Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease caused by a deficiency of N-acetylgalactosamine 4-sulfatase (arylsulfatase B, ASB). This enzyme is required for the degradation of ...dermatan sulfate. In its absence, dermatan sulfate accumulates in cells and is excreted in large quantities in urine. Specific therapeutic intervention is available; however, accurate and timely diagnosis is crucial for maximal benefit. To better understand the current practices for diagnosis and to establish diagnostic guidelines, an international MPS VI laboratory diagnostics scientific summit was held in February of 2011 in Miami, Florida.
The various steps in the diagnosis of MPS VI were discussed including urinary glycosaminoglycan (uGAG) analysis, enzyme activity analysis, and molecular analysis. The following conclusions were reached. Dilute urine samples pose a significant problem for uGAG analysis and MPS VI patients can be missed by quantitative uGAG testing alone as dermatan sulfate may not always be excreted in large quantities. Enzyme activity analysis is universally acknowledged as a key component of diagnosis; however, several caveats must be considered and the appropriate use of reference enzymes is essential. Molecular analysis supports enzyme activity test results and is essential for carrier testing, subsequent genetic counseling, and prenatal testing.
Overall the expert panel recommends caution in the use of uGAG screening alone to rule out or confirm the diagnosis of MPS VI and acknowledges enzyme activity analysis as a critical component of diagnosis. Measurement of another sulfatase enzyme to exclude multiple sulfatase deficiency was recommended prior to the initiation of therapy. When feasible, the use of molecular testing as part of the diagnosis is encouraged. A diagnostic algorithm for MPS VI is provided.
► A panel of experts provides an overview of MPS VI laboratory testing and a diagnostic algorithm. ► Quantitative and qualitative urinary GAG assays should be run in parallel and are not diagnostic. ► ASB activity is the gold standard test: Confirm sample integrity, rule out MSD/I-cell disease. ► Multiple samples and multiple tests are recommended to reach an accurate diagnosis. ► Maintain high clinical suspicion of MPS: Retest if necessary, communicate openly with lab.
Anderson–Fabry disease is a rare, X‐chromosomal lipid storage disorder caused by a deficiency of lysosomal α‐galactosidase A. Clinical manifestations of Anderson–Fabry disease include excruciating ...pain in the extremities (acroparaesthesia), skin vessel ectasia (angiokeratoma), corneal and lenticular opacity, cardiovascular disease, stroke and renal failure, only renal failure being a frequent cause of death. Heterozygote female carriers have often been reported as being asymptomatic or having an attenuated form of the disease. To evaluate the spectrum of clinical signs in heterozygotes, a comprehensive clinical examination was performed on 20 carriers of Anderson–Fabry disease. This revealed that, in addition to the skin manifestation, various other clinical manifestations of the disease are present, including acroparaesthesia, kidney dysfunction, cerebrovascular disease, and gastrointestinal and heart problems. It therefore appears that Anderson–Fabry disease affects both hemizygotes and heterozyotes and therefore should be considered to be an X‐linked dominant disease.
The lysosomal system is the main intracellular mechanism for the catabolism of naturally occurring endogenous and exogenous macromolecules and the subsequent recycling of their constituent monomeric ...components. It also plays an important part in processing essential metabolites. A genetic defect in a protein responsible for maintaining the lysosomal system results in the accumulation within lysosomes of partially degraded molecules, the initial step in the process leading to a lysosomal storage disease. The defective protein can be a luminal lysosomal enzyme or protein cofactor, a lysosomal membrane protein or a protein involved in the post-translational modification or transport of lysosomal proteins. Over 40 lysosomal storage diseases are known and they have a collective incidence of approximately 1 in 7000-8000 live births. Most of the genes for the lysosomal proteins have been cloned, permitting mutation analysis in individual cases. This information can be used for genotype/phenotype correlation, genetic counselling and the selection of patients for novel forms of therapy, such as substrate deprivation or dispersal, enzyme replacement, bone-marrow transplantation and gene transfer.
