Diagnostic workup in children with arthrogryposis: description of practices from a single reference centre, comparison with literature and suggestion of recommendations.

INTRODUCTION: Arthrogryposis multiplex congenita (AMC) refers to a clinical presentation of congenital contractures involving two or more body areas. More than 400 distinct conditions may lead to AMC, making the aetiological diagnosis challenging. The objective of this work was to set up evidence-based recommendations for the diagnosis of AMC by taking advantage of both data from our nation-wide cohort of children with AMC and from the literature. MATERIAL AND METHODS: We conducted a retrospective single-centre observational study. Patients had been evaluated at least once at a paediatric age in the AMC clinic of Grenoble University Hospital between 2007 and 2019. After gathering data about their diagnostic procedure, a literature review was performed for each paraclinical investigation to discuss their relevance. RESULTS: One hundred and twenty-five patients were included, 43% had Amyoplasia, 27% had distal arthrogryposis and 30% had other forms. A definitive aetiological diagnosis was available for 66% of cases. We recommend a two-time diagnostic process: first, non-invasive investigations that aim at classifying patients into one of the three groups, and second, selected investigations targeting a subset of patients. CONCLUSION: The aetiological management for patients with AMC remains arduous. This process will be facilitated by the increasing use of next-generation sequencing combined with detailed phenotyping. Invasive investigations should be avoided because of their limited yield.

Mutations in MYLPF Cause a Novel Segmental Amyoplasia that Manifests as Distal Arthrogryposis.

We identified ten persons in six consanguineous families with distal arthrogryposis (DA) who had congenital contractures, scoliosis, and short stature. Exome sequencing revealed that each affected person was homozygous for one of two different rare variants (c.470G>T [p.Cys157Phe] or c.469T>C [p.Cys157Arg]) affecting the same residue of myosin light chain, phosphorylatable, fast skeletal muscle (MYLPF). In a seventh family, a c.487G>A (p.Gly163Ser) variant in MYLPF arose de novo in a father, who transmitted it to his son. In an eighth family comprised of seven individuals with dominantly inherited DA, a c.98C>T (p.Ala33Val) variant segregated in all four persons tested. Variants in MYLPF underlie both dominant and recessively inherited DA. Mylpf protein models suggest that the residues associated with dominant DA interact with myosin whereas the residues altered in families with recessive DA only indirectly impair this interaction. Pathological and histological exam of a foot amputated from an affected child revealed complete absence of skeletal muscle (i.e., segmental amyoplasia). To investigate the mechanism for this finding, we generated an animal model for partial MYLPF impairment by knocking out zebrafish mylpfa. The mylpfa mutant had reduced trunk contractile force and complete pectoral fin paralysis, demonstrating that mylpf impairment most severely affects limb movement. mylpfa mutant muscle weakness was most pronounced in an appendicular muscle and was explained by reduced myosin activity and fiber degeneration. Collectively, our findings demonstrate that partial loss of MYLPF function can lead to congenital contractures, likely as a result of degeneration of skeletal muscle in the distal limb.

The range of publications on arthrogryposis multiplex congenita from 1995 to 2022-A scoping review.

Arthrogryposis multiplex congenita (AMC) is defined as "a group of congenital conditions characterized by joint contractures in two or more body areas." Given its heterogeneity, the definition of AMC has changed multiple times. This scoping review provides an overview of how AMC is defined in scientific publications, on existing knowledge and trends regarding the concept of AMC. Our review illuminates possible knowledge gaps and provides directions for future research. A scoping review was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews guidelines. Quantitative studies on AMC from 1995 to date were included. We summarized information about definitions/descriptions of AMC, study objectives, study designs, methods, funding, and involvement of patient organizations. A total of 2729 references were screened, and 141 articles fulfilled our inclusion criteria. Our scoping revealed that the majority of publications were cross-sectional or retrospective studies of children and young people, commonly about orthopedic management. Explicit or good definitions of AMC were provided in 86% of the cases. Recent publications on AMC mostly used consensus-based definitions. The research gaps were primarily related to adults, aging, etiology, and new medical treatment, in addition to implications on daily life.

Amyoplasia in monochorionic monozygotic pregnancy following interstitial laser.

