Factors affecting sports involvement in a school-based youth cohort: Implications for long-term athletic development.

The aim of the present study was to determine the factors affecting sports involvement in a school-based adolescent population. The cross-sectional cohort study assessed anthropometry, physical capacities and motor competence in 501 boys (aged 10-16 y), from junior (10-12 y) and senior (13-16 y) cohorts. Sports participation data was collected from junior participants. Multivariate analysis of covariance revealed moderate maturity, anthropometry, physical capacity and motor competence differences between sports in the senior cohort (F = 2.616, p < 0.001, η2 = .08), but not in the junior cohort. Furthermore, differences in physical fitness were revealed between playing levels (F = 2.616, p < 0.001, η2 = .08), with a discriminant analysis correctly classifying 73% of participants using aerobic fitness and vertical jump measures. Representative level participants engaged in more structured training and commenced organised competition at a later age (F = 4.332, p < 0.001, η2 = .21). This study's findings are twofold: 1) physical and motor competence profiles differ more between sports with increasing age, and 2) participants at a higher level of competition report delayed engagement in their main sport. As a result, schools may be the ideal environment in which to provide children and adolescents with the opportunity to sample different sports.

There is a need for new systemic sclerosis subset criteria. A content analytic approach.

OBJECTIVES: Systemic sclerosis (SSc) is heterogenous. The objectives of this study were to evaluate the purpose, strengths and limitations of existing SSc subset criteria, and identify ideas among experts about subsets. METHODS: We conducted semi-structured interviews with randomly sampled international SSc experts. The interview transcripts underwent an iterative process with text deconstructed to single thought units until a saturated conceptual framework with coding was achieved and respondent occurrence tabulated. Serial cross-referential analyses of clusters were developed. RESULTS: Thirty experts from 13 countries were included; 67% were male, 63% were from Europe and 37% from North America; median experience of 22.5 years, with a median of 55 new SSc patients annually. Three thematic clusters regarding subsetting were identified: research and communication; management; and prognosis (prediction of internal organ involvement, survival). The strength of the limited/diffuse system was its ease of use, however 10% stated this system had marginal value. Shortcomings of the diffuse/limited classification were the risk of misclassification, predictions/generalizations did not always hold true, and that the elbow or knee threshold was arbitrary. Eighty-seven percent use more than 2 subsets including: SSc sine scleroderma, overlap conditions, antibody-determined subsets, speed of progression, and age of onset (juvenile, elderly). CONCLUSIONS: We have synthesized an international view of the construct of SSc subsets in the modern era. We found a number of factors underlying the construct of SSc subsets. Considerations for the next phase include rate of change and hierarchal clustering (e.g. limited/diffuse, then by antibodies).

Prediction of cardiovascular risk in rheumatoid arthritis: performance of original and adapted SCORE algorithms.

OBJECTIVES: Predictive performance of cardiovascular disease (CVD) risk calculators appears suboptimal in rheumatoid arthritis (RA). A disease-specific CVD risk algorithm may improve CVD risk prediction in RA. The objectives of this study are to adapt the Systematic COronary Risk Evaluation (SCORE) algorithm with determinants of CVD risk in RA and to assess the accuracy of CVD risk prediction calculated with the adapted SCORE algorithm. METHODS: Data from the Nijmegen early RA inception cohort were used. The primary outcome was first CVD events. The SCORE algorithm was recalibrated by reweighing included traditional CVD risk factors and adapted by adding other potential predictors of CVD. Predictive performance of the recalibrated and adapted SCORE algorithms was assessed and the adapted SCORE was externally validated. RESULTS: Of the 1016 included patients with RA, 103 patients experienced a CVD event. Discriminatory ability was comparable across the original, recalibrated and adapted SCORE algorithms. The Hosmer-Lemeshow test results indicated that all three algorithms provided poor model fit (p<0.05) for the Nijmegen and external validation cohort. The adapted SCORE algorithm mainly improves CVD risk estimation in non-event cases and does not show a clear advantage in reclassifying patients with RA who develop CVD (event cases) into more appropriate risk groups. CONCLUSIONS: This study demonstrates for the first time that adaptations of the SCORE algorithm do not provide sufficient improvement in risk prediction of future CVD in RA to serve as an appropriate alternative to the original SCORE. Risk assessment using the original SCORE algorithm may underestimate CVD risk in patients with RA.

