Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals

CHOC Children's, Orange, California, USA.
Genetics in medicine: official journal of the American College of Medical Genetics (Impact Factor: 7.33). 05/2011; 13(5):457-84. DOI: 10.1097/GIM.0b013e318211a7e1
Source: PubMed


To develop educational guidelines for the diagnostic confirmation and management of individuals identified by newborn screening, family-based testing after proband identification, or carrier testing in at-risk populations, and subsequent prenatal or postnatal testing of those who are presymptomatic for a lysosomal storage disease.
Review of English language literature and discussions in a consensus development panel comprised an international group of experts in the clinical and laboratory diagnosis, treatment and management, newborn screening, and genetic aspects of lysosomal storage diseases.
Although clinical trial and longitudinal data were used when available, the evidence in the literature is limited and consequently the recommendations must be considered as expert opinion. Guidelines were developed for Fabry, Gaucher, and Niemann-Pick A/B diseases, glycogen storage type II (Pompe disease), globoid cell leukodystrophy (Krabbe disease), metachromatic leukodystrophy, and mucopolysaccharidoses types I, II, and VI.
These guidelines serve as an educational resource for confirmatory testing and subsequent clinical management of presymptomatic individuals suspected to have a lysosomal storage disease; they also help to define a research agenda for longitudinal studies such as the American College of Medical Genetics/National Institutes of Health Newborn Screening Translational Research Network.


Available from: Raymond Y Wang, Mar 11, 2014
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    • "MPS-VI (Maroteaux-Lamy syndrome) is an autosomal recessive condition due to arylsulfatase B deficiency . Although therapies are available for many MPS disorders, notably enzyme replacement therapy (ERT) and hematopoietic cell transplantation (HCT) [12] [13] [14] [15] [16] [17] [18] [19] [20], their beneficial effect on the skeleton is thought to be limited if not initiated early [21]. As new therapies become available, development of biomarkers that are associated with the skeletal manifestations in MPS disorders would be helpful for clinical trials. "
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    ABSTRACT: Purpose: Skeletal disease causes significant morbidity in mucopolysaccharidoses (MPS), and bone remodeling processes in MPS have not been well characterized. The objective of this study was to determine if biomarkers of bone turnover are abnormal in children with specific MPS disorders (i.e. MSP-I, MPS-II, and MPS-VI) compared to healthy children. Methods: A cross-sectional study was performed of serum biomarkers of bone formation (bone-specific alkaline phosphatase [BSAP], osteocalcin) and urine biomarkers of bone resorption (pyridinoline, deoxypyridinoline) in MPS and healthy controls. Measures of physical function and pain were obtained using the Children's Health Questionnaire (CHQ). Results: The cohort consisted of 39 children with MPS (MPS-I=26; MPS-II=11; MPS-VI=4) and 51 healthy children. Adjusting for sex and Tanner stage group, MPS individuals had statistically significant increases for osteocalcin (p< 0.001), with trends toward higher BSAP (p=0.054) and urinary pyridinoline (p=0.084). These biomarkers were not significantly associated with CHQ bodily pain and physical-function scores. Conclusion: Osteocalcin was increased in children with MPS disorders, with trends for increases in BSAP and urinary pyridinoline, suggesting that bone remodeling is altered in children with MPS. Future studies to assess the ability of these biomarkers to quantify and monitor MPS skeletal disease in response to therapy are needed.
    Journal of pediatric rehabilitation medicine 08/2014; 7(2):159-65. DOI:10.3233/PRM-140285
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    • "Gaucher disease (GD) is the most common lysosomal storage disorder (LSD), with an estimated prevalence in Caucasians ranging from about 1∶40,000 to 1∶60,000, although a current newborn screening in Szeged, Hungary suggests a higher prevalence of 1∶13,341 [1]–[2]. LSDs are generally characterized by a genetic defect in proteins and enzymes involved in the lysosomal degradation of macromolecules into smaller compounds resulting in the accumulation of non-degraded macromolecules [3]. "
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    ABSTRACT: Gaucher disease (GD) is the most common lysosomal storage disorder (LSD). Based on a deficient β-glucocerebrosidase it leads to an accumulation of glucosylceramide. Standard diagnostic procedures include measurement of enzyme activity, genetic testing as well as analysis of chitotriosidase and CCL18/PARC as biomarkers. Even though chitotriosidase is the most well-established biomarker in GD, it is not specific for GD. Furthermore, it may be false negative in a significant percentage of GD patients due to mutation. Additionally, chitotriosidase reflects the changes in the course of the disease belatedly. This further enhances the need for a reliable biomarker, especially for the monitoring of the disease and the impact of potential treatments. Here, we evaluated the sensitivity and specificity of the previously reported biomarker Glucosylsphingosine with regard to different control groups (healthy control vs. GD carriers vs. other LSDs). Only GD patients displayed elevated levels of Glucosylsphingosine higher than 12 ng/ml whereas the comparison controls groups revealed concentrations below the pathological cut-off, verifying the specificity of Glucosylsphingosine as a biomarker for GD. In addition, we evaluated the biomarker before and during enzyme replacement therapy (ERT) in 19 patients, demonstrating a decrease in Glucosylsphingosine over time with the most pronounced reduction within the first 6 months of ERT. Furthermore, our data reveals a correlation between the medical consequence of specific mutations and Glucosylsphingosine. In summary, Glucosylsphingosine is a very promising, reliable and specific biomarker for GD.
    PLoS ONE 11/2013; 8(11):e79732. DOI:10.1371/journal.pone.0079732 · 3.23 Impact Factor
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    • "However, GL3 and LysoGL3 levels can be difficult to correlate with organ involvement or long term disease progression in females and individuals not affected by the classic form of Fabry disease. (Wang et al. 2011 and Germain 2010) "
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    ABSTRACT: Identification and comprehensive care of individuals who have Fabry disease (FD) requires a multidisciplinary approach inclusive of genetic testing, test interpretation, genetic counseling, long term disease symptom monitoring, treatment recommendations, and coordination of therapy. The purpose of this document is to provide health care professionals with guidelines for testing, care coordination, identification of psychosocial issues, and to facilitate a better understanding of disease treatment expert recommendations for patients with Fabry disease. These recommendations are the opinions of a multicenter working group of genetic counselors, medical geneticists, and other health professionals with expertise in Fabry disease counseling, as well as representatives/founders of the two United States based Fabry disease patient advocacy groups who are themselves affected by Fabry disease. The recommendations are U.S. Preventive Task Force Class III, and they are based on clinical experience, a review of pertinent English-language articles, and reports of expert committees. This document reviews the genetics of Fabry disease, the indications for genetic testing, interpretation of results, psychosocial considerations, and references to professional and patient resources.
    Journal of Genetic Counseling 10/2013; 22(5). DOI:10.1007/s10897-013-9613-3 · 2.24 Impact Factor
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