Síndrome miasténico congénito por deficiencia de rapsina: reporte de caso con nueva mutación y heterocigosidad compuesta / Congenital myasthenic syndrome due to rapsyn deficiency: A case report with a new mutation and compound heterozygosity

INTRODUCCIÓN Los síndromes miasténicos congénitos son un grupo heterogéneo de desórdenes genéticos, caracterizados por una transmisión sináptica anormal en la placa neuromuscular. REPORTE Presentamos el caso de un paciente de dos años, varón, con hipotonía, ptosis palpebral y debilidad simétrica y de predominio proximal, características que aparecieron desde el nacimiento y que motivaron varias hospitalizaciones por neumonía e insuficiencia ventilatoria. Desde el inicio de la deambulación a los dos años, los padres notaron que la debilidad empeoraba por las tardes y con la actividad física repetida o prolongada. El examen físico a los dos años mostró ptosis palpebral, debilidad de predominio proximal y fatigabilidad con el esfuerzo sostenido. La electro-miografía evidenció decremento del 27% en el potencial de acción muscular compuesto. El análisis de tríos mostró heterocigosis compuesta por transmisión de dos mutaciones diferentes en el gen de rapsina, una ya conocida procedente del padre y la otra no reportada previa-mente, procedente de la madre. El paciente recibió piridostigmina obteniendo mejoría inmediata y logrando un desempeño óptimo en actividades escolares, deportivas y de la vida cotidiana. A la fecha, no ha presentado nuevos episodios de insuficiencia ventilatoria. CONCLUSIONES La debilidad de inicio neonatal y la fatigabilidad o agotamiento con el esfuerzo sostenido, con afección principalmente de los músculos con inervación troncal y con un decremento mayor al 10% en el potencial de acción muscular compuesto en la electromiografía, deben hacer sospechar en un síndrome miasténico congénito. Se revisan los puntos clínicos clave que permiten establecer el diagnóstico oportuno y las opciones de tratamiento efectivo para algunos de estos síndromes.

INTRODUCTION The congenital myasthenic syndromes are a heterogeneous group of genetic disorders characterized by an abnormal synaptic transmission in the neuromuscular plate. REPORT We present a two-year-old patient, male, with hypotonia, palpebral ptosis, and proximal symmetric weakness with a neonatal onset that motivated several and prolonged hospitalizations for pneumonia and respiratory failure. From two years of age, the parents noticed that the facial and general weakness worsened in the afternoons and with repeated or prolonged physical activity. The physical examination showed palpebral ptosis, predominantly proximal weakness, and fatigability with sustained muscular effort. The electromyography showed a 27% decrement in the Compound Muscular Action Potential and the case-parents genetic study showed compound heterozygosity with the transmission of two different mutations in the rapsyn gene from both parents. The patient received pyridostigmine with great improvement, achieving optimal performance in school, sports, and daily life activities. CONCLUSIONS Weakness and fatigability with neonatal onset, mainly affecting the muscles with brain stem innervation and the decrement greater than 10 percent in the Compound Muscular Action Potential in the electromyographic studies, should make us suspect in a congenital myasthenic syndrome. We review the literature and key clinical points to establish a timely diagnosis and effective treatment in some of these syndromes.

Acute electrophysiologic consequences of pyridostigmine inhibition of cholinesterase in humans

The cardiovascular electrophysiologic basis for the action of pyridostigmine, an acetylcholinesterase inhibitor, has not been investigated. The objective of the present study was to determine the cardiac electrophysiologic effects of a single dose of pyridostigmine bromide in an open-label, quasi-experimental protocol. Fifteen patients who had been indicated for diagnostic cardiac electrophysiologic study underwent two studies just before and 90-120 min after the oral administration of pyridostigmine (45 mg). Pyridostigmine was well tolerated by all patients. Wenckebach nodal anterograde atrioventricular point and basic cycle were not altered by pyridostigmine. Sinus recovery time (ms) was shorter during a 500-ms cycle stimulation (pre: 326 ± 45 vs post: 235 ± 47; P = 0.003) but not during 400-ms (pre: 275 ± 28 vs post: 248 ± 32; P = 0.490) or 600-ms (pre: 252 ± 42 vs post: 179 ± 26; P = 0.080) cycle stimulation. Pyridostigmine increased the ventricular refractory period (ms) during the 400-ms cycle stimulation (pre: 238 ± 7 vs post: 245 ± 9; P = 0.028) but not during the 500-ms (pre: 248 ± 7 vs post: 253 ± 9; P = 0.150) or 600-ms (pre: 254 ± 8 vs post: 259 ± 8; P = 0.255) cycle stimulation. We conclude that pyridostigmine did not produce conduction disturbances and, indeed, increased the ventricular refractory period at higher heart rates. While the effect explains previous results showing the anti-arrhythmic action of pyridostigmine, the clinical impact on long-term outcomes requires further investigation.

