Protein kinase C (PKC) was initially identified as a serine/threonine protein kinase dependent on calcium and phospholipids and shown to be involved in intracellular signaling pathways. PKC isoforms have been classified into four groups: Ca(2+)-dependent conventional PKC alpha, beta I, beta II, gamma; Ca(2+)-independent, novel PKC delta, epsilon, eta, phi; atypical PKC zeta, lambda, iota which are not activated by Ca2+ or diacylglycerol, and the recently discovered PKCmu. We reported that activation of the zeta PKC isoform is an important step in interleukin-2 (IL-2)-mediated proliferation (Gómez, J., Pitton, C., García, A., Martínez, A., Silva, A. and Rebollo, A., Exp. Cell Res. 1995. 218: 105.). zeta PKC is also required for mitogenic activation of fibroblasts and for the maturation pathway activated by insulin and Ras. Contradictory results have been reported regarding the subcellular redistribution of zeta PKC upon activation. We report here, using confocal microscopy, that IL-2 induces expression, translocation and association of zeta PKC to a structure coincident with the actin cytoskeleton. Furthermore, we show that zeta PKC has a role in maintaining the integrity of the actin cytoskeletal structure in IL-2-stimulated cells. On the contrary, zeta PKC is not involved in the actin cytoskeleton organization when cells are maintained in IL-4, confirming our previous results showing that IL-4-induced signal transduction is PKC independent.

SummaryObjective. To review the results and complications of the surgical treatment of craniosynostosis in 283 consecutive patients treated between 1999 and 2007.Patients and methods. Our series consisted of 330 procedures performed in 283 patients diagnosed with scaphocephaly (n=155), trigonocephaly (n=50), anterior plagiocephaly (n=28), occipital plagiocephaly (n=1), non-syndromic multi-suture synostosis (n=20), and with diverse craniofacial syndromes (n=32; 11 Crouzon, 11 Apert, 7 Pfeiffer, 2 Saethre-Chotzen, and 2 clover-leaf skull). We used the classification of Whitaker et al. to evaluate the surgical results. Complications of each technique and time of patients' hospitalization were also recorded. The surgeries were classified in 12 different types according to the techniques used. Type I comprised endoscopic assisted osteotomies for sagittal synostosis (42 cases). Type II included sagittal suturectomy and expanding osteotomies (46 cases). Type III encompassed procedures similar to type II but that included frontal dismantling or frontal osteotomies in scaphocephaly (59 cases). Type IV referred to complete cranial vault remodelling (holocranial dismantling) in scaphocephaly (13 cases). Type V belonged to fronto-orbital remodelling without fronto-orbital bandeau in trigonocephaly (50 cases). Type VI included fronto-orbital remodelling without fronto-orbital bandeau in plagiocephaly (14 cases). In Type VII cases of plagiocephaly with frontoorbital remodelling and fronto-orbital bandeau were comprised (14 cases). Type VIII consisted of occipital advancement in posterior plagiocephaly (1 case). Type IX included standard bilateral fronto-orbital advancement with expanding osteotomies (30 cases). Type X was used in multi-suture craniosynostosis (15 cases) and consisted of holocranial dismantling (complete cranial vault remodelling). Type XI included occipital and suboccipital craniectomies in multiple suture craniosynostosis (10 cases) and Type XII instances of fronto-orbital distraction (26 cases).Results. The mortality rate of the series was 2 out of 283 cases (0.7%). These 2 patients died one year after surgery. All complications were resolved without permanent deficit. Mean age at surgery was 6.75 months. According to Whitaker et al's classification, 191 patients were classified into Category I (67.49%), 51 into Category II (18.02%), 30 into Category III (10.6%) and 14 into Category IV (4.90%). Regarding to craniofacial conformation, 85.5 % of patients were considered as a good result and 15.5% of patients as a poor result. Of the patients with poor results, 6.36% were craniofacial syndromes, 2.12% had anterior plagiocephaly and 1.76% belonged to non-syndromic craniosynostosis.The most frequent complication was postoperative hyperthermia of undetermined origin (13.43% of the cases), followed by infection (7.5%), subcutaneous haematoma (5.3%), dural tears (5%), and CSF leakage (2.5%). The number of complications was higher in the group of re-operated patients (12.8% of all). In this subset of reoperations, i...

