NORD gratefully acknowledges Andrew G. Engel, MD, Department of Neurology and Muscle Research Laboratory, Mayo Clinic, for the preparation of this report.
The congenital myasthenic syndromes (CMS) are a diverse group of disorders that have an underlying defect in the transmission of signals from nerve cells to muscles. These disorders are characterized by muscle weakness, which is worsened upon exertion. The age of onset, severity of presenting symptoms, and distribution of muscle weakness can vary from one patient to another. A variety of additional symptoms affecting other organ systems can be present in specific subtypes. Severity can range from minor symptoms such as mild exercise intolerance to severe, disabling ones. Most CMS are transmitted by autosomal recessive inheritance; a few specific subtypes are transmitted by autosomal dominant inheritance. Genetic diagnosis these disorders is important because therapy that benefits one type CMS can worsen another type.
The CMS involve the neuromuscular junction which is a synapse where signals from motor nerves are passed to muscle fibers and tell the muscles fibers when to contract.
The normal neuromuscular junction consists of a presynaptic region, a synaptic space, and a postsynaptic region. The presynaptic region contains the end of a motor nerve cell called the motor nerve terminal. The motor nerve terminal overlies a specialized region of the muscle fiber called the postsynaptic region. The space between the motor nerve terminal and the postsynaptic region is called the synaptic space or synaptic cleft. The postsynaptic region displays multiple folds, known as junctional folds. The motor nerve terminal contains small vesicles that are filled by the neurotransmitter, acetylcholine, or ACh for short that acts as a chemical ‘messenger’ with instructions for the muscles to contract.
The membrane covering the motor nerve terminal and facing the synaptic space is known as the presynaptic membrane. The membrane covering the postsynaptic region is known as the postsynaptic membrane. The segment of the postsynaptic membrane that covers the tips of junctional folds is lined by molecules of the acetylcholine receptor, or AChR for short. The synaptic space is lined by a membrane known as the synaptic basement membrane. This membrane anchors molecules of acetylcholinesterase, or AChE for short, an enzyme that converts ACh to acetate and choline.
The process of how the motor nerve endings communicate with the muscle fibers is a highly specialized process and a genetic defect that impairs that communication can result in a congenital myasthenic syndrome. Understanding this process helps to understand myasthenic disorders.
When muscles are in the resting state, there is a randomly occurring release of acetylcholine from single synaptic vesicles in the motor nerve terminal. This release is known as exocytosis. The amount of ACh released from a single synaptic vesicle is referred to as a quantum of ACh.
ACh released from a synaptic vesicle travels through the synaptic space and binds to the AChRs that are concentrated on the tips of the junctional folds. When this binding occurs, it causes a channel in the center of AChR to and allows positively charged sodium and lesser amounts of calcium ions to enter the muscle fiber. This process briefly changes the electric charge across the postsynaptic membrane from negative to positive (small postsynaptic depolarization) which is referred to as a miniature endplate potential (MEPP).
When a person wants to perform a voluntary action, (e.g. raising one’s hand, dancing, kicking a ball, etc.), a series of successive nerve impulses are sent to the motor nerve terminal where they depolarize the presynaptic membrane, causing structures called voltage-gated calcium channels to open which allows calcium to enter the motor nerve terminal. This calcium influx results in a nearly synchronous release of the contents of several synaptic vesicles which results in a larger depolarization of the postsynaptic membrane, known as the endplate potential (EPP). When the EP reaches a certain threshold, it opens voltage-gated sodium channels found along the entire muscle fiber outside of the motor endplate area and this triggers a propagated muscle fiber action potential which causes the muscle fiber to contract.
The difference between the endplate potential and the depolarization required to activate the voltage-gated sodium channels is known as the safety margin of neuromuscular transmission. In healthy individuals, the amplitude of the EPP is quite large. With continued activity the EPP begins to decrease but still remains large enough to trigger a muscle fiber action potential.
After the muscle contracts, ACh is released from the AChRs into the synaptic space) where it is broken down (hydrolyzed) by AChE into two molecules, acetate and choline. Choline is transported back into the nerve terminal where it recombines with acetate under the influence of an enzyme known as choline acetyltransferase to be stored once again within the synaptic vesicles.
The factors governing the safety margin of neuromuscular transmission fall into four major categories: (1) factors that affect the number of ACh molecules in the synaptic vesicle; (2) factors that affect quantal release mechanisms; (3) the density of AChE in the synaptic space; and (4) factors that affect the efficacy of individual quanta. The efficacy of individual quanta depends on the endplate geometry, the packing density of AChRs on the tips of the junctional folds, the affinity of AChRs for ACh, and the kinetic properties of the AChR ion channel.
