Fetal akinesia: The need for clinical vigilance in first trimester with decreased fetal movements.

OBJECTIVE: We present two cases of fetal akinesia detected by first trimester ultrasound with noticing reduced fetal movements. CASE REPORT: Both of the two cases presented with reduced fetal movements. Fetal microarray results were normal. Follow-up sonographic examinations showed that Case 1 had structural anomalies with reduced fetal movements, and Case 2 had findings of reduced fetal movements and olyhydramnios. Case 1 ended with termination of pregnancy, and was confirmed to suffer from distal arthrogryposis (DA) type 5D (DA5D) with two pathogenic ECEL1 variants, NM_004826: c.110_155del46 (p.F37Cfs∗151) and c.633G > C (p.W211C). Case 2 continued to term. However, the infant developed breathing problems and severe hypotonia after birth, and died at 3 months. Nemaline myopathy was diagnosed with two NEB variants, NM_001271208.1: c.3255+1G > T and c.7165delA (p.W211C) detected in the patient. CONCLUSION: The first trimester ultrasound can detect clues that lead to the diagnosis of fetal akinesias presenting with reduced or absent fetal movements. Our results would be useful in counselling parents of affected pregnancies and in alerting physicians to plan the appropriate follow-up investigations for such cases.

Dopamine receptor polymorphism modulates the relation between antenatal maternal anxiety and fetal movement.

We determined whether the combination of fetal genotype (dopamine D4 receptor; DRD4) and mothers' anxiety during pregnancy is associated with fetal behavior. Two hundred and six pregnant women underwent an ultrasound exam. Fetal movement measures (Movement Frequency, Total Activity, Movement Duration, and Longest Quiet Time) were derived from off-line coding. A moderating role of the DRD4-III polymorphism was found: Results indicate that higher levels of antenatal maternal anxiety symptoms were associated with more frequent fetal movements among fetuses carrying a 7R allele, but not among fetuses carrying shorter alleles. Total Activity did not show full moderation by DRD4, though the measure was correlated with maternal anxiety among fetuses in the Anxious Group with a 7R allele; not among fetuses without both factors. The findings provide the first evidence of a GXE interaction in association with fetal behavior. Results also demonstrate that some individuals are inherently more susceptible to uterine environmental influences than are others.

Distress During Pregnancy: Epigenetic Regulation of Placenta Glucocorticoid-Related Genes and Fetal Neurobehavior.

OBJECTIVE: Increased risk of psychopathology is observed in children exposed to maternal prenatal distress, and elevated maternal cortisol and epigenetic regulation of placental glucocorticoid-pathway genes are potential mechanisms. The authors examined maternal distress and salivary cortisol in relation to fetal movement and heart rate ("coupling") and DNA methylation of three glucocorticoid pathway genes-HSD11B2, NR3C1, and FKBP5-in term placentas. METHOD: Mood questionnaires and salivary cortisol were collected from 61 women between 24-27 gestational weeks, and fetal assessment was conducted at 34-37 weeks. Placental CpG methylation in the three genes was analyzed using 450K Beadchips and bisulfite sequencing; correlations between maternal and fetal variables and DNA methylation were tested; and maternal distress effects on fetal behavior via DNA methylation were investigated. RESULTS: Perceived stress (Perceived Stress Scale), but not cortisol, was associated with altered CpG methylation in placentas. In the highest tertile of the Perceived Stress Scale, the Beadchip data revealed modestly elevated methylation of HSD11B2, associated with lower fetal coupling (ß=-0.51), and modestly elevated methylation of FKBP5, also with lower fetal coupling (ß=-0.47). These increases in methylation were validated by bisulfite sequencing, where they occurred in a minority of clones. CONCLUSIONS: This is the first study to link the effects of pregnant women's distress on the fetus and epigenetic changes in placental genes. Since increased DNA methylation in HSD11B2 and FKBP5 are seen in a minority of bisulfite sequencing clones, these epigenetic changes, and functional consequences, may affect subpopulations of placental cells.

Prenatal ontogeny of the dopamine-dependent neurobehavioral phenotype in Pitx3-deficient mice.

Mouse models with prenatal alterations in dopaminergic functioning can provide new opportunities to identify fetal behavioral abnormalities and the underlying neural substrates dependent on dopamine. In this study, we tested the hypothesis that prenatal loss of nigrostriatal function is associated with fetal akinesia, or difficulty initiating movement. Specific behaviors were analysed in fetal offspring derived from pregnant Pitx3(ak) /2J and C57BL/6J dams on the last 4 days before birth (E15-18 of a 19-day gestation). Using digital videography, we analysed: (i) behavioral state, by quantification of high- and low-amplitude movements, (ii) interlimb movement synchrony, a measure of the temporal relationship between spontaneous movements of limb pairs, (iii) facial wiping, a characteristic response to perioral tactile stimulation similar to the defensive response in human infants, and (iv) oral grasp of a non-nutritive nipple, a component of suckling in the human infant. Pitx3 mutants showed a selective decrease in interlimb movement synchrony rates at the shortest (0.1 s) temporal interval coupled with significantly increased latencies to exhibit facial wiping and oral grasp. Collectively, our findings provide evidence that the primary fetal neurobehavioral deficit of the Pitx3 mutation is akinesia related to nigrostriatal damage. Other findings of particular interest were the differences in neurobehavioral functioning between C57BL/6J and Pitx3 heterozygous subjects, suggesting the two groups are not equivalent controls. These results further suggest that fetal neurobehavioral assessments are sensitive indicators of emerging neural dysfunction, and may have utility for prenatal diagnosis.