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BackgroundKearns-Sayre syndrome (KSS) is a mitochondrial DNA deletion syndrome that presents with profound cerebral folate deficiency and other features. Preliminary data support the notion that folinic acid therapy might be useful in the treatment of KSS patients. Our aim was to assess the clinical and neuroimaging outcomes of KSS patients receiving folinic acid therapy.MethodsPatients: We recruited eight patients with diagnoses of KSS. Four cases were treated at 12 de Octubre Hospital, and the other two cases were treated at Sant Joan de Déu Hospital. Two patients refused to participate in the treatment protocol.Methods: Clinical, biochemical and neuroimaging data (magnetic resonance imaging or computed tomography scan) were collected in baseline conditions and at different time points after the initiation of therapy. Cerebrospinal fluid 5-methyltetrahydrofolate levels were analysed with HPLC and fluorescence detection. Large-scale mitochondrial DNA deletions were analysed by Southern blot.Treatment protocol: The follow-up periods ranged from one to eight years. Cases 1–4 received oral folinic acid at a dose of 1 mg/kg/day, and cases 6 and 8 received 3 mg/kg/day.ResultsNo adverse effects of folinic acid treatment were observed. Cerebral 5-methyltetrahydrofolate deficiencies were observed in all cases in the baseline conditions. Moreover, all three patients who accepted lumbar puncture after folinic acid therapy exhibited complete recoveries of their decreased basal cerebrospinal fluid 5-methyltetrahydrofolate levels to normal values. Two cases neurologically improved after folinic therapy. Disease worsened in the other patients.Post-treatment neuroimaging was performed for the 6 cases that received folinic acid therapy. One patient exhibited improvements in white matter abnormalities. The remaining patients displayed progressions in subcortical cerebral white matter, the cerebellum and cerebral atrophy.ConclusionsFour patients exhibited clinical and radiological progression of the disease following folinic acid treatment. Only one patient who was treated in an early stage of the disease exhibited both neurological and radiological improvements following elevated doses of folinic acid, and an additional patient experienced neurological improvement. Early treatment with high-dose folinic acid therapy seems to be advisable for the treatment of KSS.Trial registrationEudracT2007-00-6748-23Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0217-2) contains supplementary material, which is available to authorized users.

We report the case of a 9-year-old girl with early-onset developmental delay, chronic ataxia and prolonged hemiplegic migraine episodes bringing about progressive deterioration. Two days into one episode, diffusion-weighted magnetic resonance imaging disclosed unilateral striatal abnormal signal consistent with cytotoxic edema, which evolved into atrophy on follow-up scans. Mutational screen of CACNA1A gene identified a de novo p.Tyr1387Cys mutation.

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We report the case of a Caucasian Spanish origin female who showed severe psychomotor developmental delay, hypotonia, strabismus, epilepsy, short stature, and poor verbal language development. Brain magnetic resonance imaging scans showed thickened corpus callosum, cortical malformations, and dilated and abnormal configuration of the lateral ventricles without hydrocephalus. Whole-exome sequence uncovered a de novo variant in the microtubule associated serine/threonine kinase 1 gene (MAST1; NM_014975.3:c.1565G>A:p.(Gly522Glu)) that encodes for the MAST1.Only 12 patients have been identified worldwide with 10 different variants in this gene: six patients with mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations; two patients with microcephaly and cerebellar hypoplasia; two patients with autism, one patient with diplegia, and one patient with microcephaly and dysmorphism. Our patient shows a new phenotypic subtype defined by mega-corpus-callosum syndrome with cortical malformations without cerebellar hypoplasia. In conclusion, our data expand the phenotypic spectrum associated to MAST1 gene variants. K E Y W O R D S cerebellar hypoplasia, cortical malformations, growth hormone, MAST1, mega-corpus-callosum syndrome, microcephaly

We report the clinical, biochemical and genetic findings from a Spanish girl of Caucasian origin who presented with macrocephaly, dysmorphic facial features, developmental delay, hypotonia, combined oxidative phosphorylation (OxPhos) deficiency, epilepsy and anti-phospholipid antibodies (aPL). Whole-exome sequencing (WES) uncovered a heterozygous variant in the MTOR gene (NM_004958.3: c.7235A>T: p.(Asp2412Val)) that encodes for the Serine/threonine-protein kinase mTOR. The substrates phosphorylation experiments demonstrated that this variant exerts its effect by gain-offunction (GOF) and autosomal dominant mechanism. GOF variants in this protein have been associated with Smith-Kingsmore syndrome (SKS), a rare autosomal dominant disorder characterized by intellectual disability, macrocephaly, seizure, developmental delay and dysmorphic facial features. Furthermore, the mTOR pathway has been demonstrated previously to be involved in many types of endothelium injuries including the antiphospholipid syndrome (APS), a systemic autoimmune disease characterized by the production of aPL with recurrent vascular thrombosis. Therefore, our patient is the first one with an mTOR variant and diagnosed with SKS and APS. In conclusion, our data expand both the genetic and phenotypic spectrum associated with MTOR gene variants.