Congenital myasthenic syndromes are caused when there is an alteration (mutation) in a specific gene. This results in an abnormal protein or even loss of a protein that impairs some part of the process described above. The abnormal protein (disease protein) can reside in the motor nerve terminal, or the synaptic space, or in the postsynaptic region that underlies the nerve terminal, but in some patients the disease protein is also present in others tissues or organs causing not only CMS but also a variety of other symptoms.
The cardinal symptom of all myasthenic disorders is muscle weakness that is induced or worsened by exertion. This is referred to as fatigable weakness. In healthy people, physical activity causes a small decrease in the number of ACh quanta released from the nerve terminal that does not impair the safety margin of neuromuscular transmission, but it is incapacitating in myasthenic patients in whom the safety margin is already reduced.
In some patients with CMS, the weakness is confined to muscles supplied (innervated) by the cranial nerves causing double vison, droopy eyelids (eyelid ptosis), facial weakness, hypernasal or slurred speech, and swallowing difficulties. In other patients, the above symptoms are combined with weakness of the limb and torso muscles causing generalized myasthenia. In still others, the weakness is limited to the limb and torso muscles causing ‘limb-girdle myasthenia’.
The myasthenic disorders caused by defects in enzymes required for protein glycosylation can also be associated with development delay, seizures, intellectual disability, neuropathy, and metabolic abnormalities of different organs.
Several different types of CMS have been identified.1 The currently identified types are:
Each type can be subdivided into several subtypes that are discussed below.
Endplate Choline Acetyltransferase (ChAT) Deficiency
After acetylcholine is released from the nerve terminal, it binds to acetylcholine receptor for a brief period; when it is released from the receptor, it is rapidly broken down (hydrolyzed) by the enzyme acetylcholinesterase into choline and acetate. The released choline is transported to the nerve terminal where the enzyme choline acetyltransferase (ChAT) reforms (resynthesizes) acetylcholine. The resynthesized acetylcholine is then transported into the synaptic vesicles, where it becomes available to be released into the synaptic space as needed. Deleterious mutations in the CHAT gene, alone or in combination, alter the expression, catalytic efficiency, or stability of the ChAT protein.2,3
The defect in ChAT causes progressive decrease of the acetylcholine content of the synaptic vesicles during activity and hence reduces the amplitude of the EPP, which reduces the safety margin of neuromuscular transmission.
Some patients present with hypotonia (low muscle tone), paralysis of cranial and limb muscles and apnea (failure to breathe) at birth. Others are normal at birth and develop attacks of apnea during infancy or childhood precipitated by infection, excitement, or no apparent cause.3-7 In some children an acute attack is followed by respiratory failure that lasts for weeks.8 A few patients are respirator-dependent and paralyzed since birth3 and some develop brain atrophy caused by lack of oxygen (hypoxia) during episodes of apnea.3,7 Others improve with age, but still have variable eyelid drooping (ptosis), impaired movement of the ocular muscles, fatigable weakness, and recurrent episodes of cyanosis, in which there is bluish discoloration of the skin due to impaired respiration and inadequate oxygenation of the blood. Some patients complain only of mild to moderately severe fatigable weakness. The weakness is worsened by exposure to cold because this further reduces the efficiency of the mutant enzyme.5
Treatment consists of preventive (prophylactic) therapy with pyridostigmine (Mestinon) which is a medication that inhibits the activity of acetylcholinesterase (which breaks down acetylcholine in the synaptic space). This prolongs the life time of acetylcholine in the synaptic space and, consequently, the number of acetylcholine receptors it can activate. Parents of affected infants should be provided an inflatable rescue bag and a fitted mask, and should be instructed in the intramuscular injection of neostigmine methylsulfate (another inhibitor of acetylcholinesterase), and are advised to install an apnea monitor in their home.
A single patient reported to date had a severe CMS associated with an unusually exaggerated response to brain stimuli (cerebral cortical hyperexcitability), ataxia (lack of coordination), and intellectual disability.9 Genetic studies revealed a dominant single amino acid change in the gene SNAP25B, which produces an essential protein required by the synaptic vesicles to release acetylcholine (exocytosis). The endplates were structurally normal on examination by the electron microscope. Treatment with 3,4-diaminopyridine (3,4-DAP), which increases the number of quanta released by nerve impulse, improved the patient’s weakness but not her ataxia or intellectual disability.
