Central nervous system involvement in arthrogryposis multiplex congenita: Overview of causes,diagnosis, and care

Arthrogryposis or AMC, arthrogryposis multiplex congenita, is defined as multiple congenital joint contractures in more than two joints and in different body areas. The common cause of all AMC is lack of movement in utero, which in turn can have different causes, one of which is CNS involvement. Intellectual disability/CNS involvement is found in approximately 25% of all AMC. AMC with CNS involvement includes a large number of genetic syndromes. So far, more than 400 genes have been identified as linked to AMC, with and without CNS involvement. A number of neonatally lethal syndromes and syndromes resulting in severe disability due to CNS malfunction belong to this group of syndromes. There are several X‐linked disorders with AMC, which are primarily related to intellectual disability. A number of neuromuscular disorders may include AMC and CNS/brain involvement. Careful clinical evaluation by a geneticist and a pediatrician/pediatric neurologist is the first step in making a specific diagnosis. Further investigations may include MRI of the brain and spinal cord, electroencephalogram, blood chemistry for muscle enzymes, other organ investigations (ophtalmology, cardiology, gastrointestinal, and genitourinary systems). Nerve conduction studies, electromyogram, and muscle pathology may be of help when there is associated peripheral nervous system involvement. But most importantly, genetic investigations with targeted or rather whole exome or genome sequencing should be performed. A correct diagnosis is important in planning adequate treatment, in genetic counselling and also for future understanding of pathogenic mechanisms and possible new treatments. A multidiciplinary team is needed both in investigation and treatment.     

The latest FADS: Functional analysis of GLDN patient variants and classification of GLDN‐associated AMC as a type of viable fetal akinesia deformation sequence

Recessive variants in the GLDN gene, which encodes the gliomedin protein and is involved in nervous system development, have recently been associated with Arthrogryposis Multiplex Congenita (AMC), a heterogenous condition characterized by congenital contractures of more than one joint. Two cohorts of patients with GLDN‐associated AMC have previously been described, evolving the understanding of the condition from lethal to survivable with the provision of significant neonatal support. Here, we describe one additional patient currently living with the syndrome, having one novel variant, p.Leu365Phe, for which we provide functional data supporting its pathogenicity. We additionally provide experimental data for four other previously reported variants lacking functional evidence, including p.Arg393Lys, the second variant present in our patient. We discuss unique and defining clinical features, adding calcium‐related findings which appear to be recurrent in the GLDN cohort. Finally, we compare all previously reported patients and draw new conclusions about scope of illness, with emphasis on the finding of pulmonary hypoplasia, suggesting that AMC secondary to GLDN variants may be best fitted under the umbrella of fetal akinesia deformation sequence (FADS).     

The diagnostic workup in a patient with AMC: Overview of the clinical evaluation and paraclinical analyses with review of the literature

Arthrogryposis multiplex congenita, or AMC, is a clinical sign defined as congenital contractures of at least two joint levels. These joint contractures are always secondary to diminished fetal movement which can have numerous causes that affect any part of the anatomical structures implicated in movement: the central nervous system, the anterior horn cell, the nerve, the neuromuscular junction, the muscle, or the joint itself. Make a precise diagnosis of the cause in a patient with multiple joint contractures is therefore challenging. The aim of this article is to summarize the use and diagnostic value of common examinations and analyses performed postnatally in patients affected by AMC from a literature review. We also compare this data with results from our clinical practice. Even though it is difficult to give precise guidelines today, it appears that genetic studies, such as whole exome or genome analysis in all patients and chromosomal microarray analysis in patients with intellectual disability and AMC should be preferred as first tier investigations over EMG and muscle biopsy.     

Progress in therapeutic antisense applications for neuromuscular disorders

Neuromuscular disorders are a frequent cause of chronic disability in man. They often result from mutations in single genes and are thus, in principle, well suited for gene therapy. However, the tissues involved (muscle and the central nervous system) are post-mitotic, which poses a challenge for most viral vectors. In some cases, alternative approaches may use small molecules, for example, antisense oligonucleotides (AONs). These do not deliver a new gene, but rather modulate existing gene products or alter the utilization of pathways. For Duchenne muscular dystrophy, this approach is in early phase clinical trials, and for two other common neuromuscular disorders (spinal muscular atrophy and myotonic dystrophy), significant preclinical advances have recently been made.     

