Sodium channel abnormalities are infrequent in patients with long QT syndrome: identification of two novel SCN5A mutations.

Long QT syndrome (LQTS) is a heterogeneous disorder caused by mutations of at least five different loci. Three of these, LQT1, LQT2, and LQT5, encode potassium channel subunits. LQT3 encodes the cardiac-specific sodium channel, SCN5A. Previously reported LQTS-associated mutations of SCN5A include a recurring three amino acid deletion (DeltaKPQ1505-1507) in four different families, and four different missense mutations. We have examined the SCN5A gene in 88 index cases with LQTS, including four with Jervell and Lange-Nielsen syndrome and the remainder with Romano-Ward syndrome. Screening portions of DIII-DIV, where mutations have previously been found, showed that none of these patients has the three amino acid deletion, DeltaKPQ1505-1507, or the other four known mutations. We identified a novel missense mutation, T1645M, in the DIV; S4 voltage sensor immediately adjacent to the previously reported mutation R1644H. We also examined all of the additional pore-forming regions and voltage-sensing regions and discovered another novel mutation, T1304M, at the voltage-sensing region DIII; S4. Neither T1645M nor T1304M were seen in a panel of unaffected control individuals. Five of six T1304M gene carriers were symptomatic. In contrast to previous studies, QT(onset-c) was not a sensitive indicator of SCN5A-associated LQTS, at least in this family. These data suggest that mutations of SCN5A are responsible for only a small proportion of LQTS cases.

Efferent projections of the neonatal cat superior colliculus: facial and cerebellum-related brainstem structures.

The superior colliculus develops its influence over eye and pinna movements gradually during postnatal maturation. Because superior colliculus cells respond earlier in postnatal life to nonvisual than to visual cues, it seemed likely that efferents involved in pinna movements would develop earlier than those involved in eye movements. In the present study, we examined the projections of the superior colliculus to structures related to the cerebellum and facial nucleus believed to be involved in eye-head coordination and pinna movements. We did this by using the autoradiographic and horseradish peroxidase tracing techniques in 11 kittens, ranging in age from several hours to 14 days postnatal, and in seven adult cats. Even in the youngest animals studied, a dense projection was observed from the superior colliculus to each of the target structures examined. These included the parabigeminal nucleus, paralemniscal zone, dorsolateral pons, and inferior olive. Surprisingly, the only projection observed to undergo any postnatal maturational changes was the one to the paralemniscal zone (involved in the pinna-movement circuit of the superior colliculus), and the changes appeared as a reorganization of the terminal field rather than an increase in the density of transported label. Thus, no evidence was obtained to support our expectation that the superior colliculus efferents involved in orientation of the pinnae would develop earlier than those involved in visual orientation. Instead, each of the efferent projections of the superior colliculus examined in this study appears to be laid down prenatally and becomes adultlike long before functional maturity is reached. Presumably, then, the formation and elaboration of synaptic connections are the protracted postnatal processes that limit the functional properties of these neonatal efferent pathways.

Corticotectal and corticothalamic efferent projections of SIV somatosensory cortex in cat.

Substantial corticotectal (and corticothalamic) projections from the cortex of the anterior ectosylvian sulcus (AES) were demonstrated in the cat using the axonal transport methods of autoradiography and horseradish peroxidase. The corticotectal projection arises nearly exclusively from medium-large pyramidal cells in lamina V. One of the densest projecting areas of the AES is the rostral aspect of its superior bank, where a fourth somatotopic representation (SIV) has recently been demonstrated. It terminates in the intermediate and deep laminae of the superior colliculus, where somatic cells are located. The pathway is bilateral but much heavier ipsilaterally than contralaterally. In contrast to the substantial corticotectal projection from SIV and adjacent tissue, there was no unequivocal evidence for a corticotectal projection from traditional somatosensory cortex SI-SIII. This finding, that somatosensory projections to the cat superior colliculus arise from an area outside of SI-SIII, was unexpected on the basis of what is known about visual corticotectal projections. However, it is consistent with the patterns of other cortical projections that terminate in the intermediate and deep laminae of this structure and with the absence of demonstrable corticotectal influences from SI to SIII in this animal. These data are in contrast to demonstrations by other investigators that there is a corticotectal projection from SI cortex in rodents. Apparently there is a fundamental species difference in the organization of descending somatosensory pathways. A corticothalamic projection of the AES was also observed. This descending projection appeared to form a shell of labeled cells and fibers around the ventrobasal complex, but unequivocal terminal labeling within the ventrobasal complex could not be demonstrated. Dense terminal labeling was apparent in the posterior group of thalamic nuclei (PO) where thalamocortical afferents to the AES originate.

