Abstract:
BACKGROUND:Charcot-Marie-Tooth type 1A disease (CMT1A) is a rare orphan inherited neuropathy caused by an autosomal dominant duplication of a gene encoding for the structural myelin protein PMP22, which induces abnormal Schwann cell differentiation and dysmyelination, eventually leading to axonal suffering then loss and muscle wasting. We favour the idea that diseases can be more efficiently treated when targeting multiple disease-relevant pathways. In CMT1A patients, we therefore tested the potential of PXT3003, a low-dose combination of three already approved compounds (baclofen, naltrexone and sorbitol). Our study conceptually builds on preclinical experiments highlighting a pleiotropic mechanism of action that includes downregulation of PMP22. The primary objective was to assess safety and tolerability of PXT3003. The secondary objective aimed at an exploratory analysis of efficacy of PXT3003 in CMT1A, to be used for designing next clinical development stages (Phase 2b/3). METHODS:80 adult patients with mild-to-moderate CMT1A received in double-blind for 1 year Placebo or one of the three increasing doses of PXT3003 tested, in four equal groups. Safety and tolerability were assessed with the incidence of related adverse events. Efficacy was assessed using the Charcot-Marie-Tooth Neuropathy Score (CMTNS) and the Overall Neuropathy Limitations Scale (ONLS) as main endpoints, as well as various clinical and electrophysiological outcomes. RESULTS:This trial confirmed the safety and tolerability of PXT3003. The highest dose (HD) showed consistent evidence of improvement beyond stabilization. CMTNS and ONLS, with a significant improvement of respectively of 8% (0.4% - 16.2%) and 12.1% (2% - 23.2%) in the HD group versus the pool of all other groups, appear to be the most sensitive clinical endpoints to treatment despite their quasi-stability over one year under Placebo. Patients who did not deteriorate over one year were significantly more frequent in the HD group. CONCLUSIONS:These results confirm that PXT3003 deserves further investigation in adults and could greatly benefit CMT1A-diagnosed children, usually less affected than adults. TRIAL REGISTRATION:EudraCT Number: 2010-023097-40. ClinicalTrials.gov Identifier: NCT01401257. The Committee for Orphan Medicinal Products issued in February 2014 a positive opinion on the application for orphan designation for PXT3003 (EMA/OD/193/13).
journal_name
Orphanet J Rare Disjournal_title
Orphanet journal of rare diseasesauthors
Attarian S,Vallat JM,Magy L,Funalot B,Gonnaud PM,Lacour A,Péréon Y,Dubourg O,Pouget J,Micallef J,Franques J,Lefebvre MN,Ghorab K,Al-Moussawi M,Tiffreau V,Preudhomme M,Magot A,Leclair-Visonneau L,Stojkovic T,Bossi Ldoi
10.1186/s13023-014-0199-0subject
Has Abstractpub_date
2014-12-18 00:00:00pages
199issn
1750-1172pii
s13023-014-0199-0journal_volume
9pub_type
杂志文章,多中心研究,随机对照试验abstract::Paediatric chordomas are rare malignant tumours arising from primitive notochordal remnants with a high rate of recurrence. Only 5 % of them occur in the first two decades such less than 300 paediatric cases have been reported so far in the literature. In children, the average age at diagnosis is 10 years with a male-...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章,评审
doi:10.1186/s13023-015-0340-8
更新日期:2015-09-22 00:00:00
abstract:BACKGROUND:Gaucher disease (GD) is caused by deficiency of beta-glucocerebrosidase (GCase) due to biallelic variations in the GBA1 gene. Parkinson's disease (PD) is the second most common neurodegenerative condition. The classic motor symptoms of PD may be preceded by many non-motor symptoms (NMS), which include hyposm...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-019-1079-4
更新日期:2019-05-10 00:00:00
abstract:BACKGROUND:Many genetic diseases are due to defects in protein trafficking where the mutant protein is recognized by the quality control systems, retained in the endoplasmic reticulum (ER), and degraded by the proteasome. In many cases, the mutant protein retains function if it can be trafficked to its proper cellular ...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/1750-1172-8-11
更新日期:2013-01-14 00:00:00
abstract:BACKGROUND:Niemann-Pick disease Type C1 (NPC1) is a rare progressive neurodegenerative disorder caused by mutations in the NPC1 gene. The pathological mechanisms, underlying NPC1 are not yet completely understood. Especially the contribution of glial cells and gliosis to the progression of NPC1, are controversially dis...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-017-0697-y
更新日期:2017-08-25 00:00:00
abstract:BACKGROUND:The purpose of this study was to describe the natural history of severe congenital neutropenia (SCN) in 14 patients with G6PC3 mutations and enrolled in the French SCN registry. METHODS:Among 605 patients included in the French SCN registry, we identified 8 pedigrees that included 14 patients with autosomal...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-014-0183-8
更新日期:2014-12-10 00:00:00
abstract:OBJECTIVE:Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disease with many manifestations, and it involves any organ. In this study, we report a TSC patient with new type skin lesions. METHODS:A 7-month-old TSC boy with multiple cutaneous nodules was admitted in our hospital. We collected the cl...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-020-01396-7