Hypofunction of the sympathetic nervous system is an etiologic factor for a wide variety of chronic treatment-refractory pathologic disorders which all respond to therapy with sympathomimetic amines

The hypothesis set forth is that the basis for a great many chronic debilitating conditions that involve almost all of the physiologic systems of the body may have as the underlying cause and a common link between them, i.e., hypofunction of the sympathetic nervous system. The hypothesis considers that one of the main functions of the sympathetic nervous system is to diminish cellular permeability. Thus sympathetic hypofunction may lead to absorption of chemicals and toxins into tissues that were supposed to be impervious leading to inflammation and other adverse consequences which then cause a wide variety of symptoms. These symptoms may include pain or diminished muscular function leading to various pain syndromes or conditions related to diminished muscular function. Furthermore since the sympathetic nervous system is involved in body homeostasis and temperature regulation, sympathetic nervous system hypofunction could lead to disorders in these areas, e.g., vasomotor symptoms and edema. This defect in sympathetic nervous system has a genetic predisposition but relatives, e.g., siblings or children may manifest in a different manner which suggests some influence of external factors causing one physiological system to be more prone than another to malfunction under conditions of sympathetic hypofunction. Evidence to support this hypothesis has been provided by a large number of published anecdotes demonstrating the quick and long lasting considerable improvement in symptoms following treatment with the sympathomimetic amine dextroamphetamine sulfate (with return of symptoms if treatment is temporarily ceased thus diminishing the likelihood of spontaneous remission) despite failure to respond to a plethora of other pharmacologic agents and other therapies over many years. The physiological systems with various chronic disorders that have responded included the gastrointestinal system, skin, genitourinary system, the nervous system, the musculoskeletal system, the temperature regulation system, peripheral vasculature system, and the endocrine system. Despite the multitude of very convincing anecdotal reports showing its efficacy (and to date no reports refuting this hypothesis), there has only been one controlled study which showed the benefit of dextroamphetamine sulfate on edema and weight gain in diet-refractory patients. The flaw to date for general acceptance of this hypothesis is that most positive studies are coming from one clinical center. Furthermore, more controlled studies are needed. There has been a recent interest amongst physiologists and recent studies have been published confirming a deficiency of sympathetic nerve fibers in some of these disorders which hopefully will encourage more research into other physiologic systems leading to corroboration of this hypothesis.     

Postexercise depression of motor evoked potentials: a measure of central nervous system fatigue

Fatigue of voluntary muscular effort is a complex and multifaceted phenomenon. Fatigue of peripheral nervous system components, including the contractile apparatus and the neuromuscular junction, has been well studied. Central nervous system components also fatigue, but studies have lagged for want of objective methods. Transcranial magnetic stimulation is a relatively new technique that can be used to assess central nervous system excitability from the motor cortex to the alpha-motoneuron. In six normal volunteers, including four of the investigators, the amplitudes of motor evoked potentials elicited by transcranial magnetic stimulation were transiently decreased after exercise, indicating fatigue of motor pathways in the central nervous system. The decrease in amplitude was associated with a feeling of fatigue. The mechanism of this phenomenon is apparently decreased efficiency in the generation of the motor command in the motor cortex.     

Laminin alpha1 chain improves laminin alpha2 chain deficient peripheral neuropathy

Absence of laminin alpha2 chain leads to a severe form of congenital muscular dystrophy (MDC1A) associated with peripheral neuropathy. Hence, future therapies should be aimed at alleviating both muscle and neurological dysfunctions. Pre-clinical studies in animal models have mainly focused on ameliorating the muscle phenotype. Here we show that transgenic expression of laminin alpha1 chain in muscles and the peripheral nervous system of laminin alpha2 chain deficient mice reduced muscular dystrophy and largely corrected the peripheral nerve defects. The presence of laminin alpha1 chain in the peripheral nervous system resulted in near-normal myelination, restored Schwann cell basement membranes and improved rotarod performance. In summary, we postulate that laminin alpha1 chain is an excellent substitute for laminin alpha2 chain in multiple tissues and suggest that treatment with laminin alpha1 chain may be beneficial for MDC1A in humans.     

