Arthrogryposis Research Articles

Profile of Arthrogryposis Multiplex Congenita (AMC) patients on surgery treatment at single centered study in orthopaedic hospital and a brief review

Introduction: Arthrogryposis multiplex congenita (AMC) is a complex abnormal condition characterized by multiple congenital contractures in the body's joints. Although this condition is not progressive, if not treated properly, it will increase the degree of disability in children. There are two types of AMC. The most common type of AMC is amyoplasia. The second type is distal arthrogryposis (DA), a genetically inherited type characterized by congenital contractures in multiple joints and no neurologic or muscular abnormalities. The incidence of AMC 1:3000 births with clubfeet and congenital hip dislocation is the most common. In this retrospective study, the authors described the profile of AMC patients who underwent surgery at our center with the approach and management. Method: The study design was a descriptive retrospective. The population of this study is all AMC patients who underwent surgery at the orthopedic hospital of Prof. Soeharso Surakarta, Indonesia. We used the total sampling technique who underwent surgery in the 2018-2021 period. Result: In this study, we got eleven AMC patients who underwent surgery. Distribution based on sex found six boys and five girls. Half of the patients underwent surgery under the age of three years, while the other half underwent surgery after the age of five. The presence of patients who are consulted at an older age indicates a lack of public literacy about the abnormal condition of AMC or a lack of concern for the condition. Almost all AMC patients who undergo surgery are in the lower extremities. Conclusion: Rehabilitation plays a very important role in improving the quality of life for AMC patients. A multidisciplinary approach is needed in the treatment of AMC patients. Surgery is performed if stretching and external support splinting/casting cannot achieve functional ROM and repair the deformity.

Congenital vertical talus deformity in children with distal arthrogryposis: good clinical outcomes despite high rate of residual radiographic deformity.

Patients with a diagnosis of arthrogryposis often present with various orthopedic conditions, one of which is congenital vertical talus (CVT). This is the first study of this specific subset of syndromic patients to evaluate the medium-term outcomes of CVT correction using the minimally invasive Dobbs method. All patients with vertical talus and distal arthrogryposis who received treatment at our institution between January 2006 and June 2021 were identified. Radiographs, clinical notes and Patient-Reported Outcome Measurement Information System (PROMIS) scores (when available) were retrospectively reviewed. An alpha of 0.05 was used for all statistical analyses. In total 12 patients (19 feet) met all inclusion criteria and were included in the final analysis. By the time of the most recent visit, the average lateral Talar-Axis First Metatarsal Base Angle of the entire cohort increased from 13.73 ± 9.75 degrees 2 weeks postoperatively to 28.75 ± 23.73 degrees ( P = 0.0076). Radiographic recurrence of the talonavicular deformity was seen in nine feet (47.4%), 4 (21.1%) of which required additional unplanned surgery, The average PROMIS scores of the entire cohort in the pain interference, mobility and peer relationship domains were 48.97 ± 9.56, 47.9 ± 11.60 and 52.87 ± 8.31, respectively. Despite a higher radiographic recurrence rate of talonavicular deformity in this specific subset of syndromic patients, these patients still report PROMIS scores near the population average in the pain interference, mobility and peer relationships domains. We believe that the minimally invasive Dobbs method should be recommended as the first-line treatment method for these patients. Level of evidence: Level III.

Fetal akinesia deformation sequence syndrome associated with recessive TTN variants.

