Distal Arthrogryposes Research Articles

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.

Distal arthrogryposes type 5 caused by PIEZO2 gene variation

患儿 男，12岁，因“四肢关节活动受限”于2020年7月就诊于郑州大学附属儿童医院神经遗传代谢病专病门诊。主要表现为双腿屈膝，双手指屈曲。双侧肘膝关节、指（趾）间关节伸展、屈曲受限，以伸展受限为主。肌力正常，双下肢肌肉僵硬，双侧跟膝腱反射对称引出。基因检测结果示患儿PIEZO2基因存在杂合缺失c.8181_8183del，p.Glu2727del，父母及其妹妹均为野生型。PIEZO2基因变异所致远端关节挛缩5型临床罕见，为常染色体显性遗传。.

Distal Arthrogryposis Type Six and Systemic Lupus Erythematosus, in a Girl: First Pediatric Case

Arthrogryposis type six is one of the distal arthrogryposes. It associates arthrogryposis of the hands and sensorineural deafness. Male-to-male transmission was observed. No gene has been identified to date. We report a unique case of a girl presenting with congenital arthrogryposis-like hand anomaly, sensorineural deafness, and acute onset of systemic lupus erythematosus (SLE).

Findings, Phenotypes, Diagnostic Accuracy, and Treatment in Freeman-Burian Syndrome.

Freeman-Burian syndrome (FBS) is a rare congenital myopathic craniofacial syndrome. Since publication of the genotype-correlated clinical diagnostic criteria, no complete survey of the literature has been accomplished. As part of the clinical practice guideline development, we evaluate diagnostic accuracy for FBS from 1938 to 2019 and range of findings, complications, treatments, and outcomes. Published manuscripts in PubMed, Google Scholar, and OMIM describing cases with a reported diagnosis of FBS, Sheldon-Hall syndrome, and distal arthrogryposes type 1 and 3 are initially included. Articles with sufficient case-level data for diagnosis verification are analyzed further. Of 724 unique papers considered, 188 papers describing 304 unique patients are included; 101 papers and 119 patients reflect an FBS diagnosis, with 80 patients meeting the full diagnostic criteria. Most cases are re-screened as distal arthrogryposis type 1. Among all cases re-screened as FBS, the presence of FBS pathognomonic craniofacial findings is not correlated with other physical findings. There are no significant differences between patients meeting the full diagnostic criteria and those not, but both are distinct from other diagnoses. Plastic surgery demonstrates the highest cumulative diagnostic accuracy for FBS overall (86.66%), while orthopedic surgery shows the lowest (44.83%). No statistically usable treatment-related or psychosocial data are available. Quality of case reports and patient data vary widely, reducing the statistical strength and significance. Major knowledge gaps exist in treatment, psychosocial, and longitudinal outcomes. At this point, it is impossible to derive clinical practice guidelines exclusively from the literature.

Genetics and Classifications.

Arthrogryposis multiplex congenital (AMC) is a descriptive term for a group of conditions that all share the characteristic of congenital contractures. There are an estimated 400 discrete diagnoses that can lead to a child being born with arthrogryposis. The 2 biggest categories of conditions are amyoplasia and distal arthrogryposis, which combined make up ∼50% to 65% of all diagnoses within the AMC subset. Amyoplasia, the most common AMC condition, seems to be a nongenetic syndrome, leading to very characteristic upper and lower limb contractures. The distal arthrogryposes, in contrast, have an underlying genetic abnormality, which in many cases seems to target the fast twitch muscles of the developing fetus. Classifying AMC is a difficult task, given the broad range of conditions represented. Four different classification schemes are presented.

Digitotalar dysmorphism: Molecular elucidation.

Dominantly inherited digitotalar dysmorphism (DTD), which is characterised by flexion contractures of digits and 'rocker-bottom' feet due to a vertical talus, was first described in a South African family of European stock in 1972. We review the clinical manifestations and document the molecular basis for DTD in this prototype family. This family was restudied in 1995 and 2006 and biological specimens were obtained for molecular studies. Since the distal arthrogryposes (DAs) are genetically heterogeneous, an unbiased approach to mutation identification was undertaken through whole-exome next-generation sequencing of DNA from a single DTD-affected female. Venous blood specimens were obtained for DNA banking and subsequent molecular studies. Analysis of the nine genes that had previously been shown to cause DAs revealed a pathogenic mutation in exon nine of TNNT3. The presence of the p.(Arg63His) missense mutation at position 63 of TNNT3 was confirmed through direct cycle sequencing of genomic DNA in six affected family members for whom DNA had been archived.