Amyoplasia is a specific form of arthrogryposis, without any genetic cause. Six to ten percent of amyoplasia cases are one of the monozygotic twins, with the other twin being normal. Failure of maturation of anterior horn cells (AHCs) due to ischemic injury has been postulated as the primary pathological change, leading to arrest in the development of muscle fibers supplied by the affected AHCs with the typical limb positioning seen in amyoplasia. Twin-to-twin transfusion syndrome (TTTS) is an important risk factor for ischemic injury in monozygotic twin pregnancies. We present a case of monochorionic diamniotic twin pregnancy with features of TTTS at 12 weeks who underwent interstitial laser followed by the development of lower limb akinesia in the surviving fetus. Possible causes of amyoplasia are discussed.

The mystery of monozygotic twinning I: What can Amyoplasia tell us about monozygotic twinning and the possible role of twin-twin transfusion?

Amyoplasia is a very specific, nongenetic clinically recognizable form of arthrogryposis, representing about one-third of individuals with arthrogryposis surviving the newborn period. There is a markedly increased number of individuals with Amyoplasia who are one of monozygotic (MZ) twins, with the other twin being normal. Thus, it would appear that Amyoplasia is definitely associated with and may be caused by an MZ twinning event. The twin-twin transfusion seen in MZ twins could play an etiologic role in producing Amyoplasia. In this article, Amyoplasia twinning is compared to twinning in other forms of arthrogryposis. The accompanying paper examines various types of MZ twinning (Hall, 2021). Amyoplasia is primarily associated with spontaneous MZ twinning.

The mystery of monozygotic twinning II: What can monozygotic twinning tell us about Amyoplasia from a review of the various mechanisms and types of monozygotic twinning?

Monozygotic (MZ) twins ("identical twins") are essentially unique to human beings. Why and how they arise is not known. This article reviews the possible different types of MZ twinning recognized in the previous article on twins and arthrogryposis. There appear to be at least three subgroups of MZ twinning: spontaneous, familial, and those related to artificial reproductive technologies. Each is likely to have different etiologies and different secondary findings. Spontaneous MZ twinning may relate to "overripe ova." Amyoplasia, a specific nongenetic form of arthrogryposis, appears to occur in spontaneous MZ twinning and may be related to twin-twin transfusion.

Fetal cervical hyperextension in arthrogryposis.

Perhaps the most dramatic position of a newborn after delivery is when there is hyperextension of the neck and spine. It will have been presented in utero and today, almost always, such babies will have been delivered by C-section. The associated anomalies are variable. The process(es) that can lead to cervical hyperextension is/are largely unknown. The outcome is variable from lethal to completely resolve. Individuals with arthrogryposis and in particular with Amyoplasia appear to have an increased frequency of neck, cervical, and spine hyperextension at birth. We present here 41 cases of arthrogryposis (mainly Amyoplasia) with fetal cervical hyperextension. The outlook is surprisingly good if spinal cord trauma does not occur. Ultrasound late in pregnancy when arthrogryposis is recognized prenatally should determine whether cervical hyperextension has developed, so that appropriate preventive measures can be taken.

Clinical presentation and survival in a population-based cohort of infants with gastroschisis in Utah, 1997-2011.

Typically gastroschisis is considered an isolated birth defect; however, other major malformations are reported to occur in 5-35% of cases depending on inclusion criteria. This study evaluated the associated malformations, small for gestational age, and survival among a clinically well-characterized population-based gastroschisis cohort, delivered from 1997-2011. We used data from Utah's statewide population-based surveillance system, which monitors major structural birth defects among all pregnancy outcomes (i.e., live births, stillbirths, pregnancy terminations, and miscarriages). Of the initial 387 gastroschisis cases, we excluded 51 (13.2%) for the following reasons: inadequately described or macerated fetuses, part of a specific malformation complex or sequence (limb-body wall complex, amniotic band sequence, or a severe form of abdominoschisis), leaving a study sample of 336 clinically confirmed cases. Gastroschisis was isolated non-syndromic in 284 cases (84.5%). One case was syndromic (trisomy 16; 0.3%) and the remaining 51 (15.2%) were classified as multiple: one unrelated major malformation (27; 52.9%); two or more unrelated major malformation or one major with multiple minor anomalies or mild malformations (6; 11.8%); ≥ one distinctive minor anomaly or mild malformation (13; 25.5%); amyoplasia (5; 1.5%). Of the liveborn infants, 63.3% were preterm (delivered at <37 weeks of gestation) and 21.8% were small for gestational age (SGA). SGA was more common in males (38.8%) than females (16%) (P = 0.008). Overall first year survival was high (95.6%); however, preterm infants with congenital intestinal atresia had the highest mortality (13.8%). The high proportion of isolated cases (84.5%) in gastroschisis is similar to that observed in many other phenotypes and not unique to gastroschisis. Because one in every six infants with gastroschisis had a major unrelated malformation, additional malformations should be sought in every newborn with gastroschisis. Infant mortality was low overall but still a significant concern in affected preterm infants with associated congenital intestinal atresia.

