Form Of Arthrogryposis Multiplex Congenita Research Articles

Speech development in children of preschool age with arthrogryposis multiplex congenital with upper limb deformities

BACKGROUND: The difficulties or gross disturbance in motor development, which are diagnosed in children at an early age, are one of the prognostic markers of further problems in their speech development.
 AIM: This study aimed to determine the speech development of children with arthrogryposis multiplex congenita with upper limb deformities.
 MATERIALS AND METHODS: Speech examination was conducted in 21 children with arthrogryposis multiplex congenita preschool age (average age: 5.16 1.49 years) from 2020 to 2021. Patients were divided into 2 groups: group 1 (10 people) with children of younger and middle preschool age (average age 3.81 0.63 years) and group 2 (11 people) with children of older and preparatory preschool age (average age 6.39 0.78 years). The speech examination results were exposed to statistical analysis.
 RESULTS: The majority of children with arthrogryposis multiplex congenita had speech pathology (90.5%), whereas general speech underdevelopment dominated over speech development delay (78.9% and 21.1%, respectively). A high frequency of perinatal hypoxic-ischemic encephalopathy in children with arthrogryposis multiplex congenita (80.9%), a complicated perinatal anamnesis (57.1%), and a delay in early motor or speech development (100% and 52.4%, respectively) links with speech disorder development in the future. Patients with arthrogryposis have a large percentage of congenital pathology of the articulatory apparatus structure (57.1%). Of the children, 76.2% were with a total form of arthrogryposis multiplex congenita, whereas 23.8% with an isolated upper extremity lesion. No statistically significant differences were determined in the form of speech pathology between patients with various forms of arthrogryposis multiplex congenita. Children of the first age group had speech disorders in 90% of cases, whereas 90.9% in group 2. Based on the form of speech pathology, patients with general speech underdevelopment and speech development delay were determined in group 1 (55.6% and 44.4%, respectively), whereas children with general speech underdevelopment in group 2 (100%). In the clinical form of speech pathology, dysarthria prevailed in children of both age groups (80%).
 CONCLUSIONS: Children with arthrogryposis multiplex congenita with upper limb deformities have a high incidence of speech disorders. Early speech examination and speech therapy eliminated all detected disturbances.

The Clinical and Genotypic Spectrum of Scoliosis in Multiple Pterygium Syndrome: A Case Series on 12 Children

Background: Multiple pterygium syndrome (MPS) is a genetically heterogeneous rare form of arthrogryposis multiplex congenita characterized by joint contractures and webbing or pterygia, as well as distinctive facial features related to diminished fetal movement. It is divided into prenatally lethal (LMPS, MIM253290) and nonlethal (Escobar variant MPS, MIM 265000) types. Developmental spine deformities are common, may present early and progress rapidly, requiring regular fo llow-up and orthopedic management. Methods: Retrospective chart review and prospective data collection were conducted at three hospital centers. Molecular diagnosis was confirmed with whole exome or whole genome sequencing. Results: This case series describes the clinical features and scoliosis treatment on 12 patients from 11 unrelated families. A molecular diagnosis was confirmed in seven; two with MYH3 variants and five with CHRNG. Scoliosis was present in all but our youngest patient. The remaining 11 patients spanned the spectrum between mild (curve ≤ 25°) and malignant scoliosis (≥50° curve before 4 years of age); the two patients with MYH3 mutations presented with malignant scoliosis. Bracing and serial spine casting appear to be beneficial for a few years; non-fusion spinal instrumentation may be needed to modulate more severe curves during growth and spontaneous spine fusions may occur in those cases. Conclusions: Molecular diagnosis and careful monitoring of the spine is needed in children with MPS.

A 63-bp insertion in exon 2 of the porcine KIF21A gene is associated with arthrogryposis multiplex congenita.

A recessive form of arthrogryposis multiplex congenita (AMC) was detected 20years ago in the Swiss Large White (SLW) pig population. A diagnostic marker test enabled the identification of carrier animals, but the underlying causal mutation remains unknown. To identify the mutation underlying AMC, we collected SNP chip genotyping data for 11 affected piglets and 23 healthy pigs. Association testing using 47829 SNPs confirmed that AMC maps to SSC5 (P=9.4×10-13 ). Subsequent autozygosity mapping revealed a common 6.06Mb region (from 66 757970 to 72815151bp) of extended homozygosity in 11 piglets affected by AMC. Using WGS data, we detected a 63-bp insertion compatible with the recessive inheritance of AMC in the second exon of KIF21A gene encoding Kinesin Family Member 21A. The 63-bp insertion is predicted to introduce a premature stop codon in KIF21A gene (p.Val41_Phe42insTer) that truncates 1614 amino acids (~97%) from the protein. We found that this deleterious allele still segregates at a frequency of 0.1% in the SLW pig population. Carrier animals can now be detected unambiguously and excluded from breeding.

Deleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita.

Pathogenic variants in the X-linked gene ZC4H2, which encodes a zinc-finger protein, cause an infrequently described syndromic form of arthrogryposis multiplex congenita (AMC) with central and peripheral nervous system involvement. We present genetic and detailed phenotypic information on 23 newly identified families and simplex cases that include 19 affected females from 18 families and 14 affected males from nine families. Of note, the 15 females with deleterious de novo ZC4H2 variants presented with phenotypes ranging from mild to severe, and their clinical features overlapped with those seen in affected males. By contrast, of the nine carrier females with inherited ZC4H2 missense variants that were deleterious in affected male relatives, four were symptomatic. We also compared clinical phenotypes with previously published cases of both sexes and provide an overview on 48 males and 57 females from 42 families. The spectrum of ZC4H2 defects comprises novel and recurrent mostly inherited missense variants in affected males, and de novo splicing, frameshift, nonsense, and partial ZC4H2 deletions in affected females. Pathogenicity of two newly identified missense variants was further supported by studies in zebrafish. We propose ZC4H2 as a good candidate for early genetic testing of males and females with a clinical suspicion of fetal hypo-/akinesia and/or (neurogenic) AMC.

Identification of a novel CNTNAP1 mutation causing arthrogryposis multiplex congenita with cerebral and cerebellar atrophy

Arthrogryposis multiplex congenital, the occurrence of multiple joint contractures at birth, can in some cases be accompanied by insufficient myelination of peripheral nerves, muscular hypotonia, reduced tendon reflexes, and respiratory insufficiency. Recently mutations in the CASPR/CNTN1 complex have been associated with similar severe phenotypes and CNTNAP1 gene mutations, causing loss of the CASPR protein, were shown to cause severe, prenatal onset arthrogryposis multiplex congenita in four unrelated families. Here we report a consanguineous Arab family from Qatar with three children having an early lethal form of arthrogryposis multiplex congenita and a novel frameshift mutation in CNTNAP1. We further expand the existing CNTNAP1-associated phenotype to include profound cerebral and cerebellar atrophy.

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.

ZBTB42 mutation defines a novel lethal congenital contracture syndrome (LCCS6).

Lethal congenital contracture syndrome (LCCS) is a lethal autosomal recessive form of arthrogryposis multiplex congenita (AMC). LCCS is genetically heterogeneous with mutations in five genes identified to date, all with a role in the innervation or contractile apparatus of skeletal muscles. In a consanguineous Saudi family with multiple stillbirths presenting with LCCS, we excluded linkage to all known LCCS loci and combined autozygome analysis and whole-exome sequencing to identify a novel homozygous variant in ZBTB42, which had been shown to be enriched in skeletal muscles, especially at the neuromuscular junction. Knockdown experiments of zbtb42 in zebrafish consistently resulted in grossly abnormal skeletal muscle development and myofibrillar disorganization at the microscopic level. This severe muscular phenotype is successfully rescued with overexpression of the human wild-type ZBTB42 gene, but not with the mutant form of ZBTB42 that models the human missense change. Our data assign a novel muscular developmental phenotype to ZBTB42 in vertebrates and establish a new LCCS6 type caused by ZBTB42 mutation.

Nonlethal Multiple Pterygium Syndrome

Nonlethal Escobar is a rare disorder that is a variant of multiple pterygium syndromes. It is a form of arthrogryposis multiplex congenita characterized by excessive webbing (pterygia), congenital contractures (arthrogryposis), and scoliosis. It is usually diagnosed in utero on fetal ultrasound and then confirmed in the neonatal period. A case of nonlethal neonatal Escobar is reported in a 35-week-and-6-day old infant who presented in utero with decreased fetal movement, oligohydramnios, and arthrogryposis. The etiologies from maternal causes were excluded prior to birth. Subsequent workup after birth led to a highly suspected diagnosis of nonlethal Escobar by the geneticist. The diagnosis was confirmed by a positive CHRNG gene sequence analysis after discharge. The infant demonstrated contractures and bilateral hip subluxation but was feeding well and was discharged home with outpatient follow-up. Treatment after discharge has been extensive secondary to difficulties associated with this disease. The clinical presentation of nonlethal Escobar, as well as diagnosis and treatment strategies, is provided with caregiving strategies.

