Publications by authors named "Laure Delaval"

9 Publications

  • Page 1 of 1

Heterozygous HTRA1 nonsense or frameshift mutations are pathogenic.

Brain 2021 Oct;144(9):2616-2624

AP-HP, Service de Génétique Moléculaire Neurovasculaire, Hôpital Saint-Louis, France.

Heterozygous missense HTRA1 mutations have been associated with an autosomal dominant cerebral small vessel disease (CSVD) whereas the pathogenicity of heterozygous HTRA1 stop codon variants is unclear. We performed a targeted high throughput sequencing of all known CSVD genes, including HTRA1, in 3853 unrelated consecutive CSVD patients referred for molecular diagnosis. The frequency of heterozygous HTRA1 mutations leading to a premature stop codon in this patient cohort was compared with their frequency in large control databases. An analysis of HTRA1 mRNA was performed in several stop codon carrier patients. Clinical and neuroimaging features were characterized in all probands. Twenty unrelated patients carrying a heterozygous HTRA1 variant leading to a premature stop codon were identified. A highly significant difference was observed when comparing our patient cohort with control databases: gnomAD v3.1.1 [P = 3.12 × 10-17, odds ratio (OR) = 21.9], TOPMed freeze 5 (P = 7.6 × 10-18, OR = 27.1) and 1000 Genomes (P = 1.5 × 10-5). Messenger RNA analysis performed in eight patients showed a degradation of the mutated allele strongly suggesting a haploinsufficiency. Clinical and neuroimaging features are similar to those previously reported in heterozygous missense mutation carriers, except for penetrance, which seems lower. Altogether, our findings strongly suggest that heterozygous HTRA1 stop codons are pathogenic through a haploinsufficiency mechanism. Future work will help to estimate their penetrance, an important information for genetic counselling.
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http://dx.doi.org/10.1093/brain/awab271DOI Listing
October 2021

Myeloproliferative neoplasms and clonal hematopoiesis in patients with giant cell arteritis: a case-control and exploratory study.

Rheumatology (Oxford) 2021 Apr 9. Epub 2021 Apr 9.

Department of Internal Medicine, Cochin Hospital, National Referral Center for Rare Systemic Autoimmune Diseases, Paris University, Paris, France.

Objectives: Giant cell arteritis (GCA) is a large vessel vasculitis for which triggering factors remain unknown. Clonal hematopoiesis (CH) was associated with atherosclerosis through the induction of inflammation in myeloid cells, and data suggest that CH expansion and inflammation may support each other to induce a proinflammatory loop. Our objective was to describe the impact of JAK2p.V617F-mutated myeloproliferative neoplasms (MPN) on GCA and to screen MPN-free patients for CH mutations.

Methods: We performed a retrospective case-control study comparing characteristics of 21 GCA patients with MPN and 42 age and gender-matched GCA patients without MPN. Also, 18 GCA patients were screened for CH through Next Generation Sequencing.

Results: The most frequent associated MPN was essential thrombocythemia (ET) (n = 11). Compared to controls, GCA patients with MPN had less frequent cephalic symptoms (71.4 vs. 97.6%, p = 0.004) and higher platelets count at baseline [485 (346-586) vs. 346 [IQR 296-418] x 109/L, p = 0.02). There was no difference between groups for other clinical features. Overall survival was significantly shorter in patients with MPN compared to controls [HR 8.2 (95% CI 1.2-56.6), p = 0.03]. Finally, screening for CH using NGS in 15 GCA patients without MPN revealed CH in 33%.

Conclusion: GCA patients with MPN display higher platelets count and shorter overall survival than controls. This association could not be fortuitous given the possible pathophysiological relationship between the two diseases. CH was found in one third of GCA patients, which may be higher than the expected prevalence for similar age, what should be confirmed in a larger cohort.
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http://dx.doi.org/10.1093/rheumatology/keab337DOI Listing
April 2021

Reply.

Arthritis Rheumatol 2021 04 17;73(4):719-720. Epub 2021 Feb 17.

Hôpital Cochin, National Referral Center for Systemic and Autoimmune Diseases, Université de Paris, Paris, France.

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http://dx.doi.org/10.1002/art.41592DOI Listing
April 2021

Nailing the diagnosis: severe nail involvement in adult pulmonary Langerhans cell histiocytosis.

Thorax 2021 01 21;76(1):102-103. Epub 2020 Oct 21.

Université de Paris, UFR de Médecine Paris Nord, Paris, France

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http://dx.doi.org/10.1136/thoraxjnl-2020-215678DOI Listing
January 2021

Temporal Arteritis Revealing Antineutrophil Cytoplasmic Antibody-Associated Vasculitides: A Case-Control Study.

