Background:Fabry disease (FD) is a rare inherited lysosomal storage disorder caused by the deficiency of the enzyme alpha-galactosidase A. This deficiency leads to an accumulation of glycosphingolipids leading to progressive and multisystemic disease, including renal, cardiac, and neurological damages. FD may also have neuro-otological and visual impairments, which can generate postural control alterations, inner ear, and vision being involved in this function. This study aimed to evaluate the impact of FD on postural control.Methods:In total, fourteen adult patients (8 men/6 women, mean age = 37.6 ± 11.4 years) and two children (mean age = 11 years) with FD and 19 healthy adults (12 men/7 women, mean age = 36.5 ± 16.9 years) and two healthy children (mean age = 10.5 years) took part in this study. Postural control was evaluated by a sensory organization test combining three visual situations (eyes open, eyes closed, and sway referenced visual surround motion) with two platform situations (stable platform and sway referenced platform motion), aiming to calculate a composite equilibrium score (CES), a high score being representative of good postural control. Somatosensory (RSOM), visual (RVIS), and vestibular (RVEST) contributions to postural control were calculated, a low score reflecting a poor use of the indicated sensory input.Results:The CES was lower in adult patients with FD compared with the healthy subjects (p < 0.001). RVIS (p = 0.001) and RVEST (p = 0.003) were lower in patients with FD compared with the control group, whereas no difference in RSOM was observed.Conclusion:Inner ear and visual pathologies associated with the central nervous system impairments are factors of postural control impairments. Physical activities, which can also be rehabilitative, by maintaining or increasing the weight of proprioception, may help diminish dependency on altered sensorial inputs.

Background Different pulmonary hypertension (PH) mechanisms are associated with hereditary haemorrhagic telangiectasia (HHT). Methods and results We conducted a retrospective study of all suspected cases of PH (echocardiographically estimated systolic pulmonary artery pressure [sPAP] ≥ 40 mmHg) in patients with definite HHT recorded in the French National Reference Centre for HHT database. When right heart catheterization (RHC) was performed, PH cases were confirmed and classified among the PH groups according to the European guidelines. Among 2,598 patients in the database, 110 (4.2%) had suspected PH. Forty-seven of these 110 patients had RHC: 38/47 (81%) had a confirmed diagnosis of PH. The majority of these had isolated post-capillary PH (n = 20). We identified for the first time other haemodynamic profiles: pre-capillary pulmonary arterial hypertension (PAH) cases (n = 3) with slightly raised pulmonary vascular resistances (PVR), and combined post- and pre-capillary PH cases (n = 4). Compared to controls, survival probability was lower in patients with PAH. Conclusion This study revealed the diversity of PH mechanisms in HHT. The description of combined post- and pre-capillary PH with/or without high cardiac output (CO) suggests either a continuum between the pre- and post-capillary haemodynamic profiles or a different course in response to high CO.

BACKGROUND:Bevacizumab, an anti-VEGF monoclonal antibody, has recently emerged as a new option for severe forms of hereditary hemorrhagic telangiectasia (HHT). Its utilization in this orphan disease has rapidly spread despite the lack of randomized trials and international guidelines. The objective of this study is to report the main clinical data (baseline characteristics, dose schedule, efficacy, adverse events and deaths) of HHT patients treated by intravenous bevacizumab in France.METHODS:Retrospective observational study of HHT patients treated with bevacizumab for a severe form of the disease in the 14 centers of the French HHT network.RESULTS:Forty-six patients (median age: 68 years) were treated between March 2009 and May 2015. Ten patients were treated for high output cardiac failure, 20 patients for severe hemorrhages and 16 for both indications. The standard protocol (6 infusions of 5mg/kg every 2 weeks) was initially used in 89% of the cases but diverse strategies were subsequently applied. A clinical improvement was noted by the referent physician for 74% of the patients with a median effect's duration of 6 months. Wound healing complications led to 2 amputations. Arthralgia/arthritis and arterial hypertension occurred in 5 patients each. One third of the patients were dead at the time of the final update, coherently with age and the poor prognosis of these highly symptomatic patients.CONCLUSION:Intravenous bevacizumab seems to provide a clinical benefice in severe HHT patients. Precautions concerning wound healing and vascular pathologies must be respected. Prospective double blinded versus placebo trials are needed.

