Leukocyte Adhesion Deficiency II

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LAD II syndrome results from a general defect in fucose metabolism, causing the absence of SLeX and other fucosylated ligands for the selectins. LAD II was first described in two unrelated Arab consanguineous parents (Etzioni et al. 1992). This is an extremely rare condition with only six patients reported (Y akubenia and Wild 2006).

Affected children were born after uneventful pregnancies with normal height and weight. No delay in the separation of the umbilical cord was observed. They have severe mental retardation, short stature, a distinctive facial appearance, and the rare Bombay (hh) blood phenotype. From early life, they have suffered from recurrent episodes of bacterial infections, mainly pneumonia, periodontitis, otitis media, and localized cellulitis. During times of infections, the neutrophil count increases up to 150,000/|l. Several mild to moderate skin infections, without obvious pus have also been observed (Wild et al. 2002). The infections have not been life-threatening events and are usually treated in the outpatient clinic. Interestingly, after the age of 3 years, the frequency of infections has decreased and the children no longer need prophylactic antibiotics. At older age, their main infectious problem is severe perio-dontitis as is also observed in patients with LAD I (Etzioni et al. 1998).

Overall, the infections in LAD II appear to be comparable to the moderate rather than the severe phenotype of LAD I. It is possible that the ability of LAD II neutro-phils to adhere and transmigrate via p2-integrin under conditions of reduced shear forces (von Andrian et al. 1993) may permit some neutrophils to emigrate at sites of severe inflammation, where flow may be impaired, thereby allowing some level of neutrophil defense against bacterial infections. Rolling, the first step in neutrophil recruitment to site of inflammation, is mediated primarily by the binding of the se-lectins to their fucosylated glycoconjugate ligands. Using intravital microscopy, it was observed that the rolling fraction of normal donor neutrophils in this assay was around 30%, and LAD I neutrophils behaved similarly. In contrast, LAD II neutrophils rolled poorly (only 5%) and failed to emigrate (von Andrian et al. 1993).

Since the first two LAD II patients identified were the offspring of first-degree relatives and since the parents were clinically unaffected, autosomal recessive inheritance was assumed. In addition to the Bombay phenotype (absence of the H antigen), the cells of LAD II patients were also found to be Lewis A- and B-negative, and the patients were non-secretors. The three blood phenotypes (Bombay, Lewis A, and B) have in common a lack of fucosylation of glycoconjugates. These facts suggested that the primary defect in LAD II must instead be a general defect in fucose production. After the observation that the defect in the Arab patients may be localized in the de novo GDP-1-fucose biosynthesis pathway (Karsan et al. 1998), the two enzymes involved with this pathway, GMD and FX protein, were measured and were found to be normal with no mutation in cDNA isolated from LAD II patients. Another child, from a Turkish origin, was also described with LAD II in whom decreased GDP-1-fucose transport into the Golgi vesicles was detected (Lubke et al. 1999).

Using the complementation cloning technique, the human gene encoding the fucose transporter was found to be located on chromosome 11. The Turkish child was found to be homozygous for a mutation at amino acid 147 in which arginine is changed to cysteine, while the two Arab patients examined were found to have a mutation in amino acid 308 in which threonine is changed to arginine (Lubke et al. 2001). Both mutations are located in highly conserved transmembrane domains through evolution. LAD II is thus one of the group of congenital disorders of glyco-sylation (CDG) and is classified as CDG-IIc. In some cases, the mutated (nonfunctional) transporter is correctly located in the Golgi apparatus, while in two patients, the truncated transporter was unable to localize to the Golgi complex (Helmus et al. 2006). Although only four mutations were described, some genotype-phenotype correlation can be observed.

From the biochemical aspect, once the primary defect was found, several studies were carried out to clarify the defect. As growth and mental retardation are prominent features of LAD II, and Notch protein which are important in normal development contain fucose, Sturla et al. (2003) looked at the fucosylation process in LAD II. Frac-tionation and analysis of the different classes of glycans indicated that the decrease in fucose incorporation is not generalized and is mainly confined to terminal fucosylation of N-linked oligosaccharides. In contrast, the total levels of protein O-fucosylation, including that observed in Notch protein, were unaffected. Indeed, it was recently observed that the O-fucosylation process take place in the endoplasmatic compartment and not in the Golgi apparatus (Luo and Haltiwanger 2005). Thus, it is still unclear what leads to the severe developmental delay observed in LAD II.

LAD II is a very rare syndrome described so far only in six children. As the clinical phenotype is very striking, the diagnosis can be made based on the presence of recurrent, albeit mild infections, marked leukocytosis, and the Bombay blood group, in association with mental and growth retardation. An analysis of peripheral blood leukocytes by flow cytometry using a CD15s monoclonal antibody should be performed to determine SLeX expression. To confirm the diagnosis, sequence analysis of the gene encoding the GDP-fucose transporter should be performed.

Each of the patients described so far with LAD II suffered from several episodes of infections, which responded well to antibiotics. No serious consequences were observed, and prophylactic antibiotic is not needed. The patients' main chronic problem has been periodontitis, a condition that is especially difficult to treat in children with severe mental retardation (Etzioni et al. 1998). The oldest LAD II patient is now 19 years and has a severe psychomotor retardation with mild infectious problems.

Because of the proposed defect in fucose production, supplemental administration of fucose to the patients has been suggested. Indeed, fucose supplementation caused a dramatic improvement in the condition of the Turkish child (Marquardt et al. 1999). A marked decrease in leukocyte count with improved neutrophil adhesion was noted. Unfortunately, while using exactly the same protocol, no improvement in laboratory data or clinical features was seen in the two Arab children (Etzioni and Tonetti 2000). This difference may be due to the fact that the genetic defect in the Turkish child leads to a decreased affinity of the transporter for fucose, and thus an increase in the cytosolic concentration of fucose would be expected to overcome, at least in part, the defect in fucose transport.

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