Performance of four current risk algorithms in predicting cardiovascular events in patients with early rheumatoid arthritis.

OBJECTIVE: This study was undertaken to assess the predictive ability of 4 established cardiovascular (CV) risk models for the 10-year risk of fatal and non-fatal CV diseases in European patients with rheumatoid arthritis. METHODS: Prospectively collected data from the Nijmegen early rheumatoid arthritis (RA) inception cohort was used. Discriminatory ability for CV risk prediction was estimated by the area under the receiver operating characteristic curve. Calibration was assessed by comparing the observed versus expected number of events using Hosmer-Lemeshov tests and calibration plots. Sensitivity and specificity were calculated for the cut-off values of 10% and 20% predicted risk. RESULTS: Areas under the receiver operating characteristic curve were 0.78-0.80, indicating moderate to good discrimination between patients with and without a CV event. The CV risk models Systematic Coronary Risk Evaluation (SCORE), Framingham risk score (FRS) and Reynolds risk score (RRS) primarily underestimated CV risk at low and middle observed risk levels, and mostly overestimated CV risk at higher observed risk levels. The QRisk II primarily overestimated observed CV risk. For the 10% and 20% cut-off values used as indicators for CV preventive treatment, sensitivity ranged from 68-87% and 40-65%, respectively and specificity ranged from 55-76% and 77-88%, respectively. Depending on the model, up to 32% of observed CV events occurred in patients with RA who were classified as low risk (<10%) for CV disease. CONCLUSIONS: Established risk models generally underestimate (Systematic Coronary Risk Evaluation score, Framingham Risk Score, Reynolds risk score) or overestimate (QRisk II) CV risk in patients with RA.

An increased risk of non-melanoma skin cancer during TNF-inhibitor treatment in psoriasis patients compared to rheumatoid arthritis patients probably relates to disease-related factors.

BACKGROUND: Concerns exist about a risk of non-melanoma skin cancer (NMSC) in psoriasis patients and rheumatoid arthritis (RA) patients treated with TNF-inhibitors. However, current data also show that in some psoriasis patients, NMSC is diagnosed relatively short after the start of TNF-inhibitors, which suggests that these NMSC can be explained by previous therapies instead of by TNF-inhibitor therapy. OBJECTIVE: To investigate whether there was a difference in time until first NMSC and the rate of NMSC between psoriasis and RA patients on TNF-inhibitors. METHODS: Time until first NMSC and the rate of NMSC were compared between psoriasis and RA patients from the same region treated with TNF-inhibitors and followed up for at least one year in prospective cohort studies, by using Cox regression and Poisson regression. Both analyses were corrected for confounders (age, gender, disease duration, prior NMSC, duration of anti-TNF and other systemic therapies). RESULTS: The NMSC risk was significantly higher in the psoriasis group [fully adjusted HR 6.0 (1.6-22.4 95%CI)] with a shorter time until first NMSC in psoriasis compared to RA. By Poisson regression, psoriasis patients had a 5.5 (2.2-13.4 95%CI) higher rate of NMSC. CONCLUSION: The time until first NMSC was significantly shorter and the rate of NMSC was significantly higher in psoriasis compared with RA. This indicates that disease-related factors like phototherapy may be important contributing factors to NMSC diagnosed in psoriasis patients treated with TNF-inhibitors.

The Yo-Yo intermittent recovery test level 1 is reliable in young high-level soccer players.

