Expanding the Clinical Spectrum of DRP2-Associated Charcot-Marie-Tooth Disease.

BACKGROUND AND OBJECTIVES: Germline truncating variants in the DRP2 gene (encoding dystrophin-related protein 2) cause the disruption of the periaxin-DRP2-dystroglycan complex and have been linked to Charcot-Marie-Tooth disease. However, the causality and the underlying phenotype of the genetic alterations are not clearly defined. METHODS: This cross-sectional retrospective observational study includes 9 patients with Charcot-Marie-Tooth disease (CMT) with DRP2 germline variants evaluated at 6 centers throughout Spain. RESULTS: We identified 7 Spanish families with 4 different DRP2 likely pathogenic germline variants. In agreement with an X-linked inheritance, men harboring hemizygous DRP2 variants presented with an intermediate form of CMT, whereas heterozygous women were asymptomatic. Symptom onset was variable (36.6 ± 16 years), with lower limb weakness and multimodal sensory loss producing a mild-to-moderate functional impairment. Nerve echography revealed an increase in the cross-sectional area of nerve roots and proximal nerves. Lower limb muscle magnetic resonance imaging confirmed the presence of a length-dependent fatty infiltration. Immunostaining in intradermal nerve fibers demonstrated the absence of DRP2 and electron microscopy revealed abnormal myelin thickness that was also detectable in the sural nerve sections. DISCUSSION: Our findings support the causality of DRP2 pathogenic germline variants in CMT and further define the phenotype as a late-onset sensory and motor length-dependent neuropathy, with intermediate velocities and thickening of proximal nerve segments.

Real life experience of tafamidis for the treatment of Spanish patients with Val30Met transthyretin amyloidosis with polyneuropathy.

INTRODUCTION: Tafamidis is the only approved transthyretin stabiliser approved for the treatment of variant transthyretin amyloidosis (A-ATTRv) related polyneuropathy (PNP). The aim of this study is to analyse the effectiveness of tafamidis in a real-world setting in Spain. METHODS: This is a national multicenter study in which patients with V30M A-ATTR related PN treated with tafamidis for at least 1 year were included. Clinical, demographic, analytical and neurophysiological variables were analysed. RESULTS: 100 patients were recruited. Overall, 47 patients (47%) were classified as complete responders, 32 (32%) as partial responders and 21 (21%) as non-responders. The median duration of treatment with tafamidis was 35 months. Better treatment response was shown in patients with in polyneuropathy disability score (PND) I, lower neuropathy impairment score (NIS), compound muscle action potential (CMAP) and Norfolk QoL questionnaire. Higher albumin levels and lower NTproBNP levels were also associated with better treatment response. A basal NIS≥15 predicts that the patient could be a non-responder with a 60% probability. CONCLUSIONS: Our results reinforce the tafamidis efficacy to treat A-ATTRv-PNP if started early in the disease course. Patients with the V30M variant, NIS<15 and PND I are the most appropriate subjects for this treatment.

Evolution and Prognostic Significance of Patient-Reported Symptoms After Intervention in Severe Aortic Stenosis.

OBJECTIVE: To describe the evolution of symptoms in patients with symptomatic severe aortic stenosis (sSAS) undergoing valve replacement, the predictors of the persistence of these symptoms, and their prognostic significance. The evolution of symptoms after intervention in sSAS and their association with outcome are unknown. PATIENTS AND METHODS: Data from patients with sSAS who underwent intervention were collected. All-cause mortality and cardiovascular mortality were considered events. The evolution of symptoms and their association with events were studied. RESULTS: In this study, 451 consecutive patients with sSAS and no other valvular or coronary disease who were alive 30 days after intervention were included. Before valve replacement, 133 of the 451 patients (29.5%) had congestive heart failure requiring hospitalization. Of the remaining 318 patients, 287 (90.2%) had dyspnea on effort, 129 (40.6%) had angina, and 59 had syncope (18.6%). Symptoms disappeared after intervention in 192 of the 451 patients (42.6%) and remained in 259 (57.4%): 193 dyspnea, 9 angina, 17 syncope, and 60 admission for heart failure. Syncope on effort persisted in 4 of 33 patients (12.1%) and at rest in 11 of 20 (55.0%; P<.001). Age, body mass index, previous admission for heart failure, and chronic obstructive pulmonary disease were independently related to persistence of symptoms. Over a median follow-up of 56 months in our cohort of 451 patients, 129 deaths were registered (28.6%), 40 of which were cardiovascular (8.9%). Age, chronic obstructive pulmonary disease, chronic kidney disease, atrial fibrillation, heart failure, and persistence of symptoms were independently associated with all-cause mortality. CONCLUSION: Symptoms attributed to SAS remain after intervention in a high proportion of patients, particularly dyspnea on effort and syncope at rest. The persistence of symptoms after intervention identifies patients with poor outcome.