Two novel mutations in myosin binding protein C slow causing distal arthrogryposis type 2 in two large Han Chinese families may suggest important functional role of immunoglobulin domain C2.

Distal arthrogryposes (DAs) are a group of disorders that mainly involve the distal parts of the limbs and at least ten different DAs have been described to date. DAs are mostly described as autosomal dominant disorders with variable expressivity and incomplete penetrance, but recently autosomal recessive pattern was reported in distal arthrogryposis type 5D. Mutations in the contractile genes are found in about 50% of all DA patients. Of these genes, mutations in the gene encoding myosin binding protein C slow MYBPC1 were recently identified in two families with distal arthrogryposis type 1B. Here, we described two large Chinese families with autosomal dominant distal arthrogryposis type 2(DA2) with incomplete penetrance and variable expressivity. Some unique overextension contractures of the lower limbs and some distinctive facial features were present in our DA2 pedigrees. We performed follow-up DNA sequencing after linkage mapping and first identified two novel MYBPC1 mutations (c.1075G>A [p.E359K] and c.956C>T [p.P319L]) responsible for these Chinese DA2 families of which one introduced by germline mosacism. Each mutation was found to cosegregate with the DA2 phenotype in each family but not in population controls. Both substitutions occur within C2 immunoglobulin domain, which together with C1 and the M motif constitute the binding site for the S2 subfragment of myosin. Our results expand the phenotypic spectrum of MYBPC1-related arthrogryposis multiplex congenita (AMC). We also proposed the possible molecular mechanisms that may underlie the pathogenesis of DA2 myopathy associated with these two substitutions in MYBPC1.

G.P.271: Mutation update and genotype-phenotype correlations of novel and previously described mutations in TPM2 and TPM3 causing congenital myopathies

Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy (NM), cap myopathy, core-rod myopathy, congenital fibre-type disproportion, core-rod myopathy, distal arthrogryposes and Escobar syndrome. Here we correlate the clinical picture of these diseases with novel (16) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. A total of 27 Twenty-seven distinct pathogenic variants of TPM2, and 20 of TPM3, have been published or listed in the Leiden Open Variant Database ( http://www.dmd.nl/ ). Most are heterozygous changes associated with autosomal dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca2 + sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotypes more often had contractures of the limb joints (18/19) and jaw (6/19) than those with non-hypercontractile ones (2/22 and 1/22), while patients with the non-hypercontractile molecular phenotypes more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin–actin association or tropomyosin head-to-tail binding.

Mutation Update and Genotype-Phenotype Correlations of Novel and Previously Described Mutations inTPM2andTPM3Causing Congenital Myopathies

Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy, cap myopathy, core-rod myopathy, congenital fiber-type disproportion, distal arthrogryposes, and Escobar syndrome. We correlate the clinical picture of these diseases with novel (19) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Thirty distinct pathogenic variants of TPM2 and 20 of TPM3 have been published or listed in the Leiden Open Variant Database (http://www.dmd.nl/). Most are heterozygous changes associated with autosomal-dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca(2+) sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contractures of the limb joints (18/19) and jaw (6/19) than those with nonhypercontractile ones (2/22 and 1/22), whereas patients with the non-hypercontractile molecular phenotype more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin-actin association or tropomyosin head-to-tail binding.

A novel TNNI2 mutation causes Freeman–Sheldon syndrome in a Chinese family with an affected adult with only facial contractures

Distal arthrogryposes (DAs), a clinically and genetically heterogeneous group of disorders characterized by congenital contractures with predominant involvement of the hands and feet, can be classified into at least 12 different forms. These autosomal dominant disorders are of variable expressivity and reduced penetrance. Mutations in sarcomeric protein genes, including troponin I2 (TNNI2), troponin T3 (TNNT3), tropomyosin 2 (TPM2), embryonic myosin heavy chain 3 (MYH3), and myosin binding protein C1 (MYBPC1), have been identified in distal arthrogryposis type 1 (DA1, MIM 108120), type 2B (DA2B, MIM 601680) and type 2A (DA2A)/Freeman–Sheldon syndrome (FSS, MIM 193700). However, mutations causing FSS have only been reported in MYH3. Herein we describe a Chinese DA family whose members meet classical strict criteria for FSS, as well as one member of the family who has isolated facial features consistent with FSS. No disease-causing mutation was found in MYH3. Segregation of microsatellite markers flanking the TNNI2 and TNNT3 genes at 11p15.5 was compatible with linkage. Subsequent sequencing of TNNI2 revealed a novel mutation, c.A493T (p.I165F), located in the C-terminal region, which is critical for proper protein function. This mutation was found to cosegregate with the FSS phenotype in this family, and assessment using SIFT and PolyPhen-2 predicted a damaging effect. To the best of our knowledge, we report the first TNNI2 mutation in classical FSS and describe an atypical adult FSS case with only facial contractures resulting from somatic mosaicism. We infer that DA1, DA2B and FSS represent a phenotypic continuum of the same disorder and provide further genetic evidence for this hypothesis.