G.P.10.08 Fetal myasthenia and arthrogryposis multiplex congenita caused by mutation in the fetal γ-subunit of the acetylcholine receptor ( CHRNG): Escobar syndrome

Absent or limitations of movement during fetal development such as space constraints, oligohydramnion, drugs, metabolic conditions or neuromuscular disorders may lead to multiple joint contractures in the neonate. Escobar syndrome is a form of arthrogryposis multiplex congenita inherited as an autosomal recessive condition and it is characterized by multiple pterygia, congenital contractures, scoliosis and other dysmorphological features. Recently, this syndrome has been described as a prenatal myasthenia caused by disruption of the acetylcholine receptor (AChR) fetal γ-subunit.

Escobar Syndrome Is a Prenatal Myasthenia Caused by Disruption of the Acetylcholine Receptor Fetal γ Subunit

Escobar syndrome is a form of arthrogryposis multiplex congenita and features joint contractures, pterygia, and respiratory distress. Similar findings occur in newborns exposed to nicotinergic acetylcholine receptor (AChR) antibodies from myasthenic mothers. We performed linkage studies in families with Escobar syndrome and identified eight mutations within the gamma -subunit gene (CHRNG) of the AChR. Our functional studies show that gamma -subunit mutations prevent the correct localization of the fetal AChR in human embryonic kidney-cell membranes and that the expression pattern in prenatal mice corresponds to the human clinical phenotype. AChRs have five subunits. Two alpha, one beta, and one delta subunit are always present. By switching gamma to epsilon subunits in late fetal development, fetal AChRs are gradually replaced by adult AChRs. Fetal and adult AChRs are essential for neuromuscular signal transduction. In addition, the fetal AChRs seem to be the guide for the primary encounter of axon and muscle. Because of this important function in organogenesis, human mutations in the gamma subunit were thought to be lethal, as they are in gamma -knockout mice. In contrast, many mutations in other subunits have been found to be viable but cause postnatally persisting or beginning myasthenic syndromes. We conclude that Escobar syndrome is an inherited fetal myasthenic disease that also affects neuromuscular organogenesis. Because gamma expression is restricted to early development, patients have no myasthenic symptoms later in life. This is the major difference from mutations in the other AChR subunits and the striking parallel to the symptoms found in neonates with arthrogryposis when maternal AChR auto-antibodies crossed the placenta and caused the transient inactivation of the AChR pathway.

Muscle involvement and motor function in amyoplasia

The most common form of arthrogryposis multiplex congenita (AMC) is amyoplasia. Diagnostic criteria are highly specific, with decreased muscle mass, typical contractures and limb positioning at birth. Intellectual development is normal. The aims of this study were to investigate how muscle strength and contractures affect motor function in amyoplasia, and to relate current functional status to joint positions at birth. Medical records were reviewed and a clinical examination was performed, with investigation of muscle strength, range of motion, and motor function. Thirty-five patients with amyoplasia participated and were divided into three functional groups: 11 community ambulators, 11 household ambulators, and 7 non-ambulators. Six children less than 2 years old were not categorized. Community ambulators had the best muscle strength and none had knee flexion contractures extending 20 degrees. Household ambulators had severe contractures in the lower limbs, but good muscle strength in the upper limbs. Non-ambulators had most severe contractures and most severely reduced muscle strength. Most of the non-ambulators were born with hips in severe abduction, flexion and external rotation. Good and very good correlations were found between muscle strength and motor function, and only moderate correlations between range of motion and motor function. We conclude that more attention should be paid to developing muscle strength, with early stimulation of active movement, and that periods of immobilization should be minimized. Further, ultrasound or MRI of muscle tissue in the newborn period would be useful to evaluate prerequisites for future development of muscle strength and thereby anticipate response to therapy.

Ragged-red fibers and complex I deficiency in a neonate With arthrogryposis congenita

We describe a neonate with hypotonia, weakness, early death owing to respiratory failure, and a severe form of arthrogryposis multiplex congenita. Postmortem studies revealed numerous ragged-red fibers and central nervous system abnormalities consistent with a mitochondrial disease. No NADH:ubiquinone-1 oxidoreductase (complex I) activity could be detected in skeletal muscle. These findings suggest that mitochondria) cytopathies can be associated with arthrogryposis multiplex congenita and should therefore be sought in neonates presenting with severe arthrogryposis.