The aim of the study was to investigate test reliability of the Yo-Yo intermittent recovery test level 1 (YYIR1) in 36 high-level youth soccer players, aged between 13 and 18 years. Players were divided into three age groups (U15, U17 and U19) and completed three YYIR1 in three consecutive weeks. Pairwise comparisons were used to investigate test reliability (for distances and heart rate responses) using technical error (TE), coefficient of variation (CV), intra-class correlation (ICC) and limits of agreement (LOA) with Bland-Altman plots. The mean YYIR1 distances for the U15, U17 and U19 groups were 2024 ± 470 m, 2404 ± 347 m and 2547 ± 337 m, respectively. The results revealed that the TEs varied between 74 and 172 m, CVs between 3.0 and 7.5%, and ICCs between 0.87 and 0.95 across all age groups for the YYIR1 distance. For heart rate responses, the TEs varied between 1 and 6 bpm, CVs between 0.7 and 4.8%, and ICCs between 0.73 and 0.97. The small ratio LOA revealed that any two YYIR1 performances in one week will not differ by more than 9 to 28% due to measurement error. In summary, the YYIR1 performance and the physiological responses have proven to be highly reliable in a sample of Belgian high-level youth soccer players, aged between 13 and 18 years. The demonstrated high level of intermittent endurance capacity in all age groups may be used for comparison of other prospective young soccer players.

The effect of anti-TNF-α vs. DMARDs on fatigue in rheumatoid arthritis patients.

OBJECTIVES: Fatigue is experienced frequently by patients with rheumatoid arthritis (RA). Fatigue may be caused by high levels of pain and disease activity in RA but can remain present while disease activity is moderate to low. It is not clear whether RA patients receiving anti-tumour necrosis factor (TNF) treatment reach lower levels of acute fatigue than RA patients receiving disease-modifying anti-rheumatic drug (DMARD) treatment. The aim of our study was to analyse whether, in patients with RA, the effect of anti-TNF on fatigue is greater than the effect of DMARD treatment. METHOD: Sixty-seven RA patients receiving anti-TNF treatment and 104 RA patients receiving DMARDs were included. All patients were on stable treatment for at least 6 months prior to baseline measurement. Fatigue was measured monthly over 1 year with the fatigue severity subscale of the Checklist Individual Strength (CIS-fatigue). The association between persistent severe fatigue and medication group was analysed using multiple linear regression including confounders. RESULTS: In the anti-TNF group the mean (SD) level of persistent fatigue was significantly higher than in the DMARD group [32.2 (11.4) vs. 28.3 (10.9), p = 0.025] and more patients experienced persistent severe (CIS-fatigue score ≥ 35) fatigue (42% and 27% respectively, p = 0.043). However, when correcting for age, disease activity, haemoglobin, treatment duration, pain, physical disability, and clinical depression, medication type seemed to influence neither the mean level of persistent fatigue (p = 0.251) nor the percentage of patients with persistent severe fatigue (p = 0.745). CONCLUSIONS: When taking into account probable confounders including disease activity, medication type did not influence persistent fatigue in RA patients. It seems that, besides its anti-inflammatory effect, anti-TNF has no complementary effect on persistent fatigue.

Relative age, biological maturation and anaerobic characteristics in elite youth soccer players.

Being relatively older and having an advanced biological maturation status have been associated with increased likelihood of selection in young elite soccer players. The aims of the study were to investigate the presence of a relative age effect (RAE) and the influence of birth quarter on anthropometry, biological maturity and anaerobic parameters in 374 elite Belgian youth soccer players. The sample was divided into 3 age groups, each subdivided into 4 birth quarters (BQ). Players had their APHV estimated and height, weight, SBJ, CMJ, sprint 5 and 30 m were assessed. Overall, more players were born in BQ1 (42.3%) compared with players born in BQ4 (13.7%). Further, MANCOVA revealed no differences in all parameters between the 4 BQ's, controlled for age and APHV. These results suggest that relatively youngest players can offset the RAE if they enter puberty earlier. Furthermore, the results demonstrated possible differences between BQ1 and BQ4, suggesting that caution is necessary when estimating differences between players because of large discrepancies between statistical and practical significance. These findings also show that coaches should develop realistic expectations of the physical abilities of younger players and these expectations should be made in the context of biological characteristics rather than chronological age-based standards.

