Biallelic variants in PPP1R13L cause paediatric dilated cardiomyopathy.

Childhood dilated cardiomyopathy (DCM) is a leading cause of heart failure requiring cardiac transplantation and approximately 5% of cases result in sudden death. Knowledge of the underlying genetic cause can aid prognostication and clinical management and enables accurate recurrence risk counselling for the family. Here we used genomic sequencing to identify the causative genetic variant(s) in families with children affected by severe DCM. In an international collaborative effort facilitated by GeneMatcher, biallelic variants in PPP1R13L were identified in seven children with severe DCM from five unrelated families following exome or genome sequencing and inheritance-based variant filtering. PPP1R13L encodes inhibitor of apoptosis-stimulating protein of p53 protein (iASPP). In addition to roles in apoptosis, iASPP acts as a regulator of desmosomes and has been implicated in inflammatory pathways. DCM presented early (mean: 2 years 10 months; range: 3 months-9 years) and was progressive, resulting in death (n = 3) or transplant (n = 3), with one child currently awaiting transplant. Genomic sequencing technologies are valuable for the identification of novel and emerging candidate genes. Biallelic variants in PPP1R13L were previously reported in a single consanguineous family with paediatric DCM. The identification here of a further five families now provides sufficient evidence to support a robust gene-disease association between PPP1R13L and severe paediatric DCM. The PPP1R13L gene should be included in panel-based genetic testing for paediatric DCM.

Time-course effects of centrally administered native urotensin-II on motor and cardioventilatory activity in trout.

Although in most vertebrate species urotensin-II (UII) is synthesized in neurons of the central nervous system, little is known regarding the physiological actions of UII in the brain. We have investigated the effects of intracerebroventricular (ICV) administration of synthetic trout UII (1, 5, and 50 pmol) on total motor activity (ACT), ventilatory frequency (VF), ventilatory amplitude (VA), and heart rate (HR) in the unanesthetized trout. ICV injection of UII increased ACT in a dose-dependent manner, and the maximal effect was observed at a dose of 5 pmol. At doses of 1 and 5 pmol, UII did not affect VF, VA, or HR. At the highest dose tested (50 pmol), UII not only increased ACT, but also significantly activated VF, VA, and HR. In contrast, ICV injection of synthetic trout angiotensin-II (5 pmol) did not produce any effect on ACT, VF, or VA, but sharply increased HR. These data provide the first evidence that UII can act centrally to induce motor activity in a nonmammalian vertebrate species.

Intracerebroventricular injection of arginine vasotocin induces elevation of blood pressure in anesthetized trout.

The present investigation assessed the ability of the neurohypophysial nonapeptide arginine vasotocin (AVT) to centrally regulate the cardiovascular activity in fish. Intracerebroventricular (ICV) injection of AVT (0.4 to 50 ng/kg b.wt.) in anesthetized trout resulted in a dose-related increase in blood pressure (BP) without any consistent changes in heart rate. For doses of AVT ranging from 2 to 50 ng/kg b.wt., BP remained elevated during at least 25 min after ICV injection. Systemic (intraarterial) administration of the same doses of AVT appeared to be less efficient than ICV injection, except for the highest dose (50 ng/kg) which evoked a similar rise in BP as that observed after ICV administration. In contrast to AVT, a high concentration of neuropeptide Y (10 micrograms/kg b.wt., ICV) caused only a slight increase of BP. The results suggest that AVT acts centrally to regulate BP in fish. These data, together with the widespread distribution of AVT-immunoreactive fibers and AVT binding sites in the brain, support the notion that, in fish, AVT may play neuromodulator and/or neurotransmitter functions.

Effects of central and peripheral administration of arginine vasotocin and related neuropeptides on blood pressure and heart rate in the conscious trout.

