Spinal Defects Research Articles

Reconstruction of soft tissue defects caused by spinal surgery using a dorsal intercostal artery perforator flap

Purpose: The reconstruction of defects resulting from spinal surgery poses a challenge to plastic surgeons due to the curved contour and strong skin tension of the back. Implant and metal exposure can also increase the difficulty of covering such defects. This study presents our experiences of covering defects after spinal surgery using dorsal intercostal artery perforator (DICAP) flaps.Methods: From November 2018 to August 2021, 14 patients with spinal soft tissue defects underwent DICAP flap reconstructive surgery at our department. The mean age of the patients was 54.3 years (range, 35–70 years). Age, sex, etiology, the dimensions of the defect and the flap, the site of the defect, surgical technique, and postoperative complications were recorded.Results: All flaps survived, with no major complications such as total flap necrosis. Minor complications were observed in four cases. One patient developed an infection with erythematous changes and another developed partial flap necrosis. Two patients experienced wound dehiscence. These minor complications were all resolved with conservative treatment. No additional complications occurred during the follow-up period.Conclusion: The use of DICAP flaps was successful in all cases. DICAP flaps can adequately cover defects following spinal surgery and have a low complication rate. Thus, DICAP flaps are a good choice for covering defects resulting from spinal surgery.

A rare presentation of OEIS variant with a recto-bladder neck fistula: A case report and literature review.

IntroductionOmphalocele, bladder extrophy, imperforate anus and spinal defect (known as OEIS) is a very rare congenital anomaly with an unknown etiology. In this report we describe a case of an OEIS variant associated with a wide pubic diastasis, bladder extrophy with a recto-bladder neck fistula and a high ano-rectal malformation. This work has been reported in line with the SCARE 2020 criteria.Presentation of the caseA 30-year-old mother delivered a male baby at 39 weeks through a normal vaginal delivery. Examination revealed multiple congenital anomalies in the form of an Omphalocele, extrophied bladder, imperforate anus, ambiguous genitalia and a large pelvic diastasis. Fecal matter was noted at the most inferior point of the extrophied bladder, raising the suspicion of a recto- vesical fistula.An exploratory laparotomy showed a fistula between the rectum and the neck of the extrophied bladder. A sigmoid colostomy was carried out in addition to a mucous fistula. The fascial defect of the Omphalocele was approximated to the upper border of the extrophied bladder.At the age of 2 years, the baby underwent a bladder extrophy repair, a posterior sagittal anorectoplasty and bilateral osteotomies.DiscussionOEIS complex has been reported to occur with a wide variety of associated anomalies, and this necessitates a thorough investigation in order to formulate an appropriate treatment plan. A prenatal diagnosis of OEIS complex can be made by ultrasound stressing the importance of antenatal follow up and a multidisciplinary approach in management.ConclusionWe described a rare variant of an OEIS complex and management of such anomalies requires a multidisciplinary input.

The use of biological membranes for correction of congenital malformations

Many congenital malformations often require a multidisciplinary and multistep surgical treatment, including the use of biological membranes. Aims of the study were to describe the use of these membranes for the correction of malformations, their clinical performance at follow-up, and patient's tolerance to them. The study included patients treated between 2009 and November 2020 in two referral centers. They were affected by abdominal wall defects (AWD), esophageal atresia/tracheo-esophageal fistula (EA/TEF), diaphragmatic hernia (CDH), spinal defects (SD), and anorectal malformations (ARM). The human origin membranes used during surgery were amniotic membrane, fascia lata, and pericardium provided by the local tissue bank and the porcine-derived membrane available on the market. Thirty-one patients were retrieved. The sample included 10 AWD, 7 EA/TEF, 5 CDH, 4 SD, 2 ARM, and 3 miscellaneous defects. The median age at repair was 139 days (range: 10,5–1494). The median follow-up was 1021 days (range: 485,5–1535). Two patients were lost at follow-up. The defects were successfully repaired and the membranes perfectly tolerated in 28/29 cases. In 1 case of CDH the fascia lata was replaced with a Goretex patch due to recurrence of the defect. This is the largest series on the use of biological membranes in congenital malformations. The variety of tissues allows to choose the best material for each malformation. The excellent tolerance and performance of this first series of patients encourage the use of these membranes to correct different type of malformations at any age.