Synchronized turbo apoptosis induced by cold-shock.

In our research on the role of apoptosis in the pathogenesis of the autoimmune disease systemic lupus erythematosus (SLE), we aim to evaluate the effects of early and late apoptotic cells and blebs on antigen presenting cells. This requires the in vitro generation of sufficiently large and homogeneous populations of early and late apoptotic cells. Here, we present a quick method encountered by serendipity that results in highly reproducible synchronized homogeneous apoptotic cell populations. In brief, granulocytic 32Dcl3 cells are incubated on ice for 2 h and subsequently rewarmed at 37°C. After 30-90 min at 37°C more than 80-90% of the cells become early apoptotic (Annexin V positive/propidium iodide negative). After 24 h of rewarming at 37°C 98% of the cells were late apoptotic (secondary necrotic; Annexin V positive/propidium iodide positive). Cells already formed apoptotic blebs at their cell surface after approximately 20 min at 37°C. Inter-nucleosomal chromatin cleavage and caspase activation were other characteristics of this cold-shock-induced process of apoptosis. Consequently, apoptosis could be inhibited by a caspase inhibitor. Finally, SLE-derived anti-chromatin autoantibodies showed a high affinity for apoptotic blebs generated by cold-shock. Overall, cold-shock induced apoptosis is achieved without the addition of toxic compounds or antibodies, and quickly leads to synchronized homogeneous apoptotic cell populations, which can be applied for various research questions addressing apoptosis.

Preliminary criteria for the very early diagnosis of systemic sclerosis: results of a Delphi Consensus Study from EULAR Scleroderma Trials and Research Group.

OBJECTIVE: To identify a core set of preliminary items considered as important for the very early diagnosis of systemic sclerosis (SSc). METHODS: A list of items provided by European League Against Rheumatism (EULAR) Scleroderma Trial and Research(EUSTAR) centres were subjected to a Delphi exercise among 110 experts in the field of SSc. In round 1, experts were asked to choose the items they considered as the most important for the very early diagnosis of SSc. In round 2, experts were asked to reconsider the items accepted after the first stage. In round 3, the clinical relevance of selected items and their importance as measures that would lead to an early referral process were rated using appropriateness scores. RESULTS: Physicians from 85 EUSTAR centres participated in the study and provided an initial list of 121 items. After three Delphi rounds, the steering committee, with input from external experts, collapsed the 121 items into three domains containing seven items, developed as follows: skin domain (puffy fingers/puffy swollen digits turning into sclerodactily); vascular domain (Raynaud's phenomenon, abnormal capillaroscopy with scleroderma pattern) and laboratory domain (antinuclear, anticentromere and antitopoisomerase-I antibodies). Finally, the whole assembly of EUSTAR centres ratified with a majority vote the results in a final face-to-face meeting. CONCLUSION: The three Delphi rounds allowed us to identify the items considered by experts as necessary for the very early diagnosis of SSc. The validation of these items to establish diagnostic criteria is currently ongoing in a prospective observational cohort.

Clinical prediction of 5-year survival in systemic sclerosis: validation of a simple prognostic model in EUSTAR centres.