Background: The efficacy of enzyme replacement therapy (ERT) inpatients at an advanced stage of Pompe disease has only been addressed in a few studies. Our objective was to assess the long term effects of ERT in a cohort of patients with severe Pompe disease. Methods: We identified patients from the French Pompe Registry with severe respiratory failure and permanent wheelchair use (assisted walk for a few meters was allowed) when starting ERT. Patients' medical records were collected and reviewed and respiratory and motor functions, before ERT initiation and upon last evaluation were compared. Results: Twelve patients (7 males) were identified. Median age at symptom onset was 24 years [IQR = 15.5; 36.0]. At baseline ventilation was invasive in 11 patients and noninvasive in one, with a median ventilation time of 24 h [IQR = 21.88; 24.00] (min 20; max 24). ERT was initiated at a median age of 52.5 years [IQR = 35.75; 66.50]. Median treatment duration was 55 months [IQR = 39.5; 81.0]. During observational period no adverse reaction to ERT was recorded, five patients (41.67%) died, three decreased their ventilation time by 30, 60 and 90 min and two increased their assisted walking distance, by 80 and 20 m. Conclusion: Some patients at a very advanced stage of Pompe disease may show a mild benefit from ERT, in terms of increased time of autonomous ventilation and of enlarged distance in assisted walk. ERT can be initiated in these patients in order to retain their current level of independence and ability to perform daily life activities. (C) 2017 Elsevier Inc. All rights reserved.

OBJECTIVE:The aim of this study was to describe the presentation and outcomes of patients with granulomatosis with polyangiitis (GPA) presenting with CNS involvement.METHODS:Patients were included in this nationwide retrospective study if they had GPA according to ACR criteria and/or the European Medicines Agency algorithm and CNS involvement.RESULTS:Thirty-five patients were included in the study. CNS involvement was observed in 51% of patients at GPA diagnosis. Headache (66%) was the main symptom, followed by sensory (43%) and motor impairment (31%). CNS involvement was characterized by pachymeningitis in 20, cerebral ischaemic lesions in 15 and haemorrhagic lesions in 2, with hypophyseal involvement in 2 patients. According to the clinical-radiological presentation, we distinguished granulomatous (G-CNS) and vasculitic (V-CNS) phenotypes. G-CNS patients more frequently had headaches, while V-CNS patients more frequently had motor impairment and renal involvement. Induction therapy produced clinical responses in 86% of patients. Baseline modified Rankin scale was higher for V-CNS than G-CNS patients (3 vs 2, P = 0.002). Initial spinal cord pachymeningitis was significantly associated with the need for a new induction regimen for relapsing/refractory disease (P = 0.01). Long-term neurological sequelae were noted in 51% of patients, including 35% with G-CNS and 69% with V-CNS (P = 0.08). Neurological sequelae were mainly noted in cases of spinal cord pachymeningitis (100%) and ischaemic or haemorrhagic lesions (73%).CONCLUSION:The clinical-radiological phenotype distinguished different long-term outcomes in patients with GPA and CNS involvement. Long-term neurological sequelae persisted in half of patients, mainly those with spinal cord pachymeningitis and vasculitic lesions.

La dystrophie myotonique de type 1 (MD1 ou myotonie de Steinert) est la plus fréquente des dystrophies musculaires de l’adulte en Europe. L’atteinte respiratoire conditionne le pronostic de la maladie. Plusieurs études suggèrent une dysfonction de la commande ventilatoire centrale, contribuant à l’hypoventilation alvéolaire, indépendamment de l’atteinte musculaire respiratoire périphérique. Le but de notre étude est d’évaluer la relation entre la réponse ventilatoire à l’hypercapnie et la fonction respiratoire dans une population de patients MD1. Soixante-neuf patients MD1 ont été inclus de manière prospective entre 2008 et 2013 (âge moyen : 43,5 ans, 43 femmes). Chaque patient a réalisé, au cours d’une même journée, une exploration complète de la fonction respiratoire, incluant des gaz du sang artériels, une spirométrie, une pléthysmographie, une mesure des pressions maximales, ainsi qu’une évaluation de la réponse ventilatoire au CO2, selon la méthode de l’état stable. Trente et un patients (45 %) présentaient un trouble ventilatoire restrictif, 38 (55 %) étaient hypoxémiques et 15 (22 %) étaient hypercapniques. Le déclin de la capacité pulmonaire totale (CPT) était corrélé à l’hypoxémie (p = 0,0008) et à l’hypercapnie (p = 0,0013), mais n’était pas lié à la diminution de la réponse ventilatoire à l’hypercapnie (p = 0,19). La réponse ventilatoire au CO2 était en moyenne de 0,85 ± 0,67 L/min/mmHg et n’était pas corrélée à l’atteinte des muscles respiratoires. La réponse ventilatoire au CO2 n’était pas différente chez les sujets ayant un trouble ventilatoire restrictif par rapport à ceux sans trouble ventilatoire restrictif (p = 0,24). La réponse ventilatoire au CO2 chez les patients MD1 est diminuée. Elle apparaît comme étant indépendante de l’atteinte fonctionnelle et musculaire respiratoire, suggérant une cause centrale à la sensibilité réduite à l’hypercapnie. Cette dysfonction centrale du contrôle de la ventilation pourrait expliquer les apnées centrales, la somnolence diurne excessive, fréquemment observées dans cette population.