A direct selection procedure for isolating yeast mutants with an impaired segregation of artificial minichromosomes

Summary The nondisjunction of artificial yeast minichromosomes (2:0 segregation events) during mitosis is accompanied by the appearance of cells containing more than one copy of the mini-chromosome. A mathematical simulation of this process has demonstrated that under certain conditions, a nondisjunction of the minichromosomes may result in their accumulation in a considerable portion of the cell population. An increase in the copy number of artificial minichromosomes as a result of impaired segregation has been used to develop a new experimental procedure for directly selecting yeast mutants showing an impaired segregation of artificial minichromosomes during mitosis. Four new genes, AMC1, AMC2, AMC3, and AMC4, which control the segregation of artificial minichromosomes in mitosis, have been identified (AMC-3 and AMC4 are mapped to chromosome IV and VII, respectively). Mutations in the genes AMC1–AMC4 also affect the mitotic transmission of natural chromosomes. We suggest that the genes AMC1, AMC2, AMC3, and AMC4 control the segregation of natural chromosomes in yeast.     

International multidisciplinary collaboration toward an annotated definition of arthrogryposis multiplex congenita

Arthrogryposis multiplex congenita (AMC) has been described and defined in thousands of articles, but the terminology used has been inconsistent in clinical and research communities. A definition of AMC was recently developed using a modified Delphi consensus method involving 25 experts in the field of AMC from 8 countries. Participants included health care professionals, researchers, and individuals with AMC. An annotation of the definition provides more in‐depth explanations of the different sentences of the AMC definition and is useful to complement the proposed definition. The aim of this study was to provide an annotation of the proposed consensus‐based AMC definition. For the annotation process, 17 experts in AMC representing 10 disciplines across 7 countries participated. A paragraph was developed for each sentence of the definition using an iterative process involving multiple authors with varied and complementary expertise, ensuring all points of view were taken into consideration. The annotated definition provides an overview of the different topics related to AMC and is intended for all stakeholders, including youth and adults with AMC, their families, and clinicians and researchers, with the hopes of unifying the understanding of AMC in the international community.     

Congenital muscular dystrophy with neurological abnormalities: Association with Hirschsprung disease

We report on a baby girl with congenital muscular dystrophy (CMD) with neurological abnormalities (“CMD Plus” condition), who also had Hirschsprung disease. This association may indicate a category of congenital muscular dystrophy with involvement of the visceral nervous system. We propose that Hirschsprung disease be added to the list of anomalies pertaining to the “CMD Plus” array, and that CMD should be considered when Hirschsprung disease occurs with central nervous system anomalies. © 1993 Wiley-Liss, Inc.     

A rapid diagnostic method for a retrotransposal insertional mutation into the FCMD gene in Japanese patients with Fukuyama congenital muscular dystrophy

Fukuyama-type congenital muscular dystrophy (FCMD) is characterized by congenital muscular dystrophy in combination with central nervous system (CNS) abnormalities. Differential diagnosis of FCMD from Duchenne and Becker muscular dystrophies (DMD/BMD) or other types of congenital muscular dystrophy is occasionally difficult, because of their phenotypic similarity. The gene (FCMD) responsible for FCMD at 9q31 was isolated in 1998. In Japan, most FCMD-bearing chromosomes (87%) have a 3-kb retrotransposal insertion into the 3'-untranslated region (UTR) of the gene that could be derived from a single ancestral founder. Nine non-founder mutations have been identified in Japanese FCMD patients. Severe phenotype was significantly more frequent in patients who were compound heterozygotes for a point mutation and the founder mutation, than in homozygotes for the founder mutation. We developed a PCR-based diagnostic method for a rapid detection of the retrotransposal insertion mutation. Using this system, we screened 18 FCMD patients, and found 16 homozygotes and two heterozygotes for the insertion. We also evaluated the carrier frequency in the normal Japanese population. Six of 676 persons were recognized as a heterozygous carrier. Furthermore, we found three homozygotes for the FCMD founder mutation among 97 patients who had been said to have probable DMD/BMD without any DMD mutations. On the other hand, there were no FCMD homozygotes but four heterozygous carriers among 335 patients with DMD mutations. The diagnostic method we developed will provide a rapid and reliable diagnosis of FCMD, which can bring important information in genetic counseling, such as the accurate mode of inheritance, recurrence risk and a life expectancy.     

