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Genes Jul 2022Duplication and deletion of the peripheral myelin protein 22 (PMP22) gene cause Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to...
Duplication and deletion of the peripheral myelin protein 22 (PMP22) gene cause Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP), respectively, while point mutations or small insertions and deletions (indels) usually cause CMT type 1E (CMT1E) or HNPP. This study was performed to identify PMP22 mutations and to analyze the genotype−phenotype correlation in Korean CMT families. By the application of whole-exome sequencing (WES) and targeted gene panel sequencing (TS), we identified 14 pathogenic or likely pathogenic PMP22 mutations in 21 families out of 850 CMT families who were negative for 17p12 (PMP22) duplication. Most mutations were located in the well-conserved transmembrane domains. Of these, eight mutations were not reported in other populations. High frequencies of de novo mutations were observed, and the mutation sites of c.68C>G and c.215C>T were suggested as the mutational hotspots. Affected individuals showed an early onset-severe phenotype and late onset-mild phenotype, and more than 40% of the CMT1E patients showed hearing loss. Physical and electrophysiological symptoms of the CMT1E patients were more severely damaged than those of CMT1A while similar to CMT1B caused by MPZ mutations. Our results will be useful for the reference data of Korean CMT1E and the molecular diagnosis of CMT1 with or without hearing loss.
Topics: Arthrogryposis; Charcot-Marie-Tooth Disease; Deafness; Hereditary Sensory and Motor Neuropathy; Humans; Mutation; Myelin Proteins
PubMed: 35886002
DOI: 10.3390/genes13071219 -
British Medical Journal (Clinical... Jul 1981
Topics: Adult; Amniotic Fluid; Arthrogryposis; Australia; Child; Humans; United Kingdom; United States
PubMed: 6788248
DOI: No ID Found -
Pediatric Physical Therapy : the... Jul 2022Primary study objectives were to ( a ) characterize pain and explore differences between adolescents and adults with arthrogryposis multiplex congenita (AMC) and ( b )...
PURPOSE
Primary study objectives were to ( a ) characterize pain and explore differences between adolescents and adults with arthrogryposis multiplex congenita (AMC) and ( b ) evaluate associations between pain-related outcomes and mobility.
METHODS
People who can walk and with AMC completed pain-related questionnaires.
RESULTS
Sixty-three participants (28 adolescents and 35 young adults) were recruited. Pain was reported in the past week by 81% of participants; intensity ratings were similar between age groups. Per the McGill Pain Questionnaire, pain severity was significantly lower among adolescents. Adults had a greater number of painful regions compared with adolescents. Greater 7-day average pain intensity, McGill Pain Questionnaire scores, and number of painful regions were associated with reduced functional mobility.
CONCLUSIONS
As most adolescents and young adults with AMC have at least mild pain, and pain is associated with mobility, future longitudinal investigations of pain and its functional consequences are warranted.
Topics: Adolescent; Arthrogryposis; Humans; Pain; Pain Measurement; Surveys and Questionnaires; Young Adult
PubMed: 35639545
DOI: 10.1097/PEP.0000000000000913 -
Neurology. Genetics Feb 2022The main objective of this case report is to identify a gene associated with a Japanese family with autosomal dominant arthrogryposis.
OBJECTIVES
The main objective of this case report is to identify a gene associated with a Japanese family with autosomal dominant arthrogryposis.
METHODS
We performed clinicopathologic diagnosis and genomic analysis using trio-based exome sequencing.
RESULTS
A 14-year-old boy had contractures in the proximal joints, and the serum creatine kinase level was elevated. Muscle biopsy demonstrated a moth-eaten appearance in some type 1 fibers, and electron microscopic analysis revealed that type 1 fibers had Z disk streaming. We identified a heterozygous nonsense variant, c.523A>T (p.K175*), in in the family.
DISCUSSION
The altered amino acid residue is within the tropomyosin-binding site near the C-terminus, in a region homologous to the variational hotspot of Troponin I2 (TNNI2), which is associated with distal arthrogryposis type 1 and 2b. Compared with patients with variants, our patient had a milder phenotype and proximal arthrogryposis. We report here a case of proximal arthrogryposis associated with a nonsense variant, which expands the genetic and clinical spectrum of this disease. Further functional and genetic studies are required to clarify the role of in the disease.
