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Paper 3
Published in Amanda Rabone, Benedict Thomson, Nicky Dineen, Vincent Helyar, Aidan Shaw, The Final FRCR, 2020
Amanda Rabone, Benedict Thomson, Nicky Dineen, Vincent Helyar, Aidan Shaw
Adrenoleukodystrophy is X-linked, affecting young male patients. It classically has a posterior distribution affecting the occipitoparietal region, particularly the periventricular area. There is involvement of the splenium of the corpus callosum. Peripheral enhancement is frequently seen.
Therapeutic Apheresis in Children
Published in James L. MacPherson, Duke O. Kasprisin, Therapeutic Hemapheresis, 2019
Adrenoleukodystrophy is a rare sex-linked recessive genetic disorder characterized by elevated levels of very long chain fatty acids resulting in neurologic degeneration. A six year old with this disorder received PE weekly or biweekly for a three-month period but his disease continued to progress. However, when PE was discontinued, his condition deteriorated more rapidly. The investigators hypothesized that PE may slow the progression of this disease.30
Endocrinology
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Mehul Dattani, Catherine Peters
In adrenoleukodystrophy, neurological symptoms and signs may develop first, with features of adrenal insufficiency developing between the ages of 4 and 8 years. In polyglandular autoimmune syndrome, features of other autoimmune conditions such as hypoparathyroidism, diabetes mellitus, vitiligo, myasthenia gravis, coeliac disease and pernicious anaemia may also be present. Mucocutaneous candidiasis is a feature of Type 1 polyglandular autoimmune syndrome.
Extracorporeal photopheresis for the treatment of chronic graft versus host disease
Published in Hematology, 2022
Emin Kansu, David Ward, Amber P. Sanchez, Robyn Cunard, Mutlu Hayran, Beril Huseyin, Majella Vaughan, Grace Ku, Peter Curtin, Carolyn Mulroney, Caitlin Costello, Januario E. Castro, Matthew Wieduwilt, Sue Corringham, Anita Ihasz-Davis, Connie Nelson, Edward D. Ball
Table 1 summarizes the demographic and transplant characteristics of the 53 patients included in this study. Of the original 59, 6 patients were excluded and the final study cohort, therefore, included 53 patients with chronic GVHD. Thirty-seven patients were male (69.8%) and 16 were female (30.2%). The median age was 45.8 years and 77.4% of patients were Caucasian versus 9.4% African American. Indications for transplantation included non-Hodgkin’s lymphoma (15), acute myeloblastic leukemia (10), acute lymphoblastic leukemia (9), chronic lymphocytic leukemia (5), chronic myeloid leukemia (5), myelodysplastic syndrome (3), multiple myeloma (4), myelofibrosis (1) and adrenoleukodystrophy (1). A total of 50 patients received peripheral blood (94.3%), two patients received cord blood (3.8%) and one patient received bone marrow (1.9%) as the stem cell source. Most patients had a related matched donor graft (n = 25, 48.1%) or unrelated donor graft (n = 25, 48.1%). All (n = 53) patients (100%) had corticosteroid refractory chronic GVHD. Thirty-nine patients had a prior history of acute GVHD. None of these patients received ECP for treatment of acute GVHD in this study.
Treatment of cerebral adrenoleukodystrophy: allogeneic transplantation and lentiviral gene therapy
Published in Expert Opinion on Biological Therapy, 2022
Ashish O Gupta, Gerald Raymond, Elizabeth I Pierpont, Stephan Kemp, R Scott McIvor, Arpana Rayannavar, Bradley Miller, Troy C Lund, Paul J Orchard
Adrenoleukodystrophy (ALD) is an X-linked disorder with an estimated incidence of approximately one in 14–17,000 births [1–3]. The gene associated with ALD is ABCD1, which encodes for a peroxisomal membrane protein responsible for transportation of very long-chain fatty acids (VLCFA) into the peroxisome, where they are subsequently degraded via β-oxidation. The gene consists of 10 exons, encoding for a protein of 745 amino acids. Over 900 pathogenic variants have been described, and a listing of ABCD1 variants known to be disease-causing and variants of uncertain significance are maintained in a database (https://adrenoleukodystrophy.info) [4]. Due to impaired degradation within the peroxisome, and through the action of elongases such as ELOVL1, increased concentrations of saturated VLCFA >C22:0 are observed [5,6]. These accumulate in the tissues as well as the blood, and elevations of VLCFA in plasma or serum are important in diagnosis of ALD [7,8]. In females, the use of VLCFA analysis in blood is insufficient to definitively establish the presence of a heterozygous state, as there may be a false-negative rate up to 20% using VLCFA testing alone. Recently, it has been demonstrated that C26:0-lysophosphatidylcholine (C26-lysoPC) has a superior diagnostic performance with a sensitivity of >99% in diagnosing women with ALD, including those with normal plasma VLCFA levels [9]. However, because VLCFA and C26:0-lysoPC are not specific for ALD, sequencing of the ABCD1 gene is done to make this determination [10].
Designation of orphan conditions in Europe: regulatory observations and considerations after implementation of regulation 141/2000
Published in Expert Opinion on Orphan Drugs, 2020
Segundo Mariz, Kerstin Westermark, Bruno Sepodes
Prevalence of a condition does not appear to be the limiting factor regarding clustering for example in Hemophilia B which has a prevalence below 1 in 10,000 (which some would call an ultra-rare condition) has 18 designations (as of the 16th of August 2019). However low Public awareness linked to low prevalence could however be associated with lower submissions and positive opinions [9]. To illustrate this point, we have highlighted some conditions which have been designated by the COMP for which few additional positive designations have occurred. Adrenoleukodystrophy a metabolic disorder with a prevalence of 0.4 in 10,000 in Europe and first designated in 2012 has had 3 more designations to date. Wolfram Syndrome another very rare metabolic condition with a prevalence in Europe estimated to be 0.2 in 10,000 had its initial designation in 2015 and only one additional designation. Aicardi-Goutieres Syndrome (prevalence reported to be 1 in 10,000) where one center in Europe has submitted two products at the same time for designation in 2015 has had no further submissions. What the limiting factor here is difficult to establish as it can be linked to factors such as limited number of centers working on the condition or limited understanding of the underlying etiology and pathophysiology or limited patient organization interaction [10]. Although a crude measure designation clustering around a new condition can offer some perception into the interest, awareness and trends regarding medicinal research and development activities associated with the specific condition considered.