Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome

Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS) represent the two ends of a clinical spectrum of disease caused by deficiency of mevalonate kinase (MVK), the first committed enzyme of cholesterol biosynthesis. At least 30 patients with MVA and 180 patients with HIDS have been reported worldwide. MVA is characterized by psychomotor retardation, failure to thrive, progressive cerebellar ataxia, dysmorphic features, progressive visual impairment and recurrent febrile crises. The febrile episodes are commonly accompanied by hepatosplenomegaly, lymphadenopathy, abdominal symptoms, arthralgia and skin rashes. Life expectancy is often compromised. In HIDS, only febrile attacks are present, but a subgroup of patients may also develop neurological abnormalities of varying degree such as mental retardation, ataxia, ocular symptoms and epilepsy. A reduced activity of MVK and pathogenic mutations in the MVK gene have been demonstrated as the common genetic basis in both disorders. In MVA, the diagnosis is established by detection of highly elevated levels of mevalonic acid excreted in urine. Increased levels of immunoglobulin D (IgD) and, in most patients of immunoglobulin A (IgA), in combination with enhanced excretion of mevalonic acid provide strong evidence for HIDS. The diagnosis is confirmed by low activity of mevalonate kinase or by demonstration of disease-causing mutations. Genetic counseling should be offered to families at risk. There is no established successful treatment for MVA. Simvastatin, an inhibitor of HMG-CoA reductase, and anakinra have been shown to have beneficial effect in HIDS

Abnormal IgD and IgA1 O-glycosylation in hyperimmunoglobulinaemia D and periodic fever syndrome

In order to determine the glycosylation pattern for IgD, and to examine whether there are changes in the pattern of IgD and IgA1 O-glycosylation in patients with hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) during acute febrile attacks and during periods of quiescence, serum was obtained from 20 patients with HIDS and 20 control subjects. In the HIDS group, serum was obtained either during an acute febrile episode (n = 9) or during a period of quiescence (n = 11). The O-glycosylation profiles of native and desialylated IgA1 and IgD were measured in an ELISA-type system using the lectins Helix aspersa and peanut agglutinin, which bind to alternative forms of O-glycan moieties. IgD is more heavily O-galactosylated and less O-sialylated than IgA1 in healthy subjects. HIDS is associated with more extensive O-galactosylation of IgD and a reduction in O-sialylation of both IgD and IgA1. These changes are present both during acute febrile attacks and periods of quiescence. The T cell IgD receptor is a lectin with binding affinity for the O-glycans of both IgD and IgA1. The observed changes in IgD and IgA1 O-glycosylation are likely to have a significant effect on IgD/IgA1–T cell IgD receptor interactions including basal immunoglobulin synthesis, and possibly myeloid IgD receptor-mediated cytokine release

Genetic Ablation of Pannexin1 Protects Retinal Neurons from Ischemic Injury

Pannexin1 (Panx1) forms large nonselective membrane channel that is implicated in paracrine and inflammatory signaling. In vitro experiments suggested that Panx1 could play a key role in ischemic death of hippocampal neurons. Since retinal ganglion cells (RGCs) express high levels of Panx1 and are susceptible to ischemic induced injury, we hypothesized that Panx1 contributes to rapid and selective loss of these neurons in ischemia. To test this hypothesis, we induced experimental retinal ischemia followed by reperfusion in live animals with the Panx1 channel genetically ablated either in the entire mouse (Panx1 KO), or only in neurons using the conditional knockout (Panx1 CKO) technology. Here we report that two distinct neurotoxic processes are induced in RGCs by ischemia in the wild type mice but are inactivated in Panx1KO and Panx1 CKO animals. First, the post-ischemic permeation of RGC plasma membranes is suppressed, as assessed by dye transfer and calcium imaging assays ex vivo and in vitro. Second, the inflammasome-mediated activation of caspase-1 and the production of interleukin-1β in the Panx1 KO retinas are inhibited. Our findings indicate that post-ischemic neurotoxicity in the retina is mediated by previously uncharacterized pathways, which involve neuronal Panx1 and are intrinsic to RGCs. Thus, our work presents the in vivo evidence for neurotoxicity elicited by neuronal Panx1, and identifies this channel as a new therapeutic target in ischemic pathologies

Effects of the Histone Deacetylase Inhibitor ITF2357 in Autoinflammatory Syndromes

We explored the effects of the oral histone deacetylase (HDAC) inhibitor ITF2357 in patients with autoinflammatory syndrome. In this prospective open-label pilot study, eight patients were enrolled; one patient with tumor necrosis factor receptor–associated periodic syndrome (TRAPS), three patients with hyper-IgD and periodic fever syndrome (HIDS) and four patients with Schnitzler syndrome were closely followed during 90 d of ITF2357 treatment. Three patients with Schnitzler syndrome and one TRAPS patient experienced a partial remission. In four patients, there was no effect. In HIDS patients, there was a tendency toward a higher attack frequency and increasing attack severity. In two patients (one TRAPS and one HIDS), we observed a decrease of acute-phase response without signs of clinical improvement. One patient with Schnitzler syndrome showed a partial response despite an ongoing acute-phase response. In conclusion, ITF2357 monotherapy was able to induce partial response only in patients with Schnitzler syndrome and no response in patients with HIDS