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Rochelle F Hanson, Sonja Schoenwald, Benjamin E Saunders, Jason Chapman, Lawrence A Palinkas, Angela D Moreland, Alex Dopp
BACKGROUND: High rates of youth exposure to violence, either through direct victimization or witnessing, result in significant health/mental health consequences and high associated lifetime costs. Evidence-based treatments (EBTs), such as Trauma-Focused Cognitive Behavioral Therapy (TF-CBT), can prevent and/or reduce these negative effects, yet these treatments are not standard practice for therapists working with children identified by child welfare or mental health systems as needing services...
2016: International Journal of Mental Health Systems
Friederike Hörster, Stefan Kölker, J Gerard Loeber, Martina C Cornel, Georg F Hoffmann, Peter Burgard
BACKGROUND: The state of newborn screening (NBS) programmes for organic acidurias in Europe was assessed by a web-based questionnaire in the EU programme of Community Action in Public Health 2010/2011 among the - at that time - 27 EU member states, candidate countries, potential candidates and three EFTA countries. RESULTS: Thirty-seven data sets from 39 target countries were analysed. Newborn screening for glutaric aciduria type I (GA-I) was performed in ten, for isovaleric aciduria (IVA) in nine and for methylmalonic aciduria including cblA, cblB, cblC and cblD (MMACBL) as well as for propionic aciduria (PA) in seven countries...
June 26, 2016: JIMD Reports
Amra Adrovic, Nur Canpolat, Salim Caliskan, Lale Sever, Ertugrul Kıykım, Ayse Agbas, Matthias R Baumgartner
Atypical hemolytic uremic syndrome (aHUS) is mostly linked to defects in the regulation of alternative complement pathway, but a rare form is caused by an inherited defect of cobalamin 1 metabolism. Cobalamin C (cblC) deficiency is an autosomal recessive disorder of vitamin B12 metabolism that results from mutations in methylmalonic aciduria and homocysteinuria (MMACHC). The most severe form of cblC deficiency and the associated high mortality rate are mostly observed in neonates or in infants <6 months of age...
August 2016: Pediatrics International: Official Journal of the Japan Pediatric Society
Bodo B Beck, FrancJan van Spronsen, Arjan Diepstra, Rolf M F Berger, Martin Kömhoff
Methylmalonic aciduria and homocystinuria, cobalamin C (cblC) type, is the most common genetic type of functional cobalamin (vitamin B12) deficiency. This metabolic disease is characterized by marked heterogeneity of neurocognitive disease (microcephaly, seizures, developmental delay, ataxia, hypotonia) and variable extracentral nervous system involvement (failure to thrive, cardiovascular, renal, ocular) manifesting predominantly early in life, sometimes during gestation. To enhance awareness and understanding of renal disease associated with cblC defect, we studied biochemical, genetic, clinical, and histopathological data from 36 patients...
June 11, 2016: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
C Nogueira, A Marcão, H Rocha, C Sousa, H Fonseca, C Valongo, L Vilarinho
OBJECTIVE: Birth prevalence of Cobalamin (Cbl) C or D defects in Portugal is an estimated 1:85,000, one of the highest worldwide. We compared the genotype/phenotype of patients identified with CblC or CblD before and after the implementation of expanded newborn screening. METHODS: Twenty-five Portuguese CblC/D patients, 14 symptomatic and 11 identified through screening, were diagnosed using gas chromatography or tandem mass spectrometry. Molecular characterization was performed through the study of MMACHC and MMADHC genes...
June 1, 2016: Journal of Medical Screening
David Watkins, David S Rosenblatt
BACKGROUND: Over the last forty years, our laboratory has accumulated a collection of over 1000 cultured fibroblast lines derived from patients from around the world referred with signs of inborn errors of cobalamin or folate metabolism, including several hundred with complementation-confirmed diagnoses. By accurately classifying patient disorders into classes representing blocks affecting specific reactions, we have provide the basis for rational assessment of phenotypic heterogeneity, and development of methods for diagnosis, treatment and prognosis...
July 2016: Biochimie
Friedrich K Trefz, Dagmar Scheible, Georg Frauendienst-Egger, Martina Huemer, Terttu Suomala, Brian Fowler, Dorothea Haas, Matthias R Baumgartner
Cobalamin C (cblC) defect is an inherited autosomal recessive disorder that affects cobalamin metabolism. Patients are treated with hydroxycobalamin to ameliorate the clinical features of early-onset disease and prevent clinical symptoms in late-onset disease. Here we describe a patient in whom prenatal maternal treatment with 30 mg/week hydroxycobalamin and 5 mg/day folic acid from week 15 of pregnancy prevented disease manifestation in a girl who is now 11 years old with normal IQ and only mild ophthalmic findings...
