http://www.ojrd.com The latest research articles published by Orphanet Journal of Rare Diseases 2012-05-16T00:00:00Z Fanconi Anemia (FA) is a rare genetic disorder, characterized by progressive bone marrow failure and increased predisposition to cancer. Despite being highly heterogeneous, all FA patients are hypersensitive to alkylating agents, in particular to 1,2:3,4-diepoxybutane (DEB), and to oxidative damage. Recent studies point to defective mitochondria in FA cells, which is closely related with increased production of reactive oxygen species (ROS) and concomitant depletion of antioxidant defenses, of which glutathione is a well-known biomarker.The objective of the present work is to evaluate the putative protective effect of alpha-lipoic acid (alpha-LA), a mitochondrial protective agent, and N-acetylcysteine (NAC), a direct antioxidant and a known precursor for glutathione synthesis, in spontaneous and DEB-induced chromosome instability (CI) in lymphocyte cultures from FA patients.For that purpose, lymphocyte cultures from 15 FA patients and 24 healthy controls were pre-treated with 20 microM alpha-LA, 500 microM NAC and alpha-LA plus NAC at the same concentrations, and some of them exposed to DEB (0.05 microg/ml). A hundred metaphases per treatment were scored to estimate the relative frequency of spontaneous and DEB-induced chromosome breakage.The obtained results reveal that a cocktail of alpha-LA and NAC can drastically improve the genetic stability in FA lymphocytes in vitro, decreasing CI by 60% and 80% in cultures from FA patients and FA mosaic/chimera patients, respectively. These results suggest that the studied cocktail can be used as a prophylactic approach to delay progressive clinical symptoms in FA patients caused by CI, which can culminate in the delay of the progressive bone marrow failure and early cancer development. http://www.ojrd.com/content/7/1/28 Filipa Ponte Rosa Sousa Ana Fernandes Cristina Goncalves Jose Barbot Felix Carvalho Beatriz Porto Orphanet Journal of Rare Diseases 2012, null:28 2012-05-16T00:00:00Z doi:10.1186/1750-1172-7-28 Stabilizing Fanconi anemia with antioxidants A combination of antioxidants improves the genetic stability of blood cells from patients with Fanconi anemia, which could help block or delay the progression of this rare genetic disorder. /content/figures/1750-1172-7-28-toc.gif Orphanet Journal of Rare Diseases 1750-1172 ${item.volume} 28 2012-05-16T00:00:00Z PDF Background: We have previously reported the existence of a unique autosomal recessive syndrome consisting of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance mapping to chromosome 15q26. Methods: We have used whole exome sequencing on two affected members of the index family with this condition and carried out detailed bioinformatics analysis to elucidate the causative mutation. Results: Here we report the identification of a homozygous p.N1060S missense mutation in a highly conserved residue in KIF7, a regulator of Hedgehog signaling that has been recently implicated in Joubert syndrome, fetal hydrolethalus and acrocallosal syndromes. This is the first missense homozygous disease-causing mutation reported in KIF7, which might account for the unique presentation. Conclusions: The phenotype of our patients partially overlap with those previously associated with KIF7 mutations. In addition, our results expand the clinical spectrum associated with KIF7 mutations to multiple epiphyseal dysplasia. http://www.ojrd.com/content/7/1/27 Bassam Ali Jennifer Silhavy Nadia Akawi Joseph Gleeson Lihadh Al-Gazali Orphanet Journal of Rare Diseases 2012, null:27 2012-05-15T00:00:00Z doi:10.1186/1750-1172-7-27 /content/figures/1750-1172-7-27-toc.gif Orphanet Journal of Rare Diseases 1750-1172 ${item.volume} 27 2012-05-15T00:00:00Z PDF In non-diabetic adult patients, hypoglycaemia may be related to drugs, critical illness, cortisol or glucagon insufficiency, non-islet cell tumour, insulinoma, or it may be surreptitious. Nevertheless, some hypoglycaemic episodes remain unexplained, and inborn errors of metabolism (IEM) should be considered, particularly in cases of multisystemic involvement. In children, IEM are considered a differential diagnosis in cases of hypoglycaemia. In adulthood, IEM-related hypoglycaemia can persist in a previously diagnosed childhood