Pena-Shokeir phenotype (fetal akinesia deformation sequence) revisited.

BACKGROUND: Pena and Shokeir described the phenotype of two sisters in 1974, and subsequently their features have become recognized as a sequence of deformational changes related to decreased or absent fetal movement (fetal akinesia deformation sequence [FADS]), because of the work of Moessinger (1983). METHODS: Identification of reported cases by searching Online Mendelian Inheritance in Man, Medlines, the London Dysmorphology Database, and the references found in these articles. These case reports were reviewed, tabulated, and summarized. RESULTS: It is now possible to recognize at least 20 familial types of Pena-Shokeir phenotype (PSP), based on the differences found in the reports of the natural history and pathology found at fetal and newborn autopsy. In addition, characteristic changes in the central nervous system seen with embryonic/fetal vascular compromise have been recognized in many reported cases. Most of the reported cases of PSP/FADS related to vascular compromise are sporadic, but familial cases have also been reported. CONCLUSION: Lack of fetal movement (fetal akinesia) in humans produces a recognizable sequence of deformations. Many developmental processes must be accomplished for fetal movement to be normal, and for extra-uterine life to be sustainable. Prenatal diagnosis is possible through real-time ultrasound studies as early as 12 weeks. Most reported cases die in utero, at birth, or in the newborn period. Advances in embryo/fetus pathology have led to the recognition of the many familial subtypes, allowing improved genetic counseling and early recognition in subsequent pregnancies.

Dominant and recessive central core disease associated with RYR1 mutations and fetal akinesia.

We studied seven patients (fetuses/infants) from six unrelated families affected by central core disease (CCD) and presenting with a fetal akinesia syndrome. Two fetuses died before birth (at 31 and 32 weeks) and five infants presented severe symptoms at birth (multiple arthrogryposis, congenital dislocation of the hips, severe hypotonia and hypotrophy, skeletal and feet deformities, kyphoscoliosis, etc.). Histochemical and ultrastructural studies of muscle biopsies confirmed the diagnosis of CCD showing unique large eccentric cores. Molecular genetic investigations led to the identification of mutations in the ryanodine receptor (RYR1) gene in three families, two with autosomal recessive (AR) and one with autosomal dominant (AD) inheritance. RYR1 gene mutations were located in the C-terminal domain in two families (AR and AD) and in the N-terminal domain of the third one (AR). This is the first report of mutations in the RYR1 gene involved in a severe form of CCD presenting as a fetal akinesia syndrome with AD and AR inheritances.

Artrogriposis múltiple congénita (contracturas congénitas múltiples): revisión / Arthrogryposis multiplex congenita (multiple congenital contractures): a review

La artrogriposis o contracturas múltiples es la aparición de contracciones articulares de etiología variable en el período prenatal. La artrogriposis puede ser el resultado de un déficit neurológico, de alteraciones neuromusculares, de anomalías del tejido conectivo, de bridas amnióticas o de anomalías posicionales fetales. La artrogriposis puede ser el resultado de causas sin aparente relación hereditaria (neuropáticas) o proceder de factores hereditarios (la forma miopática, por ejemplo). El diagnóstico ecográfico depende de la observación de la ausencia o la escasa motilidad de los miembros y de anomalías de posición de las contracturas articulares. El pronóstico depende de la etiología específica de las contracturas. Se describe la incidencia de anomalías contracturales y otras malformaciones acompañantes sobre la base de 8 casos observados con ecografía tridimensional. (AU)

Actividad fetal durante el test basal en relación con el resultado del mismo / Fetal somatic activity is significantly higher when basal fetal heart rate monitoring is classified as reactive

Estudiamos la actividad somática durante el registro de la frecuencia cardíaca fetal en condiciones basales (test basal), comparando los resultados obtenidos en función de la reactividad fetal.Analizamos los movimientos fetales, registrados mediante un cinetocardiotocógrafo, durante el test basal realizado a 100 gestantes, y se comparó el perfil de movimientos de los registros reactivos (51 casos) con los no reactivos (47 casos). Se utilizó un modelo informático experimental para el análisis de los movimientos, tanto de forma cuantitativa (número y porcentaje) como cualitativa (pequeña, mediana y larga duración). El número de movimientos fue mayor en los registros reactivos (55,3) que en los no reactivos (35,5) (p < 0,0001). Idéntica significación estadística se obtuvo al comparar el porcentaje de movimientos entre los registros reactivos (15,7 por ciento) y los no reactivos (9,2 por ciento). La comparación por tipos de movimientos fue igualmente significativa.La actividad somática es significativamente mayor cuando el test basal de la frecuencia cardíaca fetal es clasificado como reactivo (AU)

[Very severe spinal muscular atrophy--type 0. A cause of congenital multiple arthrogryposis]. / Meget svaer spinal muskelatrofi--type 0. En årsag til arthrogryposis multiplex congenita.

