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Congenital Slow-Channel Myasthenic Syndrome Type 4A

CMS


Presentation

  • Engel / Neuromuscular Disorders 22 (2012) 99–111 PowerPoint Presentation: Exceptions In some CMS the onset is delayed There may be no similarly affected relatives EMG abnormalities may not be present in all muscles, or are present only intermittently[authorstream.com]
  • Clinical presentation  Suspected in any person presenting with  Fatigable ocular  Bulbar  Limb weakness during infancy or early childhood  With a positive family history(autosomal recessive except slow channel) 28.  Response to cholinesterase inhibitors[slideshare.net]
  • They have a varied presentation and progression and very few studies have addressed the natural history. Aim of the present study is to describe the clinical profile and natural history of patients with CMS.[annalsofian.org]
  • Neonates present with feeding problems, choking, feeble cry, and muscle weakness. Patients presenting in later childhood are seen with abnormal exercise-induced fatigue and difficulty running.[preventiongenetics.com]
  • Familiarity was present in 4 patients (mother in patients 1, 3, and 6; first cousin in patient 2).[pediatricneurosciences.com]
Weakness
  • The muscle weakness typically begins in early childhood but can also appear in adolescence or adulthood.[myaware.org]
  • Symptoms of Myasthenic syndrome, congenital, type 4a, slow-channel Clinical features : Imported from Human Phenotype Ontology (HPO) Abnormality of limbs Limb muscle weakness Abnormality of the abdomen Dysphagia Feeding difficulties in infancy Poor suck[familydiagnosis.com]
  • Engel / Neuromuscular Disorders 22 (2012) 99–111 PowerPoint Presentation: Dok-7 myasthenia Predominantly limb-girdle and axial distribution of weakness, mild facial weakness, and ptosis are common, and normal ocular ductions in most patients Significant[authorstream.com]
  • RESULTS: The proband had fatigable muscle weakness characteristic of congenital myasthenic syndrome with acute and reversible attacks of most severe muscle weakness as observed in periodic paralysis.[cervo.ulaval.ca]
  • […] into MG later in life 26.  Diagnosis  High serum concentrations of AChR binding Ab  Temporary reversal of weakness :S/c or I/V inj.[slideshare.net]
Crying
  • […] person to person and fluctuate throughout the day and they can also overlap with other muscular disorders, although people with CMS may notice the following: Babies Decreased movements of the baby inside the mother's womb before birth Weak suck and cry[myaware.org]
  • Neonates present with feeding problems, choking, feeble cry, and muscle weakness. Patients presenting in later childhood are seen with abnormal exercise-induced fatigue and difficulty running.[preventiongenetics.com]
  • .  Hypotonic in utero  Arthrogryposis  Feeding difficulties  Generalized hypotonia  Eager to feed, but ability to suck fatigues quickly  Onset within hours of birth but delay until the 3rdDay  Weakness of cry and lack of facial expression: 50%[slideshare.net]
  • She was noted to be floppy with a weak cry and had feeding difficulties.[jci.org]
  • In 11 of the patients, the disease was presented at birth with hypotonia, ptosis, ophthalmoparesis, facial weakness, weak cry and suckle, and respiratory insufficiency.[degruyter.com]
Feeding Difficulties
  • Abnormality of the digestive system Dysphagia Feeding difficulties in infancy Poor suck Abnormality of the musculature ... ...[familydiagnosis.com]
  • Due to muscle weakness, affected infants may have feeding difficulties. Development of motor skills such as crawling or walking may be delayed.[ghr.nlm.nih.gov]
  • .  Hypotonic in utero  Arthrogryposis  Feeding difficulties  Generalized hypotonia  Eager to feed, but ability to suck fatigues quickly  Onset within hours of birth but delay until the 3rdDay  Weakness of cry and lack of facial expression: 50%[slideshare.net]
  • She was noted to be floppy with a weak cry and had feeding difficulties.[jci.org]
  • The most common presentation consists of fatigable weakness of the skeletal muscles, respiratory issues including apnea and choking spells, feeding difficulty, and eyelid ptosis.[invitae.com]