PubMed: 34934811
DOI: 10.1212/NXG.0000000000000649 -
Cells Aug 2023The cholinergic system plays an essential role in brain development, physiology, and pathophysiology. Herein, we review how specific alterations in this system, through... (Review)
Review
The cholinergic system plays an essential role in brain development, physiology, and pathophysiology. Herein, we review how specific alterations in this system, through genetic mutations or abnormal receptor function, can lead to aberrant neural circuitry that triggers disease. The review focuses on the nicotinic acetylcholine receptor (nAChR) and its role in addiction and in neurodegenerative and neuropsychiatric diseases and epilepsy. Cholinergic dysfunction is associated with inflammatory processes mainly through the involvement of α7 nAChRs expressed in brain and in peripheral immune cells. Evidence suggests that these neuroinflammatory processes trigger and aggravate pathological states. We discuss the preclinical evidence demonstrating the therapeutic potential of nAChR ligands in Alzheimer disease, Parkinson disease, schizophrenia spectrum disorders, and in autosomal dominant sleep-related hypermotor epilepsy. PubMed and Google Scholar bibliographic databases were searched with the keywords indicated below.
Topics: Humans; Cell Membrane; Alzheimer Disease; Arthrogryposis; Brain; Receptors, Nicotinic
PubMed: 37626860
DOI: 10.3390/cells12162051 -
Neuropediatrics Oct 2022Arthrogryposis is characterized by the presence of multiple contractures at birth and can be caused by pathogenic variants in (). Exons and variants that are not...
INTRODUCTION
Arthrogryposis is characterized by the presence of multiple contractures at birth and can be caused by pathogenic variants in (). Exons and variants that are not expressed in one of the three major isoforms of titin are referred to as "metatranscript-only" and have been considered to be only expressed during fetal development. Recently, the metatranscript-only variant (c.39974-11T > G) in with a second truncating variant has been linked to arthrogryposis multiplex congenita and myopathy.
METHODS
Via exome sequencing we identified the c.39974-11T > G splice variant with one of three truncating variants p.Arg8922*, p.Lys32998Asnfs*63, p.Tyr10345*) in five individuals from three families. Clinical presentation and muscle ultrasound as well as MRI images were analyzed.
RESULTS
All five patients presented with generalized muscular hypotonia, reduced muscle bulk, and congenital contractures most prominently affecting the upper limbs and distal joints. Muscular hypotonia persisted and contractures improved over time. One individual, the recipient twin in the setting of twin-to-twin transfusion syndrome, died from severe cardiac hypertrophy 1 day after birth. Ultrasound and MRI imaging studies revealed a recognizable pattern of muscle involvement with striking fibrofatty involvement of the hamstrings and calves, and relative sparing of the femoral adductors and anterior segment of the thighs.
CONCLUSION
The recurrent c.39974-11T > G variant consistently causes congenital arthrogryposis and persisting myopathy providing evidence that the metatranscript-only 213 to 217 exons impact muscle elasticity during early development and beyond. There is a recognizable pattern of muscle involvement, which is distinct from other myopathies and provides valuable clues for diagnostic work-up.
Topics: Arthrogryposis; Connectin; Contracture; Humans; Infant, Newborn; Muscle Hypotonia; Muscular Diseases; Mutation; Protein Isoforms
PubMed: 35605965
DOI: 10.1055/a-1859-0800 -
Neuroscience Letters Jan 2021Development of peripheral nervous system (PNS) myelin involves a coordinated series of events between growing axons and the Schwann cell (SC) progenitors that will... (Review)
Review
Development of peripheral nervous system (PNS) myelin involves a coordinated series of events between growing axons and the Schwann cell (SC) progenitors that will eventually ensheath them. Myelin sheaths have evolved out of necessity to maintain rapid impulse propagation while accounting for body space constraints. However, myelinating SCs perform additional critical functions that are required to preserve axonal integrity including mitigating energy consumption by establishing the nodal architecture, regulating axon caliber by organizing axonal cytoskeleton networks, providing trophic and potentially metabolic support, possibly supplying genetic translation materials and protecting axons from toxic insults. The intermediate steps between the loss of these functions and the initiation of axon degeneration are unknown but the importance of these processes provides insightful clues. Prevalent demyelinating diseases of the PNS include the inherited neuropathies Charcot-Marie-Tooth Disease, Type 1 (CMT1) and Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) and the inflammatory diseases Acute Inflammatory Demyelinating Polyneuropathy (AIDP) and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP). Secondary axon degeneration is a common feature of demyelinating neuropathies and this process is often correlated with clinical deficits and long-lasting disability in patients. There is abundant electrophysiological and histological evidence for secondary axon degeneration in patients and rodent models of PNS demyelinating diseases. Fully understanding the involvement of secondary axon degeneration in these diseases is essential for expanding our knowledge of disease pathogenesis and prognosis, which will be essential for developing novel therapeutic strategies.