Efferent projections of the neonatal superior colliculus: extraoculomotor-related brain stem structures.

The development of eye movements is a prolonged process which presumably involves the efferents of the superior colliculus. In the present study we sought to determine which, if any, of the colliculus efferents that influence eye movements in adult cats were present in neonatal kittens. The autoradiographic and orthograde horseradish peroxidase tracing methods were employed in kittens ranging from 6 h to 5 weeks of age and in adult cats. Surprisingly, most of the known projections from the superior colliculus which are believed to be involved in eye movements were already present in the youngest animals studied. These included projections to (a) the ventral central gray matter overlying the oculomotor nucleus, and (b) those portions of the pontine and medullary reticular formation which provide excitatory and inhibitory inputs to abducens neurons. Apparently, the pathways over which the superior colliculus influences eye movements are elaborated quite early in life. However, in the predorsal bundle and pontomedullary reticular areas the density of transported label was less in 1-day-old kittens than in older animals. Thus, anatomical as well as functional development of portions of this circuitry appear to require a significant period of postnatal maturation.

Heart block in children. Evaluation of subsidiary ventricular pacemaker recovery times and ECG tape recordings.

To evaluate subsidiary ventricular pacemaker function in 20 children with congenital or surgically induced complete heart block, we measured recovery times following overdrive ventricular pacing. Long-term ECG tape recordings were performed in eight of these children. Ages ranged from 1 month to 17 years. The resting R-R intervals ranged from 595 to 1,740 msec. The ventricles were paced at various cycle lengths of 400 to 1,000 msec with either transvenous electrode catheters or surgically implanted epicardial electrodes. His bundle recordings showed that the site of block did not allow separation of patients with symptoms from those without symptoms. Prolonged recovery times were present in patients with block above the His bundle recording site who had symptoms of syncope or dizziness, as well as in patients who had a wide QRS. However, some asymptomatic patient with heart block above the His bundle recording site also had long recovery times. None of the asymptomatic patients who had ECG tape recordings had paroxysmal tachycardia in more than 300 hours of recordings. However, one symptomatic patient with congenital heart block and a prolonged recovery time had brief episodes of paroxysmal ventricular tachycardia that produced no symptoms at the time of recording. The results suggest that the coexistence of prolonged recovery times and paroxysmal tachycardia may be predisposing factors to the development of symptoms in patients with complete heart block. We believe that further electrophysiologic investigation of this possibility is warranted in patients with heart block.

A comparison of the intranigral distribution of nigrotectal neurons labeled with horseradish peroxidase in the monkey, cat, and rat.