Summary
Fabry disease is an X‐linked disorder of glycosphingolipid metabolism resulting from a deficiency of the lysosomal enzyme α‐galactosidase A. This deficiency leads to the progressive ...accumulation, in lysosomes of visceral tissues and in body fluids of hemizygotes, of the glycosphingolipids globotriaosylceramide (CTH, Gb3 or GL‐3) and galabiosylceramide (CDH) and to a lesser extent the blood group AB and B related glycolipids. Elevated levels of the glycosphingolipids are found in the urine of hemizygous males with the classic phenotype, but it is not known whether all symptomatic or asymptomatic heterozygotes have elevated levels. We have therefore measured CTH and CDH quantitatively in a multiplex assay using tandem mass spectrometry in urine from a large cohort (44) of genetically proven or obligate heterozygotes including four with the N215S mutation, from classic hemizygotes (28), from cardiac variant hemizygotes with the N215S mutation (6) and from normal controls. The levels of CTH and CDH were related to both creatinine and sphingomyelin. Urinary CTH was elevated in all 28 classic hemizygotes but only in 4/6 of the cardiac variants. The level was within or just above the normal reference range in the four individuals heterozygous for the N215S mutation but was elevated in 38/40 of the other heterozygotes. Similar results were obtained for CDH, except that only 34/40 heterozygotes had an elevated level. The level of CDH was not elevated in the four heterozygotes and 4/6 of the hemizygotes for the N215S mutation. Combining the levels of CTH and CDH did not improve the discrimination of heterozygotes from controls. The ratio of CDH to CTH was higher in heterozygotes than in hemizygotes. Measurement of urinary CTH gave the best discrimination of heterozygotes from controls.
The lysosomal storage disorder, mucopolysaccharidosis type I (MPS I), is caused by a deficiency of the enzyme alpha-L-iduronidase, which is involved in the breakdown of dermatan and heparan ...sulphates. There are three clinical phenotypes, ranging from the Hurler form characterised by skeletal abnormalities, hepatosplenomegaly and severe mental retardation, to the milder Scheie phenotype where there is aortic valve disease, corneal clouding, limited skeletal problems, but no mental retardation. In this study, 85 MPS I families (73 Hurler, 5 Hurler/Scheie, 7 Scheie) were screened for 9 known mutations (Q70X, A75T, 474-2a>g, L218P, A327P, W402X, P533R, R89Q, 678-7g>a). W402X was the most frequent mutation in our population (45.3%) and Q70X was the second most frequent (15.9%). In 30 families, either one or both of the mutations were not identified, which accounted for 25.9% of the total alleles. Therefore, all 14 exons of the alpha-L-iduronidase gene were screened in these patients and 23 different sequence changes were found, 17 of which were previously unknown. The novel sequence changes include 4 deletions (153delC, 628del5, 740delC, 747delG), 5 nonsense mutations (Q60X, Y167X, Q400X, R619X, R628X), 6 missense mutations (C205Y, G208V, H240R, A319V, P496R, S633L), a splice site mutation (IVS12+5g>a), and a rare polymorphism (A591T). The polymorphism and novel missense mutations were transiently expressed in COS-7 cells and all of them except the polymorphism showed complete loss of enzyme activity. In total, 165 of the 170 mutant alleles were identified in this study and despite the high frequency of W402X and Q70X, the identification of many novel mutations unique to individual families further highlights the genetic heterogeneity of MPS I.
