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Defects in amphiphysin 2 (BIN1) and triads in several forms of centronuclear myopathies

Myotubular myopathy and centronuclear myopathies (CNM) are congenital myopathies characterized by generalized muscle weakness and mislocalization of muscle fiber nuclei. Genetically distinct forms exist, and mutations in BIN1 were recently identified in autosomal recessive cases (ARCNM). Amphiphysins have been implicated in membrane remodeling in brain and skeletal muscle. Our objective was to decipher the pathogenetic mechanisms underlying different forms of CNM, with a focus on ARCNM cases. In this study, we compare the histopathological features from patients with X-linked, autosomal recessive, and dominant forms, respectively, mutated in myotubularin (MTM1), amphiphysin 2 (BIN1), and dynamin 2 (DNM2). We further characterize the ultrastructural defects in ARCNM muscles. We demonstrate that the two BIN1 isoforms expressed in skeletal muscle possess the phosphoinositide-binding domain and are specifically targeted to the triads close to the DHPR–RYR1 complex. Cardiac isoforms do not contain this domain, suggesting that splicing of BIN1 regulates its specific function in skeletal muscle. Immunofluorescence analyses of muscles from patients with BIN1 mutations reveal aberrations of BIN1 localization and triad organization. These defects are also observed in X-linked and autosomal dominant forms of CNM and in Mtm1 knockout mice. In addition to previously reported implications of BIN1 in cancer as a tumor suppressor, these findings sustain an important role for BIN1 skeletal muscle isoforms in membrane remodeling and organization of the excitation–contraction machinery. We propose that aberrant BIN1 localization and defects in triad structure are part of a common pathogenetic mechanism shared between the three forms of centronuclear myopathies.

Hyperoxic exposure leads to cell death in the developing brain

Premature infants have high incidence of motor and cognitive impairment in later life. Supraphysiological oxygen concentrations are routinely used in neonatal intensive care units and elicit injury to premature lungs and retina. Since the effects of hyperoxia on the developing brain are scarce, we studied the effects of high oxygen on this tissue. Wistar rat pups were exposed from birth until day 5 to 21% or 80% oxygen. The neuronal density and apoptosis in CA1 and dentate gyrus of hippocampus, prefrontal cortex, parietal cortex, subiculum, and retrosplenial cortex were assessed by immunohistochemistry and ELISA cell death assay. Neuronal density of the investigated brain areas were significantly decreased in the hyperoxia group. Furthermore, using ELISA cell death and TUNEL assays, we observed increased cell death in the developing brain. Our results show that hyperoxia induces cell death in the developing rat brain. This may be one of the important mechanisms that cause motor and cognitive impairment in later life of premature infants.

Mycoplasma pneumoniae: nervous system complications in childhood and review of the literature

Mycoplasma pneumoniae is an important pathogen which causes nervous system disorders during or after the course of a respiratory tract infection. The exact pathogenic mechanism which causes neurological disorders still remains unknown. Although meningoencephalitis and acute disseminated encephalomyelitis are common complications, there are few cases of acute transverse myelitis and isolated abducens nerve palsy associated with M. pneumoniae infection in childhood. The association between ocular myasthenia gravis and M. pneumoniae infection has not been described before. Here, we describe five patients with different nervous system complications associated with M. pneumoniae infection and discuss the pathological features of central nervous system involvement.

Case report of intrafamilial variability in autosomal recessive centronuclear myopathy associated to a novel BIN1 stop mutation

Centronuclear myopathies (CNM) describe a group of rare muscle diseases typically presenting an abnormal positioning of nuclei in muscle fibers. To date, three genes are known to be associated to a classical CNM phenotype. The X-linked neonatal form (XLCNM) is due to mutations in MTM1 and involves a severe and generalized muscle weakness at birth. The autosomal dominant form results from DNM2 mutations and has been described with early childhood and adult onset (ADCNM). Autosomal recessive centronuclear myopathy (ARCNM) is less characterized and has recently been associated to mutations in BIN1, encoding amphiphysin 2. Here we present the first clinical description of intrafamilal variability in two first-degree cousins with a novel BIN1 stop mutation. In addition to skeletal muscle defects, both patients have mild mental retardation and the more severely affected male also displays abnormal ventilation and cardiac arrhythmia, thus expanding the phenotypic spectrum of BIN1-related CNM to non skeletal muscle defects. We provide an up-to-date review of all previous cases with ARCNM and BIN1 mutations.

