Use of the latissimus dorsi muscle to restore elbow flexion in arthrogryposis

The successful use of ipsilateral pedicle latissimus dorsi muscle to restore elbow flexion in a child with arthrogryposis multiplex congenita is described. In appropriately selected patients, use of the latissimus dorsi muscle for elbow flexor reconstruction is a strong, reliable flexorplasty without significant donor-site morbidity.     

Arthrogryposis-like signs in trisomy 18

Summary Two cases of newborn male infants afflicted with trisomy 18 and with signs of arthrogryposis multiplex congenita (AMC) are described. Anomalies occurring in most cases of trisomy 18 such as polyhydramnios, reduced foetal activity, and skeletal muscle hypoplasia decrease articular movements and, thus, might cause AMC. Since AMC is rarely associated with trisomy 18, chromosomal aberration is not the only factor involved in these cases.     

Two Novel Mutations in Myosin Binding Protein C Slow Causing Distal Arthrogryposis Type 2 in Two Large Han Chinese Families May Suggest Important Functional Role of Immunoglobulin Domain C2

Distal arthrogryposes (DAs) are a group of disorders that mainly involve the distal parts of the limbs and at least ten different DAs have been described to date. DAs are mostly described as autosomal dominant disorders with variable expressivity and incomplete penetrance, but recently autosomal recessive pattern was reported in distal arthrogryposis type 5D. Mutations in the contractile genes are found in about 50% of all DA patients. Of these genes, mutations in the gene encoding myosin binding protein C slow MYBPC1 were recently identified in two families with distal arthrogryposis type 1B. Here, we described two large Chinese families with autosomal dominant distal arthrogryposis type 2(DA2) with incomplete penetrance and variable expressivity. Some unique overextension contractures of the lower limbs and some distinctive facial features were present in our DA2 pedigrees. We performed follow-up DNA sequencing after linkage mapping and first identified two novel MYBPC1 mutations (c.1075G>A [p.E359K] and c.956C>T [p.P319L]) responsible for these Chinese DA2 families of which one introduced by germline mosacism. Each mutation was found to cosegregate with the DA2 phenotype in each family but not in population controls. Both substitutions occur within C2 immunoglobulin domain, which together with C1 and the M motif constitute the binding site for the S2 subfragment of myosin. Our results expand the phenotypic spectrum of MYBPC1-related arthrogryposis multiplex congenita (AMC). We also proposed the possible molecular mechanisms that may underlie the pathogenesis of DA2 myopathy associated with these two substitutions in MYBPC1.     

Facial animation in children with Möbius syndrome after segmental gracilis muscle transplant

M?bius syndrome is a complex congenital anomaly involving multiple cranial nerves, including the abducens (VI) and facial (II) nerves, and often associated with limb anomalies. Muscle transplantation has been used to address the lack of facial animation, lack of lower lip support, and speech difficulties these patients experience. The purpose of this study was to investigate the results of bilateral, segmental gracilis muscle transplantation to the face using the facial vessels for revascularization and the motor nerve to the masseter for reinnervation. The outcome of the two-stage procedure was assessed in 10 consecutive children with M?bius syndrome by direct interview, speech assessment, and oral commissure movement. Preoperative data were collected from direct questioning, viewing of preoperative videotapes, notes from prior medical evaluations, and rehabilitation medicine and speech pathology assessments. All of the patients developed reinnervation and muscle movement. The children who described self-esteem to be an issue preoperatively reported a significant posttransplant improvement. The muscle transplants produced a smile with an average commissure excursion of 1.37 cm. The frequency and severity of drooling and drinking difficulties decreased postoperatively in the seven symptomatic children. Speech difficulties improved in all children. Specifically, of the six children with bilabial incompetence, three received complete correction and three had significant improvement. Despite the length and complexity of these procedures, complications were minimal. Muscle transplantation had positive effects in all problematic areas, with a high degree of patient satisfaction and improvement in drooling, drinking, speech, and facial animation. The surgical technique is described in detail and the advantages over regional muscle transfers are outlined. Segmental gracilis muscle transplantation innervated by the motor nerve to the masseter is an effective method of treating patients with M?bius syndrome.     