Anterior Vaginal Wall Mass Presenting as Prolapse in an Adolescent

Background: True pelvic organ prolapse in nulligravid young females is uncommon but if present, is typically due to underlying risk factors such as chronic lung disease, heavy lifting, malnutrition, congenital spinal defects or pelvic structural anomalies. Secondary prolapse may be due to benign or malignant para-vaginal masses or hernias and should be evaluated with imaging. Interlabial vaginal masses that are symptomatic should be managed surgically, and multidisciplinary approach is always preferred.

Mechanics-electro-adaptive multifunctional bioactive nanocomposites hydrogel for inducing spinal cord regeneration

Traumatic spinal cord injury (SCI) is one of the most serious injuries, which will cause severe sensory and motor obstacles. The current effective treatment methods remain a worldwide challenge for both clinic and research. The lack of electrical signal conduction and cell growth microenvironment in SCI is one of the main obstacles that inhibit spinal cord regeneration. Herein, we report a multifunctional polycitrate-based nanocomposite hydrogel (PMEAC) scaffold with spinal cord-biomimetic mechanical and electrical properties for promoting spinal cord repair and regeneration. PMEAC scaffolds were prepared using poly(citrate-maleic)-ε-polylysine (PME) and multi-walled carbon nanotubes (MWCNT) by the facile self-crosslinking route. PMEAC scaffolds possessed multifunctional properties including injectability, self-healing ability, tissue-adhesiveness, broad-spectrum antibacterial property and UV-shielding performance, especially the biomimetic mechanical modulus (G’ = 291.69 Pa) and electroconductivity (0.15 S/m) with spinal cord tissue. PMEAC scaffolds also exhibited good cytocompatibility, hemocompatibility and biodegradability. In vivo results from a spinal cord defect model showed that PMEAC scaffolds could significantly improve locomotion recovery (BBB score 6–7), reduce inflammation, promote remyelination and axon regeneration after SCI. This study showed that multifunctional bioactive biomaterials with mechanics-electro-biomimetic properties should be the effective strategy to promote SCI recovery and regeneration.

Biodegradation of poly(l-lactic acid) and poly(\u03b5-caprolactone) patches by human amniotic fluid in an in-vitro simulated fetal environment

Open spina bifida or myelomeningocele (MMC) is a devastating neurologic congenital defect characterized by primary failure of neural tube closure of the spinal column during the embryologic period. Cerebrospinal fluid leak caused by the MMC spinal defect in the developing fetus can result in a constellation of encephalic anomalies that include hindbrain herniation and hydrocephalus. The exposure of extruded spinal cord to amniotic fluid also poses a significant risk for inducing partial or complete paralysis of the body parts beneath the spinal aperture by progressive spinal cord damage in-utero. A randomized trial demonstrated that prenatal repair by fetal surgery, sometimes using patches, to cover the exposed spinal cord with a watertight barrier is effective in reducing the postnatal neurologic morbidity as evidenced by decreased incidence and severity of postnatal hydrocephalus and the reduced need for ventricular-peritoneal shunting. Currently, the use of inert or collagen-based patches are associated with high costs and inadequate structural properties. Specifically, the inert patches do not degrade after implantation, causing the need for a post-natal removal surgery associated with trauma for the newborn. Our present study is aimed towards in-vitro degradation studies of a newly designed patch, which potentially can serve as a superior alternative to existing patches for MMC repair. This novel patch was fabricated by blending poly(l-lactic acid) and poly(ε-caprolactone). The 16-week degradation study in amniotic fluid was focused on tracking changes in crystallinity and mechanical properties. An additional set of designed patches was exposed to phosphate-buffered saline (PBS), as a time-paired control. Crystallinity studies indicate the progress of hydrolytic degradation of the patch in both media, with a preference to bulk erosion in phosphate buffered saline and surface erosion in amniotic fluid. Mechanical testing results establish that patch integrity is not compromised up to 16 weeks of exposure either to body fluids analog (PBS) or to amniotic fluid.

