No abstract

Mutua Madrileña Foundation, Fondation de l'Université de Lausanne et Centre Hospitalier Universitaire Vaudois, Instituto Carlos III, CIBERER, National Institutes of Health, Generalitat de Catalunya, Fundació CELLEX.

Summary. Patients with acute venous thromboembolism have an increased risk for occult malignancy. Limited screening for these malignancies has become common practice but little is known about its usefulness. This is a prospective cohort followup study in consecutive patients with acute venous thromboembolism. All patients underwent a routine clinical evaluation for malignancy, if negative, followed by a limited diagnostic work-up consisting of abdominal and pelvic ultrasound and laboratory markers for malignancy. Clinical follow-up was conducted to detect screening failures. The routine clinical evaluation was performed in 864 patients and revealed malignancy in 34 (3.9%) of them. Among the remaining 830 patients the limited diagnostic work-up revealed 13 further malignancies. During follow-up, cancer became symptomatic in 14 patients who were negative for cancer at screening (sensitivity of limited diagnostic work-up, 48.1%). Malignancies that were identified by the limited diagnostic work-up were early stage in 61% of cases vs. 14% in cases occurring during follow-up. Most patients with occult cancer had idiopathic venous thromboembolism and were older than 70 years. A limited diagnostic work-up for occult cancer in patients with venous thromboembolism has the capacity to identify approximately one-half of the malignancies. Identified malignancies were predominantly in an early stage.

Stroke-like episodes (SLE) occur in phosphomannomutase deficiency (PMM2-CDG), and may complicate the course of channelopathies related to Familial Hemiplegic Migraine (FHM) caused by mutations in CACNA1A (encoding CaV2.1 channel). The underlying pathomechanisms are unknown. We analyze clinical variables to detect risk factors for SLE in a series of 43 PMM2-CDG patients. We explore the hypothesis of abnormal CaV2.1 function due to aberrant N-glycosylation as a potential novel pathomechanism of SLE and ataxia in PMM2-CDG by using whole-cell patch-clamp, N-glycosylation blockade and mutagenesis. Nine SLE were identified. Neuroimages showed no signs of stroke. Comparison of characteristics between SLE positive versus negative patients’ group showed no differences. Acute and chronic phenotypes of patients with PMM2-CDG or CACNA1A channelopathies show similarities. Hypoglycosylation of both CaV2.1 subunits (α1A and α2α) induced gain-of-function effects on channel gating that mirrored those reported for pathogenic CACNA1A mutations linked to FHM and ataxia. Unoccupied N-glycosylation site N283 at α1A contributes to a gain-of-function by lessening CaV2.1 inactivation. Hypoglycosylation of the α2δ subunit also participates in the gain-of-function effect by promoting voltage-dependent opening of the CaV2.1 channel. CaV2.1 hypoglycosylation may cause ataxia and SLEs in PMM2-CDG patients. Aberrant CaV2.1 N-glycosylation as a novel pathomechanism in PMM2-CDG opens new therapeutic possibilities.