Genetic disorders caused by mutated acetylcholine receptors

The nicotinic acetylcholine receptors (nAChRs) are members of the large family of ligand-gated ion channels and are constituted by the assembly of five subunits arranged pseudosymmetrically around the central axis that forms a cation-selective ion pore. They are widely distributed in both the nervous system and non-neuronal tissues, and can be activated by endogenous agonists such as acetylcholine or exogenous ligands such as nicotine. Mutations in neuronal nAChRs are found in a rare form of familial nocturnal frontal lobe epilepsy (ADNFLE), while mutations in the neuromuscular subtype of the nAChR are responsible for either congenital myasthenia syndromes (adult subtype of neuromuscular nAChR) or a form of arthrogryposis multiplex congenita type Escobar (fetal subtype of neuromuscular nAChR).     

Upper labial deficiency in Mobius syndrome: a previously unreported feature and its correction

Bilateral facial palsy in M?bius syndrome remains one of the greatest challenges in reconstructive plastic surgery. Facial reanimation is an invaluable aid to such patients because it allows for greater social interaction by means of the ability to smile. In performing facial reanimation surgery on patients with M?bius syndrome, it is the observation of the senior author (Harrison) that upper labial deficiency is a consistent and previously unreported feature of the syndrome. It has been the practice of the senior author to perform upper labial augmentation on M?bius syndrome patients by insertion of a lipodermal autograft, in addition to facial reanimation. Nine patients with M?bius syndrome who presented to the Department of Plastic Surgery during an 8-year period were reviewed. All nine possessed bilateral facial palsy and upper labial deficiency in addition to other abnormalities consistent with M?bius syndrome. Six patients underwent bilateral facial reanimation and upper labial augmentation alone. One patient refused facial reanimation surgery but consented to upper labial augmentation. One patient, with concomitant micrognathia, underwent bilateral facial reanimation, upper labial augmentation, and insertion of a Silastic chin implant. In one patient, a child who also exhibited micrognathia, bilateral facial reanimation alone was carried out, with further procedures for upper labial and chin cosmesis being postponed until adulthood. The indication for performing upper labial augmentation was cosmetic. The procedure improved upper labial appearance and restored balance to the mouth. Patients also expressed higher satisfaction with eating and drinking, which they related to the improved fullness of the upper lip. This was before the facial reanimation had become functional. Upper labial deficiency warrants addition to the list of facial features of M?bius syndrome and is something that must be assessed in the context of facial reanimation surgery.     

Dynamic restoration in Möbius and Möbius-like patients

M?bius syndrome is classically characterized by bilateral facial nerve and abducens nerve paralysis in combination with limb defects. In the past 110 years, physicians diagnosed children as having the syndrome on the basis of heterogeneity of symptoms and used the term "M?bius syndrome" or "M?bius-like syndrome" for patients with multiple cranial nerve involvement. The cause and the exact pathogenesis of the syndrome still elude understanding. Genetic work-ups, radiological findings, and data from autopsies differ in their approaches and their findings of the basic causes of M?bius syndrome. In the international literature, about 301 case reports are found scattered through the past century. The appearance of the facial deformity is easy to recognize, because the M?bius patient is impaired in his or her ability to communicate nonverbally. Despite ophthalmologic problems, it is the search for a smile that brings these patients to the reconstructive surgeon. Over the past 100 years, surgical efforts attempted to improve the mask-like appearance by static and dynamic procedures, usually local muscle transpositions. Today, combinations of microsurgical procedures and aesthetic techniques are being used to restore some movement to the expressionless face of these patients by nerve and muscle transplantation. This article discusses the heterogeneity of M?bius syndrome, advocates a new classification system, presents the clinical findings of 42 patients who were seen and examined in consultation, and discusses the surgical management of 20 patients who underwent dynamic restorative microsurgery. Exemplary cases illustrating the preoperative work-up regimen and possible outcomes are reported.     