Vascularized Bone Flap Options for Complex Thoracic Spinal Reconstruction.

Osseous reconstruction following total spondylectomy/vertebrectomy in the thoracic spine is indicated to restore spinal stability. To assist with bony reconstruction, vascularized bone flaps including free vascularized fibula flaps and pedicled rib flaps can be used. However, there are limited data comparing various techniques. The authors aimed to evaluate the outcomes of free vascularized fibula flaps and pedicled rib flaps used for thoracic spinal reconstruction. The authors reviewed 44 vascularized bone flaps [10 anterior pedicled rib flaps, 25 posterior pedicled rib flaps, and nine vascularized fibula flaps] for corpectomy defects spanning T1 to L1 between January of 1999 and June of 2018. Mean age and follow-up were 46 ±17 years and 74 ± 52 months, respectively. The union rate was 93 percent, with a similar mean time to union among the three groups: free vascularized fibula flaps, 9 ± 4 months; anterior pedicled rib flaps, 9 ± 6 months; and posterior pedicled rib flaps, 9 ± 5 months (p = 0.95). Surgical-site complications were found in 27 vascularized bone flaps (61 percent), and reoperations and revisions were performed in 14 (32 percent) and 10 (23 percent) vascularized bone flaps, respectively. No differences were identified among anterior pedicled rib flaps, posterior pedicled rib flaps, and vascularized fibula flaps with regard to complication, reoperation, and revision rates. Free vascularized fibula flaps and pedicled rib flaps provide durable reconstruction for thoracic spinal defects. Union, time to union, revision, and reoperation rates were similar among anterior and posterior pedicled rib flaps and vascularized fibula flaps. Given the variability in indication and defect types among the flap cohorts, the authors' results should be interpreted carefully as an insight into the outcomes of different vascularized bone flaps for the unique cases of thoracic spinal reconstruction rather than to compare the different flaps used. Therapeutic, III.

Role of ultrasonography in screening of spinal dysraphism in infants at risk

BackgroundSpinal dysraphism (SD) encompasses congenital spinal defects that result from inappropriate fusion of the different midline osseous, mesenchymal, and neural elements. The primary tools for diagnosis of SD are both spinal ultrasonography (USG) and magnetic resonance imaging (MRI). Spinal USG is growingly being used as an initial screening modality with sensitivities and accuracies equivalent to those of MRI. Anorectal malformations (ARM) have ultimate association with many other congenital abnormalities, of which spinal dysraphism is one of the most common. The main aim of study was to assess the diagnostic accuracy of spinal USG as a screening modality in comparison with MRI in infants with closed spinal dysraphism. We also endeavored to highlight the associated spinal dysraphism radiological findings in patients with either ARM or back cutaneous stigmata.ResultsOur prospective diagnostic comparative study included 33 patients, all of whom underwent both MRI and USG. Both MRI and USG showed appreciable agreement in the assessment of spinal dysraphism. In comparison with the gold standard MRI, spinal USG revealed comparable diagnostic metrics: specificity (98.6–100%), sensitivity (66.6–91.6%), PPV (90–100%) and NPV (94.1–98.7%) in diagnosis of different types of spinal dysraphism. The main clinical presentation of nineteen patients was anorectal malformation (ARM), 11 of whom (57.9%) had evidence of associated spinal dysraphism. The most common types of ARM were cloacal malformation, recto-urethral fistula, and rectal atresia with no fistula. On the other hand, sixteen patients were mainly presented with back cutaneous stigmata, 11 of whom (68.8%) had associated spinal dysraphism. The most common presenting cutaneous stigmata were low back swelling and atypical dimples.ConclusionThe front-line screening modality for infants with closed SD should be spinal USG, however, its main limitation is the restrained time window in the first 6 months of life. Infants with ARM should be screened for spinal anomalies, especially those with high and complex types. Infants with high-risk back cutaneous stigmata should be similarly screened, as well.

