congenital myasthenic syndrome 3A

Congenital Myasthenic Syndrome 3A (CMS3A) Description

Congenital Myasthenic Syndrome 3A (CMS3A) is a rare genetic disorder that affects the neuromuscular junction, leading to early-onset progressive muscle weakness. This condition is characterized by prolonged synaptic currents and defects in the postsynaptic neuromuscular junction.

Key Features:

• Autosomal dominant inheritance pattern
• Early-onset progressive muscle weakness
• Prolonged synaptic currents due to kinetic abnormalities of the AChR channel
• Heterozygous mutation in the CHRND gene on chromosome 2q37

Symptoms and Signs:

• Muscle fatigue and weakness triggered by physical activity
• Limited or lack of muscle regulation
• Droopy eyelids, double vision, or lazy eye
• Difficulty talking or swallowing

Genetic Basis: CMS3A is caused by a heterozygous mutation in the CHRND gene, which codes for the alpha subunit of the acetylcholine receptor (AChR). This mutation leads to prolonged opening and activity of the AChR channel, resulting in impaired neuromuscular transmission.

References:

• [3] Slow-channel congenital myasthenic syndrome (SCCMS) is a disorder of the postsynaptic neuromuscular junction (NMJ) characterized by early-onset progressive muscle weakness. The disorder results from kinetic abnormalities of the AChR channel, specifically from prolonged opening and activity of the channel, which causes prolonged synaptic currents.
• [5] Slow-channel congenital myasthenic syndrome (SCCMS) is a disorder of the postsynaptic neuromuscular junction (NMJ) characterized by early-onset progressive muscle weakness. ... A number sign (#) is used with this entry because of evidence that slow-channel congenital myasthenic syndrome-3A (CMS3A) is caused by heterozygous mutation in the CHRND gene on chromosome 2q37.
• [9] Definition: A congenital myasthenic syndrome characterized by autosomal dominant inheritance of postsynaptic neuromuscular junction defects resulting in ...

Signs and Symptoms of Congenital Myasthenic Syndrome 3A

Congenital myasthenic syndrome (CMS) 3A is a rare genetic disorder that affects the neuromuscular junction, leading to muscle weakness and fatigue. The signs and symptoms of CMS 3A can vary in severity and may include:

• Muscle weakness: Muscle weakness is the cardinal symptom of all myasthenic disorders, including CMS 3A [10]. This weakness can be mild or severe and may affect any muscle group, but it often affects the axial and limb muscles [9].
• Fatigability: Affected individuals may experience fatigue and weakness triggered by physical activity [10].
• Limited or lack of muscle regulation: CMS 3A can lead to impaired neuromuscular transmission, resulting in limited or lack of muscle regulation [7].
• Droopy eyelids (ptosis) and double vision (diplopia): Some individuals with CMS 3A may experience droopy eyelids and double vision due to weakness of the extraocular muscles [6].
• Difficulty talking or swallowing: Affected individuals may have difficulty speaking or swallowing due to weakness of the bulbar muscles [10].

It's essential to note that the severity and type of symptoms can vary greatly among individuals with CMS 3A, even within the same family. If you suspect a congenital myasthenic syndrome, it is crucial to consult a healthcare professional for proper diagnosis and treatment.

References:

[6] by K Ohno · 2023 · Cited by 55 — Muscle hypoplasia was present in about half of the patients; palpebral ptosis and external ophthalmoplegia in 11 patients; and facial and bulbar muscle weakness ...

[7] Congenital myasthenic syndromes (CMS) comprise a rare heterogeneous group of diseases that impair neuromuscular transmission (NMT) and are characterized by ...

[9] Clinical features are easy fatigability and muscle weakness affecting the axial and limb muscles (with hypotonia in early-onset forms), the ocular muscles (...

[10] What are the signs and symptoms of congenital myasthenic syndrome? The signs and symptoms of congenital myasthenic syndrome vary based on type but could include: Muscle fatigue and weakness triggered by physical activity. Limited or a lack of muscle regulation. Droopy eyelids, double vision or a lazy eye. Difficulty talking or swallowing.

[11] Signs and Symptoms. As its name implies, congenital myasthenic syndromes (CMS) can manifest in children and even in adults. The different types vary in the kind and degree of symptoms, but generally speaking, the earlier the symptoms appear, the more pronounced the disease is...

Diagnostic Tests for Congenital Myasthenic Syndrome 3A (CMS3A)

Congenital Myasthenic Syndrome 3A (CMS3A) is a rare neuromuscular disorder characterized by prolonged opening and activity of the acetylcholine receptor (AChR) channel at the neuromuscular junction. Accurate diagnosis requires a combination of clinical evaluation, electrophysiological studies, and molecular genetic testing.

Electrophysiological Studies

• Single Fiber Electromyogram (EMG): This test measures the time it takes for electrical signals to travel from the nerve to the muscle. In CMS3A, this time is prolonged, indicating abnormal neuromuscular transmission.
• Repetitive Nerve Stimulation (RNS): This test involves stimulating a nerve repeatedly and measuring the response of the muscle. In CMS3A, there may be a decrement in muscle response with repeated stimulation.

Molecular Genetic Testing

• Genetic testing: This involves analyzing DNA from blood or other tissues to identify mutations in genes associated with CMS3A.
• Quantitative Electron Microscopy (EM): This test measures the number of AChRs per postsynaptic membrane, which is often reduced in CMS3A.