Möbius: an integrated discrete-event modeling environment

M?bius has found numerous applications in computational biology to build and solve stochastic models of biological processes. It provides the user with a modeling workflow and several sophisticated features that are not available in the simulation tools commonly used by computational biologists. AVAILABILITY: M?bius is free for academic users. It can be downloaded from www.mobius.uiuc.edu     

Linkage mapping of the locus for inherited ovine arthrogryposis (IOA) to sheep Chromosome 5

Arthrogryposis is a congenital malformation affecting the limbs of newborn animals and infants. Previous work has demonstrated that inherited ovine arthrogryposis (IOA) has an autosomal recessive mode of inheritance. Two affected homozygous recessive (art/art) Suffolk rams were used as founders for a backcross pedigree of half-sib families segregating the IOA trait. A genome scan was performed using 187 microsatellite genetic markers and all backcross animals were phenotyped at birth for the presence and severity of arthrogryposis. Pairwise LOD scores of 1.86, 1.35, and 1.32 were detected for three microsatellites, BM741, JAZ, and RM006, that are located on sheep Chr 5 (OAR5). Additional markers in the region were identified from the genetic linkage map of BTA7 and by in silico analyses of the draft bovine genome sequence, three of which were informative. Interval mapping of all autosomes produced an F value of 21.97 (p < 0.01) for a causative locus in the region of OAR5 previously flagged by pairwise linkage analysis. Inspection of the orthologous region of HSA5 highlighted a previously fine-mapped locus for human arthrogryposis multiplex congenita neurogenic type (AMCN). A survey of the HSA5 genome sequence identified plausible candidate genes for both IOA and human AMCN.     

The topology of circular DNA]

A non-orientable structure, said M?bius stripe, is proposed for certain types of circular DNA. This structure could account for particular forms, such as dimers, double length molecules, or catenans which are molecules topologically interwomen. On the other hand, it is suggested that a second structure derived from the same principal of non-orientability could have gendered the dynamics of DNA replication at the origin of life: this is hypothesis of archetype M?bius strip.     

Characterization of a 500-kb contig spanning the region between c-Ha-Ras and MUC2 on chromosome 11p15.5

The 11p15.5 region is associated with a broad range of diseases, including childhood acute myeloid leukemia; non-small cell lung carcinoma; arthrogryposis multiplex congenita, distal type 2B; and bladder cancer. Since targets for these diseases are unknown, we have constructed a physical map consisting of BAC and PAC clones spanning the region from the HRAS1 gene to the cluster of mucin genes on 11p15.5. The contig spans approximately 500 kb and includes 13 genes (9 novel), 9 STSs (5 novel), and 1 SNP and builds upon a published physical map spanning the region from the telomere to the HRAS gene. In addition, we expand the mucin gene cluster located on 11p15.5 to include a novel mucin-like gene (MUCDHL) located less than 250 kb telomeric to MUC6. The identification of potential disease genes within an organizational and evolutionary context provides valuable clues to function and as such will benefit our understanding of this region of the genome.     

Surgical treatment of scoliosis in a rare disease: arthrogryposis

Background

The reported incidence of scoliosis in arthrogryposis varies from 30% to 67% and, in most cases, the curves progress rapidly and become stiff from early age. The authors report six cases of scoliosis in arthrogryposis to assess the role of surgical treatment.

Methods

Six cases (3 males, 3 females; mean age at surgery 13.2 years) with arthrogryposis multiplex congenita associated with the characteristic amyoplasia were reviewed: they were operated on for scoliosis at the authors' Spine Surgery Department between 1987 and 2008. Surgery was performed using the Harrington-Luque instrumentation (2 cases), the Luque system (1), a hybrid segmental technique with hooks and screws (1) and spinal anchoring with pedicle screws (2).