Natterin-like depletion by CRISPR/Cas9 impairs zebrafish (Danio rerio) embryonic development

BackgroundThe Natterin protein family was first discovered in the venom of the medically significant fish Thalassophryne nattereri, and over the last decade natterin-like genes have been identified in various organisms, notably performing immune-related functions. Previous findings support natterin-like genes as effector defense molecules able to activate multiprotein complexes driving the host innate immune response, notably due to the pore-forming function of the aerolysin superfamily members. Herein, employing a combination of the CRISPR/Cas9 depletion system, phenotype-based screening, and morphometric methods, we evaluated the role of one family member, LOC795232, in the embryonic development of zebrafish since it might be implicated in multiple roles and characterization of the null mutant is central for analysis of gene activity.ResultsMultiple sequence alignment revealed that the candidate natterin-like has the highest similarity to zebrafish aep1, a putative and better characterized fish-specific defense molecule from the same family. Compared to other species, zebrafish have many natterin-like copies. Whole-mount in situ hybridization confirmed the knockout and mutant embryos exhibited epiboly delay, growth retardation, yolk sac and heart edema, absent or diminished swim bladder, spinal defects, small eyes and head, heart dysfunction, and behavioral impairment. As previously demonstrated, ribonucleoproteins composed of Cas9 and duplex guide RNAs are effective at inducing mutations in the F0 zebrafish.ConclusionsThe considerably high natterin-like copies in zebrafish compared to other species might be due to the teleost-specific whole genome duplication and followed by subfunctionalization or neofunctionalization. In the present work, we described some of the natterin-like features in the zebrafish development and infer that natterin-like proteins potentially contribute to the embryonary development and immune response.

A hydrogel spinal dural patch with potential anti-inflammatory, pain relieving and antibacterial effects

CSFL caused by spinal dural defect is a common complication of spinal surgery, which need repair such as suture or sealants. However, low intracranial pressure symptoms, wound infection and prolonged hospital associated with pin-hole leakage or loose seal effect were often occurred after surgical suture or sealants repair. Stable, pressure resistance and high viscosity spinal dural repair patch in wet environment without suture or sealants was highly needed. Herein, a bioactive patch composed of alginate and polyacrylamide hydrogel matrix cross-linked by calcium ions, and chitosan adhesive was proposed. This fabricated patch exhibits the capabilities of promoting defect closure and good tight seal ability with the bursting pressure is more than 790 mm H2O in wet environment. In addition, the chitosan adhesive layer of the patch could inhibit the growth of bacterial in vitro, which is meaningful for the postoperative infection. Furthermore, the patch also significantly reduced the expression of GFAP, IBA-1, MBP, TNF-α, and COX-2 in early postoperative period in vivo study, exerting the effects of anti-inflammatory, analgesic and adhesion prevention. Thus, the bioactive patch expected to be applied in spinal dural repair with the good properties of withstanding high pressure, promoting defect closure and inhibiting postoperative infection.

Expanding the Clinical Phenotype of FGFR1 Internal Tandem Duplication

Closed spinal dysraphism (SD) is a type of neural tube defect originating during early embryonic development whereby the neural tissue of the spinal defect remains covered by skin, often coinciding with markers of cutaneous stigmata. It is hypothesized that these events are caused by multifactorial processes, including genetic and environmental causes. We present an infant with a unique congenital midline lesion associated with a closed SD. Through comprehensive molecular profiling of the intraspinal lesion and contiguous skin lesion, an internal tandem duplication (ITD) of the kinase domain of the fibroblast growth factor receptor 1 (FGFR1) gene was found. This ITD variant is somatic mosaic in nature as supported by a diminished variant allele frequency in the lesional tissue and by its absence in peripheral blood. FGFR1 ITD results in constitutive activation of the receptor tyrosine kinase to promote cell growth, differentiation, and survival through RAS/MAPK signaling. Identification of FGFR1 ITD outside of central nervous system tumors is exceedingly rare, and this report broadens the phenotypic spectrum of somatic mosaic FGFR1-related disease.