disease. Hypoglycaemia may sometimes be a presenting sign of the IEM. Short stature, hepatomegaly, hypogonadism, dysmorphia or muscular symptoms are signs suggestive of IEM-related hypoglycaemia. In both adults and children, hypoglycaemia can be clinically classified according to its timing. Postprandial hypoglycaemia can be an indicator of either endogenous hyperinsulinism linked to non-insulinoma pancreatogenic hypoglycaemia syndrome (NIPHS, unknown incidence in adults) or very rarely, inherited fructose intolerance. Glucokinase-activating mutations (one family) are the only genetic disorder responsible for NIPH in adults that has been clearly identified so far. Exercise-induced hyperinsulinism is linked to an activating mutation of the monocarboxylate transporter 1 (one family). Fasting hypoglycaemia may be caused by IEM that were already diagnosed in childhood and persist into adulthood: glycogen storage disease (GSD) type I, III, 0, VI and IX; glucose transporter 2 deficiency; fatty acid oxidation; ketogenesis disorders; and gluconeogenesis disorders. Fasting hypoglycaemia in adulthood can also be a rare presenting sign of an IEM, especially in GSD type III, fatty acid oxidation [medium-chain acyl-CoA dehydrogenase (MCAD), ketogenesis disorders (3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) lyase deficiency, and gluconeogenesis disorders (fructose-1,6-biphosphatase deficiency)]. http://www.ojrd.com/content/7/1/26 Claire Douillard Karine Mention Dries Dobbelaere Jean-Louis Wemeau Jean-Marie Saudubray Marie-Christine Vantyghem Orphanet Journal of Rare Diseases 2012, null:26 2012-05-15T00:00:00Z doi:10.1186/1750-1172-7-26 /content/figures/1750-1172-7-26-toc.gif Orphanet Journal of Rare Diseases 1750-1172 ${item.volume} 26 2012-05-15T00:00:00Z PDF Background: Loss of function mutations in 3-Hydroxyacyl-CoA Dehydrogenase (HADH) cause protein sensitive hyperinsulinaemic hypoglycaemia (HH). HADH encodes short chain 3-hydroxacyl-CoA dehydrogenase, an enzyme that catalyses the penultimate reaction in mitochondrial beta-oxidation of fatty acids. Mutations in GLUD1 encoding glutamate dehydrogenase, also cause protein sensitive HH (due to leucine sensitivity). Reports suggest a protein-protein interaction between HADH and GDH. This study was undertaken in order to understand the mechanism of protein sensitivity in patients with HADH mutations. Methods: An oral leucine tolerance test was conducted in controls and nine patients with HADH mutations. Basal GDH activity and the effect of GTP were determined in lymphoblast homogenates from 4 patients and 3 controls. Immunoprecipitation was conducted in patient and control lymphoblasts to investigate protein interactions. Results: Patients demonstrated severe HH (glucose range 1.7-3.2 mmol/l; insulin range 4.8-63.8mU/l) in response to the oral leucine load, this HH was not observed in control patients subjected to the same leucine load. Basal GDH activity andhalf maximal inhibitory concentration of GTP was similar in patients and controls. HADH protein could be co-immunoprecipitated with GDH protein in control samples but not in patient samples. Conclusions: We conclude that GDH and HADH have a direct protein-protein interaction, which is lost in patients with HADH mutations causing leucine induced HH. This is not associated with loss of inhibitory effect of GTP on GDH (as in patients with GLUD1 mutations).KeywordsHyperinsulinism, hypoglycaemia, leucine tolerance http://www.ojrd.com/content/7/1/25 Amanda Heslegrave Ritika Kapoor Simon Eaton Bernadette Chadefaux Teoman Ackay Enver Simsek Sarah Flanagan Sian Ellard Khalid Hussain Orphanet Journal of Rare Diseases 2012, null:25 2012-05-14T00:00:00Z doi:10.1186/1750-1172-7-25 /content/figures/1750-1172-7-25-toc.gif Orphanet Journal of Rare Diseases 1750-1172 ${item.volume} 25 2012-05-14T00:00:00Z PDF Over the past forty years the availability of coagulation factor replacement therapy has greatly contributed to the improved care of people with hemophilia. Following the blood-borne viral infections in the late 1970s and early 1980, caused by coagulation factor concentrates manufactured using non-virally inactivated pooled plasma, the need for safer treatment became crucial to the hemophilia community. The introduction of virus inactivated plasma-derived coagulation factors and then of recombinant