Topics: Animals; Arthrogryposis; Axons; Charcot-Marie-Tooth Disease; Demyelinating Diseases; Hereditary Sensory and Motor Neuropathy; Humans; Nerve Degeneration; Polyneuropathies; Schwann Cells
PubMed: 33359733
DOI: 10.1016/j.neulet.2020.135595 -
Journal of Human Genetics Mar 2022Neutral sphingomyelinases have an important role in generation of ceramide and phosphorylcholine from sphingomyelins which then act as secondary messengers in various...
Neutral sphingomyelinases have an important role in generation of ceramide and phosphorylcholine from sphingomyelins which then act as secondary messengers in various signaling pathways of the cellular machinery. They function ubiquitously with a predominant role in the central nervous system. Neutral sphingomyelinase type 3, encoded by SMPD4 gene has recently been reported to cause a severe autosomal recessive neurodevelopmental disorder with congenital arthrogryposis and microcephaly. We report a 22-month-old girl having characteristic features of neurodevelopmental delay, prenatal onset growth failure, arthrogryposis, microcephaly and brain anomalies including severe hypomyelination, simplified gyral pattern and hypoplasia of corpus callosum and brain stem. In addition, she was noted to have nystagmus and visual impairment secondary to macular dystrophy and retinal pigment epithelial stippling at posterior pole. Copy number variant analysis from trio whole exome sequencing (ES) enabled identification of a homozygous 11 kb deletion encompassing exons 18-20 of SMPD 4 gene, confirming the diagnosis of SMPD4-related disorder in her.
Topics: Arthrogryposis; Brain; Female; Humans; Infant; Microcephaly; Nervous System Malformations; Neurodevelopmental Disorders; Pregnancy
PubMed: 34621002
DOI: 10.1038/s10038-021-00981-3 -
HGG Advances Jul 2023Contraction of the human sarcomere is the result of interactions between myosin cross-bridges and actin filaments. Pathogenic variants in genes such as , , and that...
Contraction of the human sarcomere is the result of interactions between myosin cross-bridges and actin filaments. Pathogenic variants in genes such as , , and that encode parts of the cardiac sarcomere cause muscle diseases that affect the heart, such as dilated cardiomyopathy and hypertrophic cardiomyopathy. In contrast, pathogenic variants in homologous genes such as , , and that encode parts of the skeletal muscle sarcomere cause muscle diseases affecting skeletal muscle, such as distal arthrogryposis (DA) syndromes and skeletal myopathies. To date, there have been few reports of genes (e.g., ) encoding sarcomeric proteins in which the same pathogenic variant affects skeletal and cardiac muscle. Moreover, none of the known genes underlying DA have been found to contain pathogenic variants that also cause cardiac abnormalities. We report five families with DA because of heterozygous missense variants in the gene , , (). encodes a highly conserved actin that binds to myosin in cardiac and skeletal muscle. Pathogenic variants in have been found previously to underlie atrial septal defect, dilated cardiomyopathy, hypertrophic cardiomyopathy, and left ventricular noncompaction. Our discovery delineates a new DA condition because of variants in and suggests that some functions of are shared in cardiac and skeletal muscle.
Topics: Humans; Arthrogryposis; Actins; Heart Defects, Congenital; Cardiomyopathies; Cardiomyopathy, Dilated; Muscular Diseases; Myosins; Cardiomyopathy, Hypertrophic
PubMed: 37457373
DOI: 10.1016/j.xhgg.2023.100213 -
American Journal of Medical Genetics.... Sep 2019Upper extremity involvement in patients with arthrogryposis multiplex congentia is quite frequent. Treatment initially consists of stretching and splinting as...
Upper extremity involvement in patients with arthrogryposis multiplex congentia is quite frequent. Treatment initially consists of stretching and splinting as significant gains can be seen in the first years of life. The goal of any surgical procedure is to improve upper extremity function and performance of daily living activities, yet it is important to treat each patient individually and understand that areas do not always need to be addressed surgically. Despite overall lower functioning scores in this patient population, quality of life scores are comparable to the general aged adjusted population. This article will discuss the clinical presentation, treatment procedures and outcomes when addressing the upper extremities of patients presenting with arthrogryposis.
Topics: Activities of Daily Living; Arthrogryposis; Humans; Quality of Life; Treatment Outcome; Upper Extremity
PubMed: 31268234
DOI: 10.1002/ajmg.c.31722