Juvenile macular dystrophy and forearm pronation‐supination restriction presenting with features of distal arthrogryposis type 5

The distal arthrogryposes are a heterogeneous group of conditions characterized by congenital contractures of hands and feet, and autosomal dominant inheritance. The concurrence of ophthalmoplegia and additional ocular findings distinguish distal arthrogryposis type 5 (DA5). This rare subtype has been described in 33 patients to date and its clinical spectrum of physical findings is still poorly understood. We report on a family with three individuals with DA5. The index case came to our attention because of restricted forearm pronation-supination and juvenile macular dystrophy. Further examination revealed short stature, firm muscles, stiff spine with lumbar hyperlordosis, generalized mild limitation of the large joints, external rotation of the hips, unilateral ptosis, exophoria, and abnormal photopic and scotopic responses on electroretinogram testing. However, there was no overt evidence of contractures of the distal joints. Examination of other affected family members revealed restricted range of movement of the small joints together with ulnar deviation of the fingers, and clarified the diagnosis. Our observations suggest that DA5 may have a very mild musculoskeletal phenotype and it should be considered in the differential of congenital contracture syndromes even in the absence of obvious distal joint involvement. Our observations also suggest that fundoscopy and ocular electrophysiological studies might be helpful in the evaluation of patients with otherwise unclassified distal arthrogryposes.

Molecular prenatal diagnosis for hereditary distal arthrogryposis type 2B

Autosomal dominant distal arthrogryposes (DAs) are a group of muscle diseases characterized by congenital contractures of the limbs. Currently, prenatal diagnosis of DAs depends upon ultrasound examination during late gestation. Recently, five genes encoding fast switch proteins located at 9p13.2, 11p15.5 and 17q13.1 were identified. These included TPM2, TNNI2/TNNT3, and MYH3/MYH8. Last year, we discovered a novel heterozygous mutation c.523_525delAAG (p.K175del) in the TNNI2 gene, which encodes the isoform of troponinI, in a seven-generation Chinese family affected with distal arthrogryposis type 2B (DA2B). Here, we report the molecular prenatal diagnosis of 3 high-risk fetuses of two women in the family by two-point linkage inferential analysis and deletion detection of the TNNI2 gene with chorionic villus sampling (CVS) or amniocentesis. To our knowledge, this is the first description of molecular prenatal diagnosis for DAs.

Mutations in fast skeletal troponin I, troponin T, and β‐tropomyosin that cause distal arthrogryposis all increase contractile function

Distal arthrogryposes (DAs) are a group of disorders characterized by congenital contractures of distal limbs without overt neurological or muscle disease. Unexpectedly, mutations in genes encoding the fast skeletal muscle regulatory proteins troponin T (TnT), troponin I (TnI), and beta-tropomyosin (beta-TM) have been shown to cause autosomal dominant DA. We tested how these mutations affect contractile function by comparing wild-type (WT) and mutant proteins in actomyosin ATPase assays and in troponin-replaced rabbit psoas fibers. We have analyzed all four reported mutants: Arg63His TnT, Arg91Gly beta-TM, Arg174Gln TnI, and a TnI truncation mutant (Arg156ter). Thin filaments, reconstituted using actin and WT troponin and beta-TM, activated myosin subfragment-1 ATPase in a calcium-dependent, cooperative manner. Thin filaments containing either a troponin or beta-TM DA mutant produced significantly enhanced ATPase rates at all calcium concentrations without alternating calcium-sensitivity or cooperativity. In troponin-exchanged skinned fibers, each mutant caused a significant increase in Ca2+ sensitivity, and Arg156ter TnI generated significantly higher maximum force. Arg91Gly beta-TM was found to have a lower actin affinity than WT and form a less stable coiled coil. We propose the mutations cause increased contractility of developing fast-twitch skeletal muscles, thus causing muscle contractures and the development of the observed limb deformities.

The Distal Arthrogryposes

Distal arthrogryposes are a group of syndromes with congenital contractures primarily involving the hands and feet, which often are associated with abnormal facies, and are transmitted by autosomal dominant inheritance. Many affected individuals present in an orthopaedic setting. The features of these syndromes are described to allow diagnosis, establish prognosis, provide family counseling, and treatment. Increased recognition will lead to improved knowledge of the natural history.

