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Prenatal Diagnosis May 2024To examine parental experiences during pregnancies affected by Arthrogryposis Multiplex Congenita (AMC) by identifying commonalities, risk factors, and areas for...
OBJECTIVE
To examine parental experiences during pregnancies affected by Arthrogryposis Multiplex Congenita (AMC) by identifying commonalities, risk factors, and areas for improvement in detection rates, care protocols, and patient experience.
STUDY DESIGN
An online survey was distributed via AMC support groups on Facebook. Topics included demographics, risk factors, parental recall of sonographic findings, delivery characteristics and neonatal findings. Responses were divided into antenatally detected cases (ADCs) and postnatally detected cases (PDCs). Quantitative responses were analyzed with the Fisher exact test. Qualitative data were analyzed with thematic analysis.
RESULTS
The antenatal detection rate of arthrogryposis was 37%. Decreased fetal movement was reported by 53% and early bleeding by 21%. Sonographic findings in ADCs included clubfoot (83%), clenched hand (51%), decreased fetal movement (50%), elbow contracture (51%), and knee contracture (46%). Among ADCs, 29% delivered vaginally and 71% delivered by cesarean versus PDCs (44% vaginal, 56% cesarean). Neonatal intensive care unit admission rate was 63%. Bone fracture occurred in 9%. Detection led to a planned change in delivery mode in 33% and location in 50%. Among ADCs, 17% felt their concerns were not adequately addressed versus 43% of PDCs.
CONCLUSIONS
Antenatal detection of arthrogryposis was low. We propose enhanced screening criteria to aid prenatal diagnosis and promote utilization of more robust practice guidelines.
Topics: Humans; Arthrogryposis; Female; Pregnancy; Retrospective Studies; Parents; Prenatal Diagnosis; Adult; Surveys and Questionnaires; Infant, Newborn; Ultrasonography, Prenatal
PubMed: 38578615
DOI: 10.1002/pd.6569 -
Science Translational Medicine Apr 2024Troponin I (TnI) regulates thin filament activation and muscle contraction. Two isoforms, TnI-fast () and TnI-slow (), are predominantly expressed in fast- and...
Troponin I (TnI) regulates thin filament activation and muscle contraction. Two isoforms, TnI-fast () and TnI-slow (), are predominantly expressed in fast- and slow-twitch myofibers, respectively. variants are a rare cause of arthrogryposis, whereas variants have not been conclusively established to cause skeletal myopathy. We identified recessive loss-of-function variants as well as dominant gain-of-function variants as a cause of muscle disease, each with distinct physiological consequences and disease mechanisms. We identified three families with biallelic variants (F1: p.R14H/c.190-9G>A, F2 and F3: homozygous p.R14C), resulting in loss of function, manifesting with early-onset progressive muscle weakness and rod formation on histology. We also identified two families with a dominantly acting heterozygous variant (F4: p.R174Q and F5: p.K176del), resulting in gain of function, manifesting with muscle cramping, myalgias, and rod formation in F5. In zebrafish, TnI proteins with either of the missense variants (p.R14H; p.R174Q) incorporated into thin filaments. Molecular dynamics simulations suggested that the loss-of-function p.R14H variant decouples TnI from TnC, which was supported by functional studies showing a reduced force response of sarcomeres to submaximal [Ca] in patient myofibers. This contractile deficit could be reversed by a slow skeletal muscle troponin activator. In contrast, patient myofibers with the gain-of-function p.R174Q variant showed an increased force to submaximal [Ca], which was reversed by the small-molecule drug mavacamten. Our findings demonstrated that variants can cause muscle disease with variant-specific pathomechanisms, manifesting as either a hypo- or a hypercontractile phenotype, suggesting rational therapeutic strategies for each mechanism.
Topics: Animals; Humans; Calcium; Muscle Contraction; Muscle, Skeletal; Muscular Diseases; Sarcomeres; Troponin I; Zebrafish
PubMed: 38569017
DOI: 10.1126/scitranslmed.adg2841 -
American Journal of Medical Genetics.... Apr 2024Distal arthrogryposis type 5D (DA5D) is clinically characterized by knee extension contractures, distal joint contractures, clubfoot, micrognathia, ptosis, and...
Distal arthrogryposis type 5D (DA5D) is clinically characterized by knee extension contractures, distal joint contractures, clubfoot, micrognathia, ptosis, and scoliosis. We report nine affected individuals from eight unrelated Indian families with DA5D. Although the overall musculoskeletal phenotype is not very distinct from other distal arthrogryposis, the presence of fixed knee extension contractures with or without scoliosis could be an important early pointer to DA5D. We also report a possible founder variant in ECEL1 along with four novel variants and further expand the genotypic spectrum of DA5D.
PubMed: 38568023
DOI: 10.1002/ajmg.a.63592 -
Journal of Orthopaedic Case Reports Mar 2024Bilateral Sprengel deformities, mirror movements synkinesis, and arthrogryposis are described in different combinations in various syndromes but never together.
INTRODUCTION
Bilateral Sprengel deformities, mirror movements synkinesis, and arthrogryposis are described in different combinations in various syndromes but never together.
