BackgroundAtaxia Teleangiectasia [AT] is a rare neurodegenerative disease characterized by early onset ataxia, oculocutaneous teleangiectasias, immunodeficiency, recurrent infections, radiosensitivity and proneness to cancer. No therapies are available for this devastating disease. Recent observational studies in few patients showed beneficial effects of short term treatment with betamethasone. To avoid the characteristic side effects of long-term administration of steroids we developed a method for encapsulation of dexamethasone sodium phosphate (DSP) into autologous erythrocytes (EryDex) allowing slow release of dexamethasone for up to one month after dosing. Aims of the study were: the assessment of the effect of EryDex in improving neurological symptoms and adaptive behaviour of AT patients; the safety and tolerability of the therapy.MethodsTwenty two patients (F:M = 1; mean age 11.2 ± 3.5) with a confirmed diagnosis of AT and a preserved or partially supported gait were enrolled for the study. The subjects underwent for six months a monthly infusion of EryDex. Ataxia was assessed by the International Cooperative Ataxia Rating Scale (ICARS) and the adaptive behavior by Vineland Adaptive Behavior Scales (VABS). Clinical evaluations were performed at baseline and 1, 3, and 6 months.ResultsAn improvement in ICARS (reduction of the score) was detected in the intention-to-treat (ITT) population (n = 22; p = 0.02) as well as in patients completing the study (per protocol PP) (n = 18; p = 0.01), with a mean reduction of 4 points (ITT) or 5.2 points (PP). When compared to baseline, a significant improvement were also found in VABS (increase of the score) (p < 0.0001, ITT, RMANOVA), with statistically significant increases at 3 and 6 months (p < 0.0001). A large inter-patient variability in the incorporation of DSP into erythrocytes was observed, with an evident positive effect of higher infusion dose on ICARS score decline. Moreover a more marked improvement was found in less neurologically impaired patients. Finally, a 19 month-extension study involving a subgroup of patients suggested that Erydex treatment can possibly delay the natural progression of the disease.EryDex was well tolerated; the most frequent side effects were common AT pathologies.ConclusionsEryDex treatment led to a significant improvement in neurological symptoms, without association with the typical steroid side effects.Trial registrationCurrent Controlled Trial 2010-022315-19SpA

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Objective:Ataxia-telangiectasia (AT) is a rare, devastating neurodegenerative disease presenting with early-onset ataxia, oculocutaneous telangiectasia, immunodeficiency, radiosensitivity, and proneness to cancer. In a previous phase 2 study, we showed that 6 monthly infusions of autologous erythrocytes loaded with dexamethasone (EryDex; EryDel, Urbino, Italy) were effective in improving neurologic impairment in young patients with AT. The present article reports the results of the extension of this study for an additional 24-month period.Methods:After the end of the first trial, 4 patients continued to be treated with monthly EryDex infusions for an additional 24 months, and their clinical outcome was compared with that of 7 age-matched patients who stopped the treatment after the first 6 infusions. The protocol included serial assessment of ataxia (by International Cooperative Ataxia Rating Scale) and adaptive behavior (by Vineland Adaptive Behavior Scales) and clinical and laboratory tests revealing treatment- and steroid-dependent adverse effects, if present.Results:Patients in the extended study experienced a continuous neurologic improvement with respect to their pretreatment status, whereas controls showed a progressive neurologic deterioration (according to the natural history of the disease) after the discontinuation of the treatment. The delivery system we adopted proved to be safe and well-tolerated, and none of the side effects usually associated with the chronic administration of corticosteroids were observed during the entire trial.Conclusions:These promising preliminary results call for a large-scale controlled study on protracted treatment of patients with AT with dexamethasone-loaded erythrocytes.

