Review of clinical presentation and diagnosis of mucopolysaccharidosis IVA.

Mucopolysaccharidosis type IVA (MPS IVA) was described in 1929 by Luis Morquio from Uruguay and James Brailsford from England, and was later found as an autosomal recessive lysosomal storage disease. MPS IVA is caused by mutations in the gene encoding the enzyme, N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Reduced GALNS activity results in impaired catabolism of two glycosaminoglycans (GAGs), chondroitin-6-sulfate (C6S) and keratan sulfate (KS). Clinical presentations of MPS IVA reflect a spectrum of progression from a severe "classical" phenotype to a mild "attenuated" phenotype. More than 180 different mutations have been identified in the GALNS gene, which likely explains the phenotypic heterogeneity of the disorder. Accumulation of C6S and KS manifests predominantly as short stature and skeletal dysplasia (dysostosis multiplex), including atlantoaxial instability and cervical cord compression. However, abnormalities in the visual, auditory, cardiovascular, and respiratory systems can also affect individuals with MPS IVA. Diagnosis is typically based on clinical examination, skeletal radiographs, urinary GAG, and enzymatic activity of GALNS in blood cells or fibroblasts. Deficiency of GALNS activity is a common assessment for the laboratory diagnosis of MPS IVA; however, with recently increased availability, gene sequencing for MPS IVA is often used to confirm enzyme results. As multiple clinical presentations are observed, diagnosis of MPS IVA may require multi-system considerations. This review provides a history of defining MPS IVA and how the understanding of the disease manifestations has changed over time. A summary of the accumulated knowledge is presented, including information from the International Morquio Registry. The classical phenotype is contrasted with attenuated cases, which are now being recognized and diagnosed more frequently. Laboratory based diagnoses of MPS IVA are also discussed.

Multidisciplinary management of Hunter syndrome.

Hunter syndrome is a rare, X-linked disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase. In the absence of sufficient enzyme activity, glycosaminoglycans accumulate in the lysosomes of many tissues and organs and contribute to the multisystem, progressive pathologies seen in Hunter syndrome. The nervous, cardiovascular, respiratory, and musculoskeletal systems can be involved in individuals with Hunter syndrome. Although the management of some clinical problems associated with the disease may seem routine, the management is typically complex and requires the physician to be aware of the special issues surrounding the patient with Hunter syndrome, and a multidisciplinary approach should be taken. Subspecialties such as otorhinolaryngology, neurosurgery, orthopedics, cardiology, anesthesiology, pulmonology, and neurodevelopment will all have a role in management, as will specialty areas such as physiotherapy, audiology, and others. The important management topics are discussed in this review, and the use of enzyme-replacement therapy with recombinant human iduronate-2-sulfatase as a specific treatment for Hunter syndrome is presented.

Severity of iron overload in patients with sickle cell disease receiving chronic red blood cell transfusion therapy.

Chronic transfusion therapy is being used more frequently to prevent and treat the complications of sickle cell disease. Previous studies have shown that the iron overload that results from such therapy in other patient populations is associated with significant morbidity and mortality. In this study we examined the extent of iron overload as well as the presence of liver injury and the predictive value of ferritin in estimating iron overload in children with sickle cell disease who receive chronic red blood cell transfusions. A poor correlation was observed between serum ferritin and the quantitative iron on liver biopsy (mean 13.68 +/- 6.64 mg/g dry weight; R = 0.350, P =.142). Quantitative iron was highly correlated with the months of transfusion (R = 0.795, P <.001), but serum ferritin at biopsy did not correlate with months of transfusion (R = 0.308, P =.200). Sixteen patients had abnormal biopsies showing mild to moderate changes on evaluation of inflammation or fibrosis. Liver iron was correlated with fibrosis score (R = 0.50, P =.042). No complications were associated with the liver biopsy. Our data suggest that, in patients with sickle cell disease, ferritin is a poor marker for accurately assessing iron overload and should not be used to direct long-term chelation therapy. Despite high levels of liver iron, the associated liver injury was not severe.

Effects of red blood cell transfusion on resting energy expenditure in adolescents with sickle cell anemia.