Being born prematurely associates with greater cardiovascular disease (CVD) risk in adulthood. Less understood are the unique and joint associations of dietary patterns and behaviors to this elevated ...risk among adults who are born prematurely. We aimed to model the associations between term status, dietary and lifestyle behaviors with CVD risk factors while accounting for the longitudinal effects of family protection, and medical or environmental risks. In wave-VIII of a longitudinal study, 23-year olds born prematurely (PT-adults, n = 129) and full term (FT-adults, n = 38) survey-reported liking for foods/beverages and activities, constructed into indexes of dietary quality and sensation-seeking, dietary restraint and physical activity. Measured CVD risk factors included fasting serum lipids and glucose, blood pressure and adiposity. In bivariate relationships, PT-adults reported lower dietary quality (including less affinity for protein-rich foods and higher affinity for sweets), less liking for sensation-seeking foods/activities, and less restrained eating than did FT-adults. In comparison to nationally-representative values and the FT-adults, PT-adults showed greater level of CVD risk factors for blood pressure and serum lipids. In structural equation modeling, dietary quality completely mediated the association between term status and HDL-cholesterol (higher quality, lower HDL-cholesterol) yet joined term status to explain variability in systolic blood pressure (PT-adults with lowest dietary quality had highest blood pressures). Through lower dietary quality, being born prematurely was indirectly linked to higher cholesterol/HDL, higher LDL/HDL and elevated waist/hip ratios. The relationship between dietary quality and CVD risk was strongest for PT-adults who had developed greater cumulative medical risk. Protective environments failed to attenuate relationships between dietary quality and elevated CVD risk among PT-adults. In summary, less healthy dietary behaviors contribute to elevated CVD risk among young adults who are born prematurely.
•Young adults born prematurely had elevated cardiovascular risk factors and less healthy dietary behaviors.•Poor dietary quality and being born prematurely were separate and additive contributors of elevated systolic blood pressure.•Some of the preterm-cholesterol dyslipidemia relationship was explained (mediated) by poor dietary quality.•Young adults born prematurely reported low dietary restraint and low sensation seeking, including food neophobia.•A healthier diet attenuated some of the CVD risk factors among adults born prematurely and with medical risk.
Mucopolysaccharidosis type IIID is the least common of the four subtypes of Sanfilippo syndrome. It is caused by a deficiency of N-acetylglucosamine-6-sulphatase, which is one of the enzymes involved ...in the catabolism of heparan sulphate. We present the clinical, biochemical, and, for the first time, the molecular diagnosis of a patient with Sanfilippo D disease. The patient was found to be homozygous for a single base pair deletion (c1169delA), which will cause a frameshift and premature termination of the protein. Accurate carrier detection is now available for other members of this consanguineous family.
The purpose of this study was to investigate the direction and magnitude of kinematic changes in bar path and kinetic variable changes in the power clean (PC) after 4 weeks of PC training. Eighteen ...healthy adult men who had a minimum of 1 year of previous experience in the PC participated as subjects in this study. The subjects were pretested for their 1 repetition maximum (1RM) and provided with visual and verbal cues during PC training sessions, which took place 3 times per week for 4 weeks. Variables measured during data collection include pre- and post-peak force, peak power, and several bar-path kinematic variables through videography at 50, 70, and 90% of the subjects' pre-1RM. Peak force was improved at 50% of 1RM from 936 +/- 338 N to 1,299 +/- 384 N, at 70% from 1,216 +/- 315 N to 1,395 +/- 331 N, and at 90% from 1,255 +/- 329 N to 1,426 +/- 321 N. Peak power was increased at 50% of 1RM from 3,430 +/- 1,280 W to 4,230 +/- 1,326 W. All variables with respect to bar-path kinematics were improved significantly. These results indicate that both kinematic and kinetic variables improve through training and feedback. It is possible that persons beginning the PC exercise or coaches who provide instruction on the PC to beginning lifters should focus on proper bar path during the movement. This may result in force and power output to develop as technique improves. However, further investigation is required to establish the link between bar-path changes and kinetic variable performance improvements.