Pena-Shokeir phenotype associated with bilateral opercular polymicrogyria

Autopsy examination of an infant with the Pena-Shokeir phenotype revealed bilateral opercular polymicrogyria associated with neuronal loss and ferrugination in the basal ganglia, thalamus, brainstem, and spinal anterior horns. Bilateral opercular polymicrogyria previously has been linked to the developmental form of Foix-Chavany-Marie syndrome, or faciopharyngoglossomasticatory diplegia. In the Pena-Shokeir phenotype, bilateral opercular polymicrogyria may contribute to deficits in swallowing and facial movements. The pattern of brain and spinal cord injury in this case supports previous suggestions that the Pena-Shokeir phenotype (and certain other forms of arthrogryposis multiplex congenita) may be caused by hypoxic-ischemic injury to the developing central nervous system.

CT-scanning of skeletal muscle in arthrogryposis multiplex congenita

CT-scanning of skeletal muscles was performed on 14 patients with arthrogryposis multiplex congenita (AMC), according to an eight-slice protocol. Adipose tissue replacement and atrophy of muscles was found in six patients with neurogenic or myopathic origin of AMC, associated with severe muscle weakness. In the remaining patients with other forms of AMC, in which muscle weakness was less marked or absent, muscular CT-scanning was normal. It is stated that muscular CT-scanning is not a routine investigation in a screening procedure of all cases of AMC. However, CT-scanning appears to be useful in cases of severe AMC with associated muscle weakness in detecting the neurogenic and myopathic forms. It also facilitates the selection of a suitable site for EMG and biopsy and may provide important information for orthopaedic management.

Arthrogryposis multiplex congenita: An autopsy case of a fatal form

A case of a severe and fatal form of arthrogryposis multiplex congenita with a full necropsy examination is presented in which the central nervous system and many muscles of the four extremities were examined histologically. The most striking feature was a great reduction in the muscular tissue of the limbs with a marked increase in the adipose tissue. The muscular changes were thought to be caused by neurogenic atrophy, and microscopy of the spinal cord revealed developmental abnormalities, including degenerative changes of the anterior horn cells. Neonatal and fatal cases of arthrogryposis multiplex congenita reported in the literature are briefly reviewed, and the characteristics of the present case and its relation to other congenital neuromuscular disorders are discussed.

Neuropathic form of arthrogryposis multiplex congenita: Report of 3 cases with complete necropsy, including the first reported case of agenesis of muscle spindles

In 3 infants with arthrogryposis multiplex congenita (AMC) complete necropsy, including removal of the entire spinal cord, was performed. Histologically, spinal type (neurogenic) atrophy of skeletal muscles in conjunction with spinal motor neurone depletion, unaccompanied by noticeable gliosis, were the most prominent features common to all cases. In addition to these, one infant (Case 1) showed total absence of muscle spindles as evident from the examination of several hundred step-serial paraffin sections covering 11 different levels in 36 samples taken from a wide range of skeletal muscles of both upper and lower extremities. This is believed to be the first published case of agenesis of muscle spindles.

A new familial arthrogryposis without weakness.

A father and two daughters have a distinctive form of arthrogryposis multiplex congenita in which there is neither weakness nor atrophy about the affected joints despite the existence of myopathy. Contractures of the hips arid shoulders are present in all three individuals, but only the father has severe involvement of the hands and feet. Serum creatine phosphokinase values are 1.5 and three times normal in the daughters and five times normal in the father. Although it is likely that the myopathy and arthrogryposis are due to the effects of a dominantly inherited gene that appears as a new mutation in the father, the mechanism of production of the arthrogryposis in the absence of weakness is unknown.

Arthrogryposis multiplex congenita. Case due to disease of the anterior horn cells.

Introduction Arthrogryposis Multiplex Congenita is a syndrome which is characterized by congenital fixation of multiple joints. A number of associated neuromuscular and skeletal defects have been reported in affected individuals. The syndrome is not rare, and the clinical aspects have been described previously. From the few autopsy studies reported in the literature, it is clear that arthrogryposis may occur in a setting either of anterior horn cell disease or of primary disease of muscle. However, very few critical postmortem studies have been made, and the relationship of neural and muscular abnormalities to the manifest joint deformities poses many intriguing problems. We have had the opportunity to study pathologically a newborn infant with the neural form of arthrogryposis multiplex congenita. We wish to present our case partly because of the scarcity of well-studied autopsy material, but especially because our findings may provide a clue to the relationship between central nervous system