CASE REPORT
We present a 12-year-old girl who presented with bilateral shoulder deformities and difficulty in coordination while writing. On examination, she was noted to have bilateral Sprengel deformities with flexion contractures of upper-limb joints and mirror movements of both upper and lower-limb joints.
CONCLUSION
In the light of relevant literature, we may speculate that these three have a causal relation and even a genetic basis but further studies are needed to prove the same.
PubMed: 38560296
DOI: 10.13107/jocr.2024.v14.i03.4270 -
Journal of Medical Genetics Mar 2024Schaaf-Yang syndrome (SYS) is an ultra-rare neurodevelopmental disorder caused by truncating mutations in Heterologous expression of wild-type (WT) or a truncated...
Schaaf-Yang syndrome (SYS) is an ultra-rare neurodevelopmental disorder caused by truncating mutations in Heterologous expression of wild-type (WT) or a truncated (p.Gln638*) C-terminal HA-tagged MAGEL2 revealed a shift from a primarily cytoplasmic to a more nuclear localisation for the truncated protein variant. We now extend this analysis to six additional SYS mutations on a N-terminal FLAG-tagged MAGEL2. Our results replicate and extend our previous findings, showing that all the truncated MAGEL2 proteins consistently display a predominant nuclear localisation, irrespective of the C-terminal or N-terminal position and the chemistry of the tag. The variants associated with arthrogryposis multiplex congenita display a more pronounced nuclear retention phenotype, suggesting a correlation between clinical severity and the degree of nuclear mislocalisation. These results point to a neomorphic effect of truncated MAGEL2, which might contribute to the pathogenesis of SYS.
PubMed: 38548315
DOI: 10.1136/jmg-2024-109898 -
Prenatal Diagnosis Apr 2024Congenital myopathies are a genetically heterogeneous group of neuromuscular disorders that commonly present with congenital hypotonia and weakness but can also present...
Congenital myopathies are a genetically heterogeneous group of neuromuscular disorders that commonly present with congenital hypotonia and weakness but can also present broadly. The most severe presentation is neonatal with arthrogryposis and, rarely, fetal akinesia and pterygia, features also seen in lethal multiple pterygium syndrome (LMPS). We describe two fetuses with similar phenotype, including hydrops fetalis, large cystic hygromas, bilateral talipes, and fetal akinesia in the second trimester. Genetic diagnoses were made using exome sequencing. Both fetuses had a severe form of congenital myopathy. In the first fetus, we identified two novel compound heterozygous likely pathogenic variants consistent with autosomal recessive RYR1-related congenital myopathy (congenital myopathy 1B). In the second fetus, we identified two likely pathogenic variants, one of which is novel, likely in trans consistent with a diagnosis of autosomal recessive NEB-related congenital myopathy. Reaching a genetic diagnosis for these fetuses allowed the families to receive accurate genetic counseling for future pregnancies. These fetuses highlight the genetic and phenotypic heterogeneity of LMPS, and support a broad approach to genetic testing.
Topics: Female; Humans; Pregnancy; Abnormalities, Multiple; Cleft Palate; Lymphangioma, Cystic; Malignant Hyperthermia; Muscular Diseases; Ryanodine Receptor Calcium Release Channel; Skin Abnormalities; Fetal Diseases
PubMed: 38520674
DOI: 10.1002/pd.6553 -
Handchirurgie, Mikrochirurgie,... Feb 2024The treatment of obstetric brachial plexus palsy through primary reconstruction and nerve transfers has been established in the past decades. In the case of...
BACKGROUND
The treatment of obstetric brachial plexus palsy through primary reconstruction and nerve transfers has been established in the past decades. In the case of non-traumatic diseases that lead to flaccid paralysis and the inability to move the extremities, such as transverse myelitis (TM) or arthrogryposis multiplex congenita (AMC), which can have a wide variety of causes, the focus has been on rehabilitative therapy so far, while surgical interventions have been used to a lesser extent, e. g., in the form of osteotomies or muscle transfers. Our aim is to establish nerve transfers as a surgical option to improve mobility in non-traumatic amyoplasia.
PATIENTS
This work presents the needs-adapted treatment of a total of 23 patients (aged 4 months to 64 months, 18 with AMC and 5 with TM) using nerve transfers on the upper extremity.
RESULTS
We were able to show that early nerve transfers in the upper extremity enabled the reanimation of muscles in both AMC and TM.
CONCLUSION
This work shows that the treatment of non-traumatic amyoplasia in children with selective nerve grafts is a successful method. Nerve transfers allow patients to gain or regain important functions for managing independent everyday life. The surgical methods have been established in the treatment of traumatic nerve injuries. They are well-known and can be carried out safely. We believe that this is an important treatment option for paediatric patients with paralysis associated with TM or AMC, which should also be known to the treating physicians.
Topics: Humans; Child; Nerve Transfer; Brachial Plexus; Upper Extremity; Brachial Plexus Neuropathies; Arthrogryposis; Paralysis
PubMed: 38508206
DOI: 10.1055/a-2240-4781 -
Cureus Feb 2024Arthrogryposis multiplex congenita (AMC) consists of more than 400 conditions involving severe joint contractures of at least two or more body regions. Management of...