Monteiro, ER, Pescatello, LS, Winchester, JB, Corrêa Neto, VG, Brown, AF, Budde, H, Marchetti, PH, Silva, JG, Vianna, JM, and Novaes, JdS. Effects of manual therapies and resistance exercise on ...postexercise hypotension in women with normal blood pressure. J Strength Cond Res 36(4): 948-954, 2022-The purpose of this investigation was to examine the acute effects of resistance exercise (RE) and different manual therapies (static stretching and manual massage MM) performed separately or combined on blood pressure (BP) responses during recovery in women with normal BP. Sixteen recreationally strength-trained women (age: 25.1 ± 2.9 years; height: 158.9 ± 4.1 cm; body mass: 59.5 ± 4.9 kg; body mass index: 23.5 ± 1.9 kg·m-2; baseline systolic BP median: 128 mm Hg; and baseline diastolic BP median: 78 mm Hg) were recruited. All subjects performed 6 experiments in a randomized order: (a) rest control (CON), (b) RE only (RE), (c) static-stretching exercise only (SS), (d) MM only, (e) RE immediately followed by SS (RE + SS), and (f) RE immediately followed by MM (RE + MM). RE consisted of 3 sets of bilateral bench press, back squat, front pull-down, and leg press exercises at 80% of 10RM. Static stretching and MM were applied unilaterally in 2 sets of 120 seconds to each of the quadriceps, hamstring, and calf regions. Systolic (SBP) and diastolic BP were measured before (rest) and every 10 minutes for 60 minutes following (Post 10-60) each intervention. There were significant intragroup differences for RE in Post-50 (p = 0.038; d = -2.24; ∆ = -4.0 mm Hg). Similarly, SBP intragroup differences were found for the SS protocol in Post-50 (p = 0.021; d = -2.67; ∆ = -5.0 mm Hg) and Post-60 (p = 0.008; d = -2.88; ∆ = -5.0 mm Hg). Still, SBP intragroup differences were found for the MM protocol in Post-50 (p = 0.011; d = -2.61; ∆ = -4.0 mm Hg) and Post-60 (p = 0.011; d = -2.74; ∆ = -4.0 mm Hg). Finally, a single SBP intragroup difference was found for the RE + SS protocol in Post-60 (p = 0.024; d = -3.12; ∆ = -5.0 mm Hg). Practitioners should be aware that SS and MM have the potential to influence BP responses in addition to RE or by themselves and therefore should be taken into consideration for persons who are hypertensive or hypotensive.
Makaruk, H, Winchester, JB, Sadowski, J, Czaplicki, A, and Sacewicz, T. Effects of unilateral and bilateral plyometric training on power and jumping ability in women. J Strength Cond Res 25(12): ...3311-3318, 2011-The purpose of this study was to examine the effects of unilateral and bilateral plyometric exercise on peak power and jumping performance during different stages of a 12-week training and detraining in women. Forty-nine untrained but physically active female college students were randomly assigned to 1 of 3 groups: unilateral plyometric group (n = 16), bilateral plyometric group (BLE; n = 18), and a control group (n = 15). Peak power and jumping ability were assessed by means of the alternate leg tests (10-second Wingate test and 5 alternate leg bounds), bilateral leg test (countermovement jump CMJ) and unilateral leg test (unilateral CMJ). Performance indicators were measured pretraining, midtraining, posttraining, and detraining. Differences between dependent variables were assessed with a 3 × 4 (group × time) repeated analysis of variance with Tukey's post hoc test applied where appropriate. Effect size was calculated to determine the magnitude of significant differences between the researched parameters. Only the unilateral plyometric training produced significant (p < 0.05) improvement in all tests from pretraining to midtraining, but there was no significant (p < 0.05) increase in performance indicators from midtraining to posttraining. The BLE group significantly (p < 0.05) improved in all tests from pretraining to posttraining and did not significantly (p > 0.05) decrease power and jumping ability in all tests during detraining. These results suggest that unilateral plyometric exercises produce power and jumping performance during a shorter period when compared to bilateral plyometric exercises but achieved performance gains last longer after bilateral plyometric training. Practitioners should consider the inclusion of both unilateral and bilateral modes of plyometric exercise to elicit rapid improvements and guard against detraining.
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