OBJECTIVE:To describe the possible association (pathophysiologic and clinical features) between exertional heat stroke (EHS) and malignant hyperthermia (MH).BACKGROUND:Both EHS and MH are acute and life-threatening disorders. It has repeatedly been shown that EHS can occur in well-trained patients with known MH-associated mutation in the RYR1 gene in the absence of any extreme environmental conditions or extreme physical activity, thereby supporting a possible link between EHS and MH. In this case, a highly trained 30-year-old male athlete suddenly collapsed while running. He had initial hyperthermia (40.2°C) and progressive multiple organ failure requiring medical management in an intensive care unit. After he recovered completely, a maximal exercise test was performed and showed an obvious abnormality of oxidative metabolism in muscle; genetic analysis of the RYR1 gene identified a heterozygous missense variation p.K1393R. Consequently, the athlete was given appropriate information and allowed to progressively return to sport competition.DIFFERENTIAL DIAGNOSIS:Doping, use of drugs and toxic agents, exercise-associated hyponatremia, exertional heat illness.TREATMENT:Initial management started with the basic resuscitative guidelines of airway, breathing, and circulation (intubation). Cooling, administration of fresh frozen plasma, and intensive rehydration resulted in improvement.UNIQUENESS:To our knowledge, ours is the first description of this MH mutation (p.K1393R) in the RYR1 gene that was associated with exertional rhabdomyolysis involving a dramatic impairment of oxidative metabolism in muscle.CONCLUSIONS:Common features are shared by EHS and MH. Careful attention must therefore be paid to athletes who experience EHS, especially in temperate climates or when there are no other predisposing factors.

OBJECTIVE To investigate the validity of the global APS score (GAPSS) to predict thrombosis in patients with autoimmune diseases. METHODS This prospective cohort study included consecutive patients with aPL or SLE. aPL, aPS-PT and GAPSS were determined. A Cox proportional hazards model assessed the validity of GAPSS and identified other potential independent predictors of thrombosis. RESULTS One hundred and thirty-seven patients [43.5 (s.d. 15.4) years old; 107 women] were followed up for a mean duration of 43.1 (s.d. 20.7) months. Mean GAPSS was significantly higher in patients who experienced a thrombotic event compared with those without [10.88 (s.d. 5.06) vs 8.15 (s.d. 5.31), respectively, P = 0.038]. In univariate analysis, age [hazard ratio (HR) = 1.04 (95% CI 1.01, 1.08)] and GAPSS above 16 [HR = 6.86 (95% CI 1.90, 24.77)] were each significantly associated with thrombosis during follow-up, while history of arterial thrombosis [HR = 2.61 (95% CI 0.87, 7.82)] failed to reach significance. Among aPL assays, IgG aPS/PT--a component of the GAPSS--was significantly associated with thrombosis [HR = 2.95 (95% CI 1.02, 8.51)]. In multivariate analysis, GAPSS above 16 remained the only significant predictor of thrombosis [HR = 6.17 (95% CI 1.70, 22.40)]. CONCLUSION This first external validation study confirmed that GAPSS can predict thrombosis in patients with aPL and associated autoimmune diseases.