products has revolutionized the care of these people. These therapeutic weapons have improved their quality of life and that of their families and permitted home treatment, i.e., factor replacement therapy at regular intervals in order to prevent both bleeding and the resultant joint damage (i.e. primary prophylaxis). Accordingly, a near normal lifestyle and life-expectancy have been achieved. The main current problem in hemophilia is the onset of alloantibodies inactivating the infused coagulation factor, even though immune tolerance regimens based on long-term daily injections of large dosages of coagulation factors are able to eradicate inhibitors in approximately two-thirds of affected patients. In addition availability of products that bypass the intrinsic coagulation defects have dramatically improved the management of this complication. The major challenges of current treatment regimens, such the short half life of hemophilia therapeutics with need for frequent intravenous injections, encourage the current efforts to produce coagulation factors with more prolonged bioavailability. Finally, intensive research is devoted to gene transfer therapy, the only way to ultimately obtain cure in hemophilia. http://www.ojrd.com/content/7/1/24 Massimo Franchini Pier Mannucci Orphanet Journal of Rare Diseases 2012, null:24 2012-05-02T00:00:00Z doi:10.1186/1750-1172-7-24 /content/figures/1750-1172-7-24-toc.gif Orphanet Journal of Rare Diseases 1750-1172 ${item.volume} 24 2012-05-02T00:00:00Z PDF Definition and clinical picture: We propose the minimal definition of Dercum's disease to be generalised overweight or obesity in combination with painful adipose tissue. The associated symptoms in Dercum's disease include obesity, fatty deposits, easy bruisability, sleep disturbances, impaired memory, depression, difficulty concentrating, anxiety, rapid heartbeat, shortness of breath, diabetes, bloating, constipation, fatigue, weakness and joint and muscle aches.Classification: We suggest that Dercum's disease is classified into: I. Generalized diffuse form A form with diffusely widespread painful adipose tissue without clear lipomas, II. General nodular form A form with general pain in adipose tissue and intense pain in and around multiple lipomas, and III. Localized nodular form A form with pain in and around multiple lipomas IV. Juxtaarticular form A form with solitary deposits of excess fat for example at the medial aspect of the knee.Epidemiology: Dercum's disease most commonly appears between the ages of 35 and 50 years of age and is five to thirty times more common in women than in men. The prevalence of Dercum's disease has not yet been exactly established.Aetiology: Proposed, but unconfirmed aetiologies include: nervous system dysfunction, mechanical pressure on nerves, adipose tissue dysfunction and trauma.Diagnosis and diagnostic methods: Diagnosis is based on clinical criteria and should be made by systematic physical examination and thorough exclusion of differential diagnoses. Advisably, the diagnosis should be made by a physician with a broad experience of patients with painful conditions and knowledge of family medicine, internal medicine or pain management. The diagnosis should only be made when the differential diagnoses have been excludedDifferential diagnosis: Differential diagnoses include: fibromyalgia, lipoedema, panniculitis, endocrine disorders, primary psychiatric disorders, multiple symmetric lipomatosis, familial multiple lipomatosis, and adipose tissue tumours.Genetical counselling: The majority of the cases of Dercum's disease occur sporadically. A to G mutation at position A8344 of mitochondrial DNA cannot be detected in patients with Dercum's disease. HLA (human leukocyte antigen) typing has not revealed any correlation between typical antigens and the presence of the condition.Management and treatment: The following treatments have lead to some pain reduction in patients with Dercum's disease: Liposuction, analgesics, lidocaine, methotrexate and infliximab, interferon -2b, corticosteroids, calcium-channel modulators and rapid cycling hypobaric pressure. As none of the treatments have led to long lasting complete pain reduction and revolutionary results, we propose that Dercum's disease should be treated in multidisciplinary teams specialised in chronic