Arthritis Rheumatol 2021 02 21;73(2):286-294. Epub 2020 Dec 21.

Centre de Référence des Maladies Auto-Immunes Systémiques Rares d'Ile-de-France, Hôpital Cochin, and Université Paris Descartes, Paris, France.

Objective: Temporal arteritis (TA) is a typical manifestation of giant cell arteritis (GCA). Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are rarely revealed by TA manifestations, leading to a risk of misdiagnosis of GCA and inappropriate treatments. This study was undertaken to describe the clinical, biologic, and histologic presentations and outcomes in cases of TA revealing AAV (TA-AAV) compared to controls with classic GCA.

Methods: In this retrospective case-control study, the characteristics of patients with TA-AAV were compared to those of control subjects with classic GCA. Log-rank test, with hazard ratios (HRs) and 95% confidence intervals (95% CIs), was used to assess the risk of treatment failure.

Results: Fifty patients with TA-AAV (median age 70 years) were included. Thirty-three patients (66%) presented with atypical symptoms of GCA (ear, nose, and throat involvement in 32% of patients, and renal, pulmonary, and neurologic involvement in 26%, 20%, and 16% of patients, respectively). Blood samples were screened for ANCAs at the time of disease onset in 33 patients, and results were positive in 88%, leading to a diagnosis of early TA-AAV in 20 patients. The diagnosis of AAV was delayed a median interval of 15 months in 30 patients. Compared to controls with GCA, patients with TA-AAV were younger (median age 70 years versus 74 years), were more frequently men (48% versus 30%), and had high frequencies of atypical manifestations and higher C-reactive protein levels (median 10.8 mg/dl versus 7.0 mg/dl). In patients with TA-AAV, temporal artery biopsy (TAB) showed fibrinoid necrosis and small branch vasculitis in 23% of patients each, whereas neither of these characteristics was evident in controls with GCA. Treatment failure-free survival was comparable between early TA-AAV cases and GCA controls, whereas those with delayed TA-AAV had a significantly higher risk of treatment failure compared to controls (HR 3.85, 95% CI 1.97-7.51; P < 0.0001).

Conclusion: TA-AAV should be considered diagnostically in cases of atypical manifestations of GCA, refractoriness to glucocorticoid treatment, or early relapse. Analysis of TAB specimens for the detection of small branch vasculitis and/or fibrinoid necrosis could be useful. Detection of ANCAs should be performed in cases of suspected GCA with atypical clinical features and/or evidence of temporal artery abnormalities on TAB.
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http://dx.doi.org/10.1002/art.41527DOI Listing
February 2021

Large-vessel vasculitis diagnosed between 50 and 60 years: Case-control study based on 183 cases and 183 controls aged over 60 years.

Autoimmun Rev 2019 Jul 4;18(7):714-720. Epub 2019 May 4.

Department of Internal Medicine, Hôpital Lariboisière, Paris, France.

Background: Age at onset of large-vessel vasculitis (LVV) is commonly used to distinguish giant cell arteritis (GCA) and Takayasu arteritis (TA). However, LVV between age 50 and 60 years may be difficult to classify.

Methods: We conducted a retrospective study including LVV aged between 50 and 60 years at onset (LVV, cases) and compared them to LVV aged over 60 years (LVV, controls). LVV was defined histologically and/or morphologically. Controls fulfilled ACR 1990 criteria for GCA or presented isolated aortitis.

Results: We included 183 LVV and 183 gender-matched LVV. LVV had more frequent peripheral limb manifestations (23 vs. 5%), and less frequent cephalic (73 vs. 90%) and ocular signs (17 vs. 27%) than LVV. Compared to LVV, CT angiography and PET/CT scan were more frequently abnormal in LVV (74 vs. 38%, and 90 vs. 72%, respectively), with aorta being more frequently involved (78 vs. 47%). By multivariate analysis, absence of cephalic symptoms, presence of peripheral limb ischemia and aorta involvement, and increased CRP level were significantly associated with LVV presentation compared to LVV. At last follow-up, compared to LVV, LVV received significantly more lines of treatment (2 vs. 1), more frequent biologics (12 vs. 3%), had more surgery (10 vs. 0%), and had higher prednisone dose (8.8 vs. 6.5 mg/d) at last follow-up, CONCLUSION: LVV onset between 50 and 60 years identifies a subset of patients with more frequent aorta and peripheral vascular involvement and more refractory disease compared to patients with LVV onset after 60.
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http://dx.doi.org/10.1016/j.autrev.2019.05.008DOI Listing
July 2019

mTOR inhibitors may benefit kidney transplant recipients with mitochondrial diseases.