The many roles of dystroglycan in nervous system development and function

The glycoprotein dystroglycan was first identified in muscle, where it functions as part of the dystrophin glycoprotein complex to connect the extracellular matrix to the actin cytoskeleton. Mutations in genes involved in the glycosylation of dystroglycan cause a form of congenital muscular dystrophy termed dystroglycanopathy. In addition to its well-defined role in regulating muscle integrity, dystroglycan is essential for proper central and peripheral nervous system development. Patients with dystroglycanopathy can present with a wide range of neurological perturbations, but unraveling the complex role of Dag1 in the nervous system has proven to be a challenge. Over the past two decades, animal models of dystroglycanopathy have been an invaluable resource that has allowed researchers to elucidate dystroglycan's many roles in neural circuit development. In this review, we summarize the pathways involved in dystroglycan's glycosylation and its known interacting proteins, and discuss how it regulates neuronal migration, axon guidance, synapse formation, and its role in non-neuronal cells.     

A Neurogenic Component in Muscular Dystrophy

Evidence for a neurogenic component in mouse and human muscular dystrophy is briefly reviewed. Such evidence comes from certain clinical observations, electrophysiological studies, muscle pathology, nervous system pathology, transplantation experiments in animals, and tissue culture studies. The evidence is at present rather conflicting though the results of recent tissue culture experiments are more convincing. If there is a neurogenic component in dystrophy then the basic defect may have to be sought in the central nervous system rather than in the muscle itself. It is argued, however, that a neurogenic component in dystrophy cannot be simply a defect in the anterior horn cells of the spinal cord since the clinical features and the laboratory and pathological findings are quite different from those in spinal muscular atrophy.     

Immunocytochemical demonstration of 5-hydroxytryptamine (serotonin) in the nervous system of the liver fluke,Fasciola hepatica (Trematoda,Digenea)

The localisation and distribution of 5-hydroxytryptamine (5-HT or serotonin) in the nervous system ofFasciola hepatica has been determined by an indirect immunofluorescence technique. Cell bodies and nerve fibres immunoreactive to 5-HT are present in the anterior ganglia, and the longitudinal nerve cords and their commissures in the central nervous system. In the peripheral nervous system, similar immunoreactivity occurs in the nerve plexuses supplying the sub-tegumental muscle layers and the muscular lining of various reproductive ducts, including the ootype, uterus and cirrus pouch. The significance of these results in the light of previous studies on the role of 5-HT inF. hepatica is discussed.     

The effect of overstraining the sensory excitation process on the regeneration of muscle tissue in white rats

Summary The author investigated the regeneration of the anterior tibial muscle in white rats the nervous system of which was subjected to stimulation.In overstraining the cortical process of excitation in white rats with an excitable type of the nervous system the inflammatory reaction of the anterior tibial muscle is accompanied by extensive disintegration of the injured tissues, increased exudation and infiltration of the area of injurity with leukocytes. The granulation tissue shows marked vascularization. Restoration of the muscular tissue is inhibited by the active connective tissue development. The regenerative reaction in rats with a weak excitation process. i.e., in the animals with extreme inhibition, is depressed. In rats with a stronger nervous system (inhibitable, but capable of functioning) the inflammatorry reaction follows the course similar to that in control animals. Intensification of the neurotic condition induces a delayed differentiation process in the connective and muscular tissues.(Presented by Active Member of the Academy of Medical Sciences, USSR, V. N. Chernigovskii) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny Vol. 49, No. 5, pp. 104–109, May, 1960.     