OBJECTIVE: Systemic sclerosis (SSc) is associated with a significant reduction in life expectancy. A simple prognostic model to predict 5-year survival in SSc was developed in 1999 in 280 patients, but it has not been validated in other patients. The predictions of a prognostic model are usually less accurate in other patients, especially from other centres or countries. A study was undertaken to validate the prognostic model to predict 5-year survival in SSc in other centres throughout Europe. METHODS: A European multicentre cohort of patients with SSc diagnosed before 2002 was established. Patients with SSc according to the preliminary American College of Rheumatology classification criteria were eligible for the study when they were followed for at least 5 years or shorter if they died. The primary outcome was 5-year survival after diagnosis of SSc. The predefined prognostic model uses the following baseline variables: age, gender, presence of urine protein, erythrocyte sedimentation rate (ESR) and carbon monoxide diffusing capacity (DLCO). RESULTS: Data were available for 1049 patients, 119 (11%) of whom died within 5 years after diagnosis. Of the patients, 85% were female, the mean (SD) age at diagnosis was 50 (14) years and 30% were classified as having diffuse cutaneous SSc. The prognostic model with age (OR 1.03), male gender (OR 1.93), urine protein (OR 2.29), elevated ESR (1.89) and low DLCO (OR 1.94) had an area under the receiver operating characteristic curve of 0.78. Death occurred in 12 (2.2%) of 509 patients with no risk factors, 45 (13%) of 349 patients with one risk factor, 55 (33%) of 168 patients with two risk factors and 7 (30%) of 23 patients with three risk factors. CONCLUSION: A simple prognostic model using three disease factors to predict 5-year survival at diagnosis in SSc showed reasonable performance upon validation in a European multicentre study.

The first parent-child diagnosis of a multifocal squamous odontogenic tumor: A case report.

Squamous odontogenic tumors (SOT) are rare, benign, odontogenic neoplasms of the jaws. The sporadically reported cases with multifocal SOTs seem to have a marked predilection for younger African American patients. In this case report a 14-year-old Caucasian male presented with swelling of the vestibular alveolar process, slight tooth divergence, and mobility. A multifocal squamous odontogenic tumor was diagnosed and subsequently treated twice with surgical enucleation. Two and a half years earlier his mother was diagnosed and treated for a similar multifocal SOT. Next-Generation-Sequencing targeted resequencing mutational analysis of the maternal surgical specimens was performed. No potential causal mutation could be identified. Postoperative follow-up of the patient showed no recurrence of the SOT after 2 years. This case report substantiates the possibility of a familial relationship in (multifocal) SOT, possibly changing current ideas concerning the etiology and treatment of these neoplasms.

Defining minimal disease activity in psoriatic arthritis: a proposed objective target for treatment.

OBJECTIVE: To create minimal disease activity (MDA) criteria for psoriatic arthritis (PsA). With recent therapeutic advances, this is now a goal for treatment and may represent a measure to compare therapies. It defines a satisfactory state of disease activity rather than a change, and encompasses all aspects of the disease. METHODS: 40 patient profiles were sampled from an observational PsA database. Sixty experts in PsA classified these as in MDA or not. A consensus of > or =70% was accepted, identifying 13 profiles in MDA. Summary statistics created possible cut-off points for the definition. Considering the number of measures that must be met, 35 candidate definitions were created and tested using receiver operating characteristic curves (ROC) for sensitivity and specificity. RESULTS: Four candidate definitions showed high area under the curve values on ROC testing. Definitions with high outlying values were excluded as they were not considered to represent MDA. Aiming for high specificity to reduce false positives resulted in a preference for the following definition: "A patient is classified as achieving MDA when meeting 5 of the 7 following criteria: tender joint count < or =1; swollen joint count < or =1; Psoriasis Activity and Severity Index < or =1 or body surface area < or =3; patient pain visual analogue score (VAS) < or =15; patient global disease activity VAS < or =20; health assessment questionnaire < or =0.5; tender entheseal points < or =1". CONCLUSION: This study provides the first definition of a "state" of MDA in PsA and defines a target for treatment. It must now be validated in other populations and tested in clinical trials.

The use of different methods for rapid determination of the ESR induces DAS28 misclassification in clinical practice.

