch. CD68 immunohistochemistry stain labeled scattered cells within the aortic wall (Fig. 4). The vena cava and other major veins were patent and thin walled. Additional mucopolysaccharide accumulations were noted in the cartilage, trachea, central nervous system, corneal stroma, and scleral stroma. The cause of death was reported as sudden cardiac death
Fig. 2. Right coronary artery. (A)The right coronary artery was representative of all of the coronary arteries and showed diffuse concentric narrowing; (B) There was intimal expansion consisting of an increase in the extracellular matrix and distended balloon cells; (C) Masson's Trichrome stain showed increased extracellular matrix within the media layer and surrounding vascular smooth muscle cells; (D) CD68 immunohistochemistry-labeled scattered cells within the coronary artery wall; (E) Colloid iron stain showed diffuse strong staining throughout the coronary artery wall, including the vascular smooth muscle cells within the media layer.
Please cite this article as: Gniadek TJ, et al, Cardiovascular pathologies in mucopolysaccharidosis type VII (Sly Syndrome), Cardiovasc Pathol (2015), http://dx.doi.org/10.1016/j.carpath.2015.06.001
4
T.J. Gniadek et al. / Cardiovascular Pathology xxx (2015) xxx–xxx
Fig. 3. Myocardium. Colloid iron stain showed increased staining at the intercalated disc in MPS VII (A) compared to staining from an unaffected control (B). In addition, intracardiac arterioles showed a transmural increase in colloid iron staining in MPS VII (C) compared to the same unaffected control (D).
Fig. 4. Aorta. (A) The aorta was generally thickened (H&E, magnification ×10) with (B) scattered CD68 positive cells within the media layer (10×) and (C) an especially thickened intimal layer (Masson's Trichrome, 10×). (D) High power (240×) view of the media-demonstrated balloon cells (H&E) and (E) scattered CD68 positive cells (100×). (F) Masson's Trichrome (240×) and (G) Millers Elastic (240×) stains demonstrated a disrupted medial elastic lamina. (H) Colloid iron stain (100×) showed increased smooth muscle cell staining relative to an (I) unaffected control (100×).
Please cite this article as: Gniadek TJ, et al, Cardiovascular pathologies in mucopolysaccharidosis type VII (Sly Syndrome), Cardiovasc Pathol (2015), http://dx.doi.org/10.1016/j.carpath.2015.06.001
T.J. Gniadek et al. / Cardiovascular Pathology xxx (2015) xxx–xxx
secondary to left ventricular hypertrophy as a consequence of aortic valve stenosis due to MPS VII. 3. Summary This is the first extensive report of the gross and histopathologic cardiovascular findings in MPS VII (Sly Syndrome). We found changes that are consistent with, but expand on, the original description of Sly Syndrome and appear to be typical of other mucopolysaccharidoses [1,2,4]. The involvement of the coronary arteries and coronary arterioles suggests a combination of the features seen in MPS I and II (large artery thickening with intimal proliferation) as well as MPS VI (coronary arteriole intimal proliferation). Studies on murine, canine, and feline animal models of MPS VII have many of the cardiac findings reported in humans, including thickening of the cardiac valves and arterial walls. These studies suggested that some pathologic changes may be due to the protease-induced degradation of elastin, in addition to the aberrant build up of mucopolysaccharide [4]. An increase in CD68 positive cells away from accumulated GAG and disorganization/disruption of the aortic elastic lamina may hint at such a mechanism. Most importantly, our autopsy findings suggest that these animal models are consistent with the cardiovascular changes seen in human MPS VII.
5
In summary, this patient suffered from marked cardiac valvular and coronary artery disease secondary to GAG accumulation. The autopsy findings support the hypothesis that cardiac symptomatology in MPS VII is likely secondary to valvular pathology where the risk for ischemia is increased. It is not known whether an increase in mucopolysaccharide at the intercalated disc is also arrhythmogenic. However, this is the third report of a patient with MPS VII having a sudden cardiac death event.