Impacto da preservação parassimpática sobre os aspectos morfofuncionais cardíacos em ratos infartados / Parassympathic preservation impact in cardiac morphofunctional aspects in myocardial infarcted rats

Neste estudo, testamos a hipótese de que a estimulação colnérgica pela administração de piridostigmina, um agente anticolinesterásico reversível, protege o miocárdio submetido à isquemia miocárdica crônica durante 3 tempos de observação: 7, 21 e 42 dias. Para essa avaliação foram medidos a área de acinesia (índicador de área de infarto), os índíces das funções sistólica e diastólica pela ecocardiografia e por medida direta bem como marcadores da função autonômica como a sensibilidade do barorreflexo e a variabilidade da frequência cardíaca (FC) e da pressão arterial (PA). O bloqueio farmacológico do sistema nervoso autônomo e o estudo da via eferente parassimpática foram também realizados. Utilizou-se ratos Wistar machos divididos em 4 grupos: controle, controle piridostigmina, infartado e infartado piridostigmina. Os resultados mostraram os efeitos protetores da piridostigmina nos diferentes tempo de infarto com redução da área de acinesia ( maior que 80%) tanto pelo ecocardiograma quanto pela histologia. Além disso observou-se recuperação das funções sistólica e diastólica, com normalização da pressão diastólica final e das derivadas de contração e relaxamento. Essas melhoras foram mais consistentes em 21 e 42 dias, sem diferenças entre esses tempos de tratamento. Em 7 dias ainda persistiram alguns índices de disfunção ventricular, embora a função autonômica estivesse bem preservada. Parte dessa melhora se deve, provavelmente, ao aumento do tônus vagal e redução do simpático. A potenciação da bradicardia pela estimulação elétrica do vago induzida pela piridostigmina confirma seu papel com estimulador colinérgico. A sensibilidade do barorreflexo reduzida de forma semelhante pelo infarto do miocárdio aos 7, 21 e 42 dias, voltou aos valores controle após o tratamento com piridostigmina, sem diferenças devidas ao tempo de tratamento. Da mesma forma, a variabilidade da FC foi aumentada após o tratamento com o brometo de piridostigmina no grupo infartado...

In this study we tested the hypothesis that cholinergic stimulation by pyridostigmine administration, a reversible cholinergic inhibitor, protects the ischemic myocardial in three periods of follow-up: 7, 21 and 42 days. For this evaluation we measured the akinetic area (infacrtion area indicator), systolic and diastolic indexes by echocardiography and left ventricle direct measurements as well as autonomic function markers, as baroreflex sensitivity and heart rate (HR) and blood pressure (BP) variabilities. Pharmacological blockade of the autonomic nervous system and the study of the efferent parasympathetic pathway were also performed. Male Wistar rats were divided in 4 groups: control, control treated with pyridostigmine, infarcted and infarcted treated with pyridostigmine. The results showed the protective effects of pyridostigmine in the different periods of infarction, with the reduction of the akinetic area (more than 80%), either by the echocardiography and by histology. Moreover, we observed systolic and diastolic functions recovery, with normalization of the end diastolic pressure and the maximum rates of left ventricle BP rise and fall. These improvements were more consistent in 21 and 42 days, with no differences between these two periods of treatment. In 7-day treatment, some indexes of ventricular dysfunction remained, although the autonomic function seemed to be preserved. Part of these improvements is probably due to the increase in the vagal tonus and the decrease in the sympathetic tonus. The pyridostigmine effects in the potencialization of the bradycardia induced by vagus nerve electrical stimulation confirms its role as a cholinergic stimulator. The reduced baroreflex sensitivity by myocardial infarction, which was similar in 7, 21 and 42 days, returned to control values after pyridostigmine treatment, without differences related to treatment extent. Similarly, HR variability was increased after pyridostigmine treatment in the infarcted...