Falling
  • […] difficulties Children and adults Late walking May struggle with sport, exertion or activities of daily living Difficulty performing repetitive movements Frequent chest infections Stiffness in fingers and wrists Droopy eyelids Double vision Tendency to fall[myaware.org]
  • Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.[invitae.com]
  • The later onset can be characterized by a delay in the motor stages with frequent falls. [5] During childhood or in adulthood age, this affection can also appear with ophthalmoplegia, mono and bilateral ptosis, strabismus, facial muscles deficit and asthenia[pediatricneurosciences.com]
  • They usually manifest in the first year of life with bilateral ptosis, ophthalmoparesis and facial weakness or in early childhood with walking difficulties and frequent falls.[annalsofian.org]
  • She uses her hand or shoulder as support during walking and falls frequently during running. She enjoys watching TV and there has been no diurnal variation in the weakness. Her parents are first-degree cousins.[degruyter.com]
Physician
  • In 2007 he received the Distinguished Physician Award from the American Association of Neuromuscular and Electrodiagnostic Medicine. Lahey Clinic’s Medical Staff Association recognized Dr.[books.google.com]
  • Onset of symptoms is usually between 5 and 10 years of age, when parents or physicians may notice a child has begun to develop vision problems or seizures. … Peroxisome Biogenesis Disorder (Zellweger Spectrum Disorders) March 12, 2018 by Peter Ciszewski[checkrare.com]
  • METHODS: Through established Canadian Pediatric Surveillance Program methodology, physicians were anonymously surveyed for cases of pediatric myasthenia using a standardized clinical questionnaire containing deidentified data.[pediatrics.aappublications.org]
  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers.[rarediseases.info.nih.gov]
Dyspnea
  • Therefore, those having dyspnea should be hospitalized immediately in a constant observation or intensive care setting.[neupsykey.com]
Dysphagia
  • Abnormality of the digestive system Dysphagia Feeding difficulties in infancy Poor suck Abnormality of the musculature ... ...[familydiagnosis.com]
  • Ptosis, opthalmoparesis, dysphagia, feeding problems, hypotonia, bulbar muscle weakness and respiratory problems are commonly seen.[cags.org.ae]
  • He was started on tab. pyridostigmine, 60mg, in divided doses, which was subsequently increased to 90 mg/day as he showed significant improvement in ptosis, dysphagia and motor weakness.[neurologyindia.com]
  • In contrast, eyelid ptosis, diplopia, dysphagia, and respiratory failure are far less common.[neupsykey.com]
Muscle Weakness
  • Symptoms of Myasthenic syndrome, congenital, type 4a, slow-channel Clinical features : Imported from Human Phenotype Ontology (HPO) Abnormality of limbs Limb muscle weakness Abnormality of the abdomen Dysphagia Feeding difficulties in infancy Poor suck[familydiagnosis.com]
  • The muscle weakness typically begins in early childhood but can also appear in adolescence or adulthood.[myaware.org]
  • […] of congenital muscle weakness observed in an isolated but consanguineous patient.[cervo.ulaval.ca]
  • Congenital myasthenic syndrome is a group of conditions characterized by muscle weakness (myasthenia) that worsens with physical exertion. The muscle weakness typically begins in early childhood but can also appear in adolescence or adulthood.[ghr.nlm.nih.gov]
  • Ptosis, opthalmoparesis, dysphagia, feeding problems, hypotonia, bulbar muscle weakness and respiratory problems are commonly seen.[cags.org.ae]
Myopathy
  • Myopathy, centronuclear 160150 DNM2 dynamin 2 Myopathy, distal, Tateyama type 614321 CAV3 caveolin 3 Myopathy, distal, with anterior tibial onset 606768 DYSF dysferlin, limb girdle muscular dystrophy 2B (autosomal recessive) Myopathy, myofibrillar, 1[ac-gen.com]
  • […] research laboratories of Boston Children’s and other institutions, focuses on the description of novel mutations in patients with neuromuscular diseases and the application of new technologies to explore the pathogenesis and treatment of congenital myopathies[books.google.com]