Arthrogryposis multiplex congenita (AMC) [also known as multiple joints contracture or Fetal Akinesia Deformation Sequence (FADS)] is etiologically a heterogeneous condition with an estimated incidence of approximately 1 in 3000 live births and much higher incidence when prenatally diagnosed cases are included. The condition can be acquired or secondary to fetal exposures and can also be caused by a variety of single-gene disorders affecting the brain, spinal cord, peripheral nerves, neuromuscular junction, muscle, and a variety of disorders affecting the connective tissues (Niles et al., Prenatal Diagnosis, 2019; 39:720-731). The introduction of next-generation gene sequencing uncovered many genes and causative variants of AMC but also identified genes that cause both dominant and recessive inherited conditions with the variability of clinical manifestations depending on the genes and variants. Molecular diagnosis in these cases is not only important for prognostication but also for the determination of recurrence risk and for providing reproductive options including preimplantation and prenatal diagnosis. TTN, the largest known gene in the human genome, has been known to be associated with autosomal dominant dilated cardiomyopathy. However, homozygote and compound heterozygote pathogenic variants with recessive inheritance have rarely been reported. We report the effect of recessive variants located within the fetal IC and/or N2BA isoforms in association with severe FADS in three families. All parents were healthy obligate carriers and none of them had cardiac or skeletal muscle abnormalities. This report solidifies FADS as an alternative phenotypic presentation associated with homozygote/compound heterozygous pathogenic variants in the TTN.

The Effectiveness of Serial Casting in the Treatment of Recurrent Equinovarus in Children With Arthrogryposis.

Arthrogryposis multiplex congenita (AMC) is characterized by joint contractures in 2 or more body areas, often resulting in clubfoot deformities that are typically stiffer than those seen in idiopathic clubfoot deformities. While surgery is routinely used to treat clubfoot in AMC, it has a high rate of recurrence and complications. Current literature suggests serial casting (SC) could be useful in treating clubfoot in AMC, though evidence of its effectiveness is limited. Passive range of motion (PROM), dynamic foot pressure, parent-reported Pediatric Outcomes Data Collection Instrument, brace tolerance, and the need for post-casting surgery were evaluated retrospectively in children with AMC treated with SC to address clubfoot deformities. Analysis of variance or paired t tests were used as appropriate on pre-casting, short-term (within 6mo after SC) and/or longer-term (6 to 18mo after SC) parameters to determine the effectiveness of SC. Brace tolerance before and after SC was analyzed using the Global Test for Symmetry, and medical records were reviewed to determine the need for surgery post-SC. Forty-six children (6.1±3.1y old) were cast an average of 2.5±1.9 times, resulting in 206 SC episodes. PROM showed improvement in ankle dorsiflexion and forefoot abduction in the short term (P<0.05), returning to baseline measurements in the long term (P=0.09). Brace tolerance improved after casting (P<0.05). Only 15% of feet required surgery at follow-up at 10.3±5.5 years. There were no significant changes in dynamic foot pressure or Pediatric Outcomes Data Collection Instrument results after SC, except for an increase in the pain subtest (P<0.05). Serial casting in children with AMC can be effective in temporarily improving PROM and improving brace tolerance, but it does not impact dynamic barefoot position. Positive impact of conservative management in children with AMC can potentially delay or reduce the need for invasive surgical intervention by improving PROM and brace tolerance. Level III, Retrospective Comparative Study.

Altered Cerebral Processing of Videos in Children with Motor Dysfunction Suggests Broad Embodiment of Perceptual Cognitive Functions

Embodied cognition theory suggests that motor dysfunctions affect cognition. We examined this hypothesis by inspecting whether cerebral processing of movies, featuring both goal-directed movements and content without humans, differ between children with congenital motor dysfunction and healthy controls. Electroencephalography was recorded from 23 healthy children and 23 children with limited or absent arm movement due to either arthrogryposis multiplex congenita or obstetric brachial plexus palsy. Each individual patient exhibited divergent neural responses, disclosed by significantly lower inter-subject correlation (ISC) of brain activity, during the videos compared to the healthy children. We failed to observe associations between this finding and the motor-related content of the various video scenes, suggesting that differences between the patients and controls reflect modulation of perceptual-cognitive processing of videos by upper-limb motor dysfunctions not limited to the watching-mirroring of motor actions. Thus, perceptual-cognitive processes in the brain seem to be more robustly embodied than has previously been thought.