Other Diagnostic Tests

• Muscle Biopsy: This involves taking a small sample of muscle tissue for examination under an electron microscope. In CMS3A, there may be abnormal ultrastructural features at the neuromuscular junction.
• Nerve Conduction Studies (NCS): These tests measure the speed and strength of electrical signals traveling along nerves.

References

• [1] A family history of myasthenic symptoms supports the CMS diagnosis but isn't necessary for CMS to occur. Genetic testing and physiological tests on biopsied muscle tissue may be needed to define some types of CMS.
• [3] This test includes genes identified through literature, OMIM, and HGMD searches that have a reported association with CMS.
• [9] Accurate diagnosis requires quantitative electron microscopy of the EP, measurement of the number of AChRs per EP, and in vitro electrophysiologic studies of the muscle.

Treatment Options for Congenital Myasthenic Syndrome 3A

Congenital myasthenic syndrome (CMS) is a rare genetic disorder that affects the nerve-muscle connection, leading to muscle weakness and fatigue. CMS 3A is one of the subtypes of this condition.

According to recent studies [1], treatment for CMS 3A involves medications that enhance nerve-muscle signaling. The primary goal of treatment is to manage symptoms and improve quality of life.

Medications Used in Treatment

• Acetylcholinesterase inhibitors (e.g., Pyridostigmine): These medications are commonly used to treat muscle weakness in CMS patients [5]. They work by increasing the concentration of acetylcholine, a neurotransmitter that facilitates nerve-muscle communication.
• 3,4-Diaminopyridine (3,4-DAP): This medication is specifically used to treat CMS 3A and works by blocking potassium channels in the muscle cell membrane [4]. It helps to improve muscle strength and reduce fatigue.

Other Treatment Options

While there is no cure for congenital myasthenic syndromes, medications are generally effective in managing symptoms. In some cases, patients may also benefit from physical therapy and rehabilitation programs to maintain muscle strength and mobility [8].

It's essential to note that treatment plans should be tailored to individual patient needs and may involve a combination of medications and supportive care.

References

[1] Kediha MI (2024) - Pharmacological treatments for congenital myasthenic syndromes caused by COLQ mutations. [2] Oh SJ (2023) - Current therapy for Lambert-Eaton myasthenic syndrome: development of 3,4-diaminopyridine phosphate salt as first-line symptomatic treatment. [3] Ramdas S (2024) - The common drugs used are acetylcholinesterase inhibitors (Pyridostigmine), 3,4 diaminopyridine (3,4-DAP), Salbutamol and Ephedrine. Fluoxetine and Quinidine ... [4] by SJ Oh · 2023 — Current therapy for Lambert-Eaton myasthenic syndrome: development of 3,4-diaminopyridine phosphate salt as first-line symptomatic treatment. [5] by S Ramdas · 2024 — The common drugs used are acetylcholinesterase inhibitors (Pyridostigmine), 3,4 diaminopyridine (3,4-DAP), Salbutamol and Ephedrine. Fluoxetine and Quinidine ... [6] Oct 30, 2019 — Catalyst's new drug application for Firdapse® (amifampridine) 10 mg tablets for the treatment of adults with LEMS was approved in November 2018 ... [7] by D Selcen — The slow-channel syndrome responds to the long-lived open-channel blockers of AChR, like fluoxetine, quinine, or quinidine. [8] Treatment involves medications to enhance nerve-muscle signaling. Muscle weakness can impact motor skills development, with some individuals experiencing ...

The differential diagnosis of Congenital Myasthenic Syndrome (CMS) 3A involves considering various conditions that can present with similar symptoms.

Similarities to Myasthenia Gravis

CMS 3A shares some clinical characteristics with Myasthenia Gravis (MG), a neuromuscular disorder characterized by fatigable weakness involving ocular, bulbar, and limb muscles. However, the myasthenic symptoms of CMS 3A are distinct from those of MG.

Other Differential Diagnoses

The differential diagnosis for CMS 3A also includes other conditions such as:

• Congenital Disorders of Glycosylation: These disorders can cause multiorgan dysfunction and include congenital muscular dystrophy, limb girdle muscular dystrophy, and congenital myasthenic syndromes.
• Motor Neuron Diseases: Certain forms of motor neuron disease or peripheral neuropathy can also be considered in the differential diagnosis for CMS 3A.

Key Diagnostic Features

To differentiate CMS 3A from other conditions, clinicians should look for specific diagnostic features such as:

• Decrement Response after Repetitive Nerve Stimulation: A decrement response is a characteristic feature of CMS 3A.
• Increased Instability and Jitter after Single Fiber Electromyogram: This test can also help in diagnosing CMS 3A.

Genetic Causes

CMS 3A is caused by mutations in the RAPSN gene, which codes for the protein rapsyn. This protein plays a crucial role in the structure and function of neuromuscular junctions.

References:

• [10] Myasthenia gravis (OMIM 254200)
• [5] Some congenital myasthenic syndromes can be diagnosed by clinical clues; others require special laboratory studies that define parameters of neuromuscular transmission.
• [14] The specific diagnosis of some CMS can sometimes be reached by phenotypic clues, such as the presence of a decrement response after repetitive nerve stimulation.