Prevalence of carbapenemase producing gram negative bacteria in renal failure urinary tract infection patients in Tikrit City, Iraq

The kidneys’ ability to operate declines slowly and creatively as a result of chronic renal disease. It frequently results from issues with other serious medical disorders (such as spinal cord defects, hypertension, and diabetes). Due to the increased chances of acquiring end-stage renal disease (ESRD) patients, there is a higher incidence of multidrug-resistant organisms in the community, primarily methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). It is also poorly understood how gram-negative bacteria that produce carbapenemase affect ESRD patients on RRT (replacement renal treatment). 39 patients with urinary tract infections and renal failure participated in this study to determine the prevalence of gram-negative bacteria and Enterobacteriaceae that produce carbapenemase in Tiktit city. Disc diffusion method was used to determine whether the isolated and cultured bacteria were carbaqpenemase producing. According to the present study prevalence of carbapenemase producing group among renal failure patient with UTI was (78%), and not carbapenemase group was 22%. The females percentage was 40.6 % and male’s percentage was 37.5%, recurrent UTI infections history for; renal failure patients was very high 73% and in males 40% more than females 34%.

Omphalocele–Exstrophy–Imperforate Anus–Spinal Defect Complex in an Infant from Monozygotic Twins Conceived by In Vitro Fertilization: A Case Report

Omphalocele–Exstrophy–Imperforate Anus–Spinal Defect Complex in an Infant from Monozygotic Twins Conceived by <i>In Vitro</i> Fertilization: A Case Report

DEPENDENCE OF THE RESTORATIVE EFFECT OF MACROPOROUS POLY(N-[2-HYDROXYPROPYL]-METHACRYLAMIDE HYDROGEL ON THE SEVERITY OF EXPERIMENTAL LACERATIVE SPINAL CORD INJURY

restoration of the spinal cord function presents a most severe biomedical issue nowadays. The aim of the study was to detect the macroporous poly(N-[2-hydroxypropyl]-methacrylamide hydrogel (PHPMA-hydrogel, HG) restorative effect dependence on the severity of the laceration spinal cord injury in young organisms. The male rats sample (~1-month-old, ~50 g, inbred Wistar line) was represented with 4 experimental groups: 1) spinal cord lateral hemisection at the level of ~Т12–Т13 segments (Sect; n=11); 2) spinal cord lateral hemiexcision ~1 mm long at the similar level (Exc; n=8); 3) spinal cord lateral hemisection at the similar level with immediate implantation of the hydrogel fragment into the trauma region (HGsect; n=11); 4) spinal cord lateral hemiexcision at the similar level with immediate implantation of the hydrogel fragment into the affected region (HGexс; n=6). The motor function and spasticity of the paretic hindlimb was estimated respectively by the technically modified Basso–Beattie–Bresnahan (ВВВ) and Ashworth, conditionally blinded to individual characteristics of all operated animals and previous study results. The observation lasted for ~5 months. The criteria of non-inclusion were as follows: the ipsilateral hindlimb function level in a week after the injury &gt;9 points ВВВ, and the contralateral hindlimb function level during prolonged period ≤14 points ВВВ. The results were interpreted and presented according to the standardized time scale with interpolatory representation of the motor function and spasticity individual level in certain cases. Asymptotic stage differences between the studied groups and subgroups were stated during the first three weeks as well as in 8 weeks and 3 months after the injury. We found out that in a week after injury the motor function level in group Exc made up 0.9±0.5 points ВВВ, in group HGexc — 3.6±1.2 points, in group Sect — 5.9±1.1 points, in group HGsect — 6.0±1.0 points. In 5 months the motor function level in group Sect made up 9.5±1.0 points ВВВ, in group HGsect — 9.5±1.1 points, in group Exc — 0.8±0.3 points, in group HGexc — 4.5±1.8 points. At the same study stage the spasticity level in groups Sect and HGsect was, respectively, 0.8±0.2 and 0.8±0.3 points Ashworth, in group HGexc — 1.8±0.7 points, in group Exc — 3.6±0.3 points. Throughout the study no significant differences in groups Sect and HGsect have been detected, and in groups Exc і HGexc such differences were detected only in 5 weeks after the injury. The considerable difference of spasticity in groups Sect and HGsect was noted in 1 week after the injury, in groups HGexc and Exc — during first 2 months of the experiment. In groups Sect and Exc reliable difference of both motor function and spasticity level was found at all study stages. In groups HGsect and HGexc considerable difference of the motor function level was characteristic at all stages, except for the end of the 1st and 7th weeks, whereas spasticity level differences throughout the study remained insignificant. So, the tested hydrogel in young organisms shows positive effect only with severe trauma stages accompanied with extensive spinal cord defect.