Kidney Int 2019 02 22;95(2):455-466. Epub 2018 Nov 22.

Service de Néphrologie Transplantation Adultes, Hôpital Necker-Enfants Malades, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker-Enfants Malades, Paris, France; INSERM U1151, Institut Necker Enfants Malades, Hôpital Necker-Enfants Malades, Paris, France. Electronic address:

Mitochondrial diseases represent a significant clinical challenge. Substantial efforts have been devoted to identifying therapeutic strategies for mitochondrial disorders, but effective interventions have remained elusive. Recently, we reported attenuation of disease in a mouse model of the human mitochondrial disease Leigh syndrome through pharmacological inhibition of the mechanistic target of rapamycin (mTOR). The human mitochondrial disorder MELAS/MIDD (Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like Episodes/Maternally Inherited Diabetes and Deafness) shares many phenotypic characteristics with Leigh syndrome. MELAS/MIDD often leads to organ failure and transplantation and there are currently no effective treatments. To examine the therapeutic potential of mTOR inhibition in human mitochondrial disease, four kidney transplant recipients with MELAS/MIDD were switched from calcineurin inhibitors to mTOR inhibitors for immunosuppression. Primary fibroblast lines were generated from patient dermal biopsies and the impact of rapamycin was studied using cell-based end points. Metabolomic profiles of the four patients were obtained before and after the switch. pS6, a measure of mTOR signaling, was significantly increased in MELAS/MIDD cells compared to controls in the absence of treatment, demonstrating mTOR overactivation. Rapamycin rescued multiple deficits in cultured cells including mitochondrial morphology, mitochondrial membrane potential, and replicative capacity. Clinical measures of health and mitochondrial disease progression were improved in all four patients following the switch to an mTOR inhibitor. Metabolomic analysis was consistent with mitochondrial function improvement in all patients.
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http://dx.doi.org/10.1016/j.kint.2018.08.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389356PMC
February 2019

New insights on tuberculous aortitis.

J Vasc Surg 2017 07 21;66(1):209-215. Epub 2017 Feb 21.

Département de Médecine Interne, Hôpital Bichat, Université Paris Diderot, PRES Sorbonne Paris Cité, Assistance Publique Hôpitaux de Paris, Paris, France; INSERM U1149, Paris, France; Département Hospitalo-Universitaire FIRE (Fibrosis, Inflammation and Remodeling in Renal and Respiratory Diseases), Paris, France. Electronic address:

Objective: Aortitis is an exceedingly rare manifestation of tuberculosis. We describe 11 patients with tuberculous aortitis (TA).

Methods: Multicenter medical charts of patients hospitalized between 2003 and 2015 with TA in Paris, France, were reviewed. Demographic, medical history, laboratory, imaging, pathologic findings, treatment, and follow-up data were extracted from medical records. TA was considered when aortitis was diagnosed in a patient with active tuberculosis.

Results: Eleven patients (8 women; median age, 44.6 years) with TA were identified during this 12-year period. No patient had human immunodeficiency virus infection. Tuberculosis was active in all cases, with a median delay of 18 months between the first symptoms and diagnosis. At disease onset, vascular signs were mainly claudication, asymmetric blood pressure, and diminished distal pulses. Constitutional symptoms or extravascular signs were present in all patients at some point. Aortic pseudoaneurysm was the most frequent lesion, but three patients had isolated inflammatory aortic stenosis. TA appeared as extension from a contiguous infection in only three cases. Tuberculosis was considered because of clinical features, tuberculin skin or QuantiFERON-TB Gold (Quest Diagnostics, Madison, NJ) test results, pathologic findings, and improvement on antituberculosis therapy. A definite Mycobacterium tuberculosis identification was made in only three cases. All patients received antituberculosis therapy for 6 to 12 months. Surgery including Bentall procedures, aortic bypass, and open abdominal aneurysm repair was performed at diagnosis in eight patients. Seven patients received steroids as an adjunct therapy. All patients clinically improved under treatment. No patients died for a median follow-up duration of 4 years.

Conclusions: TA may result in aneurysms contiguous to regional adenitis but also in isolated inflammatory aortic stenosis. Steroids may be associated with antituberculosis therapy for inflammatory stenotic lesions. Surgery is indicated for aneurysms and in case of worsening stenotic lesions despite anti-inflammatory drugs. No patient died after such combined treatment strategy.
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http://dx.doi.org/10.1016/j.jvs.2016.11.045DOI Listing
July 2017
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