References [1] Sly WS, Quinton BA, McAlister WH, Rimoin DL. Beta glucuronidase deficiency: report of clinical, radiologic and biochemical features of a new mucopolysaccharidosis. J Pediatr 1973;82(2):249–57. [2] Coutinho MF, Lacerda L, Alves S. Glycosaminoglycan storage disorders: a review. Biochem Res Int 2012:471325. [3] Wallace SP, Prutting CA, Gerber SE. Degeneration of speech, language, and hearing in a patient with mucopolysaccharidosis VII. Int J Pediatr Otorhinolaryngol 1990;19(2): 97–107. [4] Braunlin EA, Harmatz PR, Scarpa M, Furlanetto B, Kampmann C, Loehr JP, et al. Cardiac disease in patients with mucopolysaccharidosis: presentation, diagnosis and management. J Inherit Metab Dis 2011;34(6):1183–97. [5] Vogler C, Levy B, Kyle JW, Sly WS, Williamson J, Whyte MP. Mucopolysaccharidosis VII: postmortem biochemical and pathological findings in a young adult with betaglucuronidase deficiency. Mod Pathol 1994;7(1):132–7.
Please cite this article as: Gniadek TJ, et al, Cardiovascular pathologies in mucopolysaccharidosis type VII (Sly Syndrome), Cardiovasc Pathol (2015), http://dx.doi.org/10.1016/j.carpath.2015.06.001
Contents lists available at ScienceDirect
Cardiovascular Pathology
Case Report
Cardiovascular pathologies in mucopolysaccharidosis type VII (Sly Syndrome) Thomas J. Gniadek a, Nicole Singer a, Norman J. Barker a, Philip J. Spevak b, Barbara J. Crain a, David Valle c, Marc K. Halushka a,⁎ a b c
Department of Pathology, Johns Hopkins Hospital, Baltimore, MD 21205, USA Department of Pediatrics, Division of Cardiology, Johns Hopkins Hospital, Baltimore, MD 21205, USA Department of Medicine, Institute of Genetic Medicine, Johns Hopkins Hospital, Baltimore, MD 21205, USA
a r t i c l e
i n f o
Article history: Received 9 January 2015 Received in revised form 5 May 2015 Accepted 15 June 2015 Available online xxxx Keywords: Mucopolysaccharidosis Sly Syndrome Autopsy
a b s t r a c t We present the cardiac findings from the autopsy of a 28-year-old male with mucopolysaccharidosis VII (MPS VII), also known as Sly Syndrome, whose diagnosis was confirmed by biochemical testing. The patient died a sudden cardiac death. Autopsy showed thickened and stenotic aortic valve leaflets as well as marked concentric intimal thickening of the aorta and muscular arteries. There was left ventricular hypertrophy as well as mild papillary muscle thickening and fusion. Increased colloid iron staining was seen in the smalland medium-sized arteries of the heart and at the intercalated discs. We discuss the patient's premortem echocardiographic and electrocardiographic studies. In addition, we discuss the pathogenesis of MPS VII and review previous literature on its anatomic and pathologic features. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Mucopolysaccharidosis (MPS) type VII (Sly Syndrome; OMIM #253220) was first characterized in 1973 as a rare lysosomal storage disease [1]. MPS VII is an autosomal recessive disease caused by a deficiency in the enzymatic activity of beta-glucuronidase. Lack of this enzyme causes a buildup of chondroitin sulfate, dermatan sulfate, and heparan sulfate, all of which are mucopolysaccharides (glucosaminoglycans, GAG) containing glucuronic acid. At least 49 disease-causing mutations involving the beta-glucuronidase gene have been identified. Most of these mutations are missense mutations, but nonsense mutations, deletions, and splice-site mutations have also been described. Due to the genetic heterogeneity of the disease-causing mutations, a diagnosis must be made with an enzymatic activity assay rather than nucleic acid sequencing [2]. The clinical presentation of MPS VII is variable. Patients can present early with fetal hydrops, while those who survive into adulthood exhibit coarse facial features, corneal opacities, skeletal deformities, cognitive impairment, and cardiac abnormalities [2]. In addition, patients can develop progressive hearing loss and decreased speech production [3]. Reports of the cardiac abnormalities found in patients with MPS VII are limited, but include cardiac valve thickening and valve dysfunction [4]. Only one prior autopsy report of the findings
Sources of support: none. Funding: MKH is supported by the American Heart Association 13GRNT16420015. ⁎ Corresponding author at: Ross Rm 632L, 720 Rutland Avenue, Baltimore, MD 212805. Tel.: +1-410-614-8138; fax: +1-410-502-5862. E-mail address: [email protected] (M.K. Halushka).