Hand therapy following elbow release for passive elbow flexion and long head of the triceps transfer for active elbow flexion in children with amyoplasia.

Children born with the Amyoplasia form of arthrogryposis multiplex congenita (AMC) who lack elbow flexor muscles and have elbow extension contractures usually require assistance in performing ADL's that require reaching their hand to their face, head, and upper body. For tasks involving the UE, the elbow is the key to functional independence. Children born with Amyoplasia may benefit from selective surgeries to enhance functional independence and improve quality of life. Home therapy and splinting following these surgeries is an important part of gaining motion and improving function. This abstract will review the rehab and splinting following an elbow release to gain passive elbow flexion, and a long head of the triceps transfer for active elbow flexion in children with Amyoplasia.

Amyoplasia revisited.

Amyoplasia is a specific type and the most common form of arthrogryposis (multiple congenital contractures). It is a clinical diagnosis at this time. Care should be used making the diagnosis because of the implications for recurrence, natural history, associated anomalies, and both etiology and pathogenesis. We reviewed over 600 published reports and 2,500 individual records to identify the 560 individuals reported here. Affected limbs had characteristic positions with fatty-fibrous replacement of muscle. Upper limb involvement was usually characterized by extended elbows. Lower limbs were held in various positions at birth; however, equinovarus positioning of feet was almost always present. Symmetric involvement was common. Among 560 affected individuals, subtypes were identified: four-limb symmetric involvement (331/560 = 55.9%), severe involvement (41/560 = 7.3%), three-limb involvement (27/560 = 4.8%), upper limb only Amyoplasia (ULA; 94/560 = 16.8%), and lower limb only Amyoplasia (LLA; 25/560 = 15.5%). Discordant monozygotic twinning was increased, occurring in 6.6% (37/560; OR 10.9). A variety of additional anomalies were seen, attributed to apparent vascular compromise. Gastrointestinal vascular compromise-type anomalies were present in 9.1% (51/560), trunk muscle defects in another 2.7% (15/560), digit compromise in 12.1% (68/560), constriction rings in 4.3% (24/560), and perinatal long bone fractures in 10.5% (59/560). Although prenatal ultrasound became the standard of care in 1990, only about one quarter of affected pregnancies were diagnosed prenatally since 1990. Amyoplasia appears to be completely sporadic. Novel pathogenetic mechanisms for the congenital anomalies seen in Amyoplasia need to be identified.

Amyoplasia involving only the upper limbs or only involving the lower limbs with review of the relevant differential diagnoses.

Of individuals with Amyoplasia, 16.8% (94/560) involve only the upper limbs (Upper Limb Amyoplasia-ULA) and 15.2% (85/560) involve only the lower limbs (Lower Limb Amyoplasia-LLA). The accompanying paper deals with other forms of Amyoplasia [Hall et al., 2013] and discusses etiology. An excess of one of monozygotic (MZ) twins is seen in both groups (ULA 4/94 (4.3%), LLA 5/85 (5.9%)), gastrointestinal (GI) abnormalities thought to be of vascular origin (bowel atresia and gastroschisis) (ULA 16/94 (17%), LLA 4/85 (4.7%)), small or partial absence of digits (ULA 6/94 (6.2%), LLA 8/85 (9.4%)), and umbilical cord wrapping around the limbs at birth (ULA 3/94 (3.2%), LLA 7/85 (8.2%)) (severe enough to leave a permanent groove). Pregnancy complications occurred in 42/60 (70%) of ULA and 36/54 (67%) of LLA. Prenatal diagnosis, after ultrasound usage became routine, occurred in only 7/25 (28%) of ULA and 5/12 (12%) of LLA. This series may represent an over estimate of the complications and associations occurring in ULA and LLA. Differential diagnoses separating LLA from the genetic forms of "lower limb only" arthrogryposis and ULA from "upper limb only" genetic forms of arthrogryposis and Erb's palsy is provided.

