Fetal akinesia is a broad term used to describe absent (or reduced, fetal hypokinesia) fetal movements, and it can be detected as early as the first trimester. Depending on the developmental age of onset, anything that interferes or limits the normal in utero movement results in a range of deformations affecting multiple organs and organ systems. Arthrogryposis, also termed arthrogryposis multiplex congenita (AMC), is a definitive terminology for multiple congenital contractures, with two major subgroups; amyoplasia and distal arthrogryposis (DA). The spectrum includes fetal akinesia deformation sequence (FADS), lethal congenital contracture syndrome (LCCS), and multiple pterygium syndrome (MPS). Variants in more than >400 genes are known to cause AMC, and it is increasingly recognized that variants in genes encoding critical components (including ventral horn cell, peripheral nerve, neuromuscular junction, skeletal muscle) of the extended motor unit underlie ∼40% of presentations. With unbiased screening approaches, including sequencing of comprehensive disease gene panels, exomes and genomes, novel genes and phenotypic expansions associated with known human disease genes have been uncovered in the setting of fetal akinesia. Autosomal-recessive titinopathy is the most frequent genetic cause of AMC. Accurate genetic diagnosis is critical to genetic counseling and informing family planning. Around 50% remain undiagnosed following comprehensive prenatal, diagnostic or research screening. Comprehensive phenotyping and periodic reanalysis with appropriate genomic tools are valuable strategies when faced with initial inconclusive results. There are likely many novel causative genes still to identify, which will inform our understanding of the molecular pathways underlying early human development and in utero movement.

Arthrogryposis, which represents a group of congenital disorders, includes various forms. One such form is amyoplasia, which most commonly presents in a sporadic form in addition to distal forms, among which hereditary cases may occur. This condition is characterized by limited joint mobility and muscle weakness, leading to limb deformities and various clinical manifestations. At present, the pathogenesis of this disease is not clearly understood, and its diagnosis is often complicated due to significant phenotypic diversity, which can result in delayed detection and, consequently, limited options for symptomatic treatment. In this study, a transcriptomic analysis of the affected muscles from patients diagnosed with amyoplasia was performed, and more than 2000 differentially expressed genes (DEGs) were identified. A functional analysis revealed disrupted biological processes, such as vacuole organization, cellular and aerobic respiration, regulation of mitochondrion organization, cellular adhesion, ATP synthesis, and others. The search for key nodes (hubs) in protein-protein interaction networks allowed for the identification of genes involved in mitochondrial processes.

The Ponseti serial casting method is the method of choice in treating children with congenital clubfeet. The arthrogrypotic clubfoot has traditionally been considered challenging to treat, with higher rates of recurrence and the need for more corrective surgeries. However, initial reports have found promising results in using the Ponseti method to treat arthrogrypotic feet. This study aims to compare the outcomes of idiopathic versus arthrogrypotic clubfeet following initial treatment with the Ponseti serial casting method. A retrospective review of medical records from a single institution was conducted. Data was collected from children ages 0 to 18 with idiopathic or arthrogrypotic clubfoot treated from 2002 to 2022 with Ponseti-style serial casting with a minimum 2-year follow-up. Recurrence was defined as the need for additional casting or subsequent surgeries following initial correction. Data was collected on relevant patient demographics, previous treatment, casting records, Achilles tenotomies, and surgical treatments. A total of 352 patients (546 feet) met inclusion criteria. In all, 334 idiopathic and 18 arthrogrypotic patients were analyzed with an average follow-up duration of 3.4 and 4.2 years, respectively. Twelve patients had distal arthrogryposis, and 6 had amyoplasia. In all, 93.4% of idiopathic and 72.2% of arthrogrypotic patients successfully achieved correction with Ponseti casting and Achilles tenotomy. Recurrence rates were significantly higher in the arthrogrypotic group at 83.3% compared with 44.6% in the idiopathic group ( P =0.001). A posterior or posterior medial release was performed in 35.0% of idiopathic and 66.7% arthrogrypotic feet. We report the largest series of arthrogrypotic clubfeet treated by Ponseti casting to the best of our knowledge. In contrast to earlier reports, our investigation underscores that while the Ponseti method may be able to secure initial correction in arthrogrypotic clubfeet, on average, at a 3-year follow-up, the prognosis is less favorable. These patients exhibit higher recurrence and often require operative treatment. Notably, a posterior medial release may eventually be needed in up to 6 of 10 patients. Level III-therapeutic studies-investigating the results of treatment.

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. 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. 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. 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.

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.