No abstract

To determine the effects of l‐arginine (l‐Arg) supplementation on nitric oxide metabolite (NOx) production, oral l‐Arg was given to normal controls, sickle cell disease (SCD) patients at steady state and SCD patients hospitalized with a vaso‐occlusive crisis (VOC). l‐Arg (0·1 g/kg) increased NOx formation by 18·8 ± 68% in normal controls, whereas steady‐state SCD patients demonstrated a paradoxical decrease in NOx of −16·7 ± 4% (P = 0·004). In contrast, patients with VOC demonstrated a dramatic increase in NOx production by +77·7 ± 103%, a response that was dose dependent. l‐Arg appears to be the rate‐limiting step in NOx production during VOC. Oral arginine may therefore benefit SCD patients by inducing an increase in NO production during VOC.

rs12252 was not associated with susceptibility to influenza-related critical illness in children or with critical illness severity. Our data also do not support it being a splice site.

Aim: Mucopolysaccharidosis VI (Maroteaux–Lamy syndrome) is a lysosomal storage disease caused by a deficiency of the enzyme N‐acetylgalactosamine 4‐sulphatase (ASB). Enzyme replacement therapy with recombinant human ASB (rhASB) has been studied in a randomized, double‐blind, two‐dose (0.2 and 1.0 mg/kg/week) phase I/II study (n=7) followed by an open‐label single dose (1.0 mg/kg/week) extension study. We report the pharmacokinetic profile of rhASB and the impact of antibody development. Methods: Pharmacokinetic analysis was performed at weeks 1, 2, 12, 24, 83, 84 and 96. Infusions were administered over 4 hours using a ramp‐up protocol. Plasma ASB and rhASB antibody concentrations and urine glycosaminoglycan (GAG) concentrations were determined. Results: The area under the plasma concentration–time curve (AUC0−t) for the high‐dose group increased from week 1 to week 2, but remained unchanged at weeks 12 and 24. A large difference in mean AUC0−t was observed between the low‐ and high‐dose groups. Pharmacokinetic results at weeks 83, 84 and 96 were similar to those at week 24. Six patients developed antibodies to rhASB. One patient developed high antibody levels in combination with a high ASB concentration, while a second patient also developed high antibody levels with undetectable ASB concentrations. Antibodies from the second patient blocked detection of ASB. By week 72, antibody levels had decreased in all patients. The high‐dose rhASB produced a more rapid and greater percentage reduction in urinary GAG concentrations than the lower dose (70% versus 55% at 24 weeks). Antibody levels did not appear to influence urinary GAG concentrations. Conclusion: Pharmacokinetic parameters appear to be independent of the duration of treatment and are not linear between the 0.2 and 1.0 mg/kg/week doses. Antibodies to rhASB develop in most patients, but their concentration decreases over time. Antibody formation may influence pharmacokinetic parameters during the early phases of treatment, although it appears to have limited impact on biochemical efficacy.

Background: Pompe disease is a lysosomal storage disorder caused by the deficiency of enzyme acid alphaglucosidase (GAA) which results in accumulation of glycogen, particularly in the skeletal, cardiac, and smooth muscles. The late-onset form with symptoms presenting in childhood through adulthood, is characterized by proximal muscle weakness, respiratory insufficiency, and unlike the infantile-onset form often with no cardiac involvement. Methods: We report our experience with 18 adult patients (14 males/4 females) with Pompe disease, several of whom had unique findings and novel pathogenic variants. Patients ranged in ages from 22-74 years (mean 53.7 years) and were diagnosed at an age range of 11-65 years (mean 43.6 years), often after a history of progressive muscle disease of several years' duration. All 18 patients were treated with alglucosidase alfa (Lumizyme) and their response to treatment was monitored by measurements of their pulmonary function and muscle weakness, six-minute walk test (6MWT), and other functional studies. Results: Genetic sequencing revealed that 16 out of 18 individuals had the common c.-32-13T>G splicing variant, and six patients, including two sibships had four novel pathogenic variants: c.1594G>A, c.2655_2656delCG, c.1951-1952delGGinsT, and c.1134C>G. A male with the c.1594G>A variant developed an intracerebral aneurysm at the age of 43 years treated with surgery. Two siblings with the c.2655_2656delCG developed very high antibody titers, one of whom developed a severe infusion reaction. Other clinical features included BiPAP requirement in twelve, tinnitus in seven, scoliosis in five, cardiomyopathy in three, one individual was diagnosed with a cerebral aneurysm who underwent successful Penumbra coil placement, and another individual was diagnosed with both Graves' disease and testicular cancer. Conclusions: Our study illustrates significant variability in the range of clinical features, and the variable clinical response to enzyme replacement therapy. It also alerts us to the importance of careful monitoring and early management of complications. Possible genotype-phenotype associations with the novel mutations identified may emerge with larger studies.