Metoclopramide induced dystonia in children: two case reports.

Metoclopramide is a dopamine antagonist that is widely used in gastroesophageal disease and chemotherapy-induced emesis in the paediatric population. It is also prescribed in nausea and vomiting caused by respiratory tract infections and enteritis in practice. The primary side-effect of the drug is extrapyramidal reactions with incidences as high as 25% in children. We report two cases, one of which was referred to our emergency department as encephalitis and the other as tetany, but which were just acute dystonic reactions caused by metaclopramide, even though the patients had used the drug in the recommended dosages. The adverse effects of the drug can be seen at normal doses. These dystonic reactions caused by metaclopramide can easily be confused with other diseases, because dystonia is not seen frequently in paediatric practice whatever the cause.

Diagnostic value of proton MR spectroscopy and diffusion-weighted MR imaging in childhood inherited neurometabolic brain diseases and review of the literature.

The purpose of this study is to evaluate parenchymal diffusion properties and metabolite ratios in affected brain tissues of inherited neurometabolic brain diseases with an overview of the current literature about the diagnostic data of both techniques in childhood inherited metabolic brain diseases. The study group was consisting, 19 patients (15 males, 4 females; mean age, 54 months (4.5 years); age range, 1-171 months (14.25 years)) diagnosed with inherited neurometabolic brain disease. Single- and multivoxel proton MRS was carried out and NAA/Cr, Cho/Cr, mI/Cr, Glx/Cr ratios were calculated. Presence of lactate peak and abnormal different peaks were noted. ADC values were calculated from brain lesions. Results are compared with age and sex matched normal subjects. Elevated NAA/Cr ratio (Canavan disease), galactitol peak (galactosemia) at 3.7 ppm, branched chain amino acids (Maple syrup urine disease-MSUD) at 0.9 ppm were seen on different diseases. In Leigh disease and MSUD restricted diffusion was detected. Different diffusion properties were seen only in one Glutaric aciduria lesions. NAA/Cr ratios and calculated ADC values were significantly different from normal subjects (p<0.05). DWI combined with MRS are complementary methods to routine cranial MRI for evaluating neurometabolic diseases which can give detailed information about neurochemistry of affected brain areas.

Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation

BackgroundThe kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA) (OMIM 225400) is a rare inheritable connective tissue disorder characterized by a deficiency of collagen lysyl hydroxylase 1 (LH1; EC 1.14.11.4) due to mutations in PLOD1. Biochemically this results in underhydroxylation of collagen lysyl residues and, hence, an abnormal pattern of lysyl pyridinoline (LP) and hydroxylysyl pyridinoline (HP) crosslinks excreted in the urine. Clinically the disorder is characterized by hypotonia and kyphoscoliosis at birth, joint hypermobility, and skin hyperelasticity and fragility. Severe hypotonia usually leads to delay in gross motor development, whereas cognitive development is reported to be normal.MethodsWe describe the clinical, biochemical and molecular characterisation, as well as electron microscopy findings of skin, in 15 patients newly diagnosed with this rare type of Ehlers-Danlos syndrome.ResultsAge at diagnosis ranged from 5 months to 27 years, with only 1/3 of the patients been diagnosed correctly in the first year of life. A similar disease frequency was found in females and males, however a broad disease severity spectrum (intra- and interfamilial), independent of molecular background or biochemical phenotype, was observed. Kyphoscoliosis, one of the main clinical features was not present at birth in 4 patients. Importantly we also noted the occurrence of vascular rupture antenatally and postnatally, as well as developmental delay in 5 patients.ConclusionIn view of these findings we propose that EDS VIA is a highly variable clinical entity, presenting with a broad clinical spectrum, which may also be associated with cognitive delay and an increased risk for vascular events. Genotype/phenotype association studies and additional molecular investigations in more extended EDS VIA populations will be necessary to further elucidate the cause of the variability of the disease severity.