更新日期:2020-06-12 00:00:00
abstract::Syndromic diarrhea (SD), also known as phenotypic diarrhea (PD) or tricho-hepato-enteric syndrome (THE), is a congenital enteropathy presenting with early-onset of severe diarrhea requiring parenteral nutrition (PN). To date, no epidemiological data are available. The estimated prevalence is approximately 1/300,000-40...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章,评审
doi:10.1186/1750-1172-3-6
更新日期:2008-02-28 00:00:00
abstract:BACKGROUND:Cystinosis is a rare autosomal recessive disorder caused by intracellular cystine accumulation. Proximal tubulopathy (Fanconi syndrome) is one of the first signs, leading to end-stage renal disease between the age of 12 and 16. Other symptoms occur later and encompass endocrinopathies, distal myopathy and de...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-019-1271-6
更新日期:2020-02-26 00:00:00
abstract:BACKGROUND:Morquio A syndrome (or mucopolysaccharidosis IVa) is an ultra-rare multi-organ disease, resulting in significantly impaired functional capacity, mobility and quality of life (QoL). METHODS:This patient-reported outcomes survey evaluated the global burden of Morquio A among adults (≥18 years, N = 27) and chi...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/1750-1172-9-32
更新日期:2014-03-07 00:00:00
abstract:BACKGROUND:Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder, which is usually caused by de novo mutations in the MECP2 gene. More than 70% of the disease causing MECP2 mutations are eight recurrent C to T transitions, which almost exclusively arise on the paternally derived X chromosome. About 10...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章,评审
doi:10.1186/1750-1172-6-58
更新日期:2011-08-30 00:00:00
abstract:BACKGROUND:The diagnostic accuracy of histopathological detection of transthyretin amyloid (ATTR) by Congo red staining of abdominal fat samples has been questioned since low sensitivity has been reported, especially for patients with ATTR cardiomyopathy. However, the outcome of surgically obtained fat pad biopsies has...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-020-01565-8
更新日期:2020-10-08 00:00:00
abstract:BACKGROUND:The burden of rare diseases on society and patients' families has increased in Korea. However, because of the infrequency of rare diseases, there is a lack of resources and information to address these cases and inadequate funding for the management of these patients. We investigated the average annual cumul...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-019-1032-6
更新日期:2019-02-18 00:00:00
abstract:BACKGROUND:Epidermolysis bullosa acquisita (EBA) is an orphan autoimmune disease. Several clinical phenotypes have been described, but subepidermal blistering is characteristic of all variants. Limited data on clinical and immunopathological characteristics and treatment outcomes in EBA are available. To fill this gap,...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章,meta分析
doi:10.1186/s13023-018-0896-1
更新日期:2018-09-04 00:00:00
abstract::Among the challenges confronting patients with rare diseases is a dearth of treatment options. The development of safe and effective new therapies is hampered by challenges associated with conducting clinical trials in small populations. In this article, we describe how the Duchenne muscular dystrophy community-led by...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-015-0281-2
更新日期:2015-06-24 00:00:00
abstract:BACKGROUND:X-linked Duchenne muscular dystrophy (DMD), the most frequent human hereditary skeletal muscle myopathy, inevitably leads to progressive dilated cardiomyopathy. We assessed the effect and safety of a combined treatment with the ACE-inhibitor enalapril and the β-blocker metoprolol in a German cohort of infant...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章,随机对照试验
doi:10.1186/s13023-019-1066-9
更新日期:2019-05-10 00:00:00
abstract:BACKGROUND:Short-chain enoyl-CoA hydratase (SCEH, encoded by ECHS1) catalyzes hydration of 2-trans-enoyl-CoAs to 3(S)-hydroxy-acyl-CoAs. SCEH has a broad substrate specificity and is believed to play an important role in mitochondrial fatty acid oxidation and in the metabolism of branched-chain amino acids. Recently, t...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-015-0290-1
更新日期:2015-06-18 00:00:00
abstract:BACKGROUND:A study was designed to identify the source of fever in a patient with post-polycythemia myelofibrosis, associated with clonal Janus Kinase 2 (JAK2) mutation involving duplication of exon 12. The patient presented with 1-2 day long self-limited periodic episodes of high fever that became more frequent as the...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-015-0298-6
更新日期:2015-06-30 00:00:00
abstract:BACKGROUND:It is now acknowledged that the input of patients in health outcome assessment is vital to understanding the impact of diseases and interventions for those diseases. This study is the first report of patient-reported outcome measures (PROM) in a large cohort of patients with type 1 Gaucher disease (GD1) enab...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-020-01544-z