A female infant born at term, with reduced fetal movements in utero, congenital multiple contractures, severe weakness at birth, and a short time of survival is described. The diagnosis was confirmed by identification of homozygous deletion of exons 7 and 8 of the SMNt gene. Severe spinal muscular atrophy should be considered in the differential diagnosis of reduced fetal movements.

Biopsia fetal / Fetal biopsy

No disponible

Monozygotic twins with fetal akinesia: the importance of clinicopathological work-up in predicting risks of recurrence.

Fetal Akinesia Deformation Sequence (FADS) or Pena-Shokeir Sequence is a heterogeneous group of disorders in which prolonged decrease or absence of fetal movements results in a series of deformational anomalies: multiple contractures, pulmonary hypoplasia, craniofacial anomalies, polyhydramnios, intrauterine growth retardation, and short umbilical cord. Three sets of monozygotic twins, and their affected sibs, are presented. Detailed pathological work-up established that the two pairs of twins concordant for FADS were of myogenic etiology while the set discordant was due to anoxic-ischemic damage. In the myogenic cases, the rate of recurrence was high, in agreement with the findings from the study on arthrogryposis multiplex congenita of myogenic origin. In light of these findings, in sporadic cases of myogenic FADS, counselling, a recurrence risk of 25% seems prudent. In neurogenic cases associated with primary cerebral malformations, there are cases cited in the literature that are clearly recessive as indicated by affected sibs, but many reported are isolated occurrences. Therefore, in this scenario, giving a recurrent risk of 10-15% appears appropriate. In light of autosomal recessive spinal muscular atrophy and reports of familial FADS due to primary anterior horn cell loss, counselling a 25% risk seems prudent. In cases due to anoxic-ischemic damage, offering a low recurrent risk of 1% appears justified.

Prenatal onset spinal muscular atrophy.

Five patients with severe spinal muscular atrophy (SMA) type I, all of whom presented with reduced fetal movements in utero, severe weakness at birth, and short survival time were assessed to attempt to determine whether their phenotype could be explained by their genotype. The diagnosis was confirmed by clinical, electrophysiological and histopathological features. Polymerase chain reaction assays were used to define the molecular diagnosis. A gene-dosage assay was used to assess the quantity of centromeric survival motor neuron gene (SMNc) present. In all cases the telomeric survival motor neuron gene (SMNt) was absent. The SMNc gene was present but in reduced copy number compared with a control group of children with less severe type I SMA, so may be important in determining severity. In the differential diagnosis of reduced fetal movements, SMA should be considered. The clinical classification may in future be clarified by molecular genetic findings.

Benign familial neonatal convulsions: abnormal intrauterine movements, provocation by feeding and ICTAL EEG.

An infant with benign familial neonatal convulsions had abnormal movements during the last 2 months of pregnancy suggestive of intrauterine seizures. His postnatal seizures, one of which was captured by electroencephalography, had both partial and generalized features. Most seizures appeared to be provoked by feeding.

Hydrops fetalis: role of the geneticist.

The causes of hydrops fetalis are myriad. As a result of the advent of routine Rh screening, most cases are not currently related to Rh incompatibility. Genetic, metabolic, chromosomal, and syndromic causes are among the most frequently identified causes of nonimmune hydrops. The importance of determining the underlying cause of hydrops becomes evident once issues such as prognosis, specific treatment, and risk of recurrence are considered. The medical geneticist is highly qualified to assist in the evaluation of hydrops. Clinical geneticists have undergone training in a primary care specialty followed by intensive training in the diagnosis, management, and counseling of individuals and families with genetic, chromosomal, or multifactorial syndromes or birth defects. This training prepares the medical geneticist well to serve as a consultant when hydrops is diagnosed. As knowledge of the molecular genetic and metabolic basis of disease increases, utilization of genetics laboratories continues to increase dramatically. In addition to examining the child to look for dysmorphic features, the clinical geneticist can assist with the laboratory evaluation by coordinating testing with the cytogeneticist, molecular geneticist, and biochemical geneticist as appropriate. Increased awareness of the role of the geneticist in the evaluation of such patients should prove helpful to the physicians caring for such patients and the patients' families.