OBJECTIVES: Monitoring of disease activity using DAS28 is more effective than routine RA care, but the ESR measurement is time consuming. Alternative rapid ESR determination methods can be used but effects on DAS28 classification are unknown. METHODS: Alternative rapid ESR methods, including the Starrsed 30-minute mode and Alifax Roller Test-1TH, were compared to the Westergren method. Mean difference, limits of agreement (LoA) and intraclass correlation coefficients (ICC) were calculated. Based on these results, using a longitudinal design the percentage of DAS28 misclassification for the Alifax Roller Test-1TH was measured. RESULTS: The Alifax showed acceptable ICCs, but LoA were large. ICC was 0.67 (0.56-0.76), LoA -43;34. The longitudinal study on the Alifax (n=125) showed an ICC of 0.93, a kappa of 0.61, but disease activity was misclassified in 26% of the patients. Use of the ESR from the previous visit resulted in comparable levels of misclassification. CONCLUSIONS: ESR measured by automated analysers like Alifax show acceptable ICC but LoA are large compared to the Westergren ESR. The Alifax Roller Test-1TH is very rapid but DAS28 misclassification is considerable and even as large as when using the ESR of the previous visit.

Disease activity as a risk factor for myocardial infarction in rheumatoid arthritis.

OBJECTIVE: Patients with rheumatoid arthritis (RA) are at greater risk of developing coronary heart disease than the general population. Systemic inflammation may contribute to this risk. This study investigated whether the level of disease activity is associated with the risk of developing myocardial infarction (MI) in patients with RA. METHODS: A case-control study was performed within a large prospective cohort of patients with RA. Cases were patients who developed their first MI after the diagnosis of RA, controls were patients with RA without MI. Cases and controls had similar RA disease duration. Traditional and disease-specific risk factors for MI were collected and a time-averaged disease activity score (DAS28) was calculated. The data were analysed using conditional logistic regression analysis. RESULTS: Cases of MI were significantly older, were more often male, with higher body mass index (BMI) and total cholesterol and lower high-density lipoprotein (HDL) serum levels than controls. Time-averaged disease activity was similar for cases and controls. The raw odds ratio for MI in patients with a "high" (>4.0) versus a "low" (

Development of quality indicators for monitoring of the disease course in rheumatoid arthritis.

OBJECTIVES: To suppress rheumatoid arthritis (RA) patients' disease activity, it should be periodically measured and patients should be treated on the basis of the disease activity outcomes. Insight into the actual care, by using quality indicators, is the first step in achieving optimal care. The objective of this study was to develop a set of quality indicators to evaluate RA disease course monitoring of rheumatologists in daily clinical practice. METHODS: A RAND-modified Delphi method in a five-step procedure was applied: a literature search for quality indicators and recommendations about disease course monitoring; a first questionnaire round; a consensus meeting; a second questionnaire round and drawing up the final set. RESULTS: The systematic procedure resulted in the development of 18 quality indicators: 10 process, five structure and three outcome indicators that describe seven domains of disease course monitoring: schedule follow-up visits; measure disease activity; functional impairment; structural damage; change medication; preconditions for measuring disease activity and outcome measures in terms of disease activity. CONCLUSIONS: This quality indicator set can be used to assess the quality of disease course monitoring of rheumatologists in daily clinical practice, and to determine for which aspects of disease course monitoring rheumatologists perform well, or where there is room for improvement. This information can be used to improve the quality of disease course monitoring.

Influence of age on the outcome of antitumour necrosis factor alpha therapy in rheumatoid arthritis.

OBJECTIVE: To investigate the influence of age on the effectiveness and tolerance of antitumour necrosis factor alpha (TNFalpha) therapy in rheumatoid arthritis (RA). METHODS: 730 patients of the Dutch Rheumatoid Arthritis Monitoring (DREAM) register were categorised into three groups according to their age at initiation of anti-TNFalpha therapy (<45, 45-65 and >65 years). Effectiveness of anti-TNFalpha therapy was primarily assessed by longitudinal analysis of the DAS28 during the first 12 months of treatment. RESULTS: Improvement in disease activity and physical functioning was significantly less in elderly patients, correcting for relevant confounders. Elderly patients reached the EULAR categories of good responders and remission less often than younger patients. Drug survival, co-medication use and tolerance were comparable between the three age groups. CONCLUSION: Anti-TNFalpha therapy significantly reduced disease activity in all age groups of patients; however, it appeared less effective in elderly compared with younger RA patients.