pain. Prognosis: The pain in Dercum's disease seems to be relatively constant over time. http://www.ojrd.com/content/7/1/23 Emma Hansson Henry Svensson Håkan Brorson Orphanet Journal of Rare Diseases 2012, null:23 2012-04-30T00:00:00Z doi:10.1186/1750-1172-7-23 /content/figures/1750-1172-7-23-toc.gif Orphanet Journal of Rare Diseases 1750-1172 ${item.volume} 23 2012-04-30T00:00:00Z PDF Background: Mucopolysaccharidosis type I (MPS I) is traditionally divided into three phenotypes: the severe Hurler (MPS I-H) phenotype, the intermediate Hurler-Scheie (MPS I-H/S) phenotype and the attenuated Scheie (MPS I-S) phenotype. However, there are no clear criteria for delineating the different phenotypes. Because decisions about optimal treatment (enzyme replacement therapy or hematopoietic stem cell transplantation) need to be made quickly and depend on the presumed phenotype, an assessment of phenotypic severity should be performed soon after diagnosis. Therefore, a numerical severity scale for classifying different MPS I phenotypes at diagnosis based on clinical signs and symptoms was developed. Methods: A consensus procedure based on a combined modified Delphi method and a nominal group technique was undertaken. It consisted of two written rounds and a face-to-face meeting. Sixteen MPS I experts participated in the process. The main goal was to identify the most important indicators of phenotypic severity and include these in a numerical severity scale. The correlation between the median subjective expert MPS I rating and the scores derived from this severity scale was used as an indicator of validity. Results: Full consensus was reached on six key clinical items for assessing severity: age of onset of signs and symptoms, developmental delay, joint stiffness/arthropathy/contractures, kyphosis, cardiomyopathy and large head/frontal bossing. Due to the remarkably large variability in the expert MPS I assessments, however, a reliable numerical scale could not be constructed. Because of this variability, such a scale would always result in patients whose calculated severity score differed unacceptably from the median expert severity score, which was considered to be the 'gold standard'. Conclusions: Although consensus was reached on the six key items for assessing phenotypic severity in MPS I, expert opinion on phenotypic severity at diagnosis proved to be highly variable. This subjectivity emphasizes the need for validated biomarkers and improved genotype-phenotype correlations that can be incorporated into phenotypic severity assessments at diagnosis. http://www.ojrd.com/content/7/1/22 Minke de Ru Quirine Teunissen Johanna van der Lee Michael Beck Olaf Bodamer Lorne Clarke Carla Hollak Shuan-Pei Lin Maria-Veronica Munoz Rojas Gregory Pastores Julian Raiman Maurizio Scarpa Eileen Treacy Anna Tylki-Szymanska Edmond Wraith Jiri Zeman Frits Wijburg Orphanet Journal of Rare Diseases 2012, null:22 2012-04-23T00:00:00Z doi:10.1186/1750-1172-7-22 /content/figures/1750-1172-7-22-toc.gif Orphanet Journal of Rare Diseases 1750-1172 ${item.volume} 22 2012-04-23T00:00:00Z PDF Background: Mutations in SCO2 cause cytochrome c oxidase deficiency (COX) and a fatal infantile cardioencephalomyopathy. SCO2 encodes a protein involved in COX copper metabolism; supplementation with copper salts rescues the defect in patients' cells.Bezafibrate (BZF), an approved hypolipidemic agent, ameliorates the COX deficiency in mice with mutations in COX10, another COX-assembly gene. Methods: We have investigated the effect of BZF and copper in cells with SCO2 mutations using spectrophotometric methods to analyse respiratory chain activities and a luciferase assay to measure ATP production.. Results: Individual mitochondrial enzymes displayed different responses to BZF. COX activity increased by about 40% above basal levels (both in controls and patients), with SCO2 cells reaching 75-80% COX activity compared to untreated controls. The increase in COX was paralleled by an increase in ATP production. The effect was dose-dependent: it was negligible with 100 uM BZF, and peaked at 400 uM BZF. Higher BZF concentrations were associated with a relative decline of COX activity, indicating that the therapeutic range of this drug is very narrow. Combined treatment with 100 uM CuCl2 and 200 uM BZF (which are only marginally effective when