The location of neurons in the substantia nigra's pars reticulata (SNR) that send their axons to the superior colliculus was compared in the monkey, cat, and rat using the horseradish peroxidase (HRP) retrograde cell-labeling method. Although several cases of large, unilateral HRP deposits in the superior colliculus show that in all three species, the nigrotectal cells are confined, for the most part, to the rostral one-half of SNR, the following differences were noted in the precise location of the nigrotectal neurons and in the degree of bilaterality of the nigrotectal projection. In the monkey, labeled nigrotectal cells were particularly numerous in the extreme rostrolateral portion of SNR. From this region of high concentration, a progressively decreasing number of cells spreads medially in a ventral stratum immediately dorsal to the pes pedunculi. No labeled cells were found in the extreme medial part of SNR. A substantial number of HRP-positive cells were present in the contralateral SNR in a similar distribution. In the cat, labeled cells were less selectively localized in SNR's mediolateral expanse, being distributed more or less randomly in its middle portion with a scattering of cells in both medial and lateral parts of SNR. Although some cell labeling occurred in the contralateral SNR, it was less substantial than in the monkey. In the rat, the HRP-positive cells were especially concentrated throughout the mediolateral extent of a ventral stratum of SNR immediately dorsal to the pes pedunculi. Although some cells were located more dorsally, they were far fewer in number and consistently less heavily labeled. Only one or two labeled cells could be detected in the contralateral SNR of the rat. These anatomical differences suggest that the influence of the corpus striatum on the tectal control of orienting responses may vary considerably from one mammalian species to the next.

Accessory atrioventricular pathway in an infant: prediction of location with body surface maps and ablation with cryosurgery.

A 10-month-old infant with multiple muscular ventricular septal defects, congestive heart failure, Wolff-Parkinson-White syndrome, and supraventricular tachycardia is presented. The site of ventricular pre-excitation was predicted by analysis of ST-T wave isopotential body surface maps to be in the posterior free wall of the right ventricle. The site was confirmed by epicardial mapping of the ventricles during surgery. The pathyway was cryoblated and the ventricular defects were closed. The patient has been free of pre-excitation and supraventricular tachycardia for over two years since surgery.

The force-interval relationship of the left ventricle.

We have carried out a quantitative analysis of the force-interval relationship of the human left ventricle and compared it to previous studies done in both intact subjects as well as isolated muscle. The characteristics of the force-interval relationship of the normal patient resembed those of normal isolated mammalian muscle (except when exposed to high levels of catecholamines). The relationship in group 2 (patients with increased left ventricular dimensions and normal pressure indices) resembled those obtained from isolated muscles from hypertrophied hearts. The relationship from group 3 (patients with increased left ventricular EDDs and depressed pressure indices, two of whom were in clinical heart failure) resumbled those induced in normal muscles exposed to high levels of catecholamines, and those obtained from experimentally induced heart failure. The force-interval relationships of the four patients who fell into the third group were strikingly different from the other groups. This suggests that the force-interval relationship may be useful to describe changes in the inotropic state of the patient's heart.

Sources of subcortical projections to the superior colliculus in the cat.

A comprehensive search for subcortical projections to the cat superior colliculus was conducted using the retrograde horseradish peroxidase (HRP) method. Over 40 different subcortical structures project to the superior colliculus. The more notable among these are grouped under the following categories. Visual structures: ventral lateral geniculate nucleus, parabigeminal nucleus, pretectal area (nucleus of the optic tract, posterior pretectal nucleus, nuclei of the posterior commissure). Auditory structures: inferior colliculus (external and pericentral nuclei), dorsomedial periolivary nucleus, nuclei of the trapezoid body, ventral nucleus of the lateral lemniscus. Somatosensory structures: sensory trigeminal complex (all divisions, but mainly the gamma division of nucleus oralis), dorsal column nuclei (mostly cuneate nucleus), and the lateral cervical nucleus. Catecholamine nuclei: locus coeruleus, raphe dorsalis, and the parabrachial nuclei. Cerebellum: medial, interposed, and lateral nuclei, and the perihypoglossal nuclei. Reticular areas: zona incerta, substantia nigra, midbrain tegmentum, nucleus paragigantocellularis lateralis, and the hypothalamus. Evidence is presented that only the parabigeminal nucleus, the nucleus of the optic tract, and the posterior pretectal nucleus project to the superficial collicular layers (striatum griseum superficiale and stratum opticum), while all other afferents terminate in the deeper layers of the colliculus. Also presented is information concerning the rostrocaudal distribution of some of these afferent connections. These findings stress the multiplicity and diversity of inputs to the deeper collicular layers, and more specifically, identify multiple sources of the physiologically well-known representations of the somatic and auditory modalities in the colliculus.

