Broadening the phenotypic spectrum of the presumably epilepsy-related SV2A gene variants.

Missense variants in the synaptic vesicle glycoprotein SV2A gene have been previously found in a few individuals with epilepsy. Adverse reaction to levetiracetam in individuals with various variants of this gene has recently been described. Here, we report on a family with several members affected by epilepsy. In affected members of this family, we identified a variant in the SV2A gene (NM_014849.5: c.1978 G>A, p.(Gly660Arg). This family case further supports the role of the SV2A gene in autosomal dominant epilepsy. It provides new information on the course of epilepsy in people with variants in the SV2A gene who have never been treated with SV2A agonists and specific neurodevelopmental features of this syndrome.

Reproductive losses caused by the ingestion of Poincianella pyramidalis in sheep.

Malformations have been observed in sheep and goats in the Brazilian semiarid region in areas where Poincianella pyramidalis is dominant. The objective of this trial was to determine whether Poincianella pyramidalis causes reproductive changes in pregnant sheep. Sixteen non-pregnant sheep were mated with two rams. After confirmation of the pregnancy by ultrasonography on the 18th day after mating, pregnant sheep were randomly divided into four groups (#1, 2, 3, and 4), with four animals each. Sheep received roughage in an amount equivalent to 2% of their body weight, mixed with 0%, 10%, 20% and 40% of dried leaves of P. pyramidalis for groups 1, 2, 3 and 4, respectively. In Groups 1 and 2, all animals lambed normally. In Group 3 (20% P. pyramidalis in the roughage), one lamb was born with arthrogryposis and three sheep gave birth to premature weak lambs within 128, 132, and 133 days of gestation. In Group 4 (40% P. pyramidalis in the roughage), one sheep lambed a normal lamb; another ewe had embryonic mortality after seven days of plant consumption, and two aborted on days 103 and 144 of pregnancy. One of the aborted fetuses was normal and the other showed arthrogryposis and prognathism. These results suggest that P. pyramidalis causes embryonic deaths, abortions, and malformations in sheep. Grazing pregnant sheep in areas where this plant is dominant should be avoided, and roughage for confined pregnant females should not contain more than 10% P. pyramidalis.

Congenital malformations and other reproductive losses in goats due to poisoning by Poincianella pyramidalis (Tul.) L.P. Queiroz (=Caesalpinia pyramidalis Tul.).

In the semiarid region of Brazil, in areas with vegetation composed mainly of Poincianella pyramidalis, several cases of congenital malformation and reproductive losses were observed in goats and sheep from 2012 to 2014. To determine the teratogenic effect of P. pyramidalis, two groups of eight goats each were used. Goats from Group 1 received fresh P. pyramidalis, harvested daily, as the only roughage during the whole breeding and pregnancy period. Goats in Group 2 (control) received Cynodon dactylon (tifton) hay free choice. Ultrasound examination for pregnancy diagnosis was performed every 28 days. Four goats from Group 1 were pregnant on day 28 but not on day 56, suggesting embryonic death or abortion. Another goat from Group 1 died at day 70 of pregnancy, and the fetuses exhibited micrognathia. The other three goats bore six kids, three of which showed bone malformations in the limbs, spine, ribs, sternum, and head, including arthrogryposis, scoliosis and micrognathia. One kid also showed hypoplasia of the left pulmonary lobes. In the control group, all goats bore a total of 13 kids and none of them exhibited malformations. These results demonstrated that P. pyramidalis causes congenital malformations and other reproductive losses in goats.

Maternal myasthenia gravis complicated by fetal arthrogryposis multiplex congenita.

We report the management of a 24-year-old primigravid woman who was diagnosed with myasthenia gravis at 20weeks of gestation. Maternal symptoms improved with therapeutic plasma exchange, steroids, immunoglobulin therapy and pyridostigmine. Despite this, the fetus had arthrogryposis multiplex congenita due to trans-placental transfer of anti-acetylcholine receptor antibodies. The baby was delivered by elective caesarean section at 34weeks of gestation but died in the immediate postpartum period. The mother underwent thymectomy within five weeks of delivery. The implications of myasthenia gravis for both the mother and baby are discussed.

Embriopatías asociadas al uso de misoprostol / Moebius syndrome and arthrogriposis associated to the use of misoprostol

Se presenta un caso clínico de síndrome de Moebius y artrogriposis asociado al uso de misoprostol durante el primer trimestre de gestación.

We present a case of Moebius syndrome and arthrogriposis associated to the use of misoprostol during the first trimester of gestation.