No controlled studies exist regarding the pharmaceutical reduction of ataxia symptoms in ataxia telangiectasia (A-T). In a multicenter, double-blind, randomized, placebo-controlled crossover trial, oral betamethasone (BETA) and placebo were compared in terms of their reduction of ataxia symptoms as assessed with the International Cooperative Ataxia Rating Scale (ICARS). In this study of 13 A-T children, betamethasone reduced the ICARS total score by a median of 13 points in the intent-to-treat population and 16 points in the per-protocol population (ie, median percent decreases of ataxia symptoms of 28% and 31%, respectively). In conclusion, Oral betamethasone could be a promising therapy to relieve ataxia symptoms in A-T patients; however, long-term effectiveness and safety must be established. (Current Controlled Trials, number ISRCTN08774933.)

Key pointsr Loss-of-function mutations of the skeletal muscle ClC-1 channel cause myotonia congenita with variable phenotypes.r Using patch clamp we show that F484L, located in the conducting pore, probably induces mild dominant myotonia by right-shifting the slow gating of ClC-1 channel, without exerting a dominant-negative effect on the wild-type (WT) subunit.r Molecular dynamics simulations suggest that F484L affects the slow gate by increasing the frequency and the stability of H-bond formation between E232 in helix F and Y578 in helix R.r Three other myotonic ClC-1 mutations are shown to produce distinct effects on channel function: L198P shifts the slow gate to positive potentials, V640G reduces channel activity, while L628P displays a WT-like behaviour (electrophysiology data only).r Our results provide novel insight into the molecular mechanisms underlying normal and altered ClC-1 function.Abstract Myotonia congenita is an inherited disease caused by loss-of-function mutations of the skeletal muscle ClC-1 chloride channel, characterized by impaired muscle relaxation after contraction and stiffness. In the present study, we provided an in-depth characterization of F484L, a mutation previously identified in dominant myotonia, in order to define the genotype-phenotype correlation, and to elucidate the contribution of this pore residue to the mechanisms of ClC-1 gating. Patch-clamp recordings showed that F484L reduced chloride currents at every tested potential and dramatically right-shifted the voltage dependence of slow gating, thus contributing to the mild clinical phenotype of affected heterozygote carriers. Unlike dominant mutations located at the dimer interface, no dominant-negative effect was observed when F484L mutant subunits were co-expressed with wild type. Molecular dynamics simulations further revealed that F484L affected the slow gate by increasing the frequency and stability of the H-bond formation between the pore residue E232 and the R helix residue Y578. In addition, using patch-clamp electrophysiology, we characterized three other myotonic ClC-1 mutations. We proved that the dominant L198P mutation in the channel pore also right-shifted the voltage dependence of slow gating, recapitulating mild myotonia. The recessive V640G mutant drastically reduced channel function, which probably accounts for myotonia. In contrast, the recessive L628P mutant produced currents very similar to wild type, suggesting that the occurrence of the compound truncating mutation (Q812X) or other muscle-specific mechanisms accounted for the severe symptoms observed in this family. Our results provide novel insight into the molecular mechanisms underlying normal and altered ClC-1 function.

An early orthodontic evaluation might be planned in the management of children with NF1 to prevent or decrease the need for extensive orthodontic interventions.

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Eighty children who in the first 2 years of life had signs and symptoms relating to a cerebral neoplasm were studied over an 18-year period (1970-1987), the mean follow-up being 8.2 years. In each case age at onset, clinical presentation, tumor location and pathological diagnosis, extent of surgical resection, postoperative mortality, adjuvant therapy length of survival and quality of life were assessed. Supratentorial tumors (59%) were more common than infratentorial. The most frequent clinical presenting feature (70%) was increased intracranial pressure. Sixty-three patients (79%) were operated on and in all of these cases a histological diagnosis was obtained. Astrocytomas (41%) and medulloblastomas (20%) were the most common oncotypes. Surgical mortality was 17.4% and the 5-year survival rate was 54%. Quality of life was assessed for all long-term surviving patients using a specifically designed protocol. Normal physical and intellectual performances were found in 46% of cases, and all together 75% of the patients had sufficient autonomy in daily life. The prognosis is more closely related to tumor location and type of treatment than to histological diagnosis or age at onset.