Gülsev Kale

Mutations in KLHL40 Are a Frequent Cause of Severe Autosomal-Recessive Nemaline Myopathy

Nemaline myopathy (NEM) is a common congenital myopathy. At the very severe end of the NEM clinical spectrum are genetically unresolved cases of autosomal-recessive fetal akinesia sequence. We studied a multinational cohort of 143 severe-NEM-affected families lacking genetic diagnosis. We performed whole-exome sequencing of six families and targeted gene sequencing of additional families. We identified 19 mutations in KLHL40 (kelch-like family member 40) in 28 apparently unrelated NEM kindreds of various ethnicities. Accounting for up to 28% of the tested individuals in the Japanese cohort, KLHL40 mutations were found to be the most common cause of this severe form of NEM. Clinical features of affected individuals were severe and distinctive and included fetal akinesia or hypokinesia and contractures, fractures, respiratory failure, and swallowing difficulties at birth. Molecular modeling suggested that the missense substitutions would destabilize the protein. Protein studies showed that KLHL40 is a striated-muscle-specific protein that is absent in KLHL40-associated NEM skeletal muscle. In zebrafish, klhl40a and klhl40b expression is largely confined to the myotome and skeletal muscle, and knockdown of these isoforms results in disruption of muscle structure and loss of movement. We identified KLHL40 mutations as a frequent cause of severe autosomal-recessive NEM and showed that it plays a key role in muscle development and function. Screening of KLHL40 should be a priority in individuals who are affected by autosomal-recessive NEM and who present with prenatal symptoms and/or contractures and in all Japanese individuals with severe NEM.

A Congenital Muscular Dystrophy with Mitochondrial Structural Abnormalities Caused by Defective De Novo Phosphatidylcholine Biosynthesis

Congenital muscular dystrophy is a heterogeneous group of inherited muscle diseases characterized clinically by muscle weakness and hypotonia in early infancy. A number of genes harboring causative mutations have been identified, but several cases of congenital muscular dystrophy remain molecularly unresolved. We examined 15 individuals with a congenital muscular dystrophy characterized by early-onset muscle wasting, mental retardation, and peculiar enlarged mitochondria that are prevalent toward the periphery of the fibers but are sparse in the center on muscle biopsy, and we have identified homozygous or compound heterozygous mutations in the gene encoding choline kinase beta (CHKB). This is the first enzymatic step in a biosynthetic pathway for phosphatidylcholine, the most abundant phospholipid in eukaryotes. In muscle of three affected individuals with nonsense mutations, choline kinase activities were undetectable, and phosphatidylcholine levels were decreased. We identified the human disease caused by disruption of a phospholipid de novo biosynthetic pathway, demonstrating the pivotal role of phosphatidylcholine in muscle and brain.

Occidental type cerebromuscular dystrophy: a report of eleven cases.

Occidental type cerebromuscular dystrophy (OCMD) forms a substantial distinct group within congenital muscular dystrophy (CMD). These patients invariably present with amyotrophy, multiple joint contractures, facial muscle involvement, normal or nearly normal intelligence, leukodystrophic appearance on CT scan, and dystrophic changes in muscle.

Cirrhosis in children with celiac disease

Background: Liver involvement represents an extra-intestinal feature of celiac disease (CD) and shows a clinical spectrum varying from nonspecific reactive hepatitis to cirrhosis. Here we report the association of cirrhosis with CD in 5 children. Patients and Methods: The mean age of the patients was 9.4 ± 2.8 years. Viral, metabolic, and autoimmune etiology of liver disease was ruled out. Intestinal and liver biopsies were performed to confirm the histologic diagnosis in all subjects. Results: Three of the patients had chronic diarrhea and hepatosplenomegaly in whom diagnoses of CD and cirrhosis were established at presentation simultaneously. In the other 2 patients, CD was diagnosed following an initial diagnosis of cirrhosis. At diagnosis, alanine aminotransferase (range, 64-271 IU/L) and aspartate aminotransferase (range, 90-225 IU/L) values were elevated. After 1 to 5 years of a gluten-free diet (GFD), normalization of serum aminotransferase levels and clinical improvement were observed in 3 patients with strict GFD. The other 2 patients without improvement of the liver disease had poor dietary compliance. Conclusion: CD may be associated with severe hepatic damage in children and strict GFD may have beneficial effect on the course of liver disease. Serologic screening of CD should be included in differential diagnosis of chronic liver disease of unknown origin.