  • .  Presents with progressive myopathy, associated with myasthenic syndrome (involving facial, limb and oculomotor muscles), and epidermolysis bullosa 20.  Presents since birth with very short bouts (3– 30 min) of respiratory distress and bulbar paralysis[slideshare.net]
  • Lorenzoni et al. / Pediatric Neurology 46 (2012) 141-148 PowerPoint Presentation: Agrin deficiency- Ephedrine, 3,4-DAP With tubular aggregates- Pyridostigmine Other defects( Plectin, With centronuclear myopathy )- 3,4-DAP, Pyridostigmine P.J.[authorstream.com]
  • Multiple pterygium syndrome, Escobar syndrome AR 17 34 COLQ Myasthenic syndrome, congenital AR 23 67 DOK7 Myasthenic syndrome, congenital AR 28 75 DPAGT1 Congenital disorder of glycosylation, Myasthenic syndrome, congenital AR 16 32 FLAD1 Lipid storage myopathy[blueprintgenetics.com]
Muscular Atrophy
  • Darras is site PI for the consortium conducting Pediatric Neuromuscular Clinical Research in Spinal Muscular Atrophy, and site PI/PD for the NeuroNEXT NINDS Program.[books.google.com]
  • Many a times, the CMS is misdiagnosed as congenital myopathy, central hypotonia or neurometabolic diseases, myasthenia gravis, limb-girdle or congenital muscular dystrophy and spinal muscular atrophy. [13] Delayed milestones were seen in 40% patients[annalsofian.org]
  • The chromosomal analysis was also unremarkable and the Spinal Muscular Atrophy (SMA) gene study was revealed to be negative. In addition, MRI of the brain has shown vermian hypoplasia with periventricular subcortical patchy T2 hyper-intensities.[degruyter.com]
  • ., 1995 , vol. 305 (pg. 721 - 724 ) 21 Tetanus and botulinum-B neurotox-ins block neurotransmitter release by proteolytic cleavage of synaptobrevin, Nature, 1992 , vol. 359 (pg. 832 - 835 ) 22 Mapping of a distal form of spinal muscular atrophy with upper[academic.oup.com]
Strabismus
  • Strube OUP USA, 2012/09/27 - 1386 ページ For over the past ten years Pediatric Ophthalmology and Strabismus has become the leading textbook in the specialty of pediatric ophthalmology and strabismus.[books.google.com]
  • PowerPoint Presentation: Endplate choline acetyltransferase deficiency Recurrent apneic episodes, spontaneous or with fever, vomiting, or excitement No or variable myasthenic symptoms between acute episodes Rapsyn deficiency Ophthalmoparesis in 25%; strabismus[authorstream.com]
  • The later onset can be characterized by a delay in the motor stages with frequent falls. [5] During childhood or in adulthood age, this affection can also appear with ophthalmoplegia, mono and bilateral ptosis, strabismus, facial muscles deficit and asthenia[pediatricneurosciences.com]
Diplopia
  • In contrast, eyelid ptosis, diplopia, dysphagia, and respiratory failure are far less common.[neupsykey.com]
Limb Weakness
  • Clinical presentation  Suspected in any person presenting with  Fatigable ocular  Bulbar  Limb weakness during infancy or early childhood  With a positive family history(autosomal recessive except slow channel) 28.  Response to cholinesterase inhibitors[slideshare.net]
  • . / Pediatric Neurology 46 (2012) 141- 148 CONCLUSION: CONCLUSION CMS should be suspected in any patient with fatigable ocular, bulbar, or limb weakness presenting in infancy or early childhood In older patients who are anti- AChR and anti– MuSK -antibody[authorstream.com]
  • CMS should be suspected in the neonates who present with feeding difficulties, hypotonia with or without limb weakness, ptosis, respiratory insufficiency, contractures and stridor. [14] Electrophysiology showed most common decremental response in facial[annalsofian.org]
Stroke
  • […] identified specialty as the volume and complexity of data became too much for the general pediatician or the adult neurologist to master, the discipline has now continued to evolve into so many subspecialties, such as epilepsy, neuromuscular disease, stroke[books.google.com]
  • Occasional cases of aseptic meningitis, renal failure, nephrotic syndrome, and stroke have been reported. Also, patients with selective IgA deficiency can have anaphylaxis, best avoided by screening for IgA deficiency ahead of time.[neupsykey.com]