Growth Charts for Children With Arthrogryposis Multiplex Congenita.

Children with arthrogryposis multiplex congenita (AMC) often demonstrate growth differences compared with typically developing (TD) children. However, growth charts have not been developed for this population. The purpose of this study was to create AMC-specific growth charts and to compare these values to those of TD children. A retrospective review of height/length and weight for 206 children with AMC was performed. Growth charts were developed and stratified over seven percentiles; these were then compared with growth charts of TD children. Children with AMC tend to be smaller in stature and weight compared with TD children, particularly in the first 36 months of life. Thereafter, weight values trend toward the 50th percentile of TD children, but height/length values persist around the 5th percentile of TD children. The development of AMC-specific growth charts provides health care providers an objective tool to evaluate growth patterns of patients with AMC.

Bone mineral density in adults with arthrogryposis multiplex congenita: a retrospective cohort analysis.

The primary objective of this study was to evaluate the prevalence of low femoral and lumbar spine bone mineral density (BMD) in adults with arthrogryposis multiplex congenita (AMC). We performed a retrospective cohort analysis of adults with AMC who were enrolled in the French Reference Center for AMC and in the Pediatric and Adult Registry for Arthrogryposis (PARART, NCT05673265). Patients who had undergone dual-energy X-ray absorptiometry (DXA) and/or vitamin D testing were included in the analysis. Fifty-one patients (mean age, 32.9 ± 12.6 years) were included; 46 had undergone DXA. Thirty-two (32/51, 62.7%) patients had Amyoplasia, and 19 (19/51, 37.3%) had other types of AMC (18 distal arthrogryposis, 1 Larsen). Six patients (6/42, 14.3%) had a lumbar BMD Z score less than - 2. The mean lumbar spine Z score (- 0.03 ± 1.6) was not significantly lower than the expected BMD Z score in the general population. Nine (9/40, 22.5%) and 10 (10/40, 25.0%) patients had femoral neck and total hip BMD Z scores less than - 2, respectively. The mean femoral neck (- 1.1 ± 1.1) and total hip (- 1.2 ± 1.2) BMD Z scores in patients with AMC were significantly lower than expected in the general population (p < 0.001). Femoral neck BMD correlated with height (rs = 0.39, p = 0.01), age (rs = - 0.315, p = 0.48); total hip BMD correlated with height (rs = 0.331, p = 0.04) and calcium levels (rs = 0.41, p = 0.04). Twenty-five patients (25/51, 49.0%) reported 39 fractures. Thirty-one (31/36, 86.1%) patients had 25-hydroxyvitamin D levels less than 75 nmol/l, and 6 (6/36, 16.7%) had 25-hydroxyvitamin D levels less than 75 nmol/l. Adults with AMC had lower hip BMD than expected for their age, and they more frequently showed vitamin D insufficiency. Screening for low BMD by DXA and adding vitamin D supplementation when vitamin D status is insufficient should be considered in adults with AMC, especially if there is a history of falls or fractures.

Fetuses and infants with Amyoplasia congenita in congenital Zika syndrome: The evidence of a viral cause. A narrative review of 144 cases.

OBJECTIVES: Amyoplasia congenita is the most frequent type of arthrogryposis causing fetal hypokinesia, leading to congenital contractures at birth. The pathogenesis is thought to be impaired blood circulation to the fetus early in pregnancy, with hypotension and hypoxia damaging the anterior horn cells. In animal studies however a prenatal infection with a poliomyelitis-like viral agent was demonstrated. Congenital Zika virus syndrome (CZVS) has recently been described in infants with severe microcephaly, and in 10-25% of cases arthrogryposis. METHODS: A search in PubMed for CZVS yielded 124 studies. After a selection for arthrogryposis, 35 papers were included, describing 144 cases. The studies were divided into two categories. 1) Those (87 cases) focussing on imaging or histological data of congenital brain defects, contained insufficient information to link arthrogryposis specifically to lesions of the brain or spinal motor neuron. 2) In the other 57 cases detailed clinical data could be linked to neurophysiological, imaging or histological data. RESULTS: In category 1 the most frequent brain abnormalities in imaging studies were ventriculomegaly, calcifications (subcortical, basal ganglia, cerebellum), hypoplasia of the brainstem and cerebellum, atrophy of the cerebral cortex, migration disorders and corpus callosum anomalies. In category 2, in 38 of 57 cases clinical data were indicative of Amyoplasia congenita. This diagnosis was confirmed by electromyographic findings (13 cases), by MRI (37 cases) or histology (12 cases) of the spinal cord. The latter showed small or absent lateral corticospinal tracts, and cell loss and degeneration of motor neuron cells. Zika virus-proteins and flavivirus-like particles were detected in cytoplasm of spinal neurons. CONCLUSION: The phenotype of arthrogryposis in CZVS is consistent with Amyoplasia congenita. These findings warrant search for an intrauterine infection with any neurotropic viral agent with affinity to spinal motor neurons in neonates with Amyoplasia.