Influenza Vaccine Adverse Event and Effect on Acceptability in Pediatric Residents

Despite the demonstrated benefits of influenza vaccinations, the coverage is lower than expected among health-care personnel (HCP). In this study we surveyed the attitudes of pediatric residents regarding influenza immunization and adverse reactions. Forty-five female and 35 male pediatric residents with ages ranging from 24 to 28 years were vaccinated with an influenza vaccine on 2 days in the 3rd week of September 2005 by the same nurse. Among our resident, 27 (33.7%) thought the vaccine unnecessary; their vaccine coverage was only 12% in the previous year. Thirteen residents (16%) had soreness at the vaccination site; 7 (8%) had other local reactions that did not interfere with everyday activities, and 16 (20%) had any systemic side effects. The overall rate of side effects from the vaccination was 36.5% (n=29). Twenty of the 29 vaccinees who experienced side effects stated they did not want to receive the vaccine the following year because of the side effects, while 13% in the group without side effects stated the same thing, mainly because of the cost of vaccination. We would like to recommend an influenza vaccination campaign for HCP by employers, but first we must plan to take steps to improve the acceptability of the influenza vaccine among HCP.C vaccine delivery methods for prevention of global childhood diseases carry a high risk for needle contamination, vaccine wastage, and transportation and storage difficulties. Aktiv-Dry LLC’s focus is on R&D of safe and effective microparticles of vaccines and pharmaceuticals for easier storage, greater thermal stability, and ease of use. We utilize our patented CO2-Assisted Nebulization with a Bubble Dryer® (CAN-BD) system to create stable dry microparticles of compounds for administration by needle-free aerosol inhalers, sublingual solid formulations, or safer unit-dose, all-in-one auto-reconstitution syringe devices. Recently, our work has focused on vaccine prevention of measles and hepatitis B. Aktiv-Dry has developed inhalable and sublingual vaccines for measles along with a human-powered, active dry powder inhaler called the PuffHaler® for intrapulmonary delivery of the dry powder measles vaccine. CAN-BD processed measles vaccine shelf-life stability has been shown for 4 years at 2-8oC, protective immunity after intrapulmonary delivery to rhesus macaques, and no serious adverse events reported to date during on-going clinical Phase I safety trials in 60 adult males in India. We have also demonstrated stability of CAN-BD processed and dried microparticles of hepatitis B vaccine for use in a preloaded, single-dose, field-reconstitution device for parenteral delivery. Aktiv-Dry-formulated hepatitis-B vaccine was stabilized with trehalose, processed, and determined to retain stability using in-house stability assays. Our immunogenicity results from intrapulmonary mucosal membrane delivery of measles vaccine dry powder aerosols and fundamental project goals may be extended to prevention and treatment (e.g., antibiotics and antivirals) of other pulmonary diseases (e.g., tuberculosis and influenza). Jessica M.H. Thrall et al., J Vaccines Vaccin 2013, 4:5 http://dx.doi.org/10.4172/2157-7560.S1.017

Merosin-deficient congenital muscular dystrophy with severe mental retardation and normal cranial MRI: a report of two siblings

The evidence of severe structural brain abnormalities in association with severe mental retardation is characteristic in congenital muscular dystrophy (CMD) forms other than the classical form. However, it seems that the nosology of CMD is not complete yet, as we have clinical, immunohistochemical and genetic data suggesting that there are other unclassified forms. Here we report two CMD siblings from a consanguineous family with partial merosin-deficiency in muscle biopsies, severe mental retardation and normal MRI of the brain. The disease was not linked to the LAMA2 gene (6q22-23) or to Fukuyama congenital muscular dystrophy (FCMD) (9q31-33). To our knowledge, such an association may constitute a new entity within the broad clinical spectrum of CMD.

Nonsyndromic paucity of interlobular bile ducts: clinical and laboratory findings of 10 cases.

BACKGROUNDnReports concerning nonsyndromic paucity of the interlobular bile ducts are not common.nnnMETHODSnThe clinical, biochemical, and histological features of ten such children were described.nnnRESULTSnAll presented with jaundice, starting in the first month in seven and in the fourth, seventeenth, and thirtieth month in the others. Alcoholic stools were present intermittently in seven and persistently in three patients. Pruritus was a prominent symptom in five. Liver function tests were abnormal in all but one. Liver biopsies were performed at ages of 20 days to 3 years (median 5 months). In addition to a paucity of interlobular bile ducts, histology revealed intracellular cholestasis in all, portal fibrosis in four, and regenerative nodules in two patients. Complications of fat-soluble vitamin deficiency occurred in seven. Therapy consisted of supplementation of those vitamins and administration of cholestyramine, phenobarbital, prednisolone, or ursodeoxycholic acid. While one child had a successful orthotopic liver transplantation, three died. Consanguinity rate was 80% among the parents, and five of the patients had siblings with similar symptoms.nnnCONCLUSIONSnPrognosis of these patients is variable. Differentiation from other forms of cholestasis is important especially to avoid surgery.