Corticotectal and other corticofugal projections in neonatal cat.

Adult physiological properties of cat superior colliculus cells develop gradually during the first two months of life. Since many of the neuronal properties in the adult cat appear to depend upon the integrity of visual cortex, it was postulated that the maturation of superior colliculus cells is, in large part, a reflection of corticotectal maturation. An attempt was made to study the development of the corticotectal pathway with the autoradiographic tracing technique. Injections of [3H]leucine were made in the visual cortex of kittens 6 h to 12 days of age and animals were sacrificed 20-24 h later. A dense projection from visual cortex to the superior colliculus and to the lateral geniculate nucleus was noted in all animals. Both projections appeared to be topographically organized. In addition, cortical projections to the lateral posterior-pulvinar region and sparse projections to the contralateral visual cortex were noted. Two, non-mutually exclusive, explanations for the presence of a corticotectal pathway in the absence of mature cell properties in the superior colliculus are most apparent: (a) corticotectal synapses are incompletely formed at birth and require many weeks to develop, and (b) corticotectal cells are immature during early postnatal life and cannot impress adult-like characteristics upon the superior colliculus cells until they, themselves, 'mature'.

The superior colliculus control of pinna movements in the cat: possible anatomical connections.

Possible anatomical pathways mediating superior colliculus control of pinna movements were determined in the cat using the orthograde autoradiographic tracing method and the retrograde horseradish peroxidase technique. This was done in the following manner. First, the division of the facial nucleus that innervates the pinna muscles was determined by injecting the pinna muscles with HRP and surveying the facial nucleus for retrogradely filled cells. Second, the brainstem regions that project the facial nucleus were identified using the horseradish peroxidase method. Third, the superior colliculus projections to these areas were studied using the autoradiographic tracing method. The results suggest that superior colliculus control of pinna movements is mediated entirely by indirect connections with the facial nucleus and that these connections occur mainly in a paralemniscal zone in the lateral midbrain. Of all the brainstem regions shown by the horseradish peroxidase experiments to project to the facial nucleus only this midbrain paralemniscal zone received a projection from the superior colliculus that was dense and overlapped precisely the region containing facial projecting neurons. Further autoradiographic tracing revealed that the facial nucleus was the primary brainstem target of this paralemniscal zone and that all paralemniscal fibers projecting to the facial nucleus ended in the subdivision that innervates the pinna muscles. Other paralemniscal efferents terminate in the opposite paralemniscal zone. The data suggest that other connections between the superior colliculus and the facial nucleus may occur in the cuneiform nucleus of the midbrain, the region around the oculomotor complex, and the reticular formation dorsal to the superior olive.

Ventricular tachyarrhythmia due to cardiac sarcoidosis in a child.

Cardiac involvement by systemic sarcoidosis is well known, but occurs rarely. It usually manifests as either heart block, heart failure due to direct myocardial involvement, or cor pulmonale. We present the case of a patient with cardiac sarcoidosis who had ventricular tachycardia and congestive heart failure. Although there was other organ system involvement, the cardiac manifestation was the first to become clinically apparent. Therapy consisted of quinidine sulfate to control the arrhythmias and chronic diuretic therapy to control congestive heart failure. Steroid therapy was initially associated with recurrence of the ventricular tachycardia and was discontinued. It was reinstituted 18 months later when other organ system involvement developed with no recurrence of the ventricular tachyarrhythmia. The patient responded well to therapy and is currently doing well. This case is presented to illustrate a somewhat unusual, but nevertheless important, etiology of ventricular tachyarrhythmias. The recognition of underlying sarcoidosis is critical because of the propensity for other organ system involvement by this disease process.

Thoracoabdominal ectopia cordis with mosaic Turner's syndrome: Report of a case.

A child was treated for thoracoabdominal ectopia cordis and an associated chromosomal defect. Contrary to most cases in which death is due to the externally situated heart and abdominal viscera, this patient died from congenital heart disease.