March 2016: Molecular Genetics and Metabolism Reports
Cristy A Ku, Jacqueline K Ng, Daniel J Karr, Leah Reznick, Cary O Harding, Richard G Weleber, Mark E Pennesi
BACKGROUND: Cobalamin C disease (cblC), which leads to methylmalonic acidemia with homocystinuria, is the most common inherited disorder of vitamin B12 metabolism. Reported ocular findings associated with cblC have been maculopathy, pigmentary retinopathy, and optic nerve atrophy. Cobalamin A disease (cblA) which causes an isolated methylmalonic acidemia without homocystinuria is rarer than cblC. This is the first detailed report of the ocular findings associated with cblA. We also describe the spectrum of ocular findings in our cblC patients...
March 15, 2016: Ophthalmic Genetics
Lucas Bonafede, Can H Ficicioglu, Leona Serrano, Grace Han, Jessica I W Morgan, Monte D Mills, Brian J Forbes, Stefanie L Davidson, Gil Binenbaum, Paige B Kaplan, Charles W Nichols, Patrick Verloo, Bart P Leroy, Albert M Maguire, Tomas S Aleman
PURPOSE: To describe in detail the retinal structure and function of a group of patients with cobalamin C (cblC) disease. METHODS: Patients (n = 11, age 4 months to 15 years) with cblC disease (9/11, early onset) diagnosed by newborn screening underwent complete ophthalmic examinations, fundus photography, near-infrared reflectance imaging, and spectral-domain optical coherence tomography (SD-OCT). Electroretinograms (ERGs) were performed in a subset of patients...
December 2015: Investigative Ophthalmology & Visual Science
Jenny Bellerose, Mathilde Neugnot-Cerioli, Karine Bédard, Catherine Brunel-Guitton, Grant A Mitchell, Luis H Ospina, Miriam H Beauchamp
Cobalamin C is a rare inborn disorder of metabolism that results in multisystemic abnormalities, including progressive visual deficits. Although the cellular pathophysiology of cblC is a field of active study, little attention has been dedicated to documenting the cognitive consequences of the defect. The neuropsychological assessment of nine individuals aged between 23 months and 24 years was conducted to establish cognitive profiles. Results reveal a marked heterogeneity, with intellectual functioning ranging from extremely low to average, and cognitive difficulties (e...
November 26, 2015: JIMD Reports
Jun Wang, Erzhen Li, Liwen Wang, Zhilong Wang, Shenghai Yang, Qiao Zhou, Qian Chen
Methylmalonic aciduria and homocystinuria, cblC type, is the most common disorder of intracellular vitamin B12 (cobalamin, cbl) metabolism, which results in impaired biosynthesis of methylcobalamin and adenosylcobalamin. The gene MMACHC responsible for the cblC type had been identified, which enables molecular diagnostics. Here, we report four cblC type cases, which were identified by the typical manifestations, and a new approach of next-generation sequencing platform in pediatrics for genetic diseases, further confirmed by Sanger sequencing of the whole MMACHC gene...
2015: International Journal of Clinical and Experimental Pathology
Kazuhiro Yamada, Carmen Gherasim, Ruma Banerjee, Markos Koutmos
In mammals, B12 (or cobalamin) is an essential cofactor required by methionine synthase and methylmalonyl-CoA mutase. A complex intracellular pathway supports the assimilation of cobalamin into its active cofactor forms and delivery to its target enzymes. MMADHC (the methylmalonic aciduria and homocystinuria type D protein), commonly referred to as CblD, is a key chaperone involved in intracellular cobalamin trafficking, and mutations in CblD cause methylmalonic aciduria and/or homocystinuria. Herein, we report the first crystal structure of the globular C-terminal domain of human CblD, which is sufficient for its interaction with MMADHC (the methylmalonic aciduria and homocystinuria type C protein), or CblC, and for supporting the cytoplasmic cobalamin trafficking pathway...
December 4, 2015: Journal of Biological Chemistry
Ya-Fen Yu, Fang Li, Hong-Wei Ma
OBJECTIVE: To analyze mutation types, clinical features, and treatment outcomes of cobalamin C (cblC) type combined methylmalonic aciduria and homocystinuria (MMA-HC) and to investigate the relationship of genotypes with clinical phenotypes and outcomes. METHODS: The clinical data of 16 Chinese children diagnosed with cblC type MMA-HC by gene analysis were retrospectively analyzed. According to the onset age, the patients were classified into early onset (≤1 year) and late onset (>1 year)...
August 2015: Zhongguo Dang Dai Er Ke za Zhi, Chinese Journal of Contemporary Pediatrics
Changhe Shi, Dandan Shang, Shilei Sun, Chengyuan Mao, Jie Qin, Haiyang Luo, Mingwei Shao, Zhengguang Chen, Yutao Liu, Xinjing Liu, Bo Song, Yuming Xu
Recent studies have convincingly documented that hypogonadism is a component of various hereditary disorders and is often recognized as an important clinical feature in combination with various neurological symptoms, yet, the causative genes in a few related families are still unknown. High-throughput sequencing has become an efficient method to identify causative genes in related complex hereditary disorders. In this study, we performed exome sequencing in a family presenting hypergonadotropic hypogonadism with neurological presentations of mental retardation, epilepsy, ataxia, and leukodystrophy...