The Potential Applications of Augmented Reality in Fetoscopic Surgery for Antenatal Treatment of Myelomeningocele

To develop a preoperative planning method using augmented reality (AR) of a specific surgical procedure: fetoscopy for myelomeningocele repair. Imaging data were acquired of a pregnant woman at 27 weeks of gestation whose fetus was diagnosed with myelomeningocele. The patient was identified as a candidate for fetoscopic repair of the spine defect, and an AR application for mobile device simulation was developed. The virtual customized model was created by analysis of the presurgical magnetic resonance imaging. A real-time AR interface was developed by using an application that enhanced the anatomical aspects of both mother and fetus. A virtual model for planning fetoscopy repair for myelomeningocele was developed. Preoperative and postoperative procedures were successfully carried out, emphasizing the beneficial role of the AR application. The use of the AR model allowed the multidisciplinary team to engage in discussion to determine the appropriate surgical approach. It also allowed a clearer explanation of the procedure to the parents enabling a better understanding of the parents regarding specifics characteristics of their baby's spine defect. This new preoperative platform using a virtual model represents an important tool to improve patient's comprehension, multidisciplinary discussion, and surgical planning. In addition, it can be used worldwide as a teaching tool in the fetal surgery field.

DEPENDENCE OF THE RESTORATIVE EFFECT OF MACROPOROUS POLY(N-[2- HYDROXYPROPYL]-METHACRYLAMIDE HYDROGEL ON THE SEVERITY OF EXPERIMENTAL LACERATIVE SPINAL CORD INJURY