The cardiovascular activity of neurohypophyseal peptides has been investigated in conscious trout bearing an intracerebroventricular guide cannula and a permanent intraarterial catheter. Changes in diastolic pressure, systolic pressure and heart rate were monitored during the 25-min period following intracerebroventricular or intraarterial administration of arginine vasotocin and related neuropeptides, including arginine vasopressin, oxytocin, hydrin-2, mesotocin, isotocin and conopressin-S. Intracerebroventricular injection of increasing doses of arginine vasotocin (0.62-5 pmol) induced a dose-dependent increase of diastolic and systolic pressures. The onset of the response occurred within 3-5 min after intracerebroventricular administration of arginine vasotocin and the maximal increase was reached at 10-15 min. Central administration of vasopressin and oxytocin induced a significant rise in diastolic and systolic pressures at a dose of 5 pmol while hydrin-2 only caused a significant elevation of blood pressure at a dose of 50 pmol. Central administration of mesotocin, isotocin and conopressin-S (5-500 pmol each) had no significant effect on blood pressure. No changes in heart rate occurred after intracerebroventricular injection of any of the seven neuropeptides tested. Intraarterial injection of arginine vasotocin (50 pmol) induced a significant rise in blood pressure and bradycardia. Peripheral injection of the other neuropeptides did not cause any modification of the cardiovascular activity, whatever the doses administered (5-500 pmol). The V1A receptor antagonist [d(CH2)5, Tyr(OMe)2]arginine vasopressin had no intrinsic effect on blood pressure and heart rate when injected centrally (50 pmol) or in the peripheral circulation (200 pmol). At the same doses, [d(CH2)5, Tyr(OMe)2]arginine vasopressin reduced by 50 and 66%, respectively, the increase in blood pressure evoked by intracerebroventricular (5 pmol) or intraarterial (50 pmol) injections of arginine vasotocin.(ABSTRACT TRUNCATED AT 250 WORDS)

Intracerebroventricular administration of angiotensin II increases heart rate in the conscious trout.

The central effect of angiotensin II on cardiovascular activity has been investigated in conscious trout bearing an intracerebroventricular (i.c.v.) cannula and an intra-arterial catheter. I.c.v. injection of the angiotensin II agonist [Asn1,Val5]AII (6.2-50 pmol) induced a dose-dependent increase in heart rate and arterial blood pressure. Central administration of the angiotensin II antagonist DuP 753 (5 nmol) 30 min before i.c.v. injection of [Asn1,Val5]AII totally prevented the tachycardia and reduced the hypertension induced by the angiotensin II agonist. Intra-arterial injection of arginine-vasotocin (12.5 pmol) caused a bradycardia associated with a marked increase in arterial blood pressure. I.c.v. injection of [Asn1,Val5]AII totally blocked the bradycardia induced by arginine-vasotocin and this effect was prevented by central administration of DuP 753. In contrast, [Asn1,Val5]AII did not affect the increase in blood pressure induced by arginine vasotocin. Suppression of the vagal tone by atropine treatment totally blocked the central effect of [Asn1,Val5]AII. These results show that angiotensin II acts directly on the trout brain to increase blood pressure and heart rate. The effect of angiotensin II is mediated through a receptor related to the mammalian AT1 receptor type.

Role of dorsal vagal motor nucleus in angiotensin II-mediated tachycardia in the conscious trout Oncorhynchus mykiss.

Responses of heart rate (HR) and mean arterial blood pressure (MABP) were examined following microinjection of angiotensin II ([Asn1,Val5]AI) within the dorsal vagal motor nucleus (DVN) of the conscious trout's brainstem. AII (15-125 fmol) preferentially and significantly increased HR in a dose-dependent manner, but the rise in MABP was not dose-dependent and was only significant (P < 0.05) after injection of AII at a dose of 62.5 fmol. The cardiovascular action of AII was site-specific, since administrations of the peptide at a dose of 62.5 fmol, but outside the boundaries of the DVN, were devoid of any effect on HR or MABP. All the responses to DVN injections of AII were totally prevented by DVN injection of 1 nmol of losartan, a mammalian non-peptide AII subtype 1 (AT1) receptor antagonist. The ability of DVN injection of AII to induce a tachycardic response was negatively correlated to HR basal values. In conclusion, these results indicate that, at femtomolar doses, AII exerts a central neurocardioregulatory role, involving a localized receptor closely related to the mammalian AT1 receptor subtype within the DVN of the trout.

[Distal nerve compression of the leg. Clinical and electrophysiologic study]. / Compressions nerveuses distales du membre inférieur. Etude clinique et électrophysiologique.