Case Report: Prenatal Diagnosis of Nemaline Myopathy.

Nemaline myopathy (NM) is a rare, hereditary heterogeneous myopathy. Fetal NM has a more severe disease course and a poorer prognosis and is usually lethal during the first few months of life. Hence, early prenatal diagnosis is especially important for clinical interventions and patient counseling. We report the case of a fetus with NM due to KLHL40 gene variation leading to arthrogryposis multiplex congenita (AMC). The ultrasonography and histopathology results revealed an enhanced echo intensity and decreased muscle thickness, which may be novel features providing early clues for the prenatal diagnosis of NM. Moreover, to our knowledge, this article is the first report to describe a case of NM associated with complex congenital heart disease (CHD).

Amyoplasia and distal arthrogryposis.

Arthrogryposis multiplex congenita (AMC) consists of congenital joint contractures that affect at least two joints. There are two types: in the first, arthrogryposis is an additional sign in the context of various pathologies (neuromuscular diseases); in the second, it is the main and constant symptom. In the first type, the progression of the causal underlying disease must be considered. In the second type, there are two specific forms: Amyoplasia corresponds to a significant congenital absence of muscles (epigenetic disease or vascular origin) while distal arthrogryposis has a genetic component and is transmissible. The orthopedic surgeon's purpose, which is usually to enhance movement, is not appropriate for an arthrogryposis patient. One must keep in mind that without muscle, movement is impossible. The goal differs between the upper and lower limbs: for the upper limb, it is to allow grasping, and, if possible, to bring the hand to the mouth; for the lower limb, it is to ensure ambulation with plantigrade support, and the knees extended, which is the only stable position possible with little to no muscles. The rehabilitation, orthoses and/or surgical techniques are chosen to achieve this singular aim. While it may appear modest, it is crucial for patients. The goal is to achieve useful mobility, not maximum mobility. This multidisciplinary treatment, which evolves over time, must be explained to the family to get its adherence.

Clinical and Genetic Findings in a Series of Eight Families with Arthrogryposis.

The term "arthrogryposis" is used to indicate multiple congenital contractures affecting two or more areas of the body. Arthrogryposis is the consequence of an impairment of embryofetal neuromuscular function and development. The causes of arthrogryposis are multiple, and in newborns, it is difficult to predict the molecular defect as well as the clinical evolution just based on clinical findings. We studied a consecutive series of 13 participants who had amyoplasia, distal arthrogryposis (DA), or syndromic forms of arthrogryposis with normal intellectual development and other motor abilities. The underlying pathogenic variants were identified in 11 out of 13 participants. Correlating the genotype with the clinical features indicated that prenatal findings were specific for DA; this was helpful to identify familial cases, but features were non-specific for the involved gene. Perinatal clinical findings were similar among the participants, except for amyoplasia. Dilatation of the aortic root led to the diagnosis of Loeys-Dietz syndrome (LDS) in one case. The phenotype of DA type 5D (DA5D) and Escobar syndrome became more characteristic at later ages due to more pronounced pterygia. Follow-up indicated that DA type 1 (DA1)/DA type 2B (DA2B) spectrum and LDS had a more favorable course than the other forms. Hand clenching and talipes equinovarus/rocker bottom foot showed an improvement in all participants, and adducted thumb resolved in all forms except in amyoplasia. The combination of clinical evaluation with Next Generation Sequencing (NGS) analysis in the newborn may allow for an early diagnosis and, particularly in the DAs, suggests a favorable prognosis.

A Genomic Approach to Delineating the Occurrence of Scoliosis in Arthrogryposis Multiplex Congenita.