Safety and Efficacy of Nipocalimab in Patients With Generalized Myasthenia Gravis: Results From the Randomized Phase 2 Vivacity-MG Study

BACKGROUND AND OBJECTIVES: To evaluate in a phase 2 study the safety and efficacy of IV nipocalimab, a fully human, antineonatal Fc receptor monoclonal antibody, in patients with generalized myasthenia gravis (gMG). METHODS: Patients with gMG with inadequate response to stable standard-of-care (SOC) therapy were randomized 1:1:1:1:1 to receive either IV placebo every 2 weeks (Q2W) or one of 4 IV nipocalimab treatments: 5 mg/kg once every 4 weeks (Q4W), 30 mg/kg Q4W, 60 mg/kg Q2W each for 8 weeks, or a 60 mg/kg single dose, in addition to their background SOC therapy. Infusions (placebo or nipocalimab) were Q2W in all groups to maintain blinding. The primary safety endpoint was incidence of treatment-emergent adverse events (TEAEs), including serious adverse events and adverse events of special interest. The primary efficacy endpoint was change from baseline to day 57 in Myasthenia Gravis-Activities of Daily Living (MG-ADL) total scores. Dose response of change at day 57 was analyzed with a linear trend test over the placebo, nipocalimab 5 mg/kg Q4W, nipocalimab 30 mg/kg Q4W, and nipocalimab 60 mg/kg Q2W groups. RESULTS: Sixty-eight patients (nipocalimab: n = 54; placebo, n = 14) were randomized; 64 patients (94.1%) were positive for antiacetylcholine receptor autoantibodies, and 4 patients (6%) were positive for antimuscle-specific tyrosine kinase autoantibodies. Fifty-seven patients (83.8%) completed treatment through day 57. The combined nipocalimab group compared with the placebo group demonstrated similar incidences of TEAEs (83.3% vs 78.6%, respectively) and infections (33.3% vs 21.4%, respectively). No deaths or discontinuations due to TEAEs and no TEAEs of special interest (grade ≥3 infection or hypoalbuminemia) were observed with nipocalimab treatment. A statistically significant dose response was observed for change from baseline in MG-ADL at day 57 (p = 0.031, test of linear trend). DISCUSSION: Nipocalimab was generally safe, well-tolerated, and showed evidence of dose-dependent reduction in MG-ADL scores at day 57 in this phase 2 study. These results support further evaluation of nipocalimab for the treatment of gMG. TRIAL REGISTRATION INFORMATION: Clinical Trials Registration: NCT03772587; first submitted December 10, 2018; EudraCT Number: 2018-002247-28; first submitted November 30, 2018; date of first patient dosed April 10, 2019. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with gMG, nipocalimab was well-tolerated, and it did not significantly improve MG-ADL at any individual dose but demonstrated a significant dose response for improved MG-ADL across doses.

Sex Differences in Clinical Outcomes after Aortic Valve Intervention for Isolated Severe Aortic Stenosis.

There are known pathophysiologic and clinical differences according to sex in patients with aortic stenosis (AS). To evaluate if these differences persist after valve replacement, we conducted an observational study including 451 patients with symptomatic AS who survived aortic valve intervention (AVI) in two centers. Clinical data and mortality were evaluated at a mean follow-up of 5 years. 56% of patients were women. At baseline, women were older (80.6 vs. 78 years, p = 0.013), presented higher mean gradient (48 vs. 45 mmHg, p = 0.023), lower aortic valve area (0.70 vs. 0.74 cm2, p = 0.002) and higher systolic pulmonary artery pressure (36 vs. 33 mmHg, p = 0.016). They underwent percutaneous aortic valve replacement more frequently than men (47 vs. 35.9%, p = 0.017). At 5 years follow-up, women required more admissions due to heart failure (23 vs. 9%, p = 0.046) but they did not present higher cardiovascular nor overall mortality (27.7% vs. 29.8%, p = 0.741; 11.1 vs. 10.1%, p = 0.619, respectively). Female sex was an independent predictor of heart failure hospitalization at follow-up (HR 95% 1.16-4.22, p = 0.016). Women undergo AVI at a more advanced stage than men, resulting in a higher frequency of readmissions due to heart failure during the follow-up period, but not in higher mortality.