BACKGROUND: Previous studies indicate that resting energy expenditure is elevated in children with sickle cell anemia, possibly caused in part by hemolysis and increased erythropoietic activity. The purpose of the present investigation was to determine whether erythrocyte transfusion normalizes resting energy expenditure in sickle cell anemia. METHODS: Five adolescents with sickle cell anemia (12-16 years old; 4 boys, 1 girl) were studied before and 1 week after erythrocyte transfusion before elective surgery or at the initial transfusion for growth failure. Resting energy expenditure was measured by indirect calorimetry, and laboratory measures were determined by routine, validated methods. Data comparisons were by nonparametric analysis. RESULTS: After erythrocyte transfusion, total hemoglobin levels increased (difference (D) = 15 g/l; p < 0.05), whereas hemoglobin S (D = -0.36; p < 0.05) and reticulocyte count (D = -0.12; p < 0.05) decreased. Mean pretransfusion resting energy expenditure was elevated to 124% above predicted levels (p < 0.05) and increased further to 134% above prediction (p < 0.05 vs. pretransfusion levels). Plasma triiodothyronine (T3) levels increased (D = 0.17 nmol/l; p < 0.05), reverse T3 (rT3) levels tended to decline (D = -0.04 nmol/l; p = 0.14), and rT3/T3 decreased (D = -0.03; p < 0.05). Plasma insulin-like growth factor-I (IGF-I) levels were low-normal before transfusion and did not change, despite the change in resting energy expenditure. CONCLUSIONS: The results confirm that resting energy expenditure is elevated in patients with sickle cell anemia. However, resting energy expenditure further increased after transfusion, despite decreased erythropoietic activity. A posttransfusion decrease in rT3/T3 may contribute to the increased resting energy expenditure. That there was no change in IGF-I implies that the growth hormone-IGF system is not involved in posttransfusion regulation of resting energy expenditure. Therefore, our data are not consistent with the hypothesis that increased resting energy expenditure in sickle cell anemia is directly related to erythropoietic activity. The mechanisms by which resting energy expenditure increases after transfusion in sickle cell anemia require additional investigation.

Ontogeny of Ia messenger RNA in the mouse small intestinal epithelium is modulated by age of weaning and diet.

BACKGROUND: Exogenous antigenic peptides are presented to T cells by class II major histocompatibility complex (Ia) molecules on the surface of antigen-presenting cells. Class II-associated invariant chain (Ii) is also required for effective antigen presentation. Because messenger RNAs (mRNAs) for Ii chain and for class II I-A beta chain appear in the mouse intestinal epithelium after weaning, experiments were conducted to test the effect of age of weaning and diet on the appearance of Ia and Ii mRNA. METHODS: Four litters were split at day 17; one half was weaned and the other remained with the mother until day 24. On day 23, 25, 27, and 29, enterocytes were isolated from full-length small intestine by vascular perfusion with 30 mmol/L ethylenediaminetetraacetic acid, and the RNA was extracted. RESULTS: Appearance of Ii and I-A beta was significantly delayed by late weaning, as judged by RNA hybridization blots (Ii chain) and complementary DNA amplification (I-A beta chain). In mice on elemental diets, the appearance of Ii and I-A beta chain was delayed compared with littermates reared on standard chow. Ii mRNA failed to appear in mice maintained on the elemental diet by day 40, despite normal growth. CONCLUSIONS: Appearance of mRNA for both Ia and Ii depends on the introduction of a complex diet and not the "stress" of weaning or elimination of breast milk. Introduction of foreign dietary antigens or development of an altered intestinal flora may contribute to this process.

Effect of thermal injury on transfer of IR22 IgA myeloma protein into bile in the rat.

We previously observed a 75-90% decrease in concentration of biliary IgA after thermal injury to rat skin. Decrease in biliary IgA might result from an alteration in supply of polymeric IgA delivered to the hepatocyte or from an alteration in hepatocyte transfer of polymeric IgA into bile. In the present study, we examined the transfer of intravenously administered 125I-IgA into bile. Purified IR22 rat IgA myeloma protein consisting of both monomeric and polymeric IgA was labelled with 125I. Sprague-Dawley rats (140-180 g) received a 20-30% body surface area scald-burn or sham treatment. The bile duct was cannulated 18-24 h later and 125I-IgA preparations were injected into the tail vein. Bile was collected under light ether anesthesia for 3 h. In rats injected with 125I-IR22 IgA myeloma protein there were no significant differences in total, TCA-precipitable, or immunoprecipitable radioactivity in bile from burn-injured or sham-treated animals. On Bio-Gel A-1.5 m gel permeation, the radioactivity in bile from sham-treated animals eluted in the region of polymeric IgA as expected; the radioactivity in the bile from burn-injured animals eluted equally in the same regions as polymeric IgA and monomeric IgA. In sham-treated rats injected with isolated polymeric IgA only, bile contained primarily polymeric IgA. In burn-injured rats injected with polymeric IgA only, bile contained a mixture of polymeric IgA and monomeric IgA. These findings suggest that hepatocyte processing of polymeric IgA is altered after thermal injury, resulting in the transformation of some polymeric IgA into its monomeric form.

Reduction in biliary IgA after burn injury. Role of diminished delivery via the thoracic duct and of enhanced loss from the systemic circulation.