December 15, 2015: Gene
Irini Manoli, Jennifer G Myles, Jennifer L Sloan, Nuria Carrillo-Carrasco, Eva Morava, Kevin A Strauss, Holmes Morton, Charles P Venditti
PURPOSE: Cobalamin C (cblC) deficiency impairs the biosynthesis of 5'-deoxyadenosyl-adenosyl- and methyl-cobalamin, resulting in methylmalonic acidemia combined with hyperhomocysteinemia and hypomethioninemia. However, some patients with cblC deficiency are treated with medical foods, devoid of methionine and high in leucine content, that are formulated for patients with isolated propionate oxidative defects. We examined the effects of imbalanced branched-chain amino acid intake on growth outcomes in cblC-deficient patients...
April 2016: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Yanan Zong, Ning Liu, Zhenhua Zhao, Xiangdong Kong
BACKGROUND: Combined methylmalonic aciduria and homocystinuria, cobalamin(cbl)C deficiency, is a rare disorder of intracellular vitamin B12(cbl) metabolism caused by mutations in the MMACHC gene. Both genetic and biochemical approach have been established to diagnose children and fetuses with cblC deficiency, while in China there is no report of prenatal genetic diagnosis of cblC deficiency. The aim of the present study was to characterize the mutational spectrum of cblC deficiency and investigate the feasibility of genetic-sequencing-based prenatal diagnosis for cblC deficiency...
2015: BMC Medical Genetics
Yiouli P Ktena, Trygg Ramstad, Eva H Baker, Jennifer L Sloan, Andrew J Mannes, Irini Manoli, Charles P Venditti
BACKGROUND: Methylmalonic acidemia and intracellular cobalamin metabolism disorders represent a heterogeneous group of inborn errors of metabolism. Most patients will require diagnostic and/or therapeutic procedures frequently requiring sedation or anesthetic management due to neurological and neurocognitive impairments. It has been stated that propofol is contraindicated in this population. We report our experience with propofol administration in a large series of patients. METHODS: Twenty eight patients (14 mut, seven cblC, three cblA, three cblB, one cblG) aged 2-35...
September 2015: Journal of Inherited Metabolic Disease
Simone Martinelli, Emilia Stellacci, Luca Pannone, Daniela D'Agostino, Federica Consoli, Christina Lissewski, Marianna Silvano, Giulia Cencelli, Francesca Lepri, Silvia Maitz, Silke Pauli, Anita Rauch, Giuseppe Zampino, Angelo Selicorni, Serge Melançon, Maria C Digilio, Bruce D Gelb, Alessandro De Luca, Bruno Dallapiccola, Martin Zenker, Marco Tartaglia
Noonan syndrome (NS) is a relatively common developmental disorder with a pleomorphic phenotype. Mutations causing NS alter genes encoding proteins involved in the RAS-MAPK pathway. We and others identified Casitas B-lineage lymphoma proto-oncogene (CBL), which encodes an E3-ubiquitin ligase acting as a tumor suppressor in myeloid malignancies, as a disease gene underlying a condition clinically related to NS. Here, we further explored the spectrum of germline CBL mutations and their associated phenotype. CBL mutation scanning performed on 349 affected subjects with features overlapping NS and no mutation in NS genes allowed the identification of five different variants with pathological significance...
August 2015: Human Mutation
Jens C Koenig, Frank Rutsch, Clemens Bockmeyer, Matthias Baumgartner, Bodo B Beck, Brigitta Kranz, Martin Konrad
BACKGROUND: Cobalamin C (CblC) defects are inherited autosomal recessive disorders of vitamin B12 metabolism due to mutations in the MMACHC gene. Renal manifestations include thrombotic microangiopathy (TMA), acute or chronic renal failure, tubulointerstitial nephritis, and proximal renal tubular acidosis. However, reports about glomerular pathologies are scarce. CASE REPORT: A 4-year-old boy presented with nephrotic syndrome, arterial hypertension, and chronic anemia but no signs of hemolysis...
July 2015: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Jessica Frankum, Pavel Moudry, Rachel Brough, Zdenek Hodny, Alan Ashworth, Jiri Bartek, Christopher J Lord
Based on a series of basic, preclinical and clinical studies, the Poly (ADP-ribose) Polymerase 1 (PARP1) inhibitor, olaparib, has recently been approved for use in ovarian cancer patients with BRCA1 or BRCA2 mutations. By identifying novel predictive biomarkers of tumour cell sensitivity to olaparib, it is possible that the utility of PARP inhibitors could be extended beyond this patient subgroup. Many of the known genetic determinants of PARP inhibitor response have key roles in DNA damage response (DDR) pathways...
May 10, 2015: Oncotarget
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