Synaptotagmin 2 Deficiency
Synaptotagmin 2 is another presynaptic protein. It senses the calcium concentration in the nerve terminal; when this is increased, it acts on other proteins to initiate the release of acetylcholine into the synaptic space (exocytosis). In two kinships, mutations in this gene caused limb muscle weakness, loss of the tendon reflexes, and a reduced amplitude of the muscle fiber action potential that precedes muscle fiber contraction. This response as well as the weakness was transiently improved by exercise. The treatment of this condition has not been described.10
Paucity of Synaptic Vesicles and Impaired Quantal Release
The clinical features resemble that of autoimmune myasthenic gravis, but the onset is at birth or in early infancy and tests for anti-acetylcholine receptor antibodies are negative. A specific diagnosis requires electron microscopy and electrophysiology studies of the motor endplate. A presynaptic defect is revealed by a severe decrease (to approximately 20% of normal) in quantal release of acetylcholine by nerve impulse accompanied by a proportionate decrease in the number of synaptic vesicles in the nerve terminal. This CMS responds to treatment with pyridostigmine.11
SYNAPTIC BASAL LAMINA-ASSOCIATED
Endplate Acetylcholinesterase (AChE) Deficiency
The endplate species of acetylcholinesterase (AChE) is composed of 12 catalytic subunits, which rapidly breaks down (hydrolyzes) acetylcholine, plus a collagenic subunit, called ColQ, which anchors the entire molecule to the basal lamina of the endplate. Subunits are single protein molecules that combine with other proteins to form a larger protein complex.
The ColQ protein is composed of three identical strands each of which binds to 4 catalytic subunits. Histochemical and electron microscopy studies reveal absence of acetylcholinesterase from the endplate and smaller than normal nerve terminals. Severely affected patients present at birth with apnea and generalized weakness that persists throughout life. Less severely affected patients present later in childhood.12 The patients do not respond to, or are worsened by, pyridostigmine which acts by inhibiting acetylcholinesterase. Therapy is still unsatisfactory, but ephedrine13 and albuterol14 have a gradually developing beneficial effect.
CMS Associated with β2-Laminin Deficiency
β2-laminin is a component of the basal lamina of different tissues and is highly expressed in kidney, eye, and at the endplate where the protein is important for the appropriate alignment of the nerve terminal with the postsynaptic region. β2-laminin also contributes to the development and organization of the two regions. Mutations in β2-laminin result in Pierson syndrome, a rare disorder associated with malformations of the kidneys and eyes. A patient with Pierson syndrome had a myasthenic syndrome. The kidney defect was corrected by renal transplant at age 15 months. Quantal release by nerve impulse and the MEPP amplitude were both reduced. Electron microscopy revealed abnormally small nerve endings accounting for the decreased quantal release. The synaptic space was widened and the junctional folds were simplified, accounting for the decreased MEPP amplitude.15
DEFECTS IN ACETYLCHOLINE RECEPTOR (AChR)
Primary AChR Deficiency
The acetylcholine receptor is made up 5 subunits. Subunits are single protein molecules that combine with other proteins to form a larger protein complex; in this case, the acetylcholine receptor. Two of these subunits are called alpha (α) and the remaining 3 are called beta (β), delta (δ) and epsilon (ε) in adults. Before birth, the fetal subunit contains a gamma (γ) instead of a ε subunit.
In primary AChR deficiency, the amount of AChR expressed at the endplate is reduced and the safety margin of neuromuscular transmission is impaired by the decreased amplitude of the EPP. The clinical deficits vary from mild to severe. Patients with recessive mutations in the ε subunit are generally less severely affected than those with mutations in other subunits because compensatory expression of the fetal γ subunit can partially substitute for the defective ε subunit.
The sickest patients have severe ocular, bulbar and respiratory muscle weakness from birth and survive only with respiratory support and gavage feeding. Gavage feeding is the use of a small, narrow tube inserted through an infant’s nostrils and run down the throat to the stomach to directly supply nourishment to an affected infant. Infants may be weaned from a respirator and begin to tolerate oral feedings during the first year of life, but have bouts of aspiration pneumonia and may need intermittent respiratory support during childhood and adult life.