associated with MPS VII in an adult has been published. This report contained limited information on cardiovascular findings but did describe nodular thickening of the four cardiac valves and arterial stenosis [5]. Cardiac disease is common in MPS patients, and cardiac findings associated with MPS I–VI have been relatively well reported. MPSassociated cardiac valve disease manifests as generalized thickening of the valve leaflets in addition to short, thickened chordae. Myocardial hypertrophy has been reported secondary to cardiac valve stenosis, with valvular regurgitation also being described. Sudden cardiac death, likely secondary to arrhythmia, is common in MPS. MPS I, II, and VI are most strongly associated with cardiac disease, while MPS III and IV do not cause dermatan sulfate accumulation and have a lower frequency of cardiac involvement. MPS I and II are associated with large artery thickening and diffuse concentric intimal proliferation in addition to narrowing of the aortic isthmus and subsequent systemic hypertension [4]. We recently performed an autopsy on an individual who suffered from MPS VII (Sly Syndrome) and provide the first extensive analysis of the cardiovascular pathologies in this syndrome.
2. Case presentation At the time of his death, this 28-year-old male lived under the care of his parents. His past medical history was notable for a diagnosis of MPS VII, confirmed by beta-glucuronidase enzyme activity at 3% of normal (Kennedy Krieger Institute Biochemistry Lab, Baltimore MD) over 20 years earlier. A decade prior to his death, he underwent scoliosis repair surgery that was complicated by paraplegia, subsequently he became wheelchair bound. Around this time, he developed progressively
http://dx.doi.org/10.1016/j.carpath.2015.06.001 1054-8807/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Gniadek TJ, et al, Cardiovascular pathologies in mucopolysaccharidosis type VII (Sly Syndrome), Cardiovasc Pathol (2015), http://dx.doi.org/10.1016/j.carpath.2015.06.001
2
T.J. Gniadek et al. / Cardiovascular Pathology xxx (2015) xxx–xxx
declining mental status, eventually becoming non-conversant. He was able to feed himself with assistance. His most recent echocardiogram (approximately 7 years before his death) showed a thickened aortic valve with a peak aortic gradient of 45 mmHg and a mean gradient of 22 mmHg, suggesting aortic stenosis. The echocardiogram also identified mild aortic valve regurgitation and qualitatively normal left ventricular systolic function. At that time, an electrocardiogram (EKG) demonstrated bilateral ventricular enlargement, incomplete right bundle branch block and a nonspecific ST
abnormality. He had no additional cardiac follow-up and no known cardiovascular symptomatology. Without any acute change in his baseline status, he went to sleep and was found pulseless the next morning. Autopsy revealed an enlarged heart weighing 484 g (reference range, 182–390 g) with mild four-chamber dilation. The left ventricular free wall, septum, and right ventricular free wall were 1.8, 1.9, and 0.3 cm, respectively. The four cardiac valves had reduced circumference. The valve circumferences were: tricuspid 8.5 cm (reference range, 10–12.5 cm); pulmonic 4.3 cm (reference range, 7–9 cm); mitral 6 cm
Fig. 1. Cardiac Valves. The pulmonic (A–B), tricuspid (C–D), aortic (E–F), and mitral (G–H) valves were thickened and fibrotic. The pulmonic valves appeared least nodular, while the aortic valve was most significantly nodular. The areas of nodularity contained extracellular amorphous ground substance in the aortic valve as well as focal calcification (F). Balloon cells, consistent with accumulated GAG, were seen microscopically in areas of fibrosis. There was moderate thickening and fusion of the chordae, most prominently on the mitral valve (G). Microscopy images are shown at 40× magnification.
