Aortic root dilatation in patients with mucopolysaccharidoses and the impact of enzyme replacement therapy

Poswar, Fabiano de Oliveira; Souza, Carolina Fischinger Moura de; Giugliani, Roberto; Baldo, Guilherme

doi:10.1007/s00380-018-1242-1

Cited by 19 publications

(22 citation statements)

References 25 publications

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“…In our cohort, there was no significantly higher incidence of ARD at the SoV compared to controls. In contrast, two recent publication reported a higher incidence of ARD in MPS patients, respectively in 39.1% and 35% . However, Poswar et al did not include any MPS III patients in their study, and Bolourchi et al reported the same mean ARD at the SoV in 6 MPS III patients as we report in our patients.…”

Section: Discussioncontrasting

confidence: 79%

Cardiac disease in mucopolysaccharidosis type III

Nijmeijer

Bruin‐Bon

Wijburg

et al. 2019

J of Inher Metab Disea

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Mucopolysaccharidosis type III (MPS III; Sanfilippo disease) is primarily characterized by neurocognitive decline with limited somatic disease. Only few reports addressed cardiac disease (CD) in MPS III. We investigated the prevalence of CD in a relatively large cohort of patients. In this cross‐sectional study, extensive echocardiographic studies were performed in 30 MPS III patients (16 patients <18 years), all without clinical symptoms of CD. Results were compared to data from matched controls. The mean global longitudinal strain on speckle‐tracking echocardiography (STE) was impaired in both pediatric and adult patients vs controls (resp. −18.4% vs −20.7%; mean difference 2.25, 95% CI 0.61‐3.89, P = 0.009 and −16.9% vs −19.5%; mean difference 2.64, 95% CI 0.78‐4.49, P = 0.007), indicating early systolic dysfunction. Left ventricle ejection fraction (LVEF) was normal in pediatric patients and (slightly) impaired in adult patients vs controls (48.7% vs 55.8%, P = 0.002). Tissue Doppler imaging (TDI) showed significantly slower early diastolic velocities (e′) compared to controls indicative for diastolic dysfunction. Furthermore, mitral and aortic valve abnormalities were prevalent (43% and 33% of patients, respectively). Finally, 15.6% of the patients had a first‐degree atrioventricular block on electrocardiography (ECG). The impaired STE reveals early, subclinical LV dysfunction which is supported by results of TDI. In addition, mild valvular disease and ECG abnormalities are prevalent. The lowered LVEF in adult patients suggests that the LV dysfunction is progressive, and may ultimately lead to clinical myocardial disease when patients live longer due to an effective disease‐modifying treatment of which a number of options are now in clinical trials.

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Section: Discussioncontrasting

confidence: 79%

Cardiac disease in mucopolysaccharidosis type III

Nijmeijer

Bruin‐Bon

Wijburg

et al. 2019

J of Inher Metab Disea

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“…AHI and OSAs, when evaluated, seem to be reduced by ERT, but it is clear that macroglossia and adeno-tonsils hypertrophy are not modified during long-term treatment [36,45,46,49,50,[61][62][63][64]. Although only few cases are reported, it appears that ERTs do not act on deformities of trachea, bronchi and vessels [65][66][67][68][81][82][83][84]. In the first years after ERT availability it seemed that it could have a "stabilization" role on hearing loss and corneal clouding but unfortunately the different articles do not agree on this point and the final impression is that hearing and eyes are among the difficult-to-reach targets for ERT [42,47,59,60,[85][86][87][88][89][90].…”

Section: Discussionmentioning

confidence: 99%

“…An increase of thickness was found in all the MPS patients at all ages [81]. Aortic root dilatation was recently evaluated in two different papers that showed a prevalence ≥ 35% in all MPS types with the highest occurrence in MPS IVA and MPS VI patients (>70%) [80,82]. Other studies underline the vulnerability of the cardiovascular system in MPS and especially in MPS IVA [145,146].…”

Section: Vesselsmentioning

confidence: 97%

Intravenous Enzyme Replacement Therapy in Mucopolysaccharidoses: Clinical Effectiveness and Limitations

Parini

Deodato

2020

IJMS

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The aim of this review is to summarize the evidence on efficacy, effectiveness and safety of intravenous enzyme replacement therapy (ERT) available for mucopolysaccharidoses (MPSs) I, II, IVA, VI and VII, gained in phase III clinical trials and in observational post-approval studies. Post-marketing data are sometimes conflicting or controversial, possibly depending on disease severity, differently involved organs, age at starting treatment, and development of anti-drug antibodies (ADAs). There is general agreement that ERT is effective in reducing urinary glycosaminoglycans and liver and spleen volume, while heart and joints outcomes are variable in different studies. Effectiveness on cardiac valves, trachea and bronchi, hearing and eyes is definitely poor, probably due to limited penetration in the specific tissues. ERT does not cross the blood–brain barrier, with the consequence that the central nervous system is not cured by intravenously injected ERT. All patients develop ADAs but their role in ERT tolerance and effectiveness has not been well defined yet. Lack of reliable biomarkers contributes to the uncertainties about effectiveness. The data obtained from affected siblings strongly indicates the need of neonatal screening for treatable MPSs. Currently, other treatments are under evaluation and will surely help improve the prognosis of MPS patients.

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“…Patients usually develop a progressive thickening of the cardiac valve leaflets, resulting in valvular insufficiency and/or stenosis, predominantly in the mitral and aortic valves [18]. Cardiovascular manifestations may also include left ventricle hypertrophy, systemic or pulmonary hypertension, coronary artery disease, and aortic root dilatation [19][20][21].…”

Section: Severe Phenotype (Hurler Syndrome)mentioning

confidence: 99%

Mucopolysaccharidosis Type I

et al. 2020

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Mucopolysaccharidosis type I (MPS I) is caused by the deficiency of α-l-iduronidase, leading to the storage of dermatan and heparan sulfate. There is a broad phenotypical spectrum with the presence or absence of neurological impairment. The classical form is known as Hurler syndrome, the intermediate form as Hurler–Scheie, and the most attenuated form is known as Scheie syndrome. Phenotype seems to be largely influenced by genotype. Patients usually develop several somatic symptoms such as abdominal hernias, extensive dermal melanocytosis, thoracolumbar kyphosis odontoid dysplasia, arthropathy, coxa valga and genu valgum, coarse facial features, respiratory and cardiac impairment. The diagnosis is based on the quantification of α-l-iduronidase coupled with glycosaminoglycan analysis and gene sequencing. Guidelines for treatment recommend hematopoietic stem cell transplantation for young Hurler patients (usually at less than 30 months of age). Intravenous enzyme replacement is approved and is the standard of care for attenuated—Hurler–Scheie and Scheie—forms (without cognitive impairment) and for the late-diagnosed severe—Hurler—cases. Intrathecal enzyme replacement therapy is under evaluation, but it seems to be safe and effective. Other therapeutic approaches such as gene therapy, gene editing, stop codon read through, and therapy with small molecules are under development. Newborn screening is now allowing the early identification of MPS I patients, who can then be treated within their first days of life, potentially leading to a dramatic change in the disease’s progression. Supportive care is very important to improve quality of life and might include several surgeries throughout the life course.

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Aortic root dilatation in patients with mucopolysaccharidoses and the impact of enzyme replacement therapy

Cited by 19 publications

References 25 publications

Cardiac disease in mucopolysaccharidosis type III

Cardiac disease in mucopolysaccharidosis type III

Intravenous Enzyme Replacement Therapy in Mucopolysaccharidoses: Clinical Effectiveness and Limitations

Mucopolysaccharidosis Type I

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