Results

The patients were clinically and radiologically reviewed at a mean follow-up of 4.2 years, ± 2.7 (range, 1 to 9 years). Three minor postoperative complications were encountered; a long-term pulmonary complication was seen in one case after reintervention and was successfully resolved after 10 days. Surgery was successful in the other 5 cases, where solid arthrodesis was achieved and no significant curve progression was observed at follow-up.

Conclusions

The experience acquired with the present case series leads the authors to assert that prompt action should be taken when treating such aggressive forms of scoliosis. In case of mild spinal deformities in arthrogryposis, brace treatment should be attempted, the evolution of the curves being unpredictable; however, when the curve exceeds 40° and presents with marked hyperkyphosis, hyperlordosis or pelvic obliquity, surgery should not be delayed.     

Escobar syndrome is a prenatal myasthenia caused by disruption of the acetylcholine receptor fetal gamma subunit

Escobar syndrome is a form of arthrogryposis multiplex congenita and features joint contractures, pterygia, and respiratory distress. Similar findings occur in newborns exposed to nicotinergic acetylcholine receptor (AChR) antibodies from myasthenic mothers. We performed linkage studies in families with Escobar syndrome and identified eight mutations within the gamma -subunit gene (CHRNG) of the AChR. Our functional studies show that gamma -subunit mutations prevent the correct localization of the fetal AChR in human embryonic kidney-cell membranes and that the expression pattern in prenatal mice corresponds to the human clinical phenotype. AChRs have five subunits. Two alpha, one beta, and one delta subunit are always present. By switching gamma to epsilon subunits in late fetal development, fetal AChRs are gradually replaced by adult AChRs. Fetal and adult AChRs are essential for neuromuscular signal transduction. In addition, the fetal AChRs seem to be the guide for the primary encounter of axon and muscle. Because of this important function in organogenesis, human mutations in the gamma subunit were thought to be lethal, as they are in gamma -knockout mice. In contrast, many mutations in other subunits have been found to be viable but cause postnatally persisting or beginning myasthenic syndromes. We conclude that Escobar syndrome is an inherited fetal myasthenic disease that also affects neuromuscular organogenesis. Because gamma expression is restricted to early development, patients have no myasthenic symptoms later in life. This is the major difference from mutations in the other AChR subunits and the striking parallel to the symptoms found in neonates with arthrogryposis when maternal AChR auto-antibodies crossed the placenta and caused the transient inactivation of the AChR pathway.     

Cyclotides as natural anti-HIV agents

Cyclotides are disulfide rich macrocyclic plant peptides that are defined by their unique topology in which a head-to-tail cyclized backbone is knotted by the interlocking arrangement of three disulfide bonds. This cyclic cystine knot motif gives the cyclotides exceptional resistance to thermal, chemical, or enzymatic degradation. Over 100 cyclotides have been reported and display a variety of biological activities, including a cytoprotective effect against HIV infected cells. It has been hypothesized that cyclotides from one subfamily, the M?bius subfamily, may be more appropriate than bracelet cyclotides as drug candidates given their lower toxicity to uninfected cells. Here, we report the anti-HIV and cytotoxic effects of three cyclotides, including two from the M?bius subfamily. We show that M?bius cyclotides have comparable inhibitory activity against HIV infection to bracelet cyclotides and that they are generally less cytotoxic to the target cells. To explore the structure activity relationships (SARs) of the 29 cyclotides tested so far for anti-HIV activity, we modeled the structures of the 21 cyclotides whose structures have not been previously solved. We show that within cyclotide subfamilies there is a correlation between hydrophobicity of certain loop regions and HIV inhibition. We also show that charged residues in these loops impact on the activity of the cyclotides, presumably by modulating membrane binding. In addition to providing new SAR data, this report is a mini-review that collates all cyclotide anti-HIV information reported so far and provides a resource for future studies on the therapeutic potential of cyclotides as natural anti-HIV agents.     

Soft-tissue frontal bossing

An unusual case of frontal bossing due to excess subcutaneous fibroadipose tissue in a 38-year-old woman with M?bius syndrome is presented. A relatively simple transcoronal resection of soft tissue resulted in successful elimination of this type of frontal bossing.     