Please cite this article as: Gniadek TJ, et al, Cardiovascular pathologies in mucopolysaccharidosis type VII (Sly Syndrome), Cardiovasc Pathol (2015), http://dx.doi.org/10.1016/j.carpath.2015.06.001
T.J. Gniadek et al. / Cardiovascular Pathology xxx (2015) xxx–xxx
(reference range, 8–10.5 cm); and aortic 3.5 cm (reference range, 6–7.5 cm). All the valves were thickened and fibrotic. Both the mitral and tricuspid valves demonstrated moderate chordal fusion, sclerosis, and nodular thickening of the valve leaflets. The aortic valve was severely stenotic with a fixed valve orifice diameter of ~0.4 cm. Each cusp of the aortic valve was several millimeters thick with an uneven but generally smooth surface with thickened but flexible valve leaflets. In both atria, the endocardium was smooth, pearly white, and modestly thickened. Histologically, the myocardium showed fibroelastosis (Movat Pentachrome stain). All of the valves displayed amorphous ground substance, balloon cell change, and increased colloid iron staining consistent with an intracellular collection of GAG. Minimal calcifications were noted predominately in the aortic valve (Fig. 1). The coronary arteries followed a normal anatomic course with a right dominant circulation. Grossly, the coronary arteries showed diffuse concentric narrowing with over 75% stenosis of the left anterior descending artery, 50–75% stenosis of the circumflex artery, and greater than 75% stenosis of the right coronary artery. Histologically, there was a marked concentric intimal expansion of distended mesenchymal cells and increased extracellular matrix. The vascular smooth muscle cells of the media layer showed strong diffuse colloid iron staining, consistent with GAG accumulation, and increased extracellular matrix (Masson's Trichrome stain). CD68 immunohistochemistry labeled
3
numerous cells within the coronary arterial wall, although a frank arteritis was not noted (Fig. 2). Mild, patchy interstitial fibrosis and perivascular fibrosis were present in the myocardium of the left ventricle. Intracardiac small- and medium-sized arteries showed increased colloid iron staining, consistent with GAG within endothelial and smooth muscle cells. The cardiomyocytes showed no increase in intracellular GAG; however, colloid iron showed mildly increased staining at the intercalated discs relative to a control heart (Fig. 3). The ascending aorta was of appropriate caliber with marked thickening throughout. There was minimal atherosclerosis in the abdominal aorta and in the aortic arch. Histologically, there was diffuse colloidal iron staining consistent with GAG accumulation in the endothelial and smooth muscle cells of the aorta. In addition, there was increased fibrosis, medial elastic lamina disruption, and extracellular amorphous ground substance. The large muscular arteries appeared thickened throughout the body, including the basilar artery at the base of the brain and the great vessels off the aortic arch. CD68 immunohistochemistry stain labeled scattered cells within the aortic wall (Fig. 4). The vena cava and other major veins were patent and thin walled. Additional mucopolysaccharide accumulations were noted in the cartilage, trachea, central nervous system, corneal stroma, and scleral stroma. The cause of death was reported as sudden cardiac death
Fig. 2. Right coronary artery. (A)The right coronary artery was representative of all of the coronary arteries and showed diffuse concentric narrowing; (B) There was intimal expansion consisting of an increase in the extracellular matrix and distended balloon cells; (C) Masson's Trichrome stain showed increased extracellular matrix within the media layer and surrounding vascular smooth muscle cells; (D) CD68 immunohistochemistry-labeled scattered cells within the coronary artery wall; (E) Colloid iron stain showed diffuse strong staining throughout the coronary artery wall, including the vascular smooth muscle cells within the media layer.
Please cite this article as: Gniadek TJ, et al, Cardiovascular pathologies in mucopolysaccharidosis type VII (Sly Syndrome), Cardiovasc Pathol (2015), http://dx.doi.org/10.1016/j.carpath.2015.06.001
4
T.J. Gniadek et al. / Cardiovascular Pathology xxx (2015) xxx–xxx
Fig. 3. Myocardium. Colloid iron stain showed increased staining at the intercalated disc in MPS VII (A) compared to staining from an unaffected control (B). In addition, intracardiac arterioles showed a transmural increase in colloid iron staining in MPS VII (C) compared to the same unaffected control (D).