Motor development is severely delayed; they seldom learn to take steps and can walk for only for a short distance. Older patients close their mouths by supporting their jaw with their hand and elevate their eyelids with their fingers. Facial deformities, protruding jaw, misalignment teeth (malocclusion), and abnormal curvature of the spine such as scoliosis or kyphoscoliosis become noticeable during the second decade. Muscle bulk is reduced. The tendon reflexes are normal or hypoactive.
Less severely affected patients experience moderate physical handicaps from early childhood. Limited eye movements and ptosis of the lids become apparent during the first year of life. They fatigue easily, walk and negotiate stairs with difficulty, cannot keep up with their peers in sports, but can perform most activities of daily living. Mutations in the AChR α, β, and δ subunits that reduce or prevent the expression of AChR are either lethal in embryonic life or cause marked disability and high mortality after birth.
In the least affected patients motor development is only slightly delayed; they only have mild eyelid ptosis and limitation of eye movements. They are often clumsy in sports, fatigue easily, and cannot run well, climb rope, or do pushups. In some patients, a myasthenic disorder is suspected only when they develop prolonged respiratory arrest on exposure to a neuromuscular blocking agent drug during a surgical procedure.
Treatment consists of pyridostigmine an inhibitor of acetylcholinesterase. This medication increases the lifetime of acetylcholine in the synaptic space which allows each acetylcholine molecule to bind to different acetylcholine receptors repeatedly before it leaves the synaptic space by diffusion. Many patients derive additional benefit from the use of 3,4-diaminopyridine (3,4-DAP)16 which prolongs the depolarization of the presynaptic membrane by nerve impulse. This allows more calcium to enter the nerve terminal which increases the number of acetylcholine quanta released by each nerve impulse. Finally, some patients derive still additional benefit from albuterol. 17
Kinetic Defect in AChR: The Slow-Channel Syndrome
This syndrome is caused by dominant mutations in the acetylcholine receptor (AChR) gene that leads to the abnormally slow closure of the AChR ion channel. The prolonged openings of the ion channel cause overloading of the postsynaptic region with positively charged ions, including calcium. The local increase in calcium concentration damages the junctional folds, and can damage the muscle fiber nuclei under the folds. The onset of symptoms ranges from infancy to early adult life. The disease causes selectively severe weakness and loss of bulk (atrophy) of the cervical, scapular, and of the wrist and finger extensor muscles.18
The safety margin of synaptic transmission is compromised by damage to the junctional folds with loss of acetylcholine receptors, and by the receptors becoming desensitized (unresponsive) during physiologic activity due to prolonged exposure to acetylcholine.
This syndrome does not respond to, or is worsened by, pyridostigmine but is improved by relatively high doses of fluoxetine (Prozac) which blocks (plugs) the acetylcholine receptor ion channel and thereby reduces the length of channel openings.19
Kinetic Defect in AChR: The Fast-Channel Syndrome
This syndrome is transmitted by recessive inheritance and is the physiologic and anatomic opposite of the slow-channel syndrome.18 The length of the AChR channel openings is decreased because the mutations reduce the ability of AChR to bind acetylcholine, or because they hinder the opening of the AChR ion channel, or because they cause the ion channel to become intermittently unstable. The structural integrity of the endplate is unaffected.
This syndrome becomes manifest only if the second copy of the AChR subunit gene is not expressed, or if both copies of the gene harbor the same mutation, so that the fast- channel mutation dictates the clinical consequences. The safety margin of neuromuscular transmission is reduced because the mutant gene reduces the probability and length of channel openings, which reduce the amplitude and duration of EPP. The clinical consequences vary from mild to severe. Most patients respond to combined treatment with pyridostigmine and 3,4-DAP.
Prenatal CMS Caused by Mutations in AChR Subunits and Other Specific Proteins
The first identified prenatal myasthenic syndrome was traced to mutations in the fetal AChR γ subunit. In humans, AChR harboring the fetal subunit appears on developing muscle fibers around the ninth week of gestation and becomes concentrated at early nerve-muscle junctions around the sixteenth week of gestation. Subsequently, the γ subunit is replaced by the adult ε subunit and is no longer present at fetal endplates after the thirty-first week of gestation. Thus harmful mutations of the γ-subunit reduce fetal movements (hypomotility) between the sixteenth and thirty-first week of gestation.20
The clinical consequences at birth are contractures of large joints, small muscle bulk, webbing around the neck, armpits, elbows, fingers, or behind the knees, flexion contractures of the fingers, rocker-bottom feet with prominent heels, and a characteristic facial appearance with mild eyelid ptosis and a small mouth with downturned corners. A contracture is a condition in which a joint becomes permanently fixed in a bent or straightened position, completely or partially restricting the movement of the affected joint.