Altered evoked responses for motor-related words in children with upper limb motor impairments

ObjectiveObstetric brachial plexus palsy (OBPP) and amyoplasia, the classical type of arthrogryposis multiplex congenita, manifest themselves as highly limited mobility of the upper limb. At the same time, according to the embodiment cognition theories, the motor impairments might lead to the alteration of cognitive functions in OBPP/amyoplasia patients. In the current study, we examined whether OBPP/amyoplasia children exhibit altered processing of motor-related verbs. MethodsWe conducted a case-control study using clinical population and control children. Oddball series were used to elicit mismatch negativity (MMN) EEG responses. The series consisted of limb-related verbs (deviant stimuli) and matched pseudowords (standard stimuli). 27 patients and 32 control children were included in the analysis. ResultsWe showed that MMN waveforms differed between OBPP/amyoplasia children and their control peers in the frontal and temporal electrodes when the stimuli contained hand-related verbs. In particular, the MMN peak latency in the OBPP/amyoplasia children was significantly delayed as compared with the healthy controls. At the same time, neither series with leg-related verbs nor series of pseudowords resulted in statistically significant differences. ConclusionsOur findings suggest altered processing of hand-related verbs in OBPP/amyoplasia children with hand-related disabilities. SignificanceOur results contribute to the growing evidence in support of the theory of embodied cognition, which proposes that various domains of cognition are shaped by bodily interactions with the environment.

Arthrogryposis multiplex congenita in a child with congenital fractures: a case report

BackgroundBruck syndrome is an exceedingly rare form of osteogenesis imperfecta, inherited autosomal recessively and presenting with the concurrence of bone fragility and congenital contractures of large joints. The disease usually progresses relentlessly to result in recurrent fractures, short stature, severe kyphoscoliosis, and susceptibility to recurrent respiratory tract infections.Case presentationThe index child was a male newborn to healthy, nonconsanguineous, Sinhalese parents. The child had multiple contractures involving all large joints with pterigium formation in addition to congenital fractures involving left humerus and ulna at birth. The phenotypic features in this child were highly suggestive of Bruck syndrome. Genetic counseling was offered to the parents, although specific genetic testing could not be undertaken due to lack of resources. Bone and skin biopsy were not performed since only palliative care was possible. Over the course, he developed recurrent severe chest infections due to poor muscle tone, weak cough reflex, and pooling of secretions. Unfortunately, he succumbed at the age of 7 months following severe pneumonia.ConclusionThe association of arthrogryposis with osteogenesis imperfecta is extremely rare and known as Bruck syndrome. Early diagnosis during the antenatal period is helpful in genetic counseling, assessment of severity, and exploration of therapeutic options

A nationwide survey of Schaaf-Yang syndrome in Japan.

Schaaf-Yang syndrome (SYS) is a congenital disorder characterized by developmental delay, autism spectrum disorder and congenital joint contractures. In this study, a nationwide epidemiological questionnaire-based survey of SYS in the Japanese population was conducted to establish patient numbers, clinical features and genetic information. In the primary survey, we investigated the number of SYS patients. In the secondary survey, we obtained and analyzed detailed clinical and genetic information of SYS patients. This survey collected information on 25 genetically-confirmed patients. The major clinical symptoms included neonatal hypotonia (96% of the patients), poor suck in infancy (82%), developmental delay (100%) and joint contractures (83%). Other main symptoms and findings included characteristic facial features (100%), small hands (92%), eye abnormalities (92%) and short stature (79%). Based on the information collected on activities of daily living, 71% of patients were unable to walk, while 67%, 71%, and 81% of patients required full assistance with eating, toileting and bathing, respectively. Regarding inheritability, the genetic analysis of 21 patients revealed that 14 (67%) carried de novo truncating variants in the melanoma antigen L2 (MAGEL2) gene and seven (33%) had inherited truncating variants from their fathers who were carriers. This survey revealed the clinical and genetic features in Japanese SYS patients. The majority of SYS patients required assistance in many aspects of daily living, and there were a certain number of carriers of the imprinting disorder.