Persistent/delayed toxic effects of low-dose sarin and pyridostigmine under physical stress (exercise) in mice.

Pyridostigmine bromide, a reversible anticholinesterase drug, was used by military personnel during the Gulf War. They were under physical stress and might have been exposed to low-dose nerve gas, sarin. This study examined the interactions of low-dose sarin and pyridostigmine in exercised mice. Male NIH Swiss mice were treated as follows: 1) Control; 2) Sarin (0.01 mg/kg, sc); 3) exercise; 4) sarin plus exercise; 5) pyridostigmine; 6) pyridostigmine plus exercise; 7) pyridostigmine plus sarin; 8) pyridostigmine plus sarin plus exercise. Exercise was given daily for 10 weeks on treadmill and pyridostigmine and sarin were administered daily during the 5th and 6th weeks only. Respiratory exchange ratio decreased significantly during the dosing period of 5th and 6th weeks in groups 4, 6, and 8. Animals were sacrificed 24 hours after the ten-week exercise, tissues isolated and analyzed. Sarin significantly decreased butyrylcholine esterase (BChE) activity in plasma; AChE activity in platelet, triceps muscle, and striatum; neurotoxic esterase (NTE) activity in platelets, spinal cord, cortex and striatum and malondialdehyde (MDA) levels in sciatic nerve and cord. Sarin plus exercise significantly reduced BChE activity in plasma; acetylcholinesterase (AChE) activity in platelets, muscle, nerve and striatum; NTE activity in platelets, cord, cortex and striatum; and increased creatinine phosphokinase (CK) activity in plasma and MDA levels in cord. Pyridostigmine plus exercise significantly decrease BChE activity in plasma; AChE activity in muscle and enhanced malondialdehyde (MDA) levels in muscle. Pyridostigmine plus sarin significantly decreased NTE activity in platelets, cord, cortex and striatum. Pyridostigmine plus sarin plus exercise significantly altered AChE activity and MDA levels in muscle; and NTE activity in platelets, nerve, cord and cortex. Exercise significantly augmented the changes in plasma CK activity, muscle and nerve AChE activity, platelet NTE activity and cord MDA levels induced by sarin. It is concluded that physical stress (exercise) enhanced the persistent/delayed toxic effects of low-dose sarin and pyridostigmine in specific tissues of mice.

Resting and reflex heart rate responses during cholinergic stimulation with pyridostigmine in humans

Dysfunction of the autonomic nervous system is of prognostic value for sudden death after acute myocardial infarction. Although the use of beta-blockers to counteract the adrenergic hyperactivity has been shown to decrease mortality in these patients, there have been no reports on the role of cholinomimetic drugs in the prognosis of patients after myocardial infarction. The present study was designed to investigate the effect of the administration of pyridostigmine bromide, a reversible anti-cholinesterase agent, on cardiac cholinergic activity assessed by the resting and reflex heart rate responses. Eight healthy volunteers were submitted to a conventional 12-lead electrocardiogram to obtain resting heart rate, and to three non-invasive cardiovascular tests: respiratory sinus arrhythmia, Valsalva maneuver and 4-sec exercise test. On two different days and following a randomized crossover double-blind protocol, the experiments were performed before and 120 min after oral administration of either pyridostigmine bromide (30 mg) or placebo. Pyridostigmine increased (P<0.05) the duration of the R-R intervals at rest (pre: 898 ñ 30 msec; post: 1019 ñ 45 msec; pre-placebo: 916 ñ 26 msec; post: 956 ñ 28 msec; P>0.05). Although the duration of the R-R intervals during the autonomic tests was also increased (P<0.05), the derived indexes of maximal fluctuation during the maneuvers did not change. These results indicate that oral pyridostigmine produces tonic cardiac cholinergic stimulation while exerting no effect on its reflex changes. Further studies are needed to address the potential role of the administration of pyridostigmine in the prognosis of patients with acute myocardial infarction.