Amioplasia congénita y consumo materno de cocaína / Congenital amyoplasia and maternal cocaine use

Introducción: La artrogriposis múltiple congénita (AMC) es unsíndrome caracterizado por contracturas congénitas no progresivas de dos o más articulaciones. La forma clásica de AMC llamada amioplasia es siempre esporádica. En la artrogriposis neurógena, la forma más frecuente (90%), la afectación inicial se encuentra en las neuronas del asta anterior de la médula, las raíces nerviosas o el nervio periférico. Casos clínicos: Se exponen dos casos de recién nacidos que desarrollaron una clínica similar de amioplasia. El primer niño tenía contracturas articulares, atrofia de los músculos de las extremidades inferiores e incontinencia. El segundo niño presentó paraplejía fláccida con atrofia muscular y atonía muscular abdominal. Las dos madres eran consumidoras de cocaína durante el embarazo. En ambos pacientes los exámenes neurofisiológicos demostraron una denervación a diferentes niveles de la médula espinal. Discusión: Se ha postulado como causa de amioplasia congénita una necrosis de la médula espinal fetal debida a hipotensión sistémica. En adultos se han descrito casos de episodio cerebrovascular relacionados con el consumo de cocaína. Probablemente, los mecanismos están relacionados con la estimulación adrenérgica, la vasoconstricción cerebral y cambios bruscos en la presión arterial. En ambos casos las características clínicas descritas al nacer fueron debidas a denervación de la médula espinal a diferentes niveles. Los defectos encontrados en nuestros pacientes podrían estar asociados a consumo materno de cocaína durante el embarazo, que produciría vasoconstricción del pequeño lecho vascular eisquemia-infarto por alteración vascular en la médula espinal del feto

Introduction: Arthrogryposis multiplex congenita (AMC) is a term used to describe a disorder characterized by multiple, nonprogressive joint contractures at birth. The classic form of peripheral AMC, referred to as amyoplasia, is always sporadic. In neurogenic arthrogryposis, the most frequent form (90%), the initial injury would be in the anterior horm cells of the spinal cord, the nerve roots or the peripheral nerve. Case reports: We report the cases of two newborns who presented similar clinical signs of amyoplasia. One had joint contractures, muscle atrophy and incontinence. The other has flaccid paraplegia with muscle atrophy in lower limbs and abdominal muscle atony. Both mothers consumed cocaine during pregnancy. In both patients, neurophysiological examination demonstrated denervation at different levels of spinal cord. Discussion: Necrosis of the fetal spinal cord caused by systemic hypotension has been postulated as a cause of amyoplasia. The mechanism of cocaine-related cerebrovascular accidents in adults is probably related to adrenergic stimulation, cerebral vasoconstriction adna a sudden surge in blood pressure. In our two cases, the clinical findings reported at birth were due to denervation at different levels of the spinal cord. Therefore, the defects in our patients may be associated with maternal use of cocaine during pregnancy, producing small vessel vasoconstriction and vascular disruption in the fetal spinal cord

Comparison of plasma disposition of alkaloids after lupine challenge in cattle that had given birth to calves with lupine-induced arthrogryposis or clinically normal calves.

OBJECTIVE: To compare plasma disposition of alkaloids after lupine challenge in cattle that had given birth to calves with lupine-induced arthrogryposis and cattle that had given birth to clinically normal calves and determine whether the difference in outcome was associated with differences in plasma disposition of anagyrine. ANIMALS: 6 cows that had given birth to calves with arthrogryposis and 6 cows that had given birth to clinically normal calves after being similarly exposed to lupine during pregnancy. PROCEDURES: Dried lupine (2 g/kg) was administered via gavage. Blood samples were collected before and at various time points for 48 hours after lupine administration. Anagyrine, 5,6-dehydrolupanine, and lupanine concentrations in plasma were measured by use of gas chromatography. Plasma alkaloid concentration versus time curves were generated for each alkaloid, and pharmacokinetic parameters were determined for each cow. RESULTS: No significant differences in area under the plasma concentration versus time curve, maximum plasma concentration, time to reach maximum plasma concentration, and mean residence time for the 3 alkaloids were found between groups. CONCLUSIONS AND CLINICAL RELEVANCE: Because no differences were found in plasma disposition of anagyrine following lupine challenge between cattle that had given birth to calves with arthrogryposis and those that had not, our findings do not support the hypothesis that between-cow differences in plasma disposition of anagyrine account for within-herd differences in risk for lupine-induced arthrogryposis.

Misoprostol embryotoxicity: clinical evaluation of fifteen patients with arthrogryposis.

We report on clinical evaluations of Brazilian patients with misoprostol-induced arthrogryposis. All 15 patients had growth retardation, underdeveloped bones, short feet with equinovarus, rigidity of several joints with skin dimples and webs, decreased movement of legs stemming from neurologic impairment, bilateral symmetrical hypoplasia or atrophy of limb muscles, and absent tendon reflexes. Of the 15 patients, five had upper limb deformities in addition to lower limb involvement, and one had spinal cord disruption leading secondarily to segmental sensory loss and neurogenic bladder and bowel. Electroneuromyography of five patients indicated that the abnormalities were of neurogenic origin and suggestive of anterior horn cell defects. All of their mothers took 400-4,800 mcg of misoprostol orally or vaginally at 8 to 12 weeks of pregnancy. Our observations support a previously stated caution with regard to the embryotoxicity of misoprostol.