Fig. 4. Aorta. (A) The aorta was generally thickened (H&E, magnification ×10) with (B) scattered CD68 positive cells within the media layer (10×) and (C) an especially thickened intimal layer (Masson's Trichrome, 10×). (D) High power (240×) view of the media-demonstrated balloon cells (H&E) and (E) scattered CD68 positive cells (100×). (F) Masson's Trichrome (240×) and (G) Millers Elastic (240×) stains demonstrated a disrupted medial elastic lamina. (H) Colloid iron stain (100×) showed increased smooth muscle cell staining relative to an (I) unaffected control (100×).
Please cite this article as: Gniadek TJ, et al, Cardiovascular pathologies in mucopolysaccharidosis type VII (Sly Syndrome), Cardiovasc Pathol (2015), http://dx.doi.org/10.1016/j.carpath.2015.06.001
T.J. Gniadek et al. / Cardiovascular Pathology xxx (2015) xxx–xxx
secondary to left ventricular hypertrophy as a consequence of aortic valve stenosis due to MPS VII. 3. Summary This is the first extensive report of the gross and histopathologic cardiovascular findings in MPS VII (Sly Syndrome). We found changes that are consistent with, but expand on, the original description of Sly Syndrome and appear to be typical of other mucopolysaccharidoses [1,2,4]. The involvement of the coronary arteries and coronary arterioles suggests a combination of the features seen in MPS I and II (large artery thickening with intimal proliferation) as well as MPS VI (coronary arteriole intimal proliferation). Studies on murine, canine, and feline animal models of MPS VII have many of the cardiac findings reported in humans, including thickening of the cardiac valves and arterial walls. These studies suggested that some pathologic changes may be due to the protease-induced degradation of elastin, in addition to the aberrant build up of mucopolysaccharide [4]. An increase in CD68 positive cells away from accumulated GAG and disorganization/disruption of the aortic elastic lamina may hint at such a mechanism. Most importantly, our autopsy findings suggest that these animal models are consistent with the cardiovascular changes seen in human MPS VII.
5
In summary, this patient suffered from marked cardiac valvular and coronary artery disease secondary to GAG accumulation. The autopsy findings support the hypothesis that cardiac symptomatology in MPS VII is likely secondary to valvular pathology where the risk for ischemia is increased. It is not known whether an increase in mucopolysaccharide at the intercalated disc is also arrhythmogenic. However, this is the third report of a patient with MPS VII having a sudden cardiac death event.
References [1] Sly WS, Quinton BA, McAlister WH, Rimoin DL. Beta glucuronidase deficiency: report of clinical, radiologic and biochemical features of a new mucopolysaccharidosis. J Pediatr 1973;82(2):249–57. [2] Coutinho MF, Lacerda L, Alves S. Glycosaminoglycan storage disorders: a review. Biochem Res Int 2012:471325. [3] Wallace SP, Prutting CA, Gerber SE. Degeneration of speech, language, and hearing in a patient with mucopolysaccharidosis VII. Int J Pediatr Otorhinolaryngol 1990;19(2): 97–107. [4] Braunlin EA, Harmatz PR, Scarpa M, Furlanetto B, Kampmann C, Loehr JP, et al. Cardiac disease in patients with mucopolysaccharidosis: presentation, diagnosis and management. J Inherit Metab Dis 2011;34(6):1183–97. [5] Vogler C, Levy B, Kyle JW, Sly WS, Williamson J, Whyte MP. Mucopolysaccharidosis VII: postmortem biochemical and pathological findings in a young adult with betaglucuronidase deficiency. Mod Pathol 1994;7(1):132–7.
Please cite this article as: Gniadek TJ, et al, Cardiovascular pathologies in mucopolysaccharidosis type VII (Sly Syndrome), Cardiovasc Pathol (2015), http://dx.doi.org/10.1016/j.carpath.2015.06.001