TRAPPC9-CDG: A novel congenital disorder of glycosylation with dysmorphic features and intellectual disability

PurposeTRAPPC9 deficiency is an autosomal recessive disorder mainly associated with intellectual disability (ID), microcephaly, and obesity. Previously, TRAPPC9 deficiency has not been associated with biochemical abnormalities.MethodsExome sequencing was performed in 3 individuals with ID and dysmorphic features. N-Glycosylation analyses were performed in the patients’ blood samples to test for possible congenital disorder of glycosylation (CDG). TRAPPC9 gene, TRAPPC9 protein expression, and N-glycosylation markers were assessed in patient fibroblasts. Complementation with wild-type TRAPPC9 and immunofluorescence studies to assess TRAPPC9 expression and localization were performed. The metabolic consequences of TRAPPC9 deficiency were evaluated using tracer metabolomics.ResultsAll 3 patients carried biallelic missense variants in TRAPPC9 and presented with an N-glycosylation defect in blood, consistent with CDG type I. Extensive investigations in patient fibroblasts corroborated TRAPPC9 deficiency and an N-glycosylation defect. Tracer metabolomics revealed global metabolic changes with several affected glycosylation-related metabolites.ConclusionWe identified 3 TRAPPC9 deficient patients presenting with ID, dysmorphic features, and abnormal glycosylation. On the basis of our findings, we propose that TRAPPC9 deficiency could lead to a CDG (TRAPPC9-CDG). The finding of abnormal glycosylation in these patients is highly relevant for diagnosis, further elucidation of the pathophysiology, and management of the disease.     

Apoptotic U1-70 kd is antigenically distinct from the intact form of the U1-70-kd molecule

OBJECTIVE: To determine whether immune responses to an apoptotically modified form of a human lupus autoantigen can be distinguished from immune responses to the intact form of the same antigen. METHODS: Immunoblot and enzyme-linked immunosorbent assay techniques were used to test human autoimmune sera for the presence of antibodies to apoptotic forms of the U1- 70-kd small nuclear RNP antigen, while antibody recognition of intact U1-70 kd was blocked. RESULTS: poptosis-specific U1-70-kd antibodies were identified by immunoblot in 15 of 29 sera with antibodies to intact U1-70 kd and in 2 of 25 sera without measurable antibodies to intact U1-70 kd. Bacterially produced, purified, caspase-cleaved U1-70 kd without additional posttranslational modifications was a target of apoptosis-specific antibodies in 3 of 9 U1-70-kd-positive sera tested. CONCLUSION: The apoptotic form of U1-70 kd displays B cell epitopes that are not displayed on the intact form of U1-70 kd. Caspase cleavage in the absence of additional posttranslational modifications is sufficient to induce the display of some of these epitopes. Immunity to apoptotically modified proteins can develop against caspase-cleaved forms or against forms that undergo additional posttranslational modification.     

Liver adenomatosis: serial investigation on MRI

Purpose

To describe the natural history of liver adenomatosis (LA), including complications and changes in lesion size over time.

Materials and methods

Eighteen patients with clinical diagnosis of LA were included. Clinical and biochemical information were collected. The initial and follow-up MR studies were reviewed retrospectively to determine change in lesion size and imaging features.

Results

Seventeen patients were women (94.4%). The mean age of the initial MR study was 37.0 years (18–52 years). The median size of the largest lesion was 6.7 cm (range 3.0–13.5 cm). Intratumoral bleeding was detected on MRI in 9 lesions, in 7 patients (38.8%). The median size for hemorrhagic lesions was 7.6 cm (range 4.1–13.5 cm). During the mean follow-up period of 29.4 (range 4–98) months, 10 patients had stable disease (55.6%), and 8 patients had tumor regression (44.4%). Of 8 patients who were followed without intervention, 3 patients (37.5%) had spontaneous regression. No malignant transformation or lesion progression was occurred.

Conclusion

During an over 2-year follow-up period, the majority of lesions of LA appeared to remain stable or showed tumor regression. Spontaneous tumor regression can be observed in approximately 37% of individuals in the age range of 28–53 years.     

Unsuspected rickettsioses among patients with acute febrile illness, Sri Lanka, 2007

We studied rickettsioses in southern Sri Lanka. Of 883 febrile patients with paired serum samples, 156 (17.7%) had acute rickettsioses; rickettsioses were unsuspected at presentation. Additionally, 342 (38.7%) had exposure to spotted fever and/or typhus group rickettsioses and 121 (13.7%) scrub typhus. Increased awareness of rickettsioses and better tests are needed.     