A Rare Case of Amyoplasia Type of Arthrogryposis Multiplex Congenita with Midfacial Hemangioma in a Neonate

Arthrogryposis multiplex congenita is a condition where multiple contractures of the joint develop, leading to deformity and restriction of movement. It is mostly seen in the neonatal period but the deformity may persist till adulthood also. A 1-day-old male baby presented with multiple deformities and contractures of all four limbs, with breathing difficulties. On examination, there was abnormal shoulder adduction with elbow extension and ulnar deviation of the wrist with thumb and finger deformity. In the lower limb, severe knee flexion with severe bilateral talipes equinus deformity was seen. A midfacial hemangioma and ear abnormalities were also present along with a skin dimple over both knees. The child was investigated fully for other congenital and systemic malformations. Finally, a diagnosis of the amyotrophic type of arthrogryposis congenita with facial hemangioma was made, which is a very rare association. The patient was managed by a multidisciplinary team approach and was discharged successfully. When a baby is presented with such a deformity, then the child should be screened fully and a genetic study should be done to prevent a recurrence of malformation in a subsequent pregnancy. The aim is to prevent early contractures and to restore limb function in the child and proper follow-up.

VP.03 Diagnosing Titinopathy: lessons from a multi-omics pilot study

Titinopathy, or skeletal muscular dystrophy caused by autosomal recessive mutations in Titin (<i>TTN</i>), poses a unique diagnostic challenge because of A) significant variation in clinical manifestation, B) presence of rare putative deleterious <i>TTN</i> variants amongst healthy individuals which increases likelihood of incidental findings. Altogether, this makes establishing a definite diagnosis of Titinopathy based solely on phenotypic and genotypic information virtually impossible in the absence of corroborative evidence. We report six patients with Titinopathy from four unrelated families. In each case, prior genomics-based efforts had failed to reach a conclusive diagnosis and a confirmed diagnosis was reached by co-analyzing patient genomic and transcriptomic data. The multi-omics approach provided direct evidence confirming or dismissing impact of plausible candidate variants in TTN and other genes. This clarity of information was critical in solving these cases. The phenotypic diversity of the cohort highlights the diagnostic challenge. The first family included two siblings presented with adolescent onset multiple joint contractures, slowly progressive spine rigidity and elevated Creatine Kinase (CK). The severity of condition varied amongst the siblings with elder brother exhibited mild limb girdle weakness not seen in the younger sister. The second and third families comprise of a girl and boy respectively. Both unrelated patients had similar symptoms characterized by early onset hypotonia, delayed walking and elevated CK. Both had limb girdle muscle weakness and mild scoliosis. Their motor performance had been stable, and both continued to walk independently in adulthood. The fourth family included two siblings presented with arthrogryposis multiplex congenita and hypotonia after birth. Their mother reported decreased fetal movement during both pregnancies. Both elder sister and younger brother had delayed walking and limb girdle weakness. However, their joint contractures improved with age and regular stretching. The younger brother also had autistic features. Both siblings had normal CK. All patients in the study had normal echocardiogram suggesting lack of cardiac involvement. Our multi-omics findings link individualized patient condition to the specific functional impact of their implicated mutations.

Epidemiology, aetiology, interventions and genomics in children with arthrogryposis multiplex congenita: protocol for a multisite registry

IntroductionArthrogryposis multiplex congenita (AMC) is an umbrella term including hundreds of conditions with the common clinical manifestation of multiple congenital contractures. AMC affects 1 in 3000 live births and is...

Occupational Therapy for a Child with Aplasia Cutis Congenita with Congenital Volkmann's Ischemic Contracture

Aplasia cutis congenita is a rare malformation characterized by focal or extensive absence of epidermis, dermis, and occasionally subcutaneous tissue. Congenital Volkmann's ischemic contracture is a rare neonatal compartment syndrome caused by intrauterine ischemia and external compression. This is a challenging case for an occupational therapist (OT) focusing on the improvement of hand deformities and function in a child. The objective was to assess the effectiveness of occupational therapy intervention in correcting contracture and improving hand movement. A 4-day-old male child from the neonatal intensive care unit, presented with absence of skin over the right forearm with contracture of right hand, ulnar deviation, and skin discoloration over right hand. Patient was assessed for movement, strength, and level of contracture. Treatment was focused on correcting contracture, improving hand movements, and maintaining skin integrity with the help of splinting and therapeutic exercises. A significant improvement was seen in finger ranges, wrist ranges, hand movements, and skin color. To conclude, splinting techniques helped to stretch out contracture and correct the position of the hand and improvement in hand function.

