| Congenital myasthenic syndromes | |
|---|---|
| Specialty | Neurology  |
Congenital myasthenic syndrome (CMS) is an inherited neuromuscular disorder caused by defects of several types at the neuromuscular junction. The effects of the disease are similar to Lambert-Eaton Syndrome and myasthenia gravis, the difference being that CMS is not an autoimmune disorder. There are only 600 known family cases of this disorder and it is estimated that its overall frequency in the human population is 1 in 200,000.
The types of CMS are classified into three categories: presynaptic, postsynaptic, and synaptic. [ citation needed ]
The onset of symptoms for all ages may include droopy eyelids. A particular form of postsynaptic CMS (slow-channel CMS) includes severe weakness beginning in infancy or childhood that progresses to respiratory problems, and leads to loss of mobility in adolescence or later life.[ citation needed ]
CMS is associated with genetic defects that affect proteins of the neuromuscular junction. Postsynaptic defects are the most frequent cause of CMS and often result in abnormalities in the acetylcholine receptor (AChR). In the neuromuscular junction there is a vital pathway that maintains synaptic structure and results in the aggregation and localization of AChR on the postsynaptic folds. This pathway consists of agrin, muscle-specific tyrosine kinase (MuSK), acetylcholine receptors (AChRs) and the AChR-clustering protein rapsyn, encoded by the RAPSN gene. The vast majority of mutations causing CMS are found in the AChR subunits and rapsyn genes. [1]
Out of all mutations associated with CMS, more than half are mutations in one of the four genes encoding the adult acetylcholine receptor (AChR) subunits. Mutations of the AChR often result in endplate deficiency. Most of the mutations of the AChR are mutations of the CHRNE gene. The CHRNE gene codes for the epsilon subunit of the AChR. Most mutations are autosomal recessive loss-of-function mutations and as a result there is endplate AChR deficiency. CHRNE is associated with changing the kinetic properties of the AChR. One type of mutation of the epsilon subunit of the AChR introduces an Arginine into the binding site at the α/ε subunit interface of the receptor. The addition of a cationic Arg into the anionic environment of the AChR binding site greatly reduces the kinetic properties of the receptor. The result of the newly introduced Arg is a 30-fold reduction of agonist affinity, 75-fold reduction of gating efficiency, and an extremely weakened channel opening probability. This type of mutation results in an extremely fatal form of CMS.
Another common underlying mechanism of CMS is the mutation of the rapsyn protein, coded by the RAPSN gene. Rapsyn interacts directly with the AChRs and plays a vital role in agrin-induced clustering of the AChR. Without rapsyn, functional synapses cannot be created, as the membrane folds do not form properly. Patients with CMS-related mutations of the rapsyn protein typically are either homozygous for N88K or heterozygous for N88K and a second mutation. The major effect of the mutation N88K in rapsyn is to reduce the stability of AChR clusters. The second mutation can be a determining factor in the severity of the disease. [1]
Studies have shown that most patients with CMS that have rapsyn mutations carry the common mutation N88K on at least one allele. However, research has revealed that there is a small population of patients who do not carry the N88K mutation on either of their alleles, but instead have different mutations of the RAPSN gene that codes for rapsyn on both of their alleles. Two novel missense mutations that have been found are R164C and L283P; the result is a decrease in co-clustering of AChR with rapsyn. A third mutation is the intronic base alteration IVS1-15C>A, which causes abnormal splicing of RAPSN RNA. These results show that diagnostic screening for CMS mutations of the RAPSN gene cannot be based exclusively on the detection of N88K mutations.
Dok-7 is a postsynaptic protein that binds and activates MuSK protein, which then leads to AChR clustering and typical folding of the postsynaptic membrane. Mutations of Dok-7 are yet another underlying mechanism of postsynaptic CMS. [2]
Congenital myasthenic syndrome (CMS) is "often difficult to diagnose because of a broad differential diagnosis and lack of specific laboratory findings. Identification of the underlying mutation is critical, as certain mutations lead to treatment-responsive conditions while others do not." [3] Whole exome sequencing (WES) is often used as a diagnostic tool that allows for the "initiation of specific treatment". [3]
Treatment depends on the form (category) of the disease. Although symptoms are similar to myasthenia gravis, treatments used in MG are not useful in CMS. MG is treated with immunosuppressants, but CMS is not an autoimmune disorder. Instead, CMS is genetic and responds to other forms of drug treatments. A form of presynaptic CMS is caused by an insufficient release of acetylcholine (ACh) and is treated with cholinesterase inhibitors.[ citation needed ]
Postsynaptic fast-channel CMS, in which ACh receptors do not stay open long enough, is treated with cholinesterase inhibitors and 3,4-diaminopyridine. [4] [5] In the U.S., the more stable phosphate salt formulation of 3,4-diaminopyridine (amifampridine phosphate) is under development as an orphan drug for CMS and is available to eligible patients at no cost under an expanded access program. [6] [7] Postsynaptic slow-channel CMS is treated with quinidine or fluoxetine, which blocks the ACh receptor.[ citation needed ]
Ephedrine, a β(2)-adrenergic receptor agonist with alpha activity, has been tested on patients in clinical trials and appears to be an effective treatment for DOK7 CMS. Most patients tolerate this type of treatment and improvements in strength can be substantial. The effect of ephedrine is delayed and the improvement occurs over a period of months. [2] [8]
Salbutamol, a selective β(2)-adrenergic receptor agonist, has been found, in adults, to have fewer side effects than Ephedrine and to be more easily obtained in some countries. It has been trialed in children with positive results [9]
As of 2022, the standard of care for DOK7 CMS is either ephedrine or salbutamol. [10]
Lambert–Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder characterized by muscle weakness of the limbs.