Myotonic dystrophy Type 1 (DM1) is the most common muscular dystrophy in adults. Respiratory failure is common but clinical findings support a dysregulation of the control of breathing at central level, furthermore contributing to alveolar hypoventilation independently of the severity of respiratory weakness. We therefore intended to study the relationship between the ventilatory response to CO2 and the impairment of lung function in DM1 patients. Sixty-nine DM1 patients were prospectively investigated (43.5 ± 12.7 years). Systematic pulmonary lung function evaluation including spirometry, plethysmography, measurements of respiratory muscle strength, arterial blood gas analysis and ventilatory response to CO2 were performed. Thirty-one DM1 patients (45%) presented a ventilatory restriction, 38 (55%) were hypoxaemic and 15 (22%) were hypercapnic. Total lung capacity decline was correlated to hypoxaemia (p = 0.0008) and hypercapnia (p = 0.0013), but not to a decrease in ventilatory response to CO2 (p = 0.194). Ventilatory response to CO2 was reduced to 0.85 ± 0.67 L/min/mmHg and not correlated to respiratory muscle weakness. Ventilatory response to CO2 was neither different among restricted/non-restricted patients (p = 0.2395) nor among normoxaemic/hypoxaemic subjects (p = 0.6380). The reduced ventilatory response to CO2 in DM1 patients appeared independent of lung function impairment and respiratory muscle weakness, suggesting a central cause of CO2 insensitivity.

Objectives Health-related quality of life (HRQoL) has not been fully explored in antiphospholipid syndrome (APS); therefore, we compared HRQoL between APS patients and the general population and assessed the impact of thromboembolic history. Methods HRQoL was measured in a multicentre cohort study by the Medical Outcomes Study Short-Form 36 (MOS-SF-36) questionnaire. HRQoL scores were compared to the French general population norms. Factors significantly associated with an impaired HRQoL were identified. Results A total of 115 patients with aPL and/or systemic lupus erythematosus (SLE) were included (mean age 42.7 ± 14.1 years old, 86 women). In 53 patients APS was diagnosed. Compared to general population norms, patients with APS had an impaired HRQoL. SLE-associated APS patients had the worst HRQoL scores (physical component summary (PCS)=40.8 ± 10.6; mental component summary (MCS)=40.6 ± 16.5) in comparison with SLE or aPL patients without thromboembolic history. In APS patients, history of arterial thrombosis significantly impaired HRQoL (PCS score: 42.2 ± 9.4 vs 49.2 ± 8.5; MCS score: 33.9 ± 13.7 vs 44.6 ± 10.3). Conclusion Compared to the general population, APS patients experienced a lower HRQoL. In these patients, a history of arterial thrombosis significantly impaired HRQoL. Therefore, measurements of HRQoL should be included in APS patient management to assess the burden of the disease from a patient’s perspective and to provide patients with the support they need.

OBJECTIVES:This study aimed to estimate the responsiveness to change of a generic [the 36-item Short Form Health Survey (SF-36)] and a specific health-related quality of life questionnaire [the Lupus Quality if Life questionnaire (LupusQoL)] according to SLE patients' self-reported changes in health status.METHODS:In a cohort of 185 SLE patients, quality of life (QoL) was measured three times at 3 month intervals by the LupusQoL and SF-36 questionnaires. Anchors for responsiveness were defined by patients' global assessment of disease impact according to changes in a visual analogue scale (VAS), a 7-point Likert scale and a 0-3 scale of five patient-reported symptoms. Mean change and s.d. in worsening and improving patients according to anchors were estimated using mixed models for repeated measures. Standardized response means (SRMs) were calculated in each group.RESULTS:Patients [mean age 39.6 years (s.d. 10.5), mean Safety of Estrogen in Lupus Erythematosus National Assessment-SLEDAI score 2.6 (s.d. 3.5)] answered a total of 515 questionnaires. For the VAS and Likert global anchors, worsening patients showed a significant decrease in all LupusQoL domains except for burden to others, body image and fatigue and all SF-36 domains with low to moderate responsiveness. Improving patients had a significant increase in all LupusQoL domains except for intimate relationship and all SF-36 domains except for physical functioning and global health with low to moderate responsiveness. Regarding similar domains in the SF-36 and LupusQoL, SRMs were higher in LupusQoL domains in improving patients, while SF-36 domains had larger SRMs in worsening patients.CONCLUSION:Both the SF-36 and LupusQoL were responsive to changes in QoL in SLE patients over a 3 month interval. LupusQoL seems to be more appropriate to measure improvements in QoL.