Msi2 enhances muscle dysfunction in a myotonic dystrophy type 1 mouse model.

BACKGROUND: Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by a CTG repeat expansion in the 3' untranslated region of the DM1 protein kinase gene. Characteristic degenerative muscle symptoms include myotonia, atrophy, and weakness. We previously proposed an MSI2>miR-7>autophagy axis whereby MSI2 overexpression repressed miR-7 biogenesis that subsequently de-repressed muscle catabolism through excessive autophagy. Because the DM1 HSALR mouse model expressing expanded CUG repeats shows weak muscle-wasting phenotypes, we hypothesized that MSI2 overexpression was sufficient to promote muscle dysfunction in vivo. METHODS: By means of recombinant AAV murine Msi2 was overexpressed in neonates HSALR mice skeletal muscle to induce DM1-like phenotypes RESULTS: Sustained overexpression of the murine Msi2 protein in HSALR neonates induced autophagic flux and expression of critical autophagy proteins, increased central nuclei and reduced myofibers area, and weakened muscle strength. Importantly, these changes were independent of Mbnl1, Mbnl2, and Celf1 protein levels, which remained unchanged upon Msi2 overexpression. CONCLUSIONS: Globally, molecular, histological, and functional data from these experiments in the HSALR mouse model confirms the pathological role of Msi2 expression levels as an atrophy-associated component that impacts the characteristic muscle dysfunction symptoms in DM1 patients.

Different prognostic significance of coronary artery and aortic valve calcium in patients with chest pain.

OBJECTIVES: Coronary artery calcification (CorCa) identifies high cardiovascular risk in the general population. In this setting, aortic valve calcification (AoCa) showed contradictory results. Our goal has been to assess the prognostic power of CorCa and AoCa in patients with chest pain who underwent an ECG-gated cardiac multidetector CT (cardiac-MDCT). METHODS: A total of 528 patients without previous known coronary artery disease, with chest pain who underwent a cardiac-MDCT multidetector, were retrospectively recruited. The primary endpoint included death, acute coronary syndrome, stroke, and heart failure. RESULTS: A total of 61 patients (11.6%) had an event during a mean follow-up of almost 6 years (5.95 ± 2.98). The most frequent event was acute coronary syndrome (6.4%). Total mortality was 4.5%. Patients with CorCa > 0 had more events than those without CorCa (17.3% versus 4.3%; p < 0.001). Likewise, when only patients without AoCa were considered (n = 118), clinical events were more frequent in those with CorCa (12.7% versus 3.6%; p = 0.004). After excluding patients with coronary artery disease, events were more frequent in those with CorCa (12.6% versus 4.3%; p = 0.004). The higher the Agatston score, the more frequent the events. Patients with AoCa > 0 had more events than those without (16.5% versus 7.3%; p < 0.001), but in patients without CorCa, no difference in events was seen (6.2% versus 3.6%; p = 0.471). A Cox regression analysis showed age, smoking, prior stroke, and CorCa but not AoCa to be independently related to events. CONCLUSIONS: In summary, CorCa, but not AoCa, is related to cardiovascular events in patients with chest pain who undergo a cardiac-MDCT. CLINICAL RELEVANCE STATEMENT: We show that coronary artery calcification, but not aortic valve calcification, detected in a coronary CT scan is tightly related to cardiovascular events. Although this is a message already shown by other groups in the general population, we do believe that this work is unique because it is restricted to patients with chest pain sent to coronary CT. In other words, our work deals with what we face in our routine everyday practice. KEY POINTS: • The presence and the amount of coronary artery calcification are associated with cardiovascular events in patients with chest pain. • Aortic valve calcification is not associated with cardiovascular events in patients with chest pain.

Recurrence of syncope after valve replacement in severe aortic stenosis.

