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Van Dijk F.S.,VU University Amsterdam | Nikkels P.G.J.,University Utrecht | Den Hollander N.S.,Leiden University | Nesbitt I.M.,Sheffield Molecular Genetics Service | Pals G.,VU University Amsterdam
Pediatric and Developmental Pathology | Year: 2011

We report a large consanguineous Turkish family in which multiple individuals are affected with autosomal recessive lethal or severe osteogenesis imperfecta (OI) due to a novel homozygous LEPRE1 mutation. In one affected individual histological studies of bone tissue were performed, which may indicate that the histology of LEPRE1-associated OI is indistinguishable from COL1A1/2-, CRTAP-, and PPIB-related OI. © 2011 Society for Pediatric Pathology. Source

Singh M.,General Infirmary at Leeds | Puppala S.,General Infirmary at Leeds | Pollitt R.C.,Sheffield Molecular Genetics Service | Sobey G.J.,Ehlers Danlos Syndrome National Diagnostic Service | Scott D.J.A.,Leeds Vascular Institute
European Journal of Vascular and Endovascular Surgery | Year: 2012

Vascular Ehlers-Danlos Syndrome (EDS) is a rare autosomal dominant condition resulting from a defect in type III procollagen synthesis. This causes the development of severe vascular pathologies, including arterial rupture and pseudoaneurysm formation. We present a case of a young boy previously diagnosed with vascular EDS due to a Gly975Val substitution in the collagen α1(III) chain presenting with a common femoral artery dissection secondary to minimal trauma. This was managed conservatively with serial duplex scans and gentle mobilization. At follow up the patient had returned to normal activities, with MRA and duplex scans showing complete resolution of the dissection. © 2011 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. Source

Parker M.J.,Sheffield Clinical Genetics Services | Deshpande C.,South East Thames Regional Genetics Unit | Rankin J.,Peninsula Clinical Genetics Service | Wilson L.C.,Great Ormond Street Hospital and Institute of Child Health | And 6 more authors.
American Journal of Medical Genetics, Part A | Year: 2011

Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders of bone formation, resulting in low bone mass and an increased propensity to fracture. It exhibits a broad spectrum of clinical severity, ranging from multiple fractures in utero and perinatal death, to normal adult stature and low fracture incidence. Extra-skeletal features of OI include blue sclera, hearing loss, skin hyperlaxity, joint hyperextensibility, and dentinogenesis imperfecta. The proα1(I) and proα2(I) chains of collagen 1 are encoded by the COL1A1 and COL1A2 genes, respectively; quantitative or qualitative defects in type I collagen synthesis usually manifest as types of OI or some sub-types of EDS. The majority of patients (about 90%) with a clinical diagnosis of OI have a mutation in the COL1A1 or COL1A2 genes, which shows an autosomal dominant pattern of inheritance. Six other genes, CRTAP, LEPRE1, FKBP10, PP1B, SP7/Osterix (OSX), and SERPINH1, are associated with autosomal recessive forms of OI. However, other, rare phenotypes have also been described. There are many differential diagnoses of the short, syndromic child, including chromosomal, single gene, and multifactorial causes. However, one condition of particular relevance in the context of this report is the Russell-Silver syndrome (RSS). As originally described, the RSS is a very specific condition. However, it has subsequently become an umbrella term for a heterogeneous group of conditions presenting with short stature and triangular shape to the face. A significant proportion of these are now believed to be due to imprinting defects at 11p15. However, the cause in many cases remains unknown. We describe two cases with a phenotypic overlap between OI and RSS who both have COL1A1 mutations. Thus, a type 1 collagenopathy should be considered in the differential diagnosis of syndromic short stature. © 2011 Wiley-Liss, Inc. Source

Nessa A.,Great Ormond Street Hospital for Children NHS Trust | Nessa A.,University College London | Kumaran A.,Great Ormond Street Hospital for Children NHS Trust | Kumaran A.,University College London | And 6 more authors.
Journal of Pediatric Endocrinology and Metabolism | Year: 2012

Background: Ketotic hypoglycaemia is a common form of hypoglycaemia in childhood. Biochemically, patients present with fasting hypoglycaemia but with normal hormonal and metabolite profiles (low serum alanine levels in some patients). Glycogen Storage Disease Type 0 (GSD0) is an autosomal recessive disease due to mutations in the GYS2 gene. Patients with GSD0 also present with fasting ketotic hypoglycaemia. The frequency of GSD0 in patients presenting with ketotic hypoglycaemia is not known. Objective: To understand the frequency of GSD0 in patients presenting with ketotic hypoglycaemia and to report a novel mutation in the GYS2 gene. Subjects: The GYS2 gene was sequenced in 50 patients diagnosed with ketotic hypoglycaemia. Methods: All exons (including exon and intron boundaries) of the GYS2 gene were sequenced following amplification of the coding region by polymerase chain reaction (PCR). Results: No mutations in GYS2 were found in 49 patients. One patient had a novel homozygous mutation (c.1802T > G; p. Leu601X) in exon 14 of the GYS2 gene. We believe this is the 18th mutation reported so far. This mutation is predicted to lead to premature truncation of the glycogen synthase protein with no function. This patient presented with fasting ketotic hypoglycaemia associated with postprandial hyperglycaemia and elevated lactate level. Conclusions: GSD0 is relatively rare in patients presenting with ketotic hypoglycaemia and a normal biochemical profile. Sequencing of the GYS2 gene is more likely to be positive in patients with fasting ketotic hypoglycaemia and concomitant postprandial hyperglycaemia with hyperlactataemia. Source

Crushell E.,National University of Ireland | Treacy E.P.,National University of Ireland | Dawe J.,Sheffield Molecular Genetics Service | Durkie M.,Sheffield Molecular Genetics Service | Beauchamp N.J.,Sheffield Molecular Genetics Service
Journal of Inherited Metabolic Disease | Year: 2010

Glycogen storage disease type III (GSD III) results from mutations of the AGL gene encoding the glycogen debrancher enzyme. The disease has clinical and biochemical heterogeneity reflecting the severity of the AGL mutations. We sought to characterise the molecular defects in our cohort of Irish patients with GSD III. Fifteen patients from eight unrelated Irish families were identified: six males and nine females. The age ranged from 2-39 years old, and all presented in the first 3 years of life. Four patients (of three families) had mild disease with hepatomegaly, mild hypoglycaemia and normal creatine kinase (CK) levels. Five families had more severe disease, with liver and skeletal muscle involvement and elevated CK. Eleven different mutations were identified amongst the eight families. Of the 11, six were novel: p. T512fs, p.S736fs, p.A1400fs, p.K1407fs, p.Y519X and p. D627Y. The family homozygous for p.A1400fs had the most severe phenotype (early-onset hypoglycaemia, massive hepatomegaly, myopathy and hypertrophic cardiomyopathy before age 2 years), which was not halted by aggressive carbohydrate and protein supplementation. Conversely, the only missense mutation identified in the cohort, p.D627Y, was associated with a mild phenotype. The phenotypic diversity in our GSD III cohort is mirrored by the allelic heterogeneity. We describe two novel null mutations in exon 32 in two families with severe GSD III resistant to current treatment modalities. Knowledge of the specific mutations segregating in this cohort may allow for the development of new therapeutic interventions. © SSIEM and Springer 2010. Source

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