Clinical and laboratory observation

Familial dysautonomia: A prospective study of survival*

Over the past century, generations of neuroscientists, pathologists, and clinicians have elucidated the underlying causes of autonomic failure found in neurodegenerative, inherited, and antibody-mediated autoimmune disorders, each with pathognomonic clinicopathologic features. Autonomic failure affects central autonomic nervous system components in the α-synucleinopathy, multiple system atrophy, characterized clinically by levodopa-unresponsive parkinsonism or cerebellar ataxia, and pathologically by argyrophilic glial cytoplasmic inclusions (GCIs). Two other central neurodegenerative disorders, pure autonomic failure characterized clinically by deficits in norepinephrine synthesis and release from peripheral sympathetic nerve terminals; and Parkinson's disease, with early and widespread autonomic deficits independent of the loss of striatal dopamine terminals, both express Lewy pathology. The rare congenital disorder, hereditary sensory, and autonomic neuropathy type III (or Riley–Day, familial dysautonomia) causes life-threatening autonomic failure due to a genetic mutation that results in loss of functioning baroreceptors, effectively separating afferent mechanosensing neurons from the brain. Autoimmune autonomic ganglionopathy caused by autoantibodies targeting ganglionic α3-acetylcholine receptors instead presents with subacute isolated autonomic failure affecting sympathetic, parasympathetic, and enteric nervous system function in various combinations. This chapter is an overview of these major autonomic disorders with an emphasis on their historical background, neuropathological features, etiopathogenesis, diagnosis, and treatment.

El grupo respiratorio ventral incluye el complejo de pre-Botzinger, que contiene neuronas fundamentales para la ritmogénesis respiratoria. La red de neuronas respiratorias del tronco cerebral recibe inputs de los quimiorreceptores centrales y periféricos, de los niveles de anhídrido carbónico y oxígeno sanguíneos y de estructuras cerebrales que controlan la respiración. La manifestación más importante de la alteración de esta red son las apneas de sueño, que son una alteración del ritmo respiratorio que frecuentemente se asocian con trastornos del control vasomotor simpático y cardiovagal. Las enfermedades neuromusculares son aquellas en las que la insuficiencia respiratoria es más frecuente. Por otra parte son más raras las alteraciones del control cardiorrespiratorio; estas pueden ser debidas a un ACV de tronco, compresión del mismo por tumores, siringobulbia, malformación de Chiari, lesiones de la médula cervical alta y atrofia multisistémica.

The ventral respiratory group includes pre-Bötzingen complex, which contains neurons critical for respiratory ritmogenesis. The network of brain stem respiratory neurons receive inputs of central and peripheral chemoreceptors, the levels of carbon dioxide and oxygen blood and brain structures that control breathing. The most important alteration of this network include sleep apnea, a breathing rhythm disorder that is frequently associated with disturbances of cardiovagal and sympathetic vasomotor control. Neuromuscular diseases are those in respiratory failure is more common. On the other hand are more rare disorders cardiorespiratory control. These may be due to a stroke of trunk, compression of the tumors, syringobulbia, Chiari malformation, cervical spinal injury high, and atrophy multistémica.

Familial dysautonomia (FD) is an autosomal recessive disorder, classified as a hereditary sensory and autonomic neuropathy type III, associated with growth defects affecting postnatal development. This study analysed prenatal and postnatal enamel development and postnatal calcification in upper second primary molars from FD children in comparison with healthy controls. The postnatal enamel of FD was also examined histologically for manifestation of growth insults.

The analyses were carried out on two ground sections, connecting buccal and palatinal cusp tips of mesial and distal cusps. The measurements included apical location of neonatal line, width and percentage of prenatal enamel. Chemical analyses were performed using an energy dispersive X-ray spectrometer.

The prenatal proliferative phase and prenatal apposition rate of enamel were faster on the distal cusps in FD. The postnatal enamel thickness was similar in both groups. The phosphate content of FD teeth was significantly higher and the Ca/P ratio was significantly lower. Postnatal traumatic lines were observed in all FD children and in only one healthy child.

FD upper primary second molars showed thicker prenatal enamel formation in comparison to healthy and other syndromes and better mineralisation. All FD primary molars showed large number of postnatal traumatic lines, implicating severe traumatic episodes during the first year of life.

To identify electrocardiographic predictors of mortality in patients with familial dysautonomia (FD).

Ten-minute resting high-fidelity 12-lead electrocardiograms (ECGs) were obtained from 14 FD patients and 14 age/gender-matched healthy subjects. Multiple conventional and advanced ECG parameters were studied for their ability to predict mortality over a subsequent 4.5-year period, including representative parameters of heart rate variability (HRV), QT variability (QTV), T-wave complexity, signal averaged ECG, and 3-dimensional ECG.

Four of the 14 FD patients died during the follow-up period, three with concomitant pulmonary disorder. Of the ECG parameters studied, increased non-HRV-correlated QTV and decreased HRV were the most predictive of death. Compared to controls as a group, FD patients also had significantly increased ECG voltages, JTc intervals and waveform complexity, suggestive of structural heart disease.

Increased QTV and decreased HRV are markers for increased risk of death in FD patients. When present, both markers may reflect concurrent pathological processes, especially hypoxia due to pulmonary disorders and sleep apnea.

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