OBJECTIVE: The recurrence of syncope after valve intervention in severe aortic stenosis (SAS) and its impact on outcome are unknown. We hypothesised that syncope on exertion will disappear after intervention, whereas syncope at rest might recur. Our aim has been to describe the recurrence of syncope in patients with SAS undergoing valve replacement and its impact on mortality. METHODS: Double-centre observational registry of 320 consecutive patients with symptomatic SAS without other valve disease and/or coronary artery disease who underwent valve intervention and were discharged alive. All-cause mortality and cardiovascular mortality were considered events. RESULTS: 53 patients (median age 81 years, 28 men) had syncope (29 on exertion, 21 at rest, 3 unknown). Clinical and echocardiographic variables were similar in patients with and without syncope (median vmax 4.44 m/s, mean gradient 47 mm Hg, valve area 0.7 cm2, left ventricular ejection fraction 62%). After a median follow-up of 69 months (IQR: 55-88), syncope on exertion did not recur in any patient. In contrast, 8 of the 21 patients with syncope at rest had postintervention syncope at rest (38%; p<0.001): 3 needed a pacemaker, 3 were neuromediated or hypotensive and 2 arrhythmic. Only recurrence of syncope was associated with cardiovascular mortality (HR 5.74; 95% CI 2.17 to 15.17; p<0.001). CONCLUSIONS: Syncope on exertion in patients with SAS did not recur after aortic valve intervention. Syncope at rest recurs in a high proportion of patients and identifies a population with increased mortality. According to our results, syncope at rest should be thoroughly evaluated before proceeding to aortic valve intervention.

Magnetic resonance analysis of ventricular volumes in bicuspid and trileaflet aortic regurgitation.

OBJECTIVE: To identify differences in left ventricular (LV) remodelling between patients with bicuspid aortic valve (BAV) and trileaflet aortic valve (TAV) with chronic aortic regurgitation (AR). METHODS: Retrospective cohort study of 210 consecutive patients undergoing cardiac magnetic resonance for AR evaluation. We divided the study population according to valvular morphology. Independent predictors of LV enlargement AR were evaluated. RESULTS: There were 110 patients with BAV and 100 patients with TAV. Patients with BAV were younger (mean age BAV vs TAV: 41±16 years vs 67±11 years; p<0.01), mostly male (% male BAV vs TAV: 84.5% vs 65%, p=0.01) and presented milder degrees of AR (median regurgitant fraction BAV vs TAV: 14 (6-28)% vs 22 (12-35)%, p=0.002). Both groups presented similar indexed LV volumes and ejection fraction. According to the degree of AR, at mild AR, patients with BAV presented larger LV volumes (BAV vs TAV: indexed end diastolic left ventricular volumes (iEDV): 96.5±19.7 vs 82.1±19.3 mL, p<0.01; indexed end systolic left ventricular volumes (iESV): 39.4±10.3 mL vs 33.2±10.5 mL, p=0.01). These differences disappeared at higher degrees of AR. Independent predictors of LV enlargement were regurgitant fraction (EDV: OR 1.118 (1.081-1.156), p<0.001; ESV: OR 1.067 (1.042-1.092), p<0.001), age (EDV: OR 0.940 (0.917-0.964), p<0.001, ESV: OR 0.962 (0.945-0.979), p<0.001) and weight (EDV: OR 1.054 (1.025-1.083), p<0.001). CONCLUSIONS: In chronic AR, LV enlargement is an early finding. LV volumes display a direct correlation with regurgitant fraction and an inverse association with age. Patients with BAV present larger ventricular volumes, especially at mild AR. However, these differences are attributable to demographic disparities; valve type is not independently associated with LV size.

Risdiplam in non-sitter patients aged 16 years and older with 5q spinal muscular atrophy.

INTRODUCTION/AIMS: Risdiplam has been approved for the treatment of patients with 5q spinal muscular atrophy (SMA), but data from type 2 non-sitter patients are lacking. In this study we describe our experience regarding the use of risdiplam in a series of type 2 non-sitter patients. METHODS: Type 2 SMA patients over 16 years of age were administered risdiplam through the expanded access program (NCT04256265). Patients were followed-up with a battery of scales and clinical measures. RESULTS: Six non-sitter patients (17 to 46 years old) were treated with risdiplam. One patient reported mild adverse events (dyspepsia and headache). After 1 year of treatment, all patients showed clinically meaningful improvements in at least one scale and none of them showed any clinically meaningful deterioration. Two patients showed a clinically meaningful increase in body mass index (>5%) and two others scored higher on the Revised Upper Limb Module (>2 points). Moreover, five patients had clinically meaningful improvements on the Egen Klassifikation 2 scale (>2 points), including the motor (axial and upper limbs), bulbar (speech and swallowing), and respiratory (coughing) domains. Four subjects achieved at least one of the goals set with the Goal Attainment Scale (GAS). DISCUSSION: This series suggests that risdiplam is safe and may be effective in non-sitter SMA patients older than 16 years of age. In these patients, functional scales and the GAS would be more sensitive than motor scales to detect changes, because they include axial, bulbar, and respiratory domains. Larger studies are needed to confirm these results.