Biallelic variants in ADAMTS15 cause a novel form of distal arthrogryposis.

We aimed to identify the underlying genetic cause for a novel form of distal arthrogryposis. Rare variant family-based genomics, exome sequencing, and disease-specific panel sequencing were used to detect ADAMTS15 variants in affected individuals. Adamts15 expression was analyzed at the single-cell level during murine embryogenesis. Expression patterns were characterized using in situ hybridization and RNAscope. We identified homozygous rare variant alleles of ADAMTS15 in 5 affected individuals from 4 unrelated consanguineous families presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. Radiographic investigations showed physiological interphalangeal joint morphology. Additional features included knee, Achilles tendon, and toe contractures, spinal stiffness, scoliosis, and orthodontic abnormalities. Analysis of mouse whole-embryo single-cell sequencing data revealed a tightly regulated Adamts15 expression in the limb mesenchyme between embryonic stages E11.5 and E15.0. A perimuscular and peritendinous expression was evident in in situ hybridization in the developing mouse limb. In accordance, RNAscope analysis detected a significant coexpression with Osr1, but not with markers for skeletal muscle or joint formation. In aggregate, our findings provide evidence that rare biallelic recessive trait variants in ADAMTS15 cause a novel autosomal recessive connective tissue disorder, resulting in a distal arthrogryposis syndrome.

Recognizable Pattern of Arthrogryposis and Congenital Myopathy Caused by the Recurrent TTN Metatranscript-only c.39974-11T > G Splice Variant.

Arthrogryposis is characterized by the presence of multiple contractures at birth and can be caused by pathogenic variants in TTN (Titin). Exons and variants that are not expressed in one of the three major isoforms of titin are referred to as "metatranscript-only" and have been considered to be only expressed during fetal development. Recently, the metatranscript-only variant (c.39974-11T > G) in TTN with a second truncating TTN variant has been linked to arthrogryposis multiplex congenita and myopathy. Via exome sequencing we identified the TTN c.39974-11T > G splice variant in trans with one of three truncating variants (p.Arg8922*, p.Lys32998Asnfs*63, p.Tyr10345*) in five individuals from three families. Clinical presentation and muscle ultrasound as well as MRI images were analyzed. All five patients presented with generalized muscular hypotonia, reduced muscle bulk, and congenital contractures most prominently affecting the upper limbs and distal joints. Muscular hypotonia persisted and contractures improved over time. One individual, the recipient twin in the setting of twin-to-twin transfusion syndrome, died from severe cardiac hypertrophy 1 day after birth. Ultrasound and MRI imaging studies revealed a recognizable pattern of muscle involvement with striking fibrofatty involvement of the hamstrings and calves, and relative sparing of the femoral adductors and anterior segment of the thighs. The recurrent TTN c.39974-11T > G variant consistently causes congenital arthrogryposis and persisting myopathy providing evidence that the metatranscript-only 213 to 217 exons impact muscle elasticity during early development and beyond. There is a recognizable pattern of muscle involvement, which is distinct from other myopathies and provides valuable clues for diagnostic work-up.

A TNNI2 variant c.525G>T causes distal arthrogryposis in a Chinese family.