administered individually) achieved complete rescue of COX activity in SCO2 cells. Conclusions: These data are crucial to design therapeutic trials for this otherwise fatal disorder. The additive effect of copper and BZF will allow to employ lower doses of each drug and to reduce their potential toxic effects. The exact mechanism of action of BZF remains to be determined. http://www.ojrd.com/content/7/1/21 Alberto Casarin Gianpietro Giorgi Vanessa Pertegato Roberta Siviero Cristina Cerqua Mara Doimo Giuseppe Basso Sabrina Sacconi Matteo Cassina Rosario Rizzuto Sonja Brosel Mercy Davidson Salvatore DiMauro Eric Schon Maurizio Clementi Eva Trevisson Leonardo Salviati Orphanet Journal of Rare Diseases 2012, null:21 2012-04-19T00:00:00Z doi:10.1186/1750-1172-7-21 /content/figures/1750-1172-7-21-toc.gif Orphanet Journal of Rare Diseases 1750-1172 ${item.volume} 21 2012-04-19T00:00:00Z PDF Definition of the diseaseBehcet disease (BD) is a chronic, relapsing, multisystemic disorder characterized by mucocutaneous, ocular, vascular and central nervous system manifestations.EpidemiologyBD seems to cluster along the ancient Silk Road, which extends from eastern Asia to the Mediterranean basin. European cases are often described, not exclusively in the migrant population.Clinical descriptionThe clinical spectrum includes oral and genital ulcerations, uveitis, vascular, neurological, articular, renal and gastrointestinal manifestations.EtiologyThe etiopathogenesis of the disease remains unknown, although genetic predisposition, environmental factors and immunological abnormalities have been implicated.Diagnostic methodsDiagnosis is only based on clinical criteria.Differrential diagnosisIt depends on the clinical presentation of BD, but sarcoidosis, multiple sclerosis, Crohn's disease, Takayasu's arteritis, polychondritis or antiphospholipid syndrome need to be considered.ManagementTreatment is symptomatic using steroids and immunomodulatory therapy. It is efficient depending on the rapidity of initiation, the compliance, and the duration of therapy.PrognosisThe prognosis is severe due to the ocular, neurological and arterial involvement. http://www.ojrd.com/content/7/1/20 David Saadoun Bertrand Wechsler Orphanet Journal of Rare Diseases 2012, null:20 2012-04-12T00:00:00Z doi:10.1186/1750-1172-7-20 /content/figures/1750-1172-7-20-toc.gif Orphanet Journal of Rare Diseases 1750-1172 ${item.volume} 20 2012-04-12T00:00:00Z PDF Cystinuria (OMIM 220100) is an inborn congenital disorder characterised by a defective cystine metabolism resulting in the formation of cystine stones. Among the heterogeneous group of kidney stone diseases, cystinuria is the only disorder which is exclusively caused by gene mutations. So far, two genes responsible for cystinuria have been identified: SLC3A1 (chromosome 2p21) encodes the heavy subunit rBAT of a renal b0,+ transporter while SLC7A9 (chromosome 19q12) encodes its interacting light subunit b0,+AT. Mutations in SLC3A1 are generally associated with an autosomal-recessive mode of inheritance whereas SLC7A9 variants result in a broad clinical variability even within the same family. The detection rate for mutations in these genes is larger than 85%, but it is influenced by the ethnic origin of a patient and the pathophysiological significance of the mutations. In addition to isolated cystinuria, patients suffering from the hypotonia-cystinuria syndrome have been reported carrying deletions including at least the SLC3A1 and the PREPL genes in 2p21.By extensive molecular screening studies in large cohort of patients a broad spectrum of mutations could be identified, several of these variants were functionally analysed and thereby allowed insights in the pathology of the disease as well as in the renal trafficking of cystine and the dibasic amino acids.In our review we will summarize the current knowledge on the physiological and the genetic basis of cystinuria as an inborn cause of kidney stones, and the application of this knowledge in genetic testing strategies. http://www.ojrd.com/content/7/1/19 Thomas Eggermann Andreas Venghaus Klaus Zerres Orphanet Journal of Rare Diseases 2012, null:19 2012-04-05T00:00:00Z doi:10.1186/1750-1172-7-19 /content/figures/1750-1172-7-19-toc.gif Orphanet Journal of Rare Diseases 1750-1172 ${item.volume} 19 2012-04-05T00:00:00Z PDF