Cardiovascular pathologies in mucopolysaccharidosis type VII (Sly Syndrome)

doi:10.1016/j.carpath.2015.06.001

Cardiovascular Pathology

Volume 24, Issue 5, September–October 2015, Pages 322-326

https://doi.org/10.1016/j.carpath.2015.06.001 Get rights and content

Abstract

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 small- and 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.

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 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. MPS-associated 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.

Section snippets

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 declining

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

References (5)

WS Sly et al.
Beta glucuronidase deficiency: report of clinical, radiologic and biochemical features of a new mucopolysaccharidosis
J Pediatr
(1973)
SP Wallace et al.
Degeneration of speech, language, and hearing in a patient with mucopolysaccharidosis VII
Int J Pediatr Otorhinolaryngol
(1990)

There are more references available in the full text version of this article.

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MPS VII – Extending the classical phenotype
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In the overall presentation, MPS VII has many similar features to MPS I and MPS II. The most consistent features of MPS VII can include skeletal dysplasia, coarse facies with a short neck, pulmonary involvement, corneal clouding, cardiac valve disease, intellectual disability, hepatosplenomegaly; non-immune hydrops fetalis is commonly observed in severe cases [5,7–9]. It is also one of the few lysosomal disorders with a neonatal form with clinical manifestations in utero or at birth [10–13].
Mucopolysaccharidosis VII (or Sly syndrome) is an autosomal recessive disorder characterised by a deficiency in the enzyme Beta-glucuronidase (GUSB). Partial degradation of glycosaminoglycans (GAGs); chondroitin sulfate (CS), dermatan sulfate (DS) and heparan sulfate (HS) results in the accumulation of these fragments in the lysosomes of many tissues, eventually leading to multisystem damage. In some cases, early diagnosis on clinical grounds alone can be difficult due to the extreme variability of the clinical presentation and disease progression. We present a case report of a 31-year-old male patient diagnosed with MPS VII at the age of 28, who multiple specialists saw without suspecting the diagnosis due to the unusual presentation. The patient presented with a history of developmental delay, scoliosis, kyphosis, corneal clouding, abnormal gait, short stature, hearing impairment, slightly coarse facial features and progressive deterioration of fine motor skills since childhood. The patient had inguinal hernia repair at around 12 months, bilateral hearing impairment with a left bone-anchored hearing aid, and spinal surgery. During spinal surveillance MPS VII was suspected by a spinal surgeon with interest in MPS, and the diagnosis confirmed with a deficiency in beta-glucuronidase in leucocytes and marginally elevated urinary GAGs. Next-generation sequencing identified two mutations in the GUSB gene (OMIM 611499), c.526C > T p.(Leu176Phe) and c.1820G > C p.(Gly607Ala). Although the patient exhibited features of the severe form of non-classical manifestations, his metabolic condition has remained reasonably stable, surviving into adulthood with only symptomatic treatment. We present the ever-expanding phenotypic spectrum of this ultra-rare disease.
Combined valve replacement and aortocoronary bypass in an adult mucopolysaccharidosis type VII patient
2021, Cardiovascular Pathology
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Our experience implies that prior to attributing exertion intolerance to respiratory causes, exclusion of cardiac etiology should be considered in these patients. Nonatherosclerotic coronary artery narrowings potentially resulting in hemodynamically significant stenoses have been noted in several reports describing post-mortem findings in MPS VII patients [7–9]. A total occlusion of RCA was identified using in-vivo imaging in our patient.
Mucopolysaccharidosis type VII (MPS VII) is a rare autosomal recessive lysosomal storage disorder. MPS VII is caused by mutations in the GUSB gene that encodes β-glucuronidase. Adult MPS VII patients present with musculoskeletal abnormalities, coarse features, and corneal clouding. Cardiac and valvular impairment are common; however, severe valvular disease necessitating surgery has not yet been reported. We present a 32-year-old male MPS VII patient admitted to our hospital with decompensated heart failure. We identified aortic valve disease with severe stenosis (valve area 0.69 cm²) and moderate regurgitation. Severe mitral valve stenosis (valve area 1 cm²) with moderate to severe regurgitation was also found in the patient. In addition, an occlusion of the right coronary artery (RCA) was documented. The patient underwent surgical replacement of the mitral and aortic valves with mechanical prostheses and implantation of a venous bypass graft to his RCA. The surgery led to a significant improvement of his clinical symptoms. Six months after the procedure, both mechanical valves function normally. Histopathological assessment identified chronic inflammatory infiltrates, fibrosis and calcifications in both resected valves. Foamy cytoplasmic transformation was most evident in the valvular interstitial cells. The ultrastructural vacuolar abnormality seen in these cells corresponded to storage changes observed in other MPSs. In conclusion, we describe clinical findings and valvular pathology in an MPS VII patient with the first-reported successful combined surgical valve replacement and myocardial revascularization. The histological and ultrastructural analyses revealed that the lysosomal storage predominantly affected the valvular interstitial cells.
Clinical presentation and diagnosis of mucopolysaccharidoses
2018, Molecular Genetics and Metabolism
Citation Excerpt :
Severe individuals will experience progressive degeneration of development, which begins between 1 and 3 years of age and progressively worsens. Other problems can include recurrent ear infections, poor vision, poor hearing, and sleep apnea, although these symptoms typically occur later in childhood [82]. Breathing difficulties, chronic upper respiratory tract infections, and rigid chests are typical.
Mucopolysaccharidoses (MPS) are estimated to affect1 in 25,000 live births although specific rates vary between the ethnic origin and country. MPS are a group of lysosomal storage disorders, which cause the buildup of GAG(s) due to insufficient or absent GAG-degrading enzymes. With seven types of MPS disorders and eleven subtypes, the MPS family presents unique challenges for early clinical diagnosis due to the molecular and clinical heterogeneity between groups and patients. Novel methods of early identification, particularly newborn screening through mass spectrometry, can change the flow of diagnosis, allowing enzyme and GAG quantification before the presentation of clinical symptoms improving outcomes. Genetic testing of patients and their families can also be conducted preemptively. This testing enables families to make informed decisions about family planning, leading to prenatal diagnosis.
In this review, we discuss the clinical symptoms of each MPS type as they initially appear in patients, biochemical and molecular diagnostic methods, and the future of newborn screening for this group of disorders.
Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review
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Surgical Management of Valvular Heart Disease in Mucopolysaccharidoses: A Review of Literature
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: Sources of support: none.

: Funding: MKH is supported by the American Heart Association 13GRNT16420015.

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Clinical Case ReportCardiovascular pathologies in mucopolysaccharidosis type VII (Sly Syndrome)

Abstract

Introduction

Section snippets

Case presentation

Summary

J Pediatr

Int J Pediatr Otorhinolaryngol

Clinical Case Report
Cardiovascular pathologies in mucopolysaccharidosis type VII (Sly Syndrome)