restoration of the spinal cord function presents a most severe biomedical issue nowadays. The aimof the study was to detect the macroporous poly(N-[2-hydroxypropyl]-methacrylamide hydrogel (PHPMA-hydrogel,HG) restorative effect dependence on the severity of the laceration spinal cord injury in young organisms.The male rats sample (~1-month-old, ~50 g, inbred Wistar line) was represented with 4 experimental groups: 1)spinal cord lateral hemisection at the level of ~Т12–Т13 segments (Sect; n=11); 2) spinal cord lateral hemiexcision~1 mm long at the similar level (Exc; n=8); 3) spinal cord lateral hemisection at the similar level with immediateimplantation of the hydrogel fragment into the trauma region (HGsect; n=11); 4) spinal cord lateral hemiexcisionat the similar level with immediate implantation of the hydrogel fragment into the affected region (HGexс; n=6).The motor function and spasticity of the paretic hindlimb was estimated respectively by the technically modifiedBasso–Beattie–Bresnahan (ВВВ) and Ashworth, conditionally blinded to individual characteristics of all operatedanimals and previous study results. The observation lasted for ~5 months. The criteria of non-inclusion wereas follows: the ipsilateral hindlimb function level in a week after the injury &gt;9 points ВВВ, and the contralateralhindlimb function level during prolonged period ≤14 points ВВВ. The results were interpreted and presentedaccording to the standardized time scale with interpolatory representation of the motor function and spasticityindividual level in certain cases. Asymptotic stage differences between the studied groups and subgroups werestated during the first three weeks as well as in 8 weeks and 3 months after the injury. We found out that in aweek after injury the motor function level in group Exc made up 0.9±0.5 points ВВВ, in group HGexc — 3.6±1.2points, in group Sect — 5.9±1.1 points, in group HGsect — 6.0±1.0 points. In 5 months the motor function levelin group Sect made up 9.5±1.0 points ВВВ, in group HGsect — 9.5±1.1 points, in group Exc — 0.8±0.3 points,in group HGexc — 4.5±1.8 points. At the same study stage the spasticity level in groups Sect and HGsect was,respectively, 0.8±0.2 and 0.8±0.3 points Ashworth, in group HGexc — 1.8±0.7 points, in group Exc — 3.6±0.3points. Throughout the study no significant differences in groups Sect and HGsect have been detected, and ingroups Exc і HGexc such differences were detected only in 5 weeks after the injury. The considerable difference ofspasticity in groups Sect and HGsect was noted in 1 week after the injury, in groups HGexc and Exc — during first2 months of the experiment. In groups Sect and Exc reliable difference of both motor function and spasticity levelwas found at all study stages. In groups HGsect and HGexc considerable difference of the motor function levelwas characteristic at all stages, except for the end of the 1st and 7th weeks, whereas spasticity level differences throughout the study remained insignificant. So, the tested hydrogel in young organisms shows positive effect onlywith severe trauma stages accompanied with extensive spinal cord defect.

The AIUM Practice Parameter for the Performance of an Ultrasound Examination of the Neonatal and Infant Spine.

The AIUM Practice Parameter for the Performance of an Ultrasound Examination of the Neonatal and Infant Spine.

OEIS Syndrome: Omphalocele, Exstrophy of the Cloaca, Imperforate Anus, and Spinal Defects

OEIS Syndrome: Omphalocele, Exstrophy of the Cloaca, Imperforate Anus, and Spinal Defects

MFN2 Deficiency Impairs Mitochondrial Transport and Downregulates Motor Protein Expression in Human Spinal Motor Neurons.

Charcot-Marie-Tooth (CMT) disease is one of the most common genetically inherited neurological disorders and CMT type 2A (CMT 2A) is caused by dominant mutations in the mitofusin-2 (MFN2) gene. MFN2 is located in the outer mitochondrial membrane and is a mediator of mitochondrial fusion, with an essential role in maintaining normal neuronal functions. Although loss of MFN2 induces axonal neuropathy, the detailed mechanism by which MFN2 deficiency results in axonal degeneration of human spinal motor neurons remains largely unknown. In this study, we generated MFN2-knockdown human embryonic stem cell (hESC) lines using lentivirus expressing MFN2 short hairpin RNA (shRNA). Using these hESC lines, we found that MFN2 loss did not affect spinal motor neuron differentiation from hESCs but resulted in mitochondrial fragmentation and dysfunction as determined by live-cell imaging. Notably, MFN2-knockodwn spinal motor neurons exhibited CMT2A disease-related phenotypes, including extensive perikaryal inclusions of phosphorylated neurofilament heavy chain (pNfH), frequent axonal swellings, and increased pNfH levels in long-term cultures. Importantly, MFN2 deficit impaired anterograde and retrograde mitochondrial transport within axons, and reduced the mRNA and protein levels of kinesin and dynein, indicating the interfered motor protein expression induced by MFN2 deficiency. Our results reveal that MFN2 knockdown induced axonal degeneration of spinal motor neurons and defects in mitochondrial morphology and function. The impaired mitochondrial transport in MFN2-knockdown spinal motor neurons is mediated, at least partially, by the altered motor proteins, providing potential therapeutic targets for rescuing axonal degeneration of spinal motor neurons in CMT2A disease.