Rare distal compressions of lower limb nerves include tarsal tunnel syndrome, entrapment of the first branch of the lateral plantar and medial calcaneal nerves, interdigital neuroma, compression of the deep peroneal nerve on the dorsum of the foot, entrapment of the superficial peroneal and sural nerves. Nerve conduction and electromyographic studies are essential to evaluate these peripheral nerve injuries in order to differentiate focal lower extremity nerve entrapments from ischemic mononeuropathies, lumbar radiculopathies or plexopathies, and generalized peripheral neuropathies. This review summarizes the clinical and electrophysiological findings for each of these rare entrapment syndromes and provides the necessary clues to obtain a correct differential diagnosis with other more common causes of foot and ankle pain and paresthesias.

[The effects of clomipramine on diurnal sleepiness and respiratory parameters in a a case of Prader-Willi syndrome]. / Effets de la clomipramine sur la somnolence diurne et sur les paramètres respiratoires dans un cas de syndrome de Prader-Willi.

The association of Prader-Willi-syndrome with breathing disturbances such as sleep apnea syndrome and/or hypoxemia during REM sleep, REM sleep abnormalities and excessive daytime sleepiness is well known. We report the case of an 11-year-old boy who presented with Prader-Willi syndrome, obesity (body mass index [BMI] = 45.6), severe obstructive sleep apnea syndrome and significant daytime sleepiness on multiple sleep latency test. Behavioral disorders did not allowed the use of continuous positive pressure in this patient. Therefore, clomipramine (20 mg per day) was administered. Sleep examination over 8 months showed: slight weight loss (BMI = 44.4), persistence of severe obstructive sleep apnea syndrome, slight improvement in nocturnal hypoxemia, and disappearance of excessive daytime drowsiness with mean sleep latency of 15 min 37 s (less than 2 min before treatment) and no diurnal REM sleep periods. However, clomipramine had no effect on hyperphagia.

[Presymptomatic injury of the recurrent laryngeal nerve in benign thyroid disease: contribution of electromyography]. / Atteinte récurrentielle présymptomatique au cours d'affections bénignes de la thyroïde: apport de l'électromyographie.

Diagnosis of recurrent laryngeal nerve palsy is usually possible through a clinical, laryngoscopical and electromyographical approach, but at a critical stage of the nerve injury. We observed four cases of benign thyroïd tumoral processes with a preoperative electromyographic examination showing neurogenic abnormalities in the thyroarytenoid muscle without any clinical symptoms. We presume that only laryngeal electromyography permits the diagnosis of mild, even asymptomatic laryngeal recurrent nerve injury. A recurrent laryngeal nerve palsy occurs in thyroid tumors, most often in malignant conditions, rarely in benign ones. Nevertheless early forms of nerve injury with benign thyroïd pathology could be underrated. Since the functional prognosis of symptomatic laryngeal nerve palsy is doubtful, laryngeal electromyography, through its ability to diagnose early nerve injury, provides helpful indications in thyroïd benign tumoral diseases for the therapeutic decision.

[Lesion of the deep branch of the ulnar nerve caused by fracture of the hook of the hamate]. / Atteinte de la branche profonde du cubital par fracture de l'os crochu.

We present a case of lesion of the deep branch of ulnar nerve at the wrist caused by fracture of the hook of the hamate. According to Wu's classification (1985) based on clinical and electromyographic findings and the clinicoanatomic correlations, our case corresponds to type IV of this classification with a pure motor ulnar neuropathy with sparing of hypothenar muscles. Improvement was observed after surgery.

[Adrenoleukodystrophy in the child and adrenomyeloneuropathy. Study of 2 families]. / Adrénoleucodystrophie de l'enfant et adrénomyéloneuropathie. Etude de deux familles.

