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International Journal of Molecular... Aug 2023Migraine is a disabling neurological disorder burdening patients globally. Through the increasing development of preclinical and clinical experimental migraine models,... (Review)
Review
Migraine is a disabling neurological disorder burdening patients globally. Through the increasing development of preclinical and clinical experimental migraine models, advancing appreciation of the extended clinical phenotype, and functional neuroimaging studies, we can further our understanding of the neurobiological basis of this highly disabling condition. Despite increasing understanding of the molecular and chemical architecture of migraine mechanisms, many areas require further investigation. Research over the last three decades has suggested that migraine has a strong genetic basis, based on the positive family history in most patients, and this has steered exploration into possibly implicated genes. In recent times, human genome-wide association studies and rodent genetic migraine models have facilitated our understanding, but most migraine seems polygenic, with the monogenic migraine mutations being considerably rarer, so further large-scale studies are required to elucidate fully the genetic underpinnings of migraine and the translation of these to clinical practice. The monogenic migraine mutations cause severe aura phenotypes, amongst other symptoms, and offer valuable insights into the biology of aura and the relationship between migraine and other conditions, such as vascular disease and sleep disorders. This review will provide an outlook of what is known about some monogenic migraine mutations, including familial hemiplegic migraine, familial advanced sleep-phase syndrome, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.
Topics: Humans; Genome-Wide Association Study; Migraine Disorders; Mutation; Arthrogryposis; Blindness; Cerebral Arterial Diseases
PubMed: 37628876
DOI: 10.3390/ijms241612697 -
Current Opinion in Pediatrics Feb 2020The orthopaedic treatment of children with arthrogryposis multiplex congenita has evolved steadily over the past two decades. Interrelated factors have spurred this on,... (Review)
Review
PURPOSE OF REVIEW
The orthopaedic treatment of children with arthrogryposis multiplex congenita has evolved steadily over the past two decades. Interrelated factors have spurred this on, including better appreciation of the functional potential of persons with arthrogryposis, development of newer procedures specific for the arthrogrypotic deformities, and outcomes studies that provide understanding of the overall capabilities of adults with arthrogryposis and follow-up to determine which treatments were beneficial and which were not. This article briefly sketches out of some of these advances and indicates areas that need further development.
RECENT FINDINGS
Outcome studies show that the majority of adults with arthrogryposis are ambulatory but less than half are fully independent. Adults frequently experience ongoing pain, particularly foot and back pain, limiting ambulation and standing. Advancements in the upper extremity treatment include improving elbow function, wrist repositioning, and improving thumb positioning. In the lower extremities, correction of hip and knee contractures leads to improved ambulatory potential, and treating clubfeet with serial casting decreases poor outcomes.
SUMMARY
Clinical evaluation, both physical examination and assessment of the patient's needs, are important in directing treatment in arthrogryposis. Further outcomes studies are needed to continue to refine procedures and define the appropriate candidates.
Topics: Adult; Arthrogryposis; Child; Extremities; Humans; Orthopedic Procedures; Prenatal Care; Referral and Consultation; Spinal Diseases; Treatment Outcome
PubMed: 31743218
DOI: 10.1097/MOP.0000000000000847 -
The Journal of Biological Chemistry Jun 2023Loss-of-function variants of vacuolar protein sorting proteins VPS33B and VPS16B (VIPAS39) are causative for arthrogryposis, renal dysfunction, and cholestasis syndrome,...
Loss-of-function variants of vacuolar protein sorting proteins VPS33B and VPS16B (VIPAS39) are causative for arthrogryposis, renal dysfunction, and cholestasis syndrome, where early lethality of patients indicates that VPS33B and VPS16B play essential cellular roles. VPS33B is a member of the Sec1-Munc18 protein family and thought to facilitate vesicular fusion via interaction with soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes, like its paralog VPS33A in the homotypic fusion and vacuole sorting complex. VPS33B and VPS16B are known to associate, but little is known about the composition, structure, or function of the VPS33B-VPS16B complex. We show here that human VPS33B-VPS16B is a high molecular weight complex, which we expressed in yeast to perform structural, composition, and stability analysis. Circular dichroism data indicate VPS33B-VPS16B has a well-folded α-helical secondary structure, and size-exclusion chromatography-multiangle light scattering revealed a molecular weight of ∼315 kDa. Quantitative immunoblotting indicated a VPS33B:VPS16B ratio of 2:3. Expression of arthrogryposis, renal dysfunction, and cholestasis syndrome-causing VPS33B missense variants showed L30P disrupts complex formation but not S243F or H344D. Truncated VPS16B (amino acids 143 to 316) was sufficient to form a complex with VPS33B. Small-angle X-ray scattering and negative-staining EM revealed a two-lobed shape for VPS33B-VPS16B. Avidin tagging indicated that each lobe contains a VPS33B molecule, and they are oriented in opposite directions. We propose a structure for VPS33B-VPS16B that allows the VPS33B at each end to interact with separate SNARE bundles and/or SNAREpins, plus associated membrane components. These observations reveal the only known potentially bidirectional Sec1-Munc18 protein complex.