Longitudinal evaluation of motor function in patients who underwent prenatal or postnatal neural tube defect repair.

To compare the evolution of motor function from mid-gestation to 12 months of age between prenatally and postnatally repaired cases of open neural tube defect (ONTD). This was a retrospective cohort study of all fetuses that underwent prenatal (fetoscopic or open hysterotomy) or postnatal ONTD repair at a single institution between November 2011 and December 2018. The anatomical level of the lesion was defined as the upper bony spinal defect at initial magnetic resonance imaging assessment. Prenatal motor function of the lower extremities was evaluated by ultrasound according to the metameric level of the neurological lesion, based on the methodology of Carreras et al. Fetal motor function was assessed at referral, at 6 weeks after surgery in prenatally repaired cases or 6 weeks after referral in postnatally repaired cases (6-week follow-up) and at the last scan before delivery. In addition, motor function was assessed by a detailed neurological examination at birth and 12 months of age. First sacral (S1) neurological level of the lesion was considered as intact motor function. For statistical comparisons, we attributed numerical scores to each neurological level and motor function was expressed as median (range) neurological level. Motor function (as numerical score) and the proportion of cases with intact motor function and with motor function two or more levels better than expected based on the anatomical level of the lesion were compared between the prenatal- and postnatal-repair groups. Fetal motor function was compared to the anatomical level of the lesion at referral and a better motor function was defined when it was two or more levels better than the anatomical level of the lesion. To assess the evolution of motor function, we compared motor function at referral with that at each follow-up assessment using paired t-tests. We included 127 patients with ONTD, of whom 93 underwent prenatal (51 fetoscopic and 42 open hysterotomy) and 34 postnatal repair. At the time of referral, cases in the prenatal- and postnatal-repair groups presented with a similar anatomical level of lesion (L3 (T9-S1) vs L3 (T7-S1); P = 0.52), similar motor function (S1 (L1-S1) vs S1 (L1-S1); P = 0.52) and a similar proportion of cases with intact motor function (81% vs 79%; P = 0.88) and with motor function two or more levels better than expected based on the anatomical level of the lesion (62% vs 74%; P = 0.24). When compared with prenatally repaired cases, postnatally repaired cases showed worse motor function at birth (S1 (L1-S1) vs L4 (L1-S1); P < 0.01) and at 12 months of age (S1 (L1-S1) vs L4 (L1-S1); P < 0.01). In the prenatal-repair group, motor function remained stable from the time of referral to 12 months of age (P = 0.26). Furthermore, the proportion of patients with intact motor function at referral (81% (75/93)) was similar to that at the 6-week follow-up (74% (64/87)), at the last scan before birth (74% (42/57)), at birth (68% (63/93)) and at 12 months of age (67% (39/58)) in the prenatal-repair group. In the postnatal-repair group, worse motor function, starting from the third trimester to 12 months of age, was observed. The proportion of patients with intact motor function at referral (79% (27/34)) was similar to that at 6-week follow-up (80% (12/15); P = 0.92), but was lower at the last assessment before birth (25% (2/8); P < 0.01), at birth (24% (8/34); P < 0.01) and at 12 months of age (28% (7/25); P < 0.01). Similar findings were noted when assessing the evolution of the proportion of cases with motor function two or more levels better than expected based on the anatomical level of the lesion in each group. Infants with ONTD that underwent postnatal repair had worse motor function at birth and at 12 months of age than at mid-gestation and when compared with infants that underwent prenatal ONTD repair. Prenatal motor function assessment by ultrasound is an adequate tool to identify those infants who should have a good clinical motor function after delivery. Information obtained by fetal motor function assessment can have an important role for patient counseling and case selection for surgery. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.