Neuroblastoma in Turkish children: experience of a single center.

Objective and Method The survival of the patients with neuroblastoma has improved in last few decades. But still it depends on various clinical and biological factors. To assess the clinical features and trends in survival, the data for 500 newly diagnosed patients between January 1972 and December 2004 from a single center were retrospectively analyzed. Results Histopathologic subtypes were neuroblastoma (NBL) in 462 patients (92.4%) and ganglioneuroblastoma in 38 patients (7.6%). The median age was 2.9 years and Male/Female ratio was 1.3/1. Primary tumor sites were abdomen, thorax, pelvis, neck, and others with the frequency of 72.2%, 14.9%, 3.8%, 3.2%, and 5.9%, respectively. There were 30, 49, 133, 257, 31 patients with stage 1, 2, 3, 4, 4S disease and their 10-year survival rates were 100%, 75.8%, 34.1%, 6.5%, and 59.4%, respectively. The outcome has significantly improved according to 10-year periods. The 5-year overall survival rates were 14%, 26.1%, 39.2%, and 52.4% for the years of 1970s, 1980s, 1990s, and after 2000. Surgical procedure involving total or near total tumor removal improved the survival (P=0.002). Both 5-year overall survival and event free survival rates were higher when partial resection was performed, especially in stage 3 disease (P=0.002 and P=0.02). In multivariate analysis, age above 18 months at diagnosis (P=0.01), stage 4 disease (P<0.001), abdominal primary tumor site (P<0.001), NBL subtype in histopathology (P=0.001), responsiveness to chemotherapy (P<0.001) positive or high Vanillyl mandelic acid levels (P=0.02) and male sex (P=0.008) were the determinants of poor prognosis. Conclusions The survival rates in children with local disease are comparable with the results of developed countries; however, the results in children with advanced disease are still not satisfactory. To improve the outcome, especially in children with advanced disease, more effective chemotherapy regimens and molecular therapies should be investigated. Sharing the knowledge and capacity building to improve the treatment results in NBL are also critical for developing countries.

Clinical and Histopathological Study of Merosin-deficient and Merosin-positive Congenital Muscular Dystrophy

ABSTRACT The clinical features of merosin-positive congenital muscular dystrophy (CMD) and merosin-deficient CMD are well known, with those of merosin-deficient CMD being more severe. Whether the severity of histopathological findings correlates with these clinical features remains unanswered. In this study, the clinical and histopathological findings of 39 merosin-deficient and 37 merosin-positive CMD patients were compared. Merosin-deficient CMD patients were found to be younger, with earlier onset of symptoms, age of diagnosis, and a more severe clinical state (reflecting maximum motor capacity and contractures). On histopathological evaluation, endomysial fibrosis, perimysial fibrosis, and histopathological state (reflecting fibrosis, adiposis, necrosis, and variation in fiber size) were more severe in merosin-deficient CMD. There was a correlation between clinical and histopathological states only in merosin-deficient CMD.

Renal Involvement of Non-Hodgkin’s Lymphoma and Its Prognostic Effect in Childhood

Objective: To evaluate renal involvement in childhood lymphoma and define its prognostic effects. Patients and Methods: One hundred and four patients with non-Hodgkin’s lymphoma and renal involvement on admission to a single center between 1972 and 2003 were evaluated retrospectively. Blood urea nitrogen, serum creatinine, uric acid, electrolytes, and lactate dehydrogenase levels, as well as urinalysis, were evaluated. One or more of the following imaging methods were performed: intravenous urogram, ultrasound, computed tomography, and magnetic resonance imaging. The χ2 test was used to compare the groups. The Kaplan-Meier survival method was used to calculate survival rates, and the log-rank test was used to compare groups with respect to survival. Survival rates were also compared in two different time periods (before 1991 and after 1991). Results: There were 76 boys and 28 girls with a median age of 6 (0.9–16) years. The renal infiltration pattern was nodular in 62 patients (59.6%) and diffuse in 40 patients (38.5%). Two patients had tumoral masses that originated from their kidneys (1.9%). Renal involvement was bilateral in 75 patients (72.1%); the remaining 29 patients had unilateral involvement. The overall survival rate was 42.5% with a median follow-up of 64 months. The factors that had a statistically significant impact on survival were high creatinine (p = 0.00001) and blood urea nitrogen levels (p = 0.0001), the onset of tumor lysis syndrome (p = 0.01), and the need for dialysis (p = 0.009). The survival rate was higher in the time period after 1991 (p = 0.01). Conclusion: Impaired renal function is a poor prognostic factor for non-Hodgkin’s lymphoma. Renal function should therefore be monitored closely. Renal dysfunction caused by direct tumoral involvement may complicate therapy and shorten survival.