The concentration of biliary IgA is greatly reduced after scald burn injury in the rat, thereby contributing to a deficiency in upper intestinal immune defense. This reduction in biliary IgA might have several explanations, including failure of the transhepatic transport of polymeric IgA (pIgA) from the circulation, decreased delivery of pIgA to the hepatocyte, or decreased local synthesis of IgA in the liver. The authors examined whether burn injury reduces circulating pIgA available for delivery to the hepatocyte. In initial studies, they demonstrated that burn injury induces a decrease in circulating pIgA in bile-duct-ligated rats. They then sought to determine whether this decrease in pIgA was due to increased loss from the circulation or to a decreased supply of pIgA to the circulation through the thoracic duct. After injection of purified 125I-pIgA into bile duct-ligated rats, radioactivity was removed more rapidly from the circulation of burn-injured compared with control rats. The radioactivity localized in the skin and muscle at the site of burn injury. In another group of rats with patent bile ducts, the thoracic duct was cannulated and lymph collected for 12 hours. The total amount of IgA protein in lymph was found to be reduced in burn-injured compared with control animals. Thus, burn injury is accompanied by reduced circulating pIgA, which may be attributed to its enhanced loss from the circulation and to decreased delivery of pIgA from the intestinal mucosa to the systemic circulation via the thoracic duct.

Effect of thermal injury in the rat on transfer of IgA protein into bile.

Severe thermal injury is associated with bacterial sepsis; the intestine is considered a likely source of invasive organisms. Because IgA antibody in bile accounts for much of the specific immune defense of the upper intestinal tract in the rat, the effect of thermal injury on the quantity of IgA protein in bile was examined. Sprague-Dawley rats received a 20% to 30% body surface area burn under anesthesia. Eighteen hours later the common bile duct was cannulated and bile was collected for three hours. Total IgA protein in bile decreased 90% after thermal injury. The bile volume, the concentration of bile protein, and free secretory component did not change significantly. Although blood flow to the liver 18 hours after thermal injury was not changed, there was a significant reduction in total IgA concentration in the circulation; both monomeric (m-IgA) and polymeric IgA (p-IgA) were decreased. This finding may explain, in part, the reduced concentration of IgA protein in bile. Although not examined in this study, decreased local hepatic synthesis and/or transport of p-IgA across the hepatocyte may also contribute to the reduced IgA levels in bile.

Prolactin is transported across the epithelium of the jejunum and ileum of the suckling rat.

Milk prolactin is transferred from the gastrointestinal tract to the circulation of the suckling rat. To identify the site of prolactin penetration and to determine the mechanism by which the hormone traverses the mucosal barrier, we followed the uptake of prolactin from ligated loops of jejunum or ileum in vivo by three methods: autoradiography, transport of prolactin-gold conjugates, and immunocytochemistry. Autoradiographic studies demonstrated specific binding sites for 125I-prolactin on apical membranes of the jejunum and ileum. Excess cold prolactin reduced radiolabel in apical and basal compartments. Gel autoradiography of portal sera showed the presence of intact prolactin and a prolactin fragment following jejunal transport but only a prolactin fragment following ileal transport. Uptake of prolactin-gold conjugates demonstrated that, in the jejunum, label was present at the luminal surface, within endosomal compartments and lysosomes, in basal coated and smooth vesicles, within basal coated pits, and beyond the basolateral surface. In the ileum, label was found at the luminal surface; within the tubulocisternae, endosomal vesicles, lysosomes, and basal smooth vesicles; and beyond the basolateral surface. Immunoreactive prolactin was present throughout the transepithelial pathways. This study demonstrates that prolactin is selectively and nonselectively absorbed in the jejunum and ileum and that the hormone is directed either to the lysosome for degradation or across the epithelium by means of a transcellular pathway.

Hepatobiliary clearance of IgA immune complexes formed in the circulation.

The formation and clearance of circulating IgA immune complexes from blood to bile was investigated in this study. The i.v. injection of either MOPC-315, an IgA M-component with antidinitrophenyl (DNP) specificity, or TEPC-15, an IgA M-component of a different specificity, was followed by i.v. injection of 125I-DNP10-bovine serum albumin (BSA) as the antigen. The formation and clearance of IgA immune complexes in the circulation of MOPC-315-treated, but not TEPC-15-treated animals was demonstrated by immunoprecipitation with polyacrylamide beads coated with rabbit anti-mouse IgA. IgA-125I-DNP10-BSA complexes were identified in the bile from MOPC-315-treated, but not TEPC-15-treated animals utilizing this same immunoprecipitation technique. These observations suggest that the liver or bile ducts transport IgA immune complexes from blood into bile. The clearance of 125I-DNP10-BSA from the circulation was documented by coprecipitation with rabbit anti-BSA and BSA. The clearance of this circulating antigen was slower in the MOPC-315-treated than in the TEPC-15-treated animals suggesting that under the conditions of the present experiment, circulating antigen is cleared more slowly after IgA immune complex formation.