Congenital abnormalities in Brazilian children associated with misoprostol misuse in first trimester of pregnancy.

BACKGROUND: Misoprostol is commonly used to induce abortion in Brazil, and in other countries in South and Central America where abortions are illegal. However, misoprostol is not very effective in inducing abortions, and exposure to the drug in utero can cause abnormalities in the fetus. We aimed to define the common phenotypical effects of exposure to the drug. METHODS: We studied 42 infants from São Paulo, Brazil, who were exposed to misoprostol during the first 3 months of gestation, and then born with congenital abnormalities. We interviewed each of the infants' mothers to find out about misoprostol exposure and dosage. Each infant was physically examined by a geneticist or a neuropaediatrician. FINDINGS: 17 of the infants had equinovarus with cranial-nerve defects. Ten children had equinovarus as part of more extensive arthrogryposis. The most distinctive phenotypes were arthrogryposis confined to the legs (five cases) and terminal transverse-limb defects (nine cases) with or without Mobius sequence. The most common dose of misoprostol taken was 800 microg (range 200-16000 microg). INTERPRETATION: Deformities attributed to vascular disruption were found in these children. We suggest that the uterine contractions induced by misoprostol cause vascular disruption in the fetus, including brain-stem ischaemia. Information on the effects of taking misoprostol during pregnancy should be made more widely available, to dissuade women from misusing the drug.

PIP: In Brazil and other South and Central American countries where abortion is illegal, misoprostol is widely available and commonly used to induce abortion. However, misoprostol is not very effective as an abortifacient agent and can cause fetal abnormalities. The present study reviewed the cases of 42 infants from Sao Paulo, Brazil, who were exposed to misoprostol during the first trimester of pregnancy and then born with a congenital abnormality. 17 children had equinovarus with cranial nerve deficiencies and 10 had equinovarus as part of a more extensive arthrogryposis. The most distinctive phenotypes were arthrogryposis confined to the legs (5 cases) and terminal transverse limb defects (9 cases). Congenital hydrocephalus was present in 8 children. The most commonly taken dose of misoprostol was 800 mcg (range, 200-16,000 mcg). Greater awareness of the widespread use of misoprostol to induce abortion should lead to public health interventions to prevent teratogenic effects.

Arthrogryposis multiplex congenita and bilateral mid-brain infarction following maternal overdose of co-proxamol.

We report a case of arthrogryposis multiplex congenita secondary to fetal hypokinesia in a 41-week gestation infant following antenatal central nervous system injury. The mother's pregnancy was complicated by an episode of attempted self harm, with an overdose of co-proxamol at 22 weeks of gestational age, and by the use of cocaine in combination with excess alcohol intake. Magnetic resonance imaging showed bilateral mid-brain cysts and marked atrophy of the basal ganglia and thalami.

Effect of coniine on the developing chick embryo.

Coniine, an alkaloid from Conium maculatum (poison hemlock), has been shown to be teratogenic in livestock. The major teratogenic outcome is arthrogryposis, presumably due to nicotinic receptor blockade. However, coniine has failed to produce arthrogryposis in rats or mice and is only weakly teratogenic in rabbits. The purpose of this study was to evaluate and compare the effects of coniine and nicotine in the developing chick. Concentrations of coniine and nicotine sulfate were 0.015%, 0.03%, 0.075%, 0.15%, 0.75%, 1.5%, 3%, and 6% and 1%, 5%, and 10%, respectively. Both compounds caused deformations and lethality in a dose-dependent manner. All concentrations of nicotine sulfate caused some lethality but a no effect level for coniine lethality was 0.75%. The deformations caused by both coniine and nicotine sulfate were excessive flexion or extension of one or more toes. No histopathological alterations or differences in bone formation were seen in the limbs or toes of any chicks from any group; however, extensive cranial hemorrhage occurred in all nicotine sulfate-treated chicks. There was a statistically significant (P < or = 0.01) decrease in movement in coniine and nicotine sulfate treated chicks as determined by ultrasound. Control chicks were in motion an average of 33.67% of the time, while coniine-treated chicks were only moving 8.95% of a 5-min interval, and no movement was observed for nicotine sulfate treated chicks. In summary, the chick embryo provides a reliable and simple experimental animal model of coniine-induced arthrogryposis. Data from this model support a mechanism involving nicotinic receptor blockade with subsequent decreased fetal movement.

Evaluation of developmental toxicity of coniine to rats and rabbits.