Distal arthrogryposis (DA) is a group of congenital autosomal-dominant disorders secondary to defects in joint and muscle function, characterized by multiple joint contractures of the hands and feet. DA can be divided into 10 types according to clinical features. DA has been confirmed to be caused by mutations in genes encoding components of the contractile apparatus of skeletal muscle fibers, such as troponin I2 (TNNI2). In this study, we report a three-generation DA family belonging to the DA2B type. The clinical characteristics of affected members are genetically stable and consistent, with severe deformities in hands and feet, and two affected adults had short stature. None exhibited facial abnormalities. Blood from three affected and three healthy members were collected for whole-exome sequencing and Sanger sequencing. A missense variant in TNNI2 (NM_003282.4: c.525G>T: p.K175N) was successfully identified, which resulted in the substitution of amino acid at position 175 of TNNI2 from lysine to asparagines. The variant c.525G>T in TNNI2 explains the cause of DA in the family. This variant was identified in Chinese people for the first time, and the same variant had been reported in another study but no description of clinical symptoms. Our study comprehensively characterized the c.525G>T variant in TNNI2.

EP27.05: Prenatal diagnosis of fetal akinesia deformation sequence caused by RAPSN gene mutations: a case report

EP27.05: Prenatal diagnosis of fetal akinesia deformation sequence caused by RAPSN gene mutations: a case report

Loss of Protein Function Causing Severe Phenotypes of Female-Restricted Wieacker Wolff Syndrome due to a Novel Nonsense Mutation in the ZC4H2 Gene.

Pathogenic variants of zinc finger C4H2-type containing (ZC4H2) on the X chromosome cause a group of genetic diseases termed ZC4H2-associated rare disorders (ZARD), including Wieacker-Wolff Syndrome (WRWF) and Female-restricted Wieacker-Wolff Syndrome (WRWFFR). In the current study, a de novo c.352C>T (p.Gln118*) mutation in ZC4H2 (NM_018684.4) was identified in a female neonate born with severe arthrogryposis multiplex congenita (AMC) and Pierre-Robin sequence (cleft palate and micrognathia). Plasmids containing the wild-type (WT), mutant-type (MT) ZC4H2, or GFP report gene (N) were transfected in 293T cell lines, respectively. RT-qPCR and western blot analysis showed that ZC4H2 protein could not be detected in the 293T cells transfected with MT ZC4H2. The RNA seq results revealed that the expression profile of the MT group was similar to that of the N group but differed significantly from the WT group, indicating that the c.352C>T mutation resulted in the loss of function of ZC4H2. Differentially expressed genes (DEGs) enrichment analysis showed that c.352C>T mutation inhibited the expression levels of a series of genes involved in the oxidative phosphorylation pathway. Subsequently, expression levels of ZC4H2 were knocked down in neural stem cells (NSCs) derived from induced pluripotent stem cells (iPSCs) by lentiviral-expressed small hairpin RNAs (shRNAs) against ZC4H2. The results also demonstrated that decreasing the expression of ZC4H2 significantly reduced the growth of NSCs by affecting the expression of genes related to the oxidative phosphorylation signaling pathway. Taken together, our results strongly suggest that ZC4H2 c.352C>T (p.Gln118*) mutation resulted in the loss of protein function and caused WRWFFR.

TTN as a candidate gene for distal arthrogryposis type 10 pathogenesis

BackgroundArthrogryposis is a medical term used to describe congenital contractures which often affect multiple limbs. Distal arthrogryposis (DA) is one of the major categories of arthrogryposis that primarily affects the distal parts of the body, i.e., the hands and the legs. Although ten different types and several subtypes of DAs have been described, the genes associated with each of these DAs are yet to be characterized. Distal arthrogryposis type 10 (DA10) is a rare genetic disease, which is distinguished from the other arthrogryposis types by plantar flexion contractures resulting in toe-walking during infancy as well as variability in contractures of the hip, hamstring, elbow, wrist and finger joints with no ocular or neurological abnormalities. Symptoms of DA10 indicate impairment specifically in the musculoskeletal system. DA10 is still poorly studied. AimThe objective of this study was to identify the candidate gene for DA10 by scrutinizing the protein-protein interaction (PPI) networks using in silico tools. ResultsAmong the genes that reside within the previously reported genomic coordinates (human chromosome assembly 38 or GRCh38 coordinates 2:179,700,000–188,500,000) of the causative agent of DA10, only TTN (the gene that codes for the protein Titin or TTN) follows the expression pattern similar to the other known DA associated genes and its expression is predominant in the skeletal and heart muscles. Titin also participates in biological pathways and processes relevant to arthrogryposes. TTN-related known skeletal muscle disorders follow the autosomal-dominant pattern of inheritance, which is a common characteristic of distal arthrogryposes as well. ConclusionBased on the findings of the analyses and their correlation with previous reports, TTN appears to be the candidate gene for DA10. Our attempt to discover a potential candidate gene may eventually lead to an understanding of disease mechanism and possible treatment strategies, as well as demonstrate the suitability of PPI in the search for candidate genes.