Effect of erythropoietin on oxygen-induced brain injury in the newborn rat.

The developing nervous system is sensitive to supraphysiological oxygen concentrations. Recent studies showed that exposure to hyperoxia in infant rats leads to extensive apoptotic degeneration in the cortex and white matter of the developing brain. A wide variety of experimental studies have shown that erythropoietin exerts a remarkable neuroprotection in both cell cultures and in animal models of nervous system disorders. In the present study, we investigated the effect of erythropoietin against hyperoxia-induced neurodegeneration in the developing brain. Eighteen Wistar rat pups were divided into three groups: control group, hyperoxia+saline-treated group and hyperoxia+erythropoietin-treated group. Hyperoxia groups were exposed to 80% oxygen (n=12) in a plexiglas chamber in which the oxygen concentration was monitored twice daily from birth until postnatal day 5. Hyperoxia exposure was 24h/day for 5 days. The hyperoxia+erythropoietin group received an intraperitoneal injection of recombinant human erythropoietin at a dose of 1000U/(kgday). At postnatal day 5, all animals were sacrificed. Neuronal cell death and apoptosis were evaluated. Histopathological examination showed that erythropoietin significantly diminished apoptosis in the CA1 region and dentate gyrus of hippocampus and parietal cortex in hyperoxia+erythropoietin-treated group. Regarding the safety profile of erythropoietin in premature and mature infants, this agent may be potentially beneficial in preventing hyperoxic brain injury.

Differential diagnosis of muscular hypotonia in infants: The kyphoscoliotic type of Ehlers–Danlos syndrome (EDS VI)

The kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VI) (OMIM 225400) is an inherited connective tissue disorder characterized by hypotonia and kyphoscoliosis at birth, joint hypermobility, and skin hyperelasticity and fragility. Biochemically, it is characterized by a deficiency of collagen lysyl hydroxylase (EC 1.14.11.4) due to mutations in PLOD1. This deficiency results in underhydroxylation of collagen lysyl residues and, hence, an abnormal pattern of lysyl pyridinoline (LP) and hydroxylysyl pyridinoline (HP) crosslinks excreted in the urine. Because of hypotonia and delay in gross motor development, a neuromuscular disease is usually suspected, and in most cases the diagnosis is considered only very late, after performing an invasive neuromuscular work-up with normal results. We report a 12-month-old boy with kyphoscoliosis and delayed gross motor development, in whom the differential diagnosis of kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VI) was initially suspected and successively confirmed by the abnormal urinary ratio of total pyridinolines (LP to HP), and by mutation analysis. We advocate the analysis of urinary pyridinolines in all infants with severe hypotonia which is highly specific and sensitive, quick and inexpensive.

Multiple Erythematous Nodules and Ecthyma Gangrenosum as a Manifestation of Pseudomonas aeruginosa Sepsis in a Previously Healthy Infant

Abstract:  Pseudomonas aeruginosa septicemia is rare in healthy infants and children. Also not common, dermatologic manifestations such as ecthyma gangrenosum and indurated erythematous nodular lesions may be the first signs of pseudomonas infection, or may appear later in the course of the disease. Peripheral facial paralysis and mastoiditis are also rare and serious complications of acute otitis media caused by P. aeruginosa. We report a previously healthy 6‐month‐old boy who had an uncommon presentation and rare complications during the course of P. aeruginosa sepsis.