Osteoporosis and Cardiovascular Risk Among Premenopausal Women in Sri Lanka

We examined the association between bone mineral density (BMD) and cardiovascular risk in a group of premenopausal women selected from the Southern province of Sri Lanka. One hundred six previously healthy premenopausal volunteers (aged 30–54 yr) were recruited by open invitations. Subjects with previous history of diabetes, hypertension, epilepsy, chronic renal or liver disease, hyperlipidemia, ischemic heart disease, endocrine diseases, or prolonged inflammatory conditions were excluded. Subjects who were taking medications that can affect bone density, blood sugar, serum lipids, or blood pressure (BP) were also excluded. Women with the history of previous fractures were not excluded. BMDs in the spine, hip, and total body (TB) were measured using a Hologic Discovery scanner (Hologic Inc, Bedford, MA). BP, fasting glucose, and fasting lipids were also measured. Independent of body mass index (BMI) and age, TB bone mineral content (BMC) and spine BMD showed inverse and significant correlations with total cholesterol (TC), low density cholesterol, and the ratio between TC and high density lipoprotein cholesterol (r ranged from ?0.24 to ?0.27, p < 0.05 for all). The highest mean lipid levels were seen among the women in the lowest third of spine BMD, whereas women in the upper third of spine BMD had the lowest lipid levels. The number of women with metabolic syndrome in the 3 tirtiles of spine BMD was not significantly different. Fasting glucose or BP had no association with either BMD or BMC. In conclusion, our data demonstrates an association, independent of age and BMI, between BMD and BMC or lipid levels among previously healthy, premenopausal women. This may explain the high cardiovascular risk seen in women with osteoporosis in old age.     

Sarcomere length changes during end-held (isometric) contractions in intact mammalian (rat) fast and slow muscle fibres

The sarcomere length change, within a 2 mm region, during end-held isometric contractions in intact rat fast and slow muscle fibre bundles was investigated at 20°C and an initial sarcomere length of 2.68 m using He–Ne laser diffraction. In some experiments, the fibre segment displacement was monitored with markers (pieces of human hair) placed at regular intervals on the surface of the muscle fibre bundles. The sarcomere length changes, monitored near the proximal end of the bundle (transducer end), during tetanic contractions were similar to those previously reported in frog muscle fibres. Thus, throughout the tension plateau, sarcomere length remained constant (and shortened) but showed evidence of non-uniform sarcomere behaviour (further shortening) during the rapid tension relaxation phase. Such non-uniform behaviour was not seen during twitch contractions. During a twitch contraction, sarcomeres at the proximal end shortened rapidly at first and continued to shorten – or remained shortened – until the tension had relaxed to between 20–23% of its peak value before lengthening back to the original length. The maximum twitch sarcomere shortening (mean ± SEM) was 5.9 ± 0.2% (n = 16) in fast and 5.4 ± 0.3% (n = 14) in slow fibre bundles at 20°C; sarcomere shortening near body temperature (35°C) was greater, 8.8 ± 0.2% (n = 7) in fast and 8.1 ± 0.2% (n = 5) in slow fibre bundles. Increasing the initial sarcomere length of a preparation decreased the extent of sarcomere shortening and reducing the amount of sarcomere shortening, by sarcomere length clamping, markedly increased the peak twitch tension without significantly altering the twitch time course. When examined at different positions along muscle fibres, a sarcomere shortening was observed along much of the fibre length in most preparations. However, in about a third of the preparations some sarcomere lengthening was recorded in the distal end, but its amplitude was too small to accommodate the fibre shortening elsewhere. Complementary data were obtained using the surface marker technique. The displacement was largest and in opposite – but fibre shortening – direction in the markers placed 0.5–1.0 mm away from the two tendon attachments; the markers placed at or near the centre of the fibre bundle showed the least amount of displacement. The findings suggest that the compliant region, where lengthening occurs, is at fibre ends, i.e. near myotendinous junction.     

Pressure-induced changes in the isometric contractions of single intact frog muscle fibres at low temperatures

Summary Effects of increased hydrostatic pressure (range 0.1–10 MPa) on isometric twitch and tetanic contractions of single intact muscle fibres, isolated from frog tibialis anterior muscle, were examined at 4–12° C. The tension changes produced on exposure to steady high pressures are compared with those produced on exposure to low concentrations of caffeine (0.5 mm, subthreshold for contracture) and when pressure is rapidly released during a contraction. The peak twitch tension was potentiated by pressure accompanied by increased rate of tension rise and increased duration; the pressure sensitivity of twitch tension was 8% mPa^-1. The correlation between the rate of tension rise and peak tension in caffeine-induced twitch tension potentiation was quantitatively similar to that in pressure-induced twitch potentiation. Experiments involving the rapid release of pressure (2 ms) during twitch contractions demonstrate that high pressure need only be maintained for a brief period during the early part of tension development to elicit full twitch potentiation. The tetanic tension was depressed by pressure (1% MPa^-1). Results demonstrate that the major effect of increased hydrostatic pressure on intact muscle fibres, which results in tension potentiation, is complete very early during contraction and is similar to that of caffeine.