Arthrogryposis multiplex congenita (AMC) describes a group of conditions characterized by the presence of non-progressive congenital contractures in multiple body areas. Scoliosis, defined as a coronal plane spine curvature of ≥10 degrees as measured radiographically, has been reported to occur in approximately 20% of children with AMC. To identify genes that are associated with both scoliosis as a clinical outcome and AMC, we first queried the DECIPHER database for copy number variations (CNVs). Upon query, we identified only two patients with both AMC and scoliosis (AMC-SC). The first patient contained CNVs in three genes (FBN2, MGF10, and PITX1), while the second case had a CNV in ZC4H2. Looking into small variants, using a combination of Human Phenotype Ontogeny and literature searching, 908 genes linked with scoliosis and 444 genes linked with AMC were identified. From these lists, 227 genes were associated with AMC-SC. Ingenuity Pathway Analysis (IPA) was performed on the final gene list to gain insight into the functional interactions of genes and various categories. To summarize, this group of genes encompasses a diverse group of cellular functions including transcription regulation, transmembrane receptor, growth factor, and ion channels. These results provide a focal point for further research using genomics and animal models to facilitate the identification of prognostic factors and therapeutic targets for AMC.

Arthrogryposis in children: Etiological assessments and preparation of a protocol for etiological investigations.

INTRODUCTION: Arthrogryposis is a descriptive term defining a sign. It describes a set of joint contractures, sometimes identifiable in utero, present from birth and nonprogressive. This term includes a heterogeneous group of diseases, of neurological, neuromuscular, genetic or mechanical origin. The common physiopathological mechanism is fetal immobility syndrome. Two types of classification have been developed: a clinical one (types I, II and III) and an etiological one. The main aim of this study was to define a standardized protocol for etiological investigation based on a descriptive analysis of the various etiologies identified in a population of children followed up for arthrogryposis. Its secondary aim was to assess first the comprehensiveness and relevance of the complementary assessment and second the way in which the classifications proposed by Professor Judith Goslin Hall are applied. MATERIAL AND METHODS: Retrospective multicenter observational study. We enrolled pediatric patients with arthrogryposis being treated at a reference center for neuromuscular diseases, i.e., in three university hospital pediatric neurology units, between February 1997 and January 2017. RESULTS: Forty-two patients (25 boys and 17 girls) were enrolled. According to the clinical classification (Hall et al.), this population consisted of eight cases of type 1 arthrogryposis (19.1%), 14 type II (33.3%) and 20 type III (47.6%). The main etiology was neurological (19.1%), predominantly involving problems with gyration of a polymicrogyria type. Myopathic origin accounted for 9.5% of the population, predominantly involving genotyped distal arthrogryposis (ECEL1 gene). Additional tests produced a diagnosis of 25% type I, 43% type II and 75% type III. CONCLUSION: Arthrogryposis is a sign suggesting multiple etiologies. The main ones are neurological. Several genes have recently been identified, explaining the physiopathological mechanisms. The diagnostic process must be rigorous and coordinated within a multidisciplinary team, following a shared protocol for analysis.

Development and simulation of a passive upper extremity orthosis for amyoplasia.

INTRODUCTION: People who are born with arthrogryposis multiplex congenita are typically not able to perform activities of daily living (ADL) due to decreased muscle mass, joint contractures and unnatural upper extremity positioning. They are, therefore, potential users of an assistive device capable of aiding in ADL and increasing their independence. A passive orthosis can support the weight of their arm against gravity, allowing them to perform movements with less effort. METHODS: This study presents a prototype design with four degrees-of-freedom that uses musculoskeletal modelling to optimize the stiffness of the springs in the device to partially gravity balance the upper extremity while compensating for the usual internally rotated glenohumeral joint. A single subject-specific musculoskeletal model was developed to simulate the effects of the passive orthosis during 10 static postures during ADL. RESULTS: For a given configuration using a mono- and a bi-articular spring, the simulations showed that spring stiffnesses of 400 Nm-1 and of 1029 Nm-1, respectively, were able to lower the maximal muscle activity estimated by the musculoskeletal model to a level in which the 10 postures can be realized. CONCLUSION: By augmenting residual muscle strength with a partially gravity-balanced passive orthosis, ADLs may be achievable for people with arthrogryposis multiplex congenita.