Limb-girdle myopathy and mild intellectual disability: The expanding spectrum of TANGO2-related disease.

TANGO2-related disease is an autosomal recessive multisystem disease associated with developmental delay and infancy-onset recurrent metabolic crises with early mortality. Several studies have reported dysfunction in endoplasmic reticulum-to-Golgi traffic and mitochondrial homoeostasis as the underlying pathophysiology. We report a 40-year-old woman affected by limb-girdle weakness and mild intellectual disability caused by the recurrent deletion of exons 3-9 in homozygosity in the TANGO2 gene. Physical examination revealed hyperlordosis, waddling gait, calf pseudohypertrophy, and Aquilian tendon retractions. Laboratory investigations revealed elevation of serum biomarkers suggestive of mitochondrial dysfunction together with hypothyroidism. At the age of 24, the patient suffered a metabolic crisis with severe rhabdomyolysis and malignant cardiac arrhythmia. After recovery, no metabolic or arrhythmic crisis has recurred. Muscle histology two years later revealed increased endomysial fibrosis and other myopathic changes. Our findings illustrate the mildest end of the phenotypic spectrum of TANGO2-related disease and reveal further aspects related to chronic muscle damage in this disorder.

Syncope in Patients With Severe Aortic Stenosis: More Than Just an Obstruction Issue.

BACKGROUND: Severe aortic stenosis (AoS) is considered a primary cause of syncope. However, other mechanisms may be present in these patients and accurate diagnosis can have important clinical implications. The aim of this study is to assess the different etiologies of syncope in patients with severe AoS and the impact on prognosis of attaining a certain or highly probable diagnosis for the syncope. METHODS: Out of a cohort of 331 patients with AoS and syncope, 61 had severe AoS and were included in the study. Main cause of syncope and adverse cardiac events were assessed. RESULTS: In 40 patients (65.6%), we reached a certain or highly probable diagnosis of the main cause of the syncope. AoS was considered the primary cause of the syncope in only 7 patients (17.5% of the patients with known etiology). Atrioventricular block (14 patients, 35.0%) and vasovagal syncope (6 patients, 15.0%) were the most frequently diagnosed causes. The presence of a known cause for syncope during the admission was not associated with a lower incidence of recurrence during follow-up (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.20-2.40). Syncope of unknown etiology was independently associated with greater mortality during 1-year follow-up (HR 5.4, 95% CI 1.3-21.6) and 3-year follow-up (HR 3.5, 95% CI 1.2-10.3). CONCLUSIONS: In a high proportion of patients with severe AoS admitted for syncope, the valvulopathy was not the main cause of the syncope. Syncope in two-thirds of this population was caused by either bradyarrhythmia or reflex causes. Syncope of unknown cause was associated with increased short- and medium-term mortality, independently from treatment of the valve disease. An exhaustive work-up should be conducted to determine the main cause for syncope.

Overview of the contribution of recent clinical trials to advancement of syncope management.

In this communication we review those trials that have contributed in recent years to improving our knowledge on the management (diagnosis and treatment) of syncope. In this regard, most recent trials focus on vasovagal syncope (VVS) and consequently these will be the focus of this manuscript. In essence, from a diagnostic perspective the ISSUE studies demonstrate the value of insertable loop recorders (ILR), while in terms of treatment, in the case of VVS current data strongly support use of non-pharmacologic treatment as a primary approach. There is no clear evidence supporting pharmacologic treatment with the possible exception of midodrine. Further, the most recent ISSUE trials suggest that in older very symptomatic patients with VVS in whom an asystole has been documented during spontaneous episode or possibly after ATP administration, implantation of a permanent pacemaker (PPM) can be effective. Which pacing or programming mode will be the more beneficial has not been completely clarified. Management of other forms of neurally-mediated syncope (e.g., carotid sinus syndrome) or other causes of syncope has not been addressed by clinical trials. In those cases, direction is provided by older evidence, the vast majority of which is based on observational reports or small non-randomized patient series.

Pacemaker therapy in syncope.

The current evidence for pacemaker therapy is reviewed in 2 different syncopal conditions: reflex syncope with cardioinhibitory response and syncope in patients with bundle branch block. Although recent trials support the use of pacemaker therapy in selected patients with reflex syncope in whom an asystole is documented during spontaneous syncope or in whom an asystole is provoked with adenosine-5'-triphosphate administration, the best strategy in these patients and in those with syncope and bundle branch block is not well established. Ongoing clinical trials will answer this question.

Syncope.

Syncope, which can be defined as a transient loss of consciousness caused by transient global cerebral hypoperfusion and characterised by rapid onset, short duration, and spontaneous complete recovery, is a common condition. This definition is useful for differentiating syncope from other clinical conditions that also involve real or apparent transient loss of consciousness, but in which the mechanism is not global cerebral hypoperfusion, such as epilepsy, falls, or psychiatric pseudosyncope. We reviewed the etiological classification of syncope and found that reflex syncope is the most common etiology in the general population, with a good prognosis, whereas cardiac syncope increases with age and has a worse prognosis. We also reviewed the role and limitations of different tests, specifically referring to the interpretation of the results of carotid sinus massage, the role of tilt-table testing, the diagnostic strategy in patients with syncope and bundle branch block, the adenosine test, and the emerging role of prolonged electrocardiographic monitoring. Furthermore, we reviewed the different therapeutic options available. The importance of establishing syncope units with the aim of improving the diagnostic process and optimizing resources is also emphasized.