Conium maculatum (poison hemlock, CM) is teratogenic in several domestic species, presumably due to its piperidine alkaloids, including coniine, which has been verified to be teratogenic in cattle. Coniine/CM teratogenicity culminates in production of arthrogryposis. The purpose of this study was to evaluate coniine-induced teratogenicity in two laboratory animal species, Sprague-Dawley rats and New Zealand white rabbits. Pregnant rats were given coniine (25 mg/kg body weight) by oral gavage at 8-hour intervals on gestation days 16-18. Pregnant rabbits were given coniine (40 mg/kg body weight) by oral gavage at 8-hour intervals on gestation days 20-24. Rats were killed on day 19 and rabbits on day 29. Fetuses were immediately removed, weighed, and examined for external abnormalities. Alternate fetuses were either stained for skeletal examinations with alizarin red-S or fixed in Bouin's solution for visceral examination. Symptoms of maternal intoxication due to coniine administration were observed in both the rat and the rabbit, and higher doses were uniformly lethal. Rabbits treated with coniine appeared to lose more weight and eat less than controls, but there was no statistically significant difference between groups. Fetal weights were significantly lower in coniine-exposed rat and rabbit fetuses indicating fetotoxicity. The only statistically significant treatment-related visceral or skeletal malformation was a reduction of cranial ossification of rabbit fetuses, probably related to maternal toxicity. Coniine-exposed rabbit litters tended to be affected by arthrogryposis (no bony deformities noted on skeletal exam) more than controls (2/6 vs. 0/9).

Amyoplasia congenita-like condition and maternal malathion exposure.

This report concerns an amyoplasia-like condition in a case with maternal exposure to malathion during the 11th to 12th week of pregnancy. Malathion is an agent acting on the neuromuscular system. The possibility of a causal association is discussed.

Teratogenicity in swine of the tobacco alkaloid anabasine isolated from Nicotiana glauca.

Nicotiana glauca, wild tree tobacco, induces arthrogrypotic congenital defects in piglets similar to those induced by Nicotiana tabacum, common tobacco. The present work was conducted to isolate the principal alkaloid of N. glauca, anabasine, in large quantity and good purity and to test the teratogenicity of the compound in pigs. The isolated compound was established to be anabasine and to be of suitable purity by chemical characterization. It proved to be teratogenic. Typical arthrogrypotic defects were induced in 21 of 26 offspring (three of three litters) when dams ingested 2.6 mg of the compound per kg body weight twice daily during the 43rd-53rd days of gestation. Of three dams dosed with 1.66 g/kg/day of the dried plant material during the 43rd-53rd days, one delivered deformed offspring representing one-third of all offspring in that group. These arthrogrypotic defects induced by anabasine were indistinguishable clinically from defects induced by either N. glauca or N. tabacum. In addition, anabasine at a dose of 2.6 mg/kg twice daily or N. glauca plant material at 1.66 gm/kg daily induced cleft palate in over three-fourths of offspring (100% of litters) when dams ingested either during the 30th-37th days of gestation or during longer periods that included those days.

Teratogens associated with congenital contractures in humans and in animals.

An evaluation of over 350 patients in a study of congenital contractures of the joints (arthrogryposis) included a review of family, pregnancy, and delivery histories for teratogenic exposures. Fifteen out of the total 350 patients studied had a possible teratogenic exposure: an infectious agent (viral or bacterial), maternal drug or toxin ingestion, chronic maternal neurologic or muscular illness, or a direct physical insult such as a structural uterine anomaly. Literature was reviewed for all human and animal cases reported with congenital contractures of the joints with an associated teratogenic insult. Those findings are discussed here.

Congenital defects in calves from maternal ingestion of Nicotiana glauca of high anabasine content.

Administration of Nicotiana glauca to four cows from the 50th to the 75th days of gestation induced congenital deformities in their calves. All four calves had arthrogryposis of forelimbs and one also had spinal curvature and rib cage deformity. The plant material contained 0.113% of the piperidine alkaloid anabasine as authenticated by gas chromatography and by infrared spectroscopy. Because of the presence of anabasine at a high concentration and because of its structural relationship to known teratogens, anabasine may be responsible teratogen.

Teratogenic effects in cattle of Conium maculatum and conium alkaloids and analogs.

The plant Conium maculatum produced congenital defects in calves born to cows gavaged the fresh green plant during days 50-75 of gestation. Both arthrogryposis and spinal curvature were produced and were similar to the defects produced by the piperidine alkaloid coniine. The arthrogrypotic manifestations of the condition markedly increased in severity as the animals aged. Animals gavaged dry plant had either normal or equivocally deformed offspring. A number of chain length and ring saturation analogs of coniine were not teratogenic. No congenital defects arose in offspring from maternal inhalation of either the teratogenic alkaloid coniine, or from the teratogenic green plant.