Evaluating guidelines on continuation of anti-tumour necrosis factor treatment after 3 months: clinical effectiveness and costs of observed care and different alternative strategies.

OBJECTIVE: To study the adherence of rheumatologists to the Dutch guidelines for anti-tumour necrosis factor alpha (TNF-alpha) treatment. The secondary objective was to evaluate alternatives to the present guidelines with regard to the percentage of responders and costs. METHODS: The response (>1.2 DAS28 decrease) in patients who started on anti-TNF-alpha treatment for the first time was evaluated at 3 and 6 months after initiation. How many patients continued or discontinued their initial anti-TNF-alpha treatment was evaluated. Possible alternative guidelines were evaluated by means of a decision tree, with regard to the expected percentage of successfully (responders) and unsuccessfully treated patients and expected costs. RESULTS: At 3 months 56% (N = 306) and 44% (N = 233) of all 539 evaluable patients were classified as responders or non-responders, respectively. Despite the guidelines, most (81%) (N = 189) of the non-responders continued treatment. 37% of the non-responders who continued anti-TNF-alpha treatment were eventually classified as responders at 6 months. Decision analytical modelling showed that with equal expected costs all alternative strategies would result in more responders than according to theoretical full adherence with the guidelines. "Continuation in case of partial response" had the best trade-off between successfully treated patients (64%) and unsuccessfully treated patients (17%). CONCLUSION: There was suboptimal adherence to the Dutch guidelines for treatment with anti-TNF-alpha for rheumatoid arthritis patients. This seemed to be justified by the fact that a delayed response up to 6 months was shown. If treatment is continued despite a non-response at 3 months, this is only recommended in patients with at least a partial response (at least 0.6 DAS28 improvement).

Naturally occurring mutations in intestinal sucrase-isomaltase provide evidence for the existence of an intracellular sorting signal in the isomaltase subunit.

Mutations in the sucrase-isomaltase gene can lead to the synthesis of transport-incompetent or functionally altered enzyme in congenital sucrase-isomaltase deficiency (CSID) (Naim, H. Y., J. Roth, E. Sterchi, M. Lentze, P. Milla, J. Schmitz, and H. P. Hauri. J. Clin. Invest. 82:667-679). In this paper we have characterized two novel mutant phenotypes of CSID at the subcellular and protein levels. The first phenotype revealed a sucrase-isomaltase protein that is synthesized as a single chain, mannose-rich polypeptide precursor (pro-SI) and is electrophoretically indistinguishable from pro-SI in normal controls. By contrast to normal controls, however, pro-SI does not undergo terminal glycosylation in the Golgi apparatus. Subcellular localization of pro-SI by immunoelectron microscopy revealed unusual labeling of the molecule in the basolateral membrane and no labeling in the brush border membrane thus indicating that pro-SI is missorted to the basolateral membrane. Mapping of biosynthetically labeled pro-SI with four epitope- and conformation-specific monoclonal antibodies suggested that conformational and/or structural alterations in the pro-SI protein have prevented posttranslational processing of the carbohydrate chains of the mannose-rich precursor and have lead to its missorting to the basolateral membrane. The second phenotype revealed two variants of pro-SI precursors that differ in their content of mannose-rich oligosaccharides. Conversion of these forms to a complex glycosylated polypeptide occurs at a slow rate and is incomplete. Unlike its counterpart in normal controls, pro-SI in this phenotype is intracellularly cleaved. This cleavage produces an isomaltase-like subunit that is transport competent and is correctly sorted to the brush border membrane since it could be localized in the brush border membrane by anti-isomaltase mAb. The sucrase subunit is not transported to the cell surface and is most likely degraded intracellularly. We conclude that structural features in the isomaltase region of pro-SI are required for transport and sorting of the sucrase-isomaltase complex.