A retrospective study of pregnancy complications among 828 cases of arthrogryposis

828 cases with multiple congenital contractures (arthrogryposis) were categorized and histories were reviewed to identify pregnancy complications. 53.0% of cases had a specified diagnosis or known cause and no diagnosis was found for 47.0% of which 27.2% were though to probably have a genetic basis and 19.8% were of unknown etiology. Our data provides no evidence to support the suggestion that arthrogryposis is frequently a result of environmental or structural causes including uterine structural anomaly, intra-uterine infection, etc. Normal frequencies of bleeding, hormone treatment during gestation, amniotic fluid leakage, uterine anomaly, maternal illness, and maternal and paternal age were noted. Apparent, increased frequencies of twinning, severe nausea, polyhydramnios and oligohydramnios were observed. In particular, the frequency of polyhydramnios was dramatically increased among lethal cases (vs survivors) and thus, polyhydramnios appears to be a poor prognostic sign when associated with decreased fetal movement. Large case control studies with complete pregnancy histories are needed to confirm these results and to definitively identify pregnancy complications that are useful "flags" to indicate decreased fetal movement in utero and thus, aid in the identification of primary causes of arthrogryposis.     

The Role of Maternal Stress in Early Pregnancy in the Aetiology of Gastroschisis: An Incident Case Control Study

Objective

The incidence of gastroschisis, a congenital anomaly where the infant abdominal wall is defective and intestines protrude from the abdominal cavity, is increasing in many countries. The role of maternal stress in some adverse birth outcomes is now well established. We tested the hypothesis that major stressful life events in the first trimester are risk factors for gastroschisis, and social support protective, in a case-control study in the United Kingdom.

Methods

Gastroschisis cases and three controls per case (matched for maternal age) were identified at routine 18-20 week fetal anomaly ultrasound scan, in 2007-2010. Face to face questionnaire interviews were carried out during the antenatal period (median 24 weeks gestation) asking about serious stressful events and social support in the first trimester. Data were analysed using conditional logistic regression.

Results

Two or more stressful life events in the first trimester (adjusted OR 4.9; 95% CI 1.2-19.4), and moving address in the first trimester (aOR 4.9; 95% CI 1.7-13.9) were strongly associated with risk of gastroschisis, independent of behavioural risk factors including smoking, alcohol, and poor diet. Perceived availability of social support was not associated with reduced risk of gastroschisis (aOR 0.8; 95% CI 0.2-3.1).

Conclusions

Stressful maternal life events in the first trimester of pregnancy including change of address were strongly associated with a substantial increase in the risk of gastroschisis, independent of stress related high risk behaviours such as smoking, alcohol consumption and poor diet. This suggests that stress pathways are involved in the aetiology of gastroschisis.     

A 63-bp insertion in exon 2 of the porcine KIF21A gene is associated with arthrogryposis multiplex congenita

A recessive form of arthrogryposis multiplex congenita (AMC) was detected 20 years ago in the Swiss Large White (SLW) pig population. A diagnostic marker test enabled the identification of carrier animals, but the underlying causal mutation remains unknown. To identify the mutation underlying AMC, we collected SNP chip genotyping data for 11 affected piglets and 23 healthy pigs. Association testing using 47 829 SNPs confirmed that AMC maps to SSC5 (P = 9.4 × 10⁻¹³). Subsequent autozygosity mapping revealed a common 6.06 Mb region (from 66 757 970 to 72 815 151 bp) of extended homozygosity in 11 piglets affected by AMC. Using WGS data, we detected a 63-bp insertion compatible with the recessive inheritance of AMC in the second exon of KIF21A gene encoding Kinesin Family Member 21A. The 63-bp insertion is predicted to introduce a premature stop codon in KIF21A gene (p.Val41_Phe42insTer) that truncates 1614 amino acids (~97%) from the protein. We found that this deleterious allele still segregates at a frequency of 0.1% in the SLW pig population. Carrier animals can now be detected unambiguously and excluded from breeding.