更新日期:2020-10-13 00:00:00
abstract:BACKGROUND:Hepatic macrophage (Kupffer cell) hyperplasia is often described in Wilson's disease (WD). In many liver diseases, Kupffer cell activation is related to disease severity, liver function, and fibrosis but the importance in WD is unknown. Kupffer cell activation can be assessed by the P-concentration of solubl...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-018-0910-7
更新日期:2018-09-21 00:00:00
abstract::Glutamine synthetase (GS) is ubiquitously expressed in mammalian organisms and is a key enzyme in nitrogen metabolism. It is the only known enzyme capable of synthesising glutamine, an amino acid with many critical roles in the human organism. A defect in GLUL, encoding for GS, leads to congenital systemic glutamine d...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/1750-1172-7-48
更新日期:2012-07-25 00:00:00
abstract:BACKGROUND:Rubinstein-Taybi syndrome (RTS) is a rare, congenital, plurimalformative, and neurodevelopmental disorder. Previous studies have reported that large deletions contribute to more severe RTS phenotypes than those caused by CREBBP point mutations, suggesting a concurrent pathogenetic role of flanking genes, typ...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-020-01378-9
更新日期:2020-04-22 00:00:00
abstract::Schnitzler's syndrome is an auto-inflammatory disorder which is characterized by two mandatory features: an urticarial rash and a monoclonal gammopathy. Although the pathophysiology of this syndrome is not yet fully understood, a role for interleukin-1 seems apparent. While this presumed link between interleukin-1 and...
journal_title:Orphanet journal of rare diseases
pub_type: 信件
doi:10.1186/s13023-019-1117-2
更新日期:2019-06-22 00:00:00
abstract:BACKGROUND:Orphan designated medicinal products benefit from regulatory and economic incentives for orphan drug development. Approximately 40% of orphan designations target rare neoplastic disorders, referring to rare cancers. In order to provide more insights in drugs for rare neoplastic disorders that are under devel...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-017-0578-4
更新日期:2017-02-16 00:00:00
abstract:BACKGROUND:PWS is a severe neurodevelopmental genetic disorder now usually diagnosed in the neonatal period from hypotonia and feeding difficulties. Our study analyzed the birth incidence and care of infants with early diagnosis. METHODS:Data were collected on 61 infants with a molecular diagnosis of PWS born in 2012 ...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-017-0673-6
更新日期:2017-06-28 00:00:00
abstract:BACKGROUND:Alpha-1 antitrypsin deficiency (AATD) is a rare hereditary condition that leads to decreased circulating alpha-1 antitrypsin (AAT) levels, significantly increasing the risk of serious lung and/or liver disease in children and adults, in which some aspects remain unresolved. METHODS:In this review, we summar...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章,评审
doi:10.1186/s13023-018-0856-9
更新日期:2018-07-11 00:00:00
abstract:BACKGROUND:Acute hepatic porphyria (AHP) consists of three rare metabolic disorders. We investigated the risk of long-term sick leave, disability pension, and premature death in individuals with AHP compared to the general population. METHODS:In a nationwide cohort study from 1992 to 2017, records of 333 persons (tota...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-019-1273-4
更新日期:2020-02-21 00:00:00
abstract:BACKGROUND:Niemann-Pick disease type C (NP-C) is a rare neurovisceral disease characterised by progressive neurological degeneration, where the rate of neurological disease progression varies depending on age at neurological onset. We report longitudinal data on functional disease progression and safety observations in...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-015-0284-z
更新日期:2015-05-28 00:00:00
abstract:BACKGROUND:While skin carcinomas are reported in chronic ulcers and in patients treated with hydroxyurea (HU) for myeloproliferative neoplasms, no skin carcinoma has been reported in patients with sickle cell disease (SCD), presenting chronic skin ulcers or treated with HU. The objective was to estimate the risk of cut...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-020-1341-9
更新日期:2020-03-06 00:00:00
abstract:BACKGROUND:Treatment of phenylketonuria (PKU) with sapropterin dihydrochloride in responsive patients from an early age can have many advantages for the patient over dietary restriction alone. Accordingly, approval of sapropterin in the European Union was extended in 2015 to include patients aged 0-4 years, bringing th...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-018-0911-6
更新日期:2018-09-29 00:00:00
abstract:BACKGROUND:The diagnosis of rare diseases poses a particular challenge to clinicians. This study analyzes whether patients' pain drawings (PDs) help in the differentiation of two pain-associated rare diseases, Ehlers-Danlos Syndrome (EDS) and Guillain-Barré Syndrome (GBS). METHOD:The study was designed as a prospectiv...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-020-01542-1
更新日期:2020-11-17 00:00:00