A reverse genetics and genomics approach to gene paralog function and disease: Myokymia and the juxtaparanode

The leucine-rich glioma-inactivated (LGI) family consists of four highly conserved paralogous genes, LGI1-4, that are highly expressed in mammalian central and/or peripheral nervous systems. LGI1 antibodies are detected in subjects with autoimmune limbic encephalitis and peripheral nerve hyperexcitability syndromes (PNHSs) such as Isaacs and Morvan syndromes. Pathogenic variations of LGI1 and LGI4 are associated with neurological disorders as disease traits including familial temporal lobe epilepsy and neurogenic arthrogryposis multiplex congenita 1 with myelin defects, respectively. No human disease has been reported associated with either LGI2 or LGI3. We implemented exome sequencing and family-based genomics to identify individuals with deleterious variants in LGI3 and utilized GeneMatcher to connect practitioners and researchers worldwide to investigate the clinical and electrophysiological phenotype in affected subjects. We also generated Lgi3-null mice and performed peripheral nerve dissection and immunohistochemistry to examine the juxtaparanode LGI3 microarchitecture. As a result, we identified 16 individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. Deep phenotypic characterization showed LGI3 LoF causes a potentially clinically recognizable PNHS trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons. Our data demonstrate bi-allelic LoF variants in LGI3 cause a clinically distinguishable disease trait of PNHS, most likely caused by disturbed Kv1 channel distribution in the absence of LGI3.

Использование большой грудной мышцы для восстановления активного сгибания предплечья у детей с амиоплазией

Introduction Amyoplasia is the most common type of arthrogryposis multiplex congenita. Some patients may lack active elbow flexion due to aplasia of the forearm flexor muscles. The objective was to identify the optimal age for pectoralis major muscle transfer to improve elbow flexion in children with amyoplasia and estimate outcomes of the procedure depending on the level of spinal cord injury. Material and methods Restoration of active elbow flexion was performed for 34 children with amyoplasia (39 upper limbs) between 2011 and 2020 using partial monopolar pectoralis major muscle transfer. The age of patients ranged between 1.5 and 15.5 years (6.24 ± 4.24 years). The patients were divided into 3 groups depending on the level of spinal cord injury: C6–C7 (n = 4; 11.8 %), C5–C7 (n = 24; 70.6 %), C5–Th1 (n = 6; 17.6 %). The outcomes were estimated at 6 to 99 months (44.53 ± 31.72 months). The patients underwent preoperative and postoperative clinical and neurological examination. The results were statistically analyzed. Results Active elbow flexion improved by 56.8 degrees (p &lt; 0.0001), forearm flexor muscles strengthened by 2.0 points (p &lt; 0.0001) and extension deficit improved by 14.5 degrees (p &lt; 0.0001) were postoperatively statistically significant. Results were rated as good in 15 (38.5 %); as fair, in 8 (20.5 %) and poor in 16 (41 %) cases. Greater differences were found between the group of patients with the level of C6-C7 spinal cord injury in relation to the group of patients with the level of C5-Th1 (p &lt; 0.05). There were no statistically significant differences between patients with C6–C7 and C5–C7 lesion levels (p &gt; 0.05). Children of different age groups showed no differences in the results of treatment (p &gt; 0.05). Conclusion Pectoralis major muscle could be used for active elbow flexion restoration in patients with amyoplasia. The best results were observed in patients with C6–C7, C5–C7 segmental lesions of the spinal cord. There was no correlation between age of patient at the time of surgery and the effectiveness of operation.