Topics: Humans; Munc18 Proteins; Renal Insufficiency; SNARE Proteins; Syndrome; Vesicular Transport Proteins
PubMed: 37062417
DOI: 10.1016/j.jbc.2023.104718 -
Prenatal Diagnosis Jun 2023Arthrogryposis, also termed arthrogryposis multiplex congenita, is a descriptive term for conditions with multiple congenital contractures (MCC). The etiology is... (Review)
Review
Arthrogryposis, also termed arthrogryposis multiplex congenita, is a descriptive term for conditions with multiple congenital contractures (MCC). The etiology is extremely heterogeneous. More than 400 specific disorders have been identified so far, which may lead to or are associated with MCC and/or fetal hypo- and akinesia as a clinical sign. With improved sensitivity of prenatal ultrasound and expanding prenatal diagnostic options, clinicians are tasked with providing early detection in order to counsel the prospective parents regarding further prenatal diagnostic as well as management options. We summarize the most important knowledge to raise awareness for early detection in pregnancy. We review essential points for counseling when MCC is detected in order to provide answers to common questions, which, however, cannot replace interdisciplinary expert opinion in the individual case.
Topics: Pregnancy; Female; Humans; Arthrogryposis; Prospective Studies; Ultrasonography, Prenatal; Prenatal Care; Parents
PubMed: 36588183
DOI: 10.1002/pd.6299 -
Brain : a Journal of Neurology Oct 2023In utero exposure to maternal antibodies targeting the fetal acetylcholine receptor isoform (fAChR) can impair fetal movement, leading to arthrogryposis multiplex...
In utero exposure to maternal antibodies targeting the fetal acetylcholine receptor isoform (fAChR) can impair fetal movement, leading to arthrogryposis multiplex congenita (AMC). Fetal AChR antibodies have also been implicated in apparently rare, milder myopathic presentations termed fetal acetylcholine receptor inactivation syndrome (FARIS). The full spectrum associated with fAChR antibodies is still poorly understood. Moreover, since some mothers have no myasthenic symptoms, the condition is likely underreported, resulting in failure to implement effective preventive strategies. Here we report clinical and immunological data from a multicentre cohort (n = 46 cases) associated with maternal fAChR antibodies, including 29 novel and 17 previously reported with novel follow-up data. Remarkably, in 50% of mothers there was no previously established myasthenia gravis (MG) diagnosis. All mothers (n = 30) had AChR antibodies and, when tested, binding to fAChR was often much greater than that to the adult AChR isoform. Offspring death occurred in 11/46 (23.9%) cases, mainly antenatally due to termination of pregnancy prompted by severe AMC (7/46, 15.2%), or during early infancy, mainly from respiratory failure (4/46, 8.7%). Weakness, contractures, bulbar and respiratory involvement were prominent early in life, but improved gradually over time. Facial (25/34; 73.5%) and variable peripheral weakness (14/32; 43.8%), velopharyngeal insufficiency (18/24; 75%) and feeding difficulties (16/36; 44.4%) were the most common sequelae in long-term survivors. Other unexpected features included hearing loss (12/32; 37.5%), diaphragmatic paresis (5/35; 14.3%), CNS involvement (7/40; 17.5%) and pyloric stenosis (3/37; 8.1%). Oral salbutamol used empirically in 16/37 (43.2%) offspring resulted in symptom improvement in 13/16 (81.3%). Combining our series with all previously published cases, we identified 21/85 mothers treated with variable combinations of immunotherapies (corticosteroids/intravenous immunoglobulin/plasmapheresis) during pregnancy either for maternal MG symptom control (12/21 cases) or for fetal protection (9/21 cases). Compared to untreated pregnancies (64/85), maternal treatment resulted in a significant reduction in offspring deaths (P < 0.05) and other complications, with treatment approaches involving intravenous immunoglobulin/ plasmapheresis administered early in pregnancy most effective. We conclude that presentations due to in utero exposure to maternal (fetal) AChR antibodies are more common than currently recognized and may mimic a wide range of neuromuscular disorders. Considering the wide clinical spectrum and likely diversity of underlying mechanisms, we propose 'fetal acetylcholine receptor antibody-related disorders' (FARAD) as the most accurate term for these presentations. FARAD is vitally important to recognize, to institute appropriate management strategies for affected offspring and to improve outcomes in future pregnancies. Oral salbutamol is a symptomatic treatment option in survivors.