Mutations in Genes Encoding Fast-Twitch Contractile Proteins Cause Distal Arthrogryposis Syndromes

The distal arthrogryposes (DAs) are a group of disorders characterized by multiple congenital contractures of the limbs. We previously mapped a locus for DA type 2B (DA2B), the most common of the DAs, to chromosome 11. We now report that DA2B is caused by mutations in TNNI2 that are predicted to disrupt the carboxy-terminal domain of an isoform of troponin I (TnI) specific to the troponin-tropomyosin (Tc-Tm) complex of fast-twitch myofibers. Because the DAs are genetically heterogeneous, we sought additional candidate genes by examining modifiers of mutant Drosophila isoforms of TnI. One of these modifiers, Tm2, encodes tropomyosin, another component of the Tc-Tm complex. A human homologue of Tm2, TPM2, encodes beta-tropomyosin and maps to the critical interval of DA type 1 (DA1). We discovered that DA1 is caused by substitution of a highly conserved amino acid residue in beta-tropomyosin. These findings suggest that DAs, in general, may be caused by mutations in genes encoding proteins of the contractile apparatus specific to fast-twitch myofibers. This provides a new opportunity to directly study the etiology and pathogenesis of multiple-congenital-contracture syndromes.

Arthrogryposis multiplex congenita

The common factor causing congenital arthrogryposis is lack of fetal movements. This can result from a large number of disorders. They may be neuropathic, affecting the brain, the spinal cord, or the peripheral nerves; they may be abnormalities of the muscles, such as myasthenia gravis, congenital muscular dystrophies or mitochondrial cytopathies; they may be diseases of the connective tissues; or they may be conditions which limit the space within the uterus; or they may result from defects of the uterine environment. These are discussed in turn. Typical clinical findings are given and it is emphasised that the arthrogryposis is often a manifestation of certain syndromes, some the result of abnormal chromosomes. Although it is not within the scope of this review article to describe these in detail, examples are given. In particular the subgroup of distal arthrogryposes and amyoplasia are considered. The importance of trying to define a cause is especially the need to give reliable genetic advice to the parents and also to establish a prognosis. The diagnosis will often be made by the associated symptoms and signs, and sometimes by tests such as electromyography and muscle biopsy. Although some of the diseases will be fatal early in life, there are many instances when the child will survive into adult life; if due attention is given to the treatment, particularly orthopedic procedures, and to social and educational management. This can only be done realistically if there is a good idea of the natural history of the condition underlying the arthrogryposis.

A revised and extended classification of the distal arthrogryposes.

Since the group of disorders known as the distal arthrogryposes (DAs) were defined, additional disorders characterized by multiple congenital contractures of the distal limbs were described, and the distribution of phenotypic findings in the DAs has been expanded. The breadth of disorders labeled as DAs has diminished the usefulness of the DA classification. We propose a strict definition of DA and diagnostic criteria for DA disorders. Subsequently, we use these standards and propose a revised classification of discrete conditions that should be labeled DAs. Optimally, this serves as a framework for a DA classification based on underlying molecular and physiologic abnormalities.

The distal arthrogryposes: Delineation of new entities – review and nosologic discussion

We report on 44 patients (18 with additional affected family members), with congenital distal limb contractures identified from a large study of over 350 patients with congenital joint contractures. Fourteen propositi (seven familial cases, seven isolated cases) had a newly recognized form of arthrogryposis, which we have designated distal arthrogryposis type 1, with the predominant manifestations of autosomal dominant inheritance; tightly clenched fists at birth, with medially overlapping fingers, ulnar deviation, and camptodactyly in adults; and positional foot deformities. Contractures at other major joints are variable. There are no associated visceral anomalies; intelligence is normal. There can be marked intrafamilial and interfamilial variability. Twenty-two propositi with similar distal contractures had additional findings and were classified into five subcategories of distal arthrogryposis (type IIA-E). Among type II patients cleft palate, cleft lip, small tongue, trismus, ptosis, epicanthal folds, keratoconus, short stature, scoliosis, a unique hand position, and dull normal intelligence were seen. These characteristics were seen in various combinations and patterns and allowed sorting into groups that were the basis for the categorization. The remaining eight propositi were recognized to have previously described conditions with distal contractures and autosomal dominant inheritance, ie, the Freeman-Sheldon syndrome, trismus-pseudo-camptodactyly syndrome, congenital contractural arachnodactyly, and familial camptodactyly. Pathogenetically we postulate similar underlying defects of abnormal tendon attachments, attenuation, and absence; careful nosologic comparisons are important for prognostic counseling and habilitative management.