PURPOSE
Arthrogryposis multiplex congenita (AMC) consists of more than 400 conditions involving severe joint contractures of at least two or more body regions. Management of clubfoot in patients with AMC is notoriously challenging, with a higher likelihood of recurrence than idiopathic clubfoot, which can be treated using the Ponseti technique to avoid or delay more invasive procedures. The purpose of this study is to determine the utility of multiple serial casting as a treatment of clubfoot in AMC using Pirani scores as an objective measure of deformity.
METHODS
Pirani scores were retrospectively collected from 17 AMC patients with a total of 30 clubfeet and two years follow-up from initiation of treatment. Patients with a minimum of three casting series were included. Pre-treatment and post-treatment deformity scores were examined across casting series using analysis of variance (ANOVA) statistical analysis.
RESULTS
The first series pre-treatment Pirani score improved from 4.80±1.54 to 1.68±1.48 (p<0.001). The second series improved from 4.23±1.03 to 2.72±0.916 (p<0.001). The third series had the smallest improvement from 3.87±1.07 to 2.82±1.02 (p<0.001). Change in Pirani scores showed a significant decrease from the first series to the second (p=0.001) and third (p<0.001). In addition, the number of casting days was found to significantly affect the change in scores during the third series (p=0.038).
CONCLUSIONS
The Ponseti technique can improve clubfoot in AMC as measured by the Pirani score. Data shows that early intervention yields better results, with a diminished yet effective ability to elicit change over time.
PubMed: 38505444
DOI: 10.7759/cureus.54398 -
Der Nervenarzt Apr 2024There is evidence that gender-specific differences can influence the diagnostics, treatment and long-term disease course of myasthenia gravis (MG). In women the... (Review)
Review
BACKGROUND
There is evidence that gender-specific differences can influence the diagnostics, treatment and long-term disease course of myasthenia gravis (MG). In women the diagnosis is often made during childbearing age.
OBJECTIVE
Gender-specific differences in MG and relevant aspects in routine clinical practice are presented. In addition, current studies on family planning, pregnancy and childbirth in MG are highlighted and treatment recommendations are derived.
MATERIAL AND METHODS
Narrative literature review.
RESULTS
In addition to sociodemographic data, gender-specific differences encompass clinical as well as paraclinical factors, such as disease severity and antibody status. With few exceptions pregnancy is possible with good maternal and neonatal outcome. During pregnancy and peripartum, children of MG patients should be closely monitored for early detection and treatment of potential syndromes caused by diaplacental transfer of maternal antibodies.
CONCLUSION
Gender-specific factors can influence the course of MG. Adequate medical counselling and multidisciplinary collaboration are essential for MG patients who wish to have children.
Topics: Pregnancy; Child; Infant, Newborn; Humans; Female; Family Planning Services; Myasthenia Gravis; Autoantibodies; Family; Pregnancy Complications
PubMed: 38499774
DOI: 10.1007/s00115-024-01640-6 -
Archives of Gynecology and Obstetrics Jul 2024Myasthenia gravis (MG) is a rare, potentially life-threatening autoimmune disease with fluctuating muscle weakness frequently affecting women of childbearing age. MG can...
PURPOSE
Myasthenia gravis (MG) is a rare, potentially life-threatening autoimmune disease with fluctuating muscle weakness frequently affecting women of childbearing age. MG can affect maternal as well as neonatal outcome with risk of worsening of myasthenic symptoms in the mothers and risk of transient neonatal myasthenia gravis (TNMG) and arthrogryposis multiplex congenita (AMC) or foetal acetylcholine receptor antibody-associated disorders (FARAD) in the neonates.
METHODS
Retrospective analysis of maternal and neonatal outcome in a cohort of pregnant MG patients treated at a tertiary care centre in Germany.
RESULTS
Overall, 66 pregnancies were analysed. During 40 (63%) pregnancies, women experienced a worsening of myasthenic symptoms, of whom 10 patients (15.7%) needed acute therapy with IVIg or plasma exchange. There was no case of myasthenic crisis. Rate of caesarean section was comparable to the overall C-section rate at our centre (38% vs. 40%). However, there was a slightly higher rate for operative vaginal delivery (15% vs. 10%) as potential indicator for fatiguing striated musculature in MG patients during the expulsion stage. Rate of TNMG as well as AMC was 3% (two cases each).
CONCLUSIONS
Maternal and neonatal outcome in our cohort was favourable with a low rate of myasthenic exacerbations requiring acute therapies and a low rate of TNMG and AMC/FARAD. Our data might help neurologists and obstetricians to advice MG patients with desire to have children.
Topics: Humans; Female; Pregnancy; Retrospective Studies; Myasthenia Gravis; Adult; Tertiary Care Centers; Germany; Infant, Newborn; Pregnancy Complications; Pregnancy Outcome; Immunoglobulins, Intravenous; Cesarean Section; Plasma Exchange; Myasthenia Gravis, Neonatal; Young Adult
PubMed: 38492082
DOI: 10.1007/s00404-024-07436-y