Findings from the Longitudinal CINRG Becker Natural History Study

BACKGROUND: Becker muscular dystrophy is an X-linked, genetic disorder causing progressive degeneration of skeletal and cardiac muscle, with a widely variable phenotype. OBJECTIVE: A 3-year, longitudinal, prospective dataset contributed by patients with confirmed Becker muscular dystrophy was analyzed to characterize the natural history of this disorder. A better understanding of the natural history is crucial to rigorous therapeutic trials. METHODS: A cohort of 83 patients with Becker muscular dystrophy (5-75 years at baseline) were followed for up to 3 years with annual assessments. Muscle and pulmonary function outcomes were analyzed herein. Age-stratified statistical analysis and modeling were conducted to analyze cross-sectional data, time-to-event data, and longitudinal data to characterize these clinical outcomes. RESULTS: Deletion mutations of dystrophin exons 45-47 or 45-48 were most common. Subgroup analysis showed greater pairwise association between motor outcomes at baseline than association between these outcomes and age. Stronger correlations between outcomes for adults than for those under 18 years were also observed. Using cross-sectional binning analysis, a ceiling effect was seen for North Star Ambulatory Assessment but not for other functional outcomes. Longitudinal analysis showed a decline in percentage predicted forced vital capacity over the life span. There was relative stability or improved median function for motor functional outcomes through childhood and adolescence and decreasing function with age thereafter. CONCLUSIONS: There is variable progression of outcomes resulting in significant heterogeneity of the clinical phenotype of Becker muscular dystrophy. Disease progression is largely manifest in adulthood. There are implications for clinical trial design revealed by this longitudinal analysis of a Becker natural history dataset

Pompe disease diagnosis and management guideline

ACMG standards and guidelines are designed primarily as an educational resource for physicians and other health care providers to help them provide quality medical genetic services. Adherence to these standards and guidelines does not necessarily ensure a successful medical outcome. These standards and guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. in determining the propriety of any specific procedure or test, the geneticist should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. It may be prudent, however, to document in the patient's record the rationale for any significant deviation from these standards and guidelines.Duke Univ, Med Ctr, Durham, NC 27706 USAOregon Hlth Sci Univ, Portland, OR 97201 USANYU, Sch Med, New York, NY USAUniv Florida, Coll Med, Powell Gene Therapy Ctr, Gainesville, FL 32611 USAIndiana Univ, Bloomington, in 47405 USAUniv Miami, Miller Sch Med, Coral Gables, FL 33124 USAHarvard Univ, Childrens Hosp, Sch Med, Cambridge, MA 02138 USAUniversidade Federal de São Paulo, São Paulo, BrazilColumbia Univ, New York, NY 10027 USANYU, Bellevue Hosp, Sch Med, New York, NY USAColumbia Univ, Med Ctr, New York, NY 10027 USAUniversidade Federal de São Paulo, São Paulo, BrazilWeb of Scienc

A rapid testing procedure for Fabry disease: alpha-galadosidase A assay in dried blood spots

Background: Fabry disease is a rare X-linked disorder characterized by complete deficiency or reduced activity of the lysosomal enzyme -galactosidase A. Patients with Fabry disease present with a heterogeneous spectrum of symptoms due to the progressive accumulation of glycosphingolipids in bodily tissues. Clinical onset usually occurs during late childhood or adolescence, but the correct diagnosis is rarely reached before the third decade of life. Enzyme replacement therapy is available for the treatment of patients with confirmed -galactosidase A deficiency. Aim: To report on a rapid testing procedure for measuring -galactosidase A activity in dried blood spots. Methods and results: Dried blood spots represent a convenient and cost-effective way to collect blood samples. We analysed five different populations: 116 healthy adults, 147 newborns, three hemizygous males and four heterozygous females with Fabry disease, and ten individuals affected by other lysosomal storage diseases (LSDs). We obtained the following enzyme activity ranges: healthy adults, 6.0\u201321.4 pmoles/punch/h; newborns, 5.0\u201352.3 pmoles/ punch/h; hemizygous males, 0.3\u20133.2 pmoles/punch/h; heterozygous females, 5.4\u201310.3 pmoles/punch/h; individuals affected by other LSDs, 5.9\u201319.4 pmoles/punch/h. The dried blood spot test was able to differentiate male patients with Fabry disease, but not females, from healthy volunteers. Conclusion: Given that the prevalence of Fabry disease appears to be underestimated, especially in patients with cardiac and renal dysfunction, we propose this microassay as a non-invasive, cost-effective and quick method for screening at-risk adult populations

Rapid diagnostic testing procedures for lysosomal storage disorders: alpha-glucosidase and beta-galactosidase assays on dried blood spots

BACKGROUND: Lysosomal storage disorders (LSDs) are pathologies caused by the deficit of lysosomal enzymes; late diagnosis may render therapeutic programs less effective. As early, pre-symptomatic detection could change the natural history of the disease, we are setting up rapid microassays using dried blood spots (DBS) on filter paper. Here we report alpha-glucosidase and beta-galactosidase assays. METHODS: Enzymatic activities were evaluated on DBS from five different groups of subjects including healthy controls and patients affected with an LSD. A 260-day monitoring of DBS preservation at five different temperatures and a comparison of the enzymatic activities measured in DBS obtained from a single (sDBS) or a double (dDBS) blood drop were performed as well. RESULTS: Both assays could clearly distinguish the affected patients from the other subjects analyzed. Storage of DBS at 4 degrees C and below allowed a longer preservation of the enzymatic activities. No significant differences were detected between sDBS and dDBS. CONCLUSIONS: DBS can be used for non-invasive, easy, inexpensive lysosomal enzyme assays. Reliability of assays on DBS needs to be checked using a control enzyme such as beta-galactosidase. DBS can be still reliably analyzed even if generated incidentally by two overlapped drops