Ten subjects from 2 families with adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN), hereditary X-linked diseases, were systematically explored. We performed endocrinological, biochemical assays and neurophysiological tests; the latter consisted of nerve conductions (CNV), Hoffmann's reflex and multimodal evoked potentials: visual (flash and pattern, VEP), brainstem auditory (BAEP) and somesthetic (SEP) using median nerve stimulation at the wrist. We only considered values above 2 SD. The purpose of our study was to determine the correlation between neurophysiological and endocrinological perturbations and the presence of pathological traits. Our results suggest that the correlation is high in diseased male patients, lower for the ALD carriers (BAEP, SEP and CNV were more frequently abnormal) and very low for the AMN carriers. Only the biochemical assays appeared to have any value for the characterization of female carriers of ALD and AMN.

[Long-term effects of treatment with SMS 201-995 on sleep apnea syndrome associated with acromegaly]. / Effets à long terme du traitement par SMS 201-995 sur un syndrome d'apnées du sommeil associé à une acromégalie.

A 60-year-old woman with acromegaly associated with sleep apnea was treated with the somatostatin analogue SMS 201-995 (Sandoz) for several months. Growth hormone levels were normalized and a rapid improvement in sleep apnea was controlled with polygraphic nocturnal monitoring. Hypophysectomy seems to have variable effects on sleep apnea in acromegaly. The origin of obstructive apnea in acromegaly is therefore unclear.

[Axonal neuropathy and chronic Codobromyl poisoning]. / Neuropathie axonale et intoxication chronique au Codobromyl.

We report a 56 year-old woman with a severe axonal neuropathy due to a chronic intoxication by a cough soothing (Codobromyl). Symptoms of codeine and alcohol intoxication were present. The problems of self medication are considered.

[Regressive leukoencephalopathy induced by an overdose of cyclosporine A]. / Leucoencéphalopathie régressive au cours d'un surdosage en cyclosporine A.

We report a case of leucoencephalopathy with tremor and generalized motor seizures a few days after introduction of cyclosporin A (Cy A) in a kidney recipient. There was a relationship between acute neurological symptoms and high and sudden blood level of Cy A (1 260 ng/ml; therapeutic range: 120-275 ng/ml). White-matter hypodensities at CT scanning and severe slow-waves abnormalities at EEG were present. All neurological symptoms were reversible after Cy A level was lowered. Three months later, a blood Cy A level at 217 ng/ml due to nicardipine co-administration resulted in severe tremor and was reversed by decreasing blood Cy A level to 126 ng/ml.

[Pituitary adenoma secreting somatotropic hormone. Gigantism and peripheral neuropathy. A case]. / Adénome hypophysaire sécrétant de l'hormone somatotrope. Gigantisme et neuropathie périphérique. Une observation.

Gigantism, an extremely rare condition, develops before puberty or in subjects in whom puberty is not yet completed. Hypersecretion of somatotropic hormone results in a tremendous surge in growth (our patient was 2.36 m tall). Among other clinical symptoms disabling peripheral neuropathy predominates and changes in nerve conduction velocity are not merely due to the increase in height. The increase in growth hormone concentrations combined with hypogonadotrophic hypogonadism with normal prolactinaemia is associated with peculiar cutaneous symptoms and with low levels of sex hormone-binding protein.

[Nerve paralysis after surgery of the hip. Apropos of 48 cases]. / Les complications paralytiques de la chirurgie de la hanche. A propos de 48 obervations.

This study is based on 48 cases of paralysis of the femoral or sciatic nerves complicating hip surgery, mostly total hip arthroplasty. Most of these lesions arose during difficult operations. The diagnosis was clinical and electromyographic, but it was not always made from the outset. The prognosis was better for the cases of paralysis of the femoral or peroneal nerves than for the cases of generalised sciatic paralysis in which the recovery, slower as it was, was only satisfactory in 15 cases out of 26. The treatment was primarily medical and required reeducation. A surgical treatment was considered when the electrical exploration showed no improvement after 6 weeks.

[Victor Segalen's death: a medical view-point]. / La mort de Victor Segalen: un point de vue médical.

Victor Segalen, born in Brest in 1878, naval physician and writer, died in Huelgoat forest, in Brittany. Accident or self-murder? After analysis of his personality, psychic antecedents, events of his death, and evidences of friends, his suicide seems probable. It is possible that Yvonne, his wife, and Hélène Hilpert, a woman-friend, expected this end. The accident was asserted. Comparison with death of his heroes reinforces suicide hypothesis.