Myasthenia gravis (MG) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing. It can result in double vision, drooping eyelids, and difficulties in talking and walking. Onset can be sudden. Those affected often have a large thymus or develop a thymoma.
An acetylcholine receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.
An excitatory synapse is a synapse in which an action potential in a presynaptic neuron increases the probability of an action potential occurring in a postsynaptic cell. Neurons form networks through which nerve impulses travels, each neuron often making numerous connections with other cells of neurons. These electrical signals may be excitatory or inhibitory, and, if the total of excitatory influences exceeds that of the inhibitory influences, the neuron will generate a new action potential at its axon hillock, thus transmitting the information to yet another cell.
Edrophonium is a readily reversible acetylcholinesterase inhibitor. It prevents breakdown of the neurotransmitter acetylcholine and acts by competitively inhibiting the enzyme acetylcholinesterase, mainly at the neuromuscular junction. It is sold under the trade names Tensilon and Enlon.
A neuromuscular junction is a chemical synapse between a motor neuron and a muscle fiber.
Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral nervous system, muscle, and many other tissues of many organisms. At the neuromuscular junction they are the primary receptor in muscle for motor nerve-muscle communication that controls muscle contraction. In the peripheral nervous system: (1) they transmit outgoing signals from the presynaptic to the postsynaptic cells within the sympathetic and parasympathetic nervous system, and (2) they are the receptors found on skeletal muscle that receive acetylcholine released to signal for muscular contraction. In the immune system, nAChRs regulate inflammatory processes and signal through distinct intracellular pathways. In insects, the cholinergic system is limited to the central nervous system.
End plate potentials (EPPs) are the voltages which cause depolarization of skeletal muscle fibers caused by neurotransmitters binding to the postsynaptic membrane in the neuromuscular junction. They are called "end plates" because the postsynaptic terminals of muscle fibers have a large, saucer-like appearance. When an action potential reaches the axon terminal of a motor neuron, vesicles carrying neurotransmitters are exocytosed and the contents are released into the neuromuscular junction. These neurotransmitters bind to receptors on the postsynaptic membrane and lead to its depolarization. In the absence of an action potential, acetylcholine vesicles spontaneously leak into the neuromuscular junction and cause very small depolarizations in the postsynaptic membrane. This small response (~0.4mV) is called a miniature end plate potential (MEPP) and is generated by one acetylcholine-containing vesicle. It represents the smallest possible depolarization which can be induced in a muscle.
MuSK is a receptor tyrosine kinase required for the formation and maintenance of the neuromuscular junction. It is activated by a nerve-derived proteoglycan called agrin, which is similarly also required for neuromuscular junction formation.
A neuromuscular disease is any disease affecting the peripheral nervous system (PNS), the neuromuscular junctions, or skeletal muscles, all of which are components of the motor unit. Damage to any of these structures can cause muscle atrophy and weakness. Issues with sensation can also occur.
Agrin is a large proteoglycan whose best-characterised role is in the development of the neuromuscular junction during embryogenesis. Agrin is named based on its involvement in the aggregation of acetylcholine receptors during synaptogenesis. In humans, this protein is encoded by the AGRN gene.
Dok-7 is a non-catalytic cytoplasmic adaptor protein that is expressed specifically in muscle and is essential for the formation of neuromuscular synapses. Further, Dok-7 contains pleckstrin homology (PH) and phosphotyrosine-binding (PTB) domains that are critical for Dok-7 function. Finally, mutations in Dok-7 are commonly found in patients with limb-girdle congenital myasthenia.
43 kDa receptor-associated protein of the synapse (rapsyn) is a protein that in humans is encoded by the RAPSN gene.
Acetylcholine receptor subunit epsilon is a protein that in humans is encoded by the CHRNE gene.
Neuronal acetylcholine receptor subunit alpha-1, also known as nAChRα1, is a protein that in humans is encoded by the CHRNA1 gene. The protein encoded by this gene is a subunit of certain nicotinic acetylcholine receptors (nAchR).
Acetylcholine receptor subunit delta is a protein that in humans is encoded by the CHRND gene.
Acetylcholine receptor subunit beta is a protein that in humans is encoded by the CHRNB1 gene.
Neuromuscular junction disease is a medical condition where the normal conduction through the neuromuscular junction fails to function correctly.
Repetitive nerve stimulation is a variant of the nerve conduction study where electrical stimulation is delivered to a motor nerve repeatedly several times per second. By observing the change in the muscle electrical response (CMAP) after several stimulations, a physician can assess for the presence of a neuromuscular junction disease, and differentiate between presynaptic and postsynaptic conditions. The test was first described by German neurologist Friedrich Jolly in 1895, and is also known as Jolly's test.
Autoimmune autonomic ganglionopathy is a type of immune-mediated autonomic failure that is associated with antibodies against the ganglionic nicotinic acetylcholine receptor present in sympathetic, parasympathetic, and enteric ganglia. Typical symptoms include gastrointestinal dysmotility, orthostatic hypotension, and tonic pupils. Many cases have a sudden onset, but others worsen over time, resembling degenerative forms of autonomic dysfunction. For milder cases, supportive treatment is used to manage symptoms. Plasma exchange, intravenous immunoglobulin, corticosteroids, or immunosuppression have been used successfully to treat more severe cases.
As with other rare childhood neurological conditions, CMS is often difficult to diagnose because of a broad differential diagnosis and lack of specific laboratory findings. Identification of the underlying mutation is critical, as certain mutations lead to treatment-responsive conditions while others do not. This case serves to highlight the importance of WES as a diagnostic tool that will assist in proper diagnosis, and in some circumstances, allow for initiation of specific treatment.