Measurement of vegetations in infective endocarditis: An inaccurate method to decide the therapeutical approach.

BACKGROUND: The European Society of Cardiology and American Heart Association guidelines give a central role to the maximal vegetation diameter in the indication for surgery to prevent embolism in left sided infective endocarditis. Vegetation measuring is likely to be inaccurate. The hypothesis herein, is that the vegetation diameter is not an appropriate surgical criterion given the variability of its measurement. METHODS: Two trained echocardiographers independently measured the maximal vegetation diameter by transesophageal echocardiogram of 76 vegetations in 67 consecutive patients with definite infective endocarditis in an off-line workstation. The interobserver variability was calculated by the interclass correlation coefficient. The relationship between the strength of agreement for the cut-off points of 10 and 15 mm was also calculated. Finally, the number of patients whose surgical indication would have changed depending on which operator measured the vegetation was evaluated. RESULTS: Interobserver interclass correlation coefficient in the measurement of the maximal longitudinal diameter of the vegetations was 0.757 (0.642-0.839). The strength of agreement of the interobserver analysis for the cut-off point of 10 mm was 0.533 (0.327-0.759). For the cut-off point of 15 mm it was 0.475 (0.270-0.679). If heart failure or uncontrolled infections had been absent, the surgical indication would have changed in a total of 33 patients (33/76; 43%) depending on which operator measured the vegetation. CONCLUSIONS: The variability in the measurements of the maximal longitudinal diameter by transesophageal echocardiogram is high. Surgical indications based on the cut-off points recommended by the international guidelines should be revised.

Quantitative magnetic resonance imaging assessment of muscle composition in myotonic dystrophy mice.

Myotonic dystrophy type 1 (DM1) is a severe autosomal dominant neuromuscular disease in which the musculoskeletal system contributes substantially to overall mortality and morbidity. DM1 stems from a noncoding CTG trinucleotide repeat expansion in the DMPK gene. The human skeletal actin long repeat (HSALR) mouse model reproduces several aspects of the disease, but the muscle-wasting phenotype of this model has never been characterized in vivo. Herein, we used quantitative MRI to measure the fat and muscle volumes in the leg compartment (LC) of mice. These acquired data were processed to extract relevant parameters such as fat fraction and fat infiltration (fat LC/LC) in HSALR and control (FBV) muscles. These results showed increased fat volume (fat LC) and fat infiltration within the muscle tissue of the leg compartment (muscle LC), in agreement with necropsies, in which fatty clumps were observed, and consistent with previous findings in DM1 patients. Model mice did not reproduce the characteristic impaired fat fraction, widespread fat replacement through the muscles, or reduced muscle volume reported in patients. Taken together, the observed abnormal replacement of skeletal muscle by fat in the HSALR mice indicates that these mice partially reproduced the muscle phenotype observed in humans.

Phenotype and clinical outcomes of Glu89Lys hereditary transthyretin amyloidosis: a new endemic variant in Spain.

BACKGROUND: The p.Glu109Lys variant (Glu89Lys) is a rare cause of hereditary transthyretin amyloidosis (ATTRv) for which clinical spectrum remains unresolved. We sought to describe the clinical characteristics and outcomes of ATTR Glu89Lys amyloidosis and assess a potential founder effect in Spain. METHODS: Patients with the p.Glu109Lys ATTRv variant from 14 families were recruited at 7 centres. Demographics, complementary tests and clinical course were analysed. Haplotype analysis was performed in 7 unrelated individuals. RESULTS: Thirty-eight individuals (13 probands, mean age 40.4 ± 13.1 years) were studied. After median follow-up of 5.1 years (IQR 1.7-9.6), 7 patients died and 7 required heart transplantation (median age at transplantation 50.5 years). Onset of cardiac and neurological manifestations occurred at a mean age of 48.4 and 46.8 years, respectively. Median survival from birth was 61.6 years and no individual survived beyond 65 years. Patients treated with disease-modifying therapies exhibited better prognosis (p < 0.001). Haplotype analysis revealed a common origin from an ancestor who lived ∼500 years ago in southeast Spain. CONCLUSIONS: Glu89Lys ATTRv is a TTR variant with a founder effect in Spain. It is associated with near complete penetrance, early onset and mixed cardiac and neurologic phenotype. Patients have poor prognosis, particularly if not treated with disease-modifying therapies.