Topics: Pregnancy; Female; Adult; Humans; Immunoglobulins, Intravenous; Receptors, Cholinergic; Myasthenia Gravis; Autoantibodies; Neuromuscular Diseases; Arthrogryposis
PubMed: 37186601
DOI: 10.1093/brain/awad153 -
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 -
American Journal of Medical Genetics.... Sep 2019Perhaps the most dramatic position of a newborn after delivery is when there is hyperextension of the neck and spine. It will have been presented in utero and today,...
Perhaps the most dramatic position of a newborn after delivery is when there is hyperextension of the neck and spine. It will have been presented in utero and today, almost always, such babies will have been delivered by C-section. The associated anomalies are variable. The process(es) that can lead to cervical hyperextension is/are largely unknown. The outcome is variable from lethal to completely resolve. Individuals with arthrogryposis and in particular with Amyoplasia appear to have an increased frequency of neck, cervical, and spine hyperextension at birth. We present here 41 cases of arthrogryposis (mainly Amyoplasia) with fetal cervical hyperextension. The outlook is surprisingly good if spinal cord trauma does not occur. Ultrasound late in pregnancy when arthrogryposis is recognized prenatally should determine whether cervical hyperextension has developed, so that appropriate preventive measures can be taken.
Topics: Arthrogryposis; Female; Fetus; Humans; Neck; Prenatal Care; Spine
PubMed: 31350810
DOI: 10.1002/ajmg.c.31727 -
Der Nervenarzt Apr 2024There is evidence that gender-specific differences can influence the diagnostics, treatment and long-term disease course of myasthenia gravis (MG). In women the... (Review)
Review
BACKGROUND
There is evidence that gender-specific differences can influence the diagnostics, treatment and long-term disease course of myasthenia gravis (MG). In women the diagnosis is often made during childbearing age.
OBJECTIVE
Gender-specific differences in MG and relevant aspects in routine clinical practice are presented. In addition, current studies on family planning, pregnancy and childbirth in MG are highlighted and treatment recommendations are derived.
MATERIAL AND METHODS
Narrative literature review.
RESULTS
In addition to sociodemographic data, gender-specific differences encompass clinical as well as paraclinical factors, such as disease severity and antibody status. With few exceptions pregnancy is possible with good maternal and neonatal outcome. During pregnancy and peripartum, children of MG patients should be closely monitored for early detection and treatment of potential syndromes caused by diaplacental transfer of maternal antibodies.
CONCLUSION
Gender-specific factors can influence the course of MG. Adequate medical counselling and multidisciplinary collaboration are essential for MG patients who wish to have children.
Topics: Pregnancy; Child; Infant, Newborn; Humans; Female; Family Planning Services; Myasthenia Gravis; Autoantibodies; Family; Pregnancy Complications
PubMed: 38499774
DOI: 10.1007/s00115-024-01640-6 -
Physical & Occupational Therapy in... 2020To explore what is currently known regarding participation among children and youth with arthrogryposis multiplex congenita (AMC) using empirical studies, gray... (Review)
Review
AIM
To explore what is currently known regarding participation among children and youth with arthrogryposis multiplex congenita (AMC) using empirical studies, gray literature, and YouTube videos. The secondary objectives included identifying activity types, outcome measures used, interventions provided, and barriers and facilitators to participation.
METHOD
Empirical studies and gray literature were searched through electronic databases and videos were searched on YouTube. Articles and videos pertaining to participation and youth with AMC were included by two reviewers. Data regarding activity types, location, outcomes measures, interventions, and barriers and facilitators to participation was extracted. Data was critically appraised using specific evaluation criteria.
RESULT
Eleven empirical studies, six gray literature articles and 71 videos met the inclusion criteria. The most common activity types reported in the empirical studies and YouTube videos were active-physical, social, and skill-based activities. Outcome measures included evaluations and questionnaires, none of which were designed to address participation. Interventions did not target participation although the environments could affect participation.
CONCLUSION
The paucity of research indicates a need for future studies of participation in this population. Interventions should target participation and address environmental barriers. Videos provide insight for clinicians, youth, and families to help promote participation in the natural environment.
Topics: Adolescent; Arthrogryposis; Child; Disabled Children; Humans; Leisure Activities; Social Participation; Surveys and Questionnaires
PubMed: 32299279
DOI: 10.1080/01942638.2020.1754319