Development of an online registry for adults with arthrogryposis multiplex congenita: A protocol paper

Arthrogryposis multiplex congenita (AMC) is considered a rare disorder resulting in multiple congenital contractures in two or more areas. Considerable literature is available on managing the contractures during an affected child's development but little information is available to those managing these ongoing issues in adulthood. Due to the heterogeneity etiological factors and presentation of AMC, and the small sample sizes of previous studies, it has been difficult to generalize results to the adult population. This current study presents the several steps taken to create an international AMC database for adults to populate with their own data over time. The methods included a scoping review of the literature for valid and reliable outcome measures used for AMC, a Delphi methodology to create the database with a team of clinicians, researchers and patients, a Beta testing of the database, and a final launch of the Adult AMC Registry. This registry includes 48 nonstandardized questions and 12 standardized questionnaires. It takes 35–45 min for a participant to complete. A shorter version will be created for participants to complete for years 2 and 3, followed by this longer version every 4 years. The protocol for referring English‐speaking patients and access to the registry is provided. Data will be reviewed every year to ensure quality. The registry will be maintained for a minimum of 10 years and data will be comprehensively analyzed every 5 years. Our goal is to have 500 adults with AMC from around the world as participants.     

Characterization of two amphioxus Wnt genes (AmphiWnt4 and AmphiWnt7b) with early expression in the developing central nervous system.

Full-length sequences and developmental expression patterns of two amphioxus Wnt genes (AmphiWnt4 and AmphiWnt7b) are described for the first time. The dynamic expression pattern of AmphiWnt4 suggests roles in the development of the posterior mesoderm, central nervous system, muscular somites, heart, and endostyle (a homolog of the vertebrate thyroid). The less diverse expression domains of AmphiWnt7b indicate that this gene may be involved only in the development of the central nervous system and the endostyle. In contrast to amphioxus, vertebrate embryos do not express Wnt4 homologues in the posterior mesoderm, somites, or heart; instead, Wnt genes of other subfamilies are expressed in these developing vertebrate organs. Because the developmental genetic programs of amphioxus may approximate those in the invertebrate chordate ancestor of the vertebrates, it is possible that some developmental functions of an ancestral Wnt4 gene may have been assumed by genes of other Wnt subfamilies during vertebrate evolution, possibly as a result of functional redundancy among Wnt subfamilies.     

Expression of GABA-immunoreactivity by spinal motoneurons of some vertebrates

Electrophysiological and biochemical investigations have shown that gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the vertebrate central nervous system. However, the present study shows that some motoneurons located in the spinal cord of young chickens and adult monkeys display a GABA-like immunoreactivity. The expression of GABA immunoreactivity in vertebrate motoneurons suggests that this inhibitory amino acid is colocalized with acetylcholine and could play a role in the neuromuscular transmission.     

Pain among children and adults living with arthrogryposis multiplex congenita: A scoping review

Clinical interventions and research have mostly focused on the orthopedic and genetic outcomes of individuals with arthrogryposis multiplex congenita (AMC), and although pain has gained recognition as an important issue experienced by individuals with AMC, it has received little attention within the AMC literature. The aims of this scoping review were to describe the pain experiences of children and adults with AMC, to identify pain assessment tools and management techniques, and document the impact of pain on participation in everyday activities among children and adults with AMC. A search of the literature was conducted in four search engines and identified a total of 89 articles. Once study eligibility was reviewed, 21 studies met the selection criteria and were included in this review. Pain appears to be more commonly experienced in adults with AMC compared with children with AMC, with individuals having undergone multiple corrective procedures self‐reporting pain more often. In adult populations, musculoskeletal chronic pain is a significant problem, resulting in restrictions in activities of daily living, mobility, and participation. Researchers and clinicians must agree on the use of validated measures appropriate for evaluating pain in AMC and the use of appropriate pain management techniques to relieve pain. Pediatric studies should focus on determining how commonly pain is experienced in infants, children, and adolescents with AMC. Pain in adults with AMC should be acknowledged to offer proper client‐centered interventions throughout the lifespan.