Workup

  • For developmental delay, she has been evaluated by the Pediatric Neurology and Medical Genetics units and her workup is as follows: Tandem Mass Spectrometry (TMS), urine Gas Chromatography–Mass Spectrometry (GC-MS), Microarray Comparative Genomic Hybridization[degruyter.com]
  • This will allow close monitoring and early intervention in the case of respiratory failure and will also expedite the diagnostic workup and initiation of therapy. 4.[neupsykey.com]

Treatment

  • Treatments for CMS Autosomal recessive inheritance CMS Type Affected Genes Treatment AChR Deficiency - postsynaptic CHRNA1, CHRNB1, CHRND, CHRNE Pyridostigmine, 3,4-DAP, Salbutamol* / Ephedrine* RAPSYN CMS - postsynaptic RAPSN Pyridostigmine, 3,4-DAP[myaware.org]
  • This network is dedicated to the acceleration of clinical trials in search of effective treatments for SMA.[books.google.com]
  • ". [6] Treatment depends on the form (category) of the disease.[en.wikipedia.org]
  • The patient showed modest benefits from standard treatment with fluoxetine, but there was dramatic improvement when salbutamol was combined with fluoxetine.[pediatricfocus.wordpress.com]
  • There are no guidelines for treatment of myasthenic crisis in CMS patient, which are rare and usually managed with supportive treatment. The improvement in our patient could have been spontaneous or due to IVIg.[annalsofian.org]

Prognosis

  • Congenital myasthenic syndromes: Natural history and long-term prognosis. Ann Indian Acad Neurol 2013;16:338-41 How to cite this URL: Jagtap SA, Abraham K, Sarada C, Nair M D. Congenital myasthenic syndromes: Natural history and long-term prognosis.[annalsofian.org]
  • Prognosis in CMS is variable and largely depends on the pathophysiological and genetic defect. Subtypes showing progression and life-threatening crises with apneas are generally less favorable than others.[link.springer.com]
  • ., Congenital myasthenic syndromes: Natural history and long-term prognosis, Ann. Indian Acad.[degruyter.com]
  • Prognosis. Natural course: Appropriate management of the patient with autoimmune MG requires understanding of the natural course of the disease. The long-term natural course of MG is highly variable but generalizations are as follows.[neupsykey.com]

Etiology

  • CMS diagnosis typically depends on a combination of factors, including clinical presentation, family history, genetic etiology, negative anti-ACh and anti-MuSK serum studies, and decremental electromyographic findings (PMID: 23622369).[invitae.com]

Pathophysiology

  • Genetic heterogeneity and pathophysiological mechanisms in congenital myasthenic syndromes. Eur J Paediatr Neurol. 2011 May;15(3):189-96. doi: 10.1016/j.ejpn.2011.03.006. Epub 2011 Apr 17. Review.[ghr.nlm.nih.gov]
  • Prognosis in CMS is variable and largely depends on the pathophysiological and genetic defect. Subtypes showing progression and life-threatening crises with apneas are generally less favorable than others.[link.springer.com]
  • The disease manifestations differ according to the time of its onset and the underlying neuromuscular pathophysiology [ 3 ].[degruyter.com]

Prevention

  • Prevention A specific diagnosis of CMS is critical as some medications that benefit one type of CMS can be detrimental in another type (Engel, A., 2007. PubMed ID:17395135).[preventiongenetics.com]
  • .  Immediate treatment of respiratory distress  Prevention of infections and of malnutrition as a result of swallowing disorders  Orthopaedic surveillance of spinal complications and retractions 33.  Cholinesterase inhibitors are efficient in all[slideshare.net]
  • Prophylactic anti-cholinesterase therapy has been recommended to prevent sudden respiratory insufficiency or apneic attacks provoked by fever or infections in those with mutations in ChAT or RAPSN. [ 9 ] Parents of an affected infant must be advised to[degruyter.com]
  • In vitro functional expression studies showed that the I58K substitution prevented expression of the delta subunit and was a null mutation.[genome.jp]
  • The Center for Disease Control and Prevention (CDC) recommends administration of one vial of antitoxin for adult patients with botulism as soon as diagnosis is made, without waiting for laboratory confirmation; before administration of antitoxin, consider[neupsykey.com]

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