Les maladies lysosomales (ML) constituent un groupe hétérogène de désordres métaboliques génétiques. Le déficit enzymatique résultant entraîne une accumulation de son substrat dans le lysosome.

Background and objective: Myotonic dystrophy Type 1 (MD1) is the most common muscular dystrophies in adults. Respiratory dysfunction is common and clinical findings support a dysregulation of the control of breathing at central level, furthermore contributing to alveolar hypoventilation independently of the severity of respiratory weakness. We therefore intended to study the relationship between the ventilatory response to CO2 and the impairment of lung function in a group of MD1 patients. Methods: 69 MD1 patients were prospectively investigated (43.5 +/- 12.7 years, 43 females). Systematic pulmonary lung function evaluation including spirometry, plethysmography, measurements of respiratory muscle strenght, arterial blood gas analysis and ventilatory response to CO2 (steady state method) were performed. Results: 31 MD1 patients (45%) presented a ventilatory restriction, 38 (55%) were hypoxaemic and 15 (22%) were hypercapnic. Total lung capacity decline was correlated to respiratory muscles weakness (p=0.011), hypoxaemia (0.0008) and hypercapnia (0.0013) but not to a decrease in ventilatory response to CO2 (p=0.194). Ventilatory response to CO2 was reduced to 0.85 +/- 0.67 L/min/mmHg and not correlated to respiratory muscle weakness. Ventilatory response to CO2 was neither different among restricted patients (p=0.354) nor among hypoxaemic subjects (p=0.872). Conclusion: The reduced ventilatory response to CO2 in MD1 patients appeared independent from lung function impairment and respiratory muscle weakness suggesting a central cause of CO2 insensitivity.

BackgroundSeveral arrhythmias were reported in myotonic dystrophy (MD).ObjectivesTo evaluate the prevalence of atrial fibrillation (AF) and atrial flutter (AFL) in MD and the clinical consequences.MethodsOne hundred sixty‐one patients, mean age 41 ± 14 years, were referred for a type 1 MD. All patients were asymptomatic except four patients and followed during 5 ± 4 years. Electrocardiogram (ECG), echocardiography assessing left ventricular ejection fraction, and Holter monitoring were obtained and repeated.ResultsTwenty‐seven patients (17%) presented sustained (>1 hour) AF (n = 15) or AFL (n = 12); two of them presented syncope‐related 1/1 AFL. In one of them, 16 years of age, cardiac defibrillator was implanted for a diagnosis of ventricular tachycardia, but the true diagnosis was established after inappropriate shocks. AFL ablation was performed in five patients, but four developed AF. The other seven patients with AFL developed AF. During the follow‐up, 22 patients died (14%) from cardiac and respiratory failure; eight patients with AF/AFL died (30%) while only 14 without AF/AFL died (10%; P < 0.01). Univariate analysis indicated that age >40 years (death: 48 ± 14 vs 40 ± 8 in alive patients), abnormal ECG, and occurrence of AF/AFL were significant factors of death. At multivariate analysis, AF at ECG (odds ratio: 3.12) and age >40 (odds ratio: 3.14) were the sole independent variables predicting death.ConclusionsAF and AFL were frequent in MD and increased mortality. AFL could present as 1/1 AFL with a poor tolerance and a risk of misdiagnosis despite frequent conduction disturbances. This arrhythmia could explain wide QRS tachycardia occurring in MD and interpreted as VT.

Quality of life and prognosis of patients with myotonic dystrophy type 1 (MD1) often depend on the degree of lung function impairment. This study was designed to assess the respective prevalence of ventilatory restriction, hypoxaemia and hypercapnia in MD1 patients and to determine whether postural changes in lung function could contribute to the early diagnosis of poor respiratory outcome. Fifty-eight patients (42.6±12.9 years) with MD1 were prospectively evaluated from April 2008 to June 2010 to determine their supine and upright lung function and arterial blood gases. The prevalence of ventilatory restriction was 36% and increased with the severity of muscular disability (from 7.7% to 70.6%). The prevalence of hypoxaemia and hypercapnia was 37.9% and 25.9%, respectively. Multiple regression analysis showed that the supine fall in FEV1 was the only variable associated with ventilatory restriction, hypoxaemia and hypercapnia. Our data indicate that supine evaluation of lung function could be helpful to predict poor respiratory outcome, which is closely correlated with hypoxaemia and/or hypercapnia.