Myasthenic symptoms are absent after birth because by then the normal adult ε subunit is expressed at the endplates.21 Recent studies also identified lethal fetal akinesia syndromes arising from deleterious null mutations in both copies of the AChR α, β, and δ subunits as well as in other CMS disease genes.
CMS CAUSED BY DEFECTS IN ENDPLATE DEVELOPMENT OR MAINTENANCE
To date, mutations have been detected in genes for proteins that are essential for motor endplate development and maintenance. As with the communication of nerve signals from nerve cells to muscle fibers described above, the health and development of the motor endplate depends upon a sequence of interrelated, chemical reactions involving multiple genes and their protein products.
These genes are MuSK, Agrin, LRP4, and DOK-7. Agrin is secreted into the synaptic space by the nerve terminal where it binds to the lipoprotein-related protein LRP4 in the postsynaptic membrane creating an agrin-LRP4 protein complex. The Agrin-LRP4 complex then binds to and activates MuSK. This enhances MuSK phosphorylation and leads to clustering of LRP4 and MuSK. Activated MuSK in concert with postsynaptic DOK-7 and other postsynaptic proteins acts on Rapsyn to concentrate AChR in the postsynaptic membrane, enhances synapse specific gene expression by postsynaptic nuclei, and promotes postsynaptic differentiation. Clustered LRP4, in turn, promotes differentiation of motor axons. The agrin-LRP4-MuSK-Dok-7 signaling system is also essential for maintaining the structure of the adult neuromuscular junction.22
Only a few patients with agrin-related CMS have been reported. The severity of the symptoms varies according to the location of the mutations in the agrin gene and whether or not the mutations affect agrin expression.23,24,25 The consequences are severe when a mutation that hinders attachment of agrin to LRP4 dominates the clinical picture. In such a patient the synaptic contacts were dispersed, the postsynaptic regions were poorly differentiated, the nerve terminals were small, and there were degenerative changes in the muscle fibers under the junctional folds.24 Another report describes three kinships in which the agrin mutations were associated with slowly progressive wasting of the distal leg and later of the upper arm muscles.25 Treatment of the agrin-related CMS is unsatisfactory, but one patient responded partially to ephedrine.24
There are only two reports of LRP4-related CMS. The first report described a 17-year-old girl with moderately severe fatigable limb-girdle weakness, irregularly shaped synaptic contacts, and mild endplate AChR deficiency. In a muscle located between the ribs (intercostal muscle) of this patient the MEPPs and EPPs were of normal amplitude indicating the identified mutations could spare neuromuscular transmission in some muscles.26 Subsequently, two sisters with moderately severe CMS and harboring a homozygous mutation that hinders LRP4 from activating MuSK were shown to have structurally and functionally abnormal endplates and endplate AChR deficiency.27
This disease presents at birth or in early life with eyelid ptosis or respiratory distress. Subsequently, it involves the ocular, facial and proximal limb muscles, and in some kinships the bulbar muscles as well.28,29,30,31,32 Introduction of the mutant gene in mice results in recurrent cycles of focal loss of nerve supply (denervation) and reestablishment of nerve supply (reinnervation) resulting in extensive remodeling of the endplates.33 Pyridostigmine therapy is ineffective or worsens the disease.31 A recent report indicates that therapy with albuterol has been highly effective in two brothers.34 No clear genotype-phenotype correlations (correlation between a given mutation and the clinical features) have been observed.
DOK-7 is expressed within developing and mature muscle fibers. In developing muscle fibers it serves as an intrinsic activator of MuSK.35 In mature muscle, it is activated by MuSK to activate rapsyn to concentrate acetylcholine receptors on the junctional folds and to promote the development and maintenance of the endplate. This CMS can be mild or severe. The pathogenic mutations can curtail DOK-7 expression or prevent DOK-7 to activate, or be activated by, other intracellular proteins. There appears to be no consistent correlation between the identified mutations and the clinical features.
All affected patients have limb-girdle weakness with lesser facial and neck muscle weakness but a few have severe bulbar weakness and few have significant limitation of the eye movements.36,37 The clinical course is mild to severe. Impaired maintenance of the endplates is evidenced by ongoing destruction and remodeling of the endplates. Neuromuscular transmission is compromised by the decreased quantal release from the nerve terminal by nerve impulse and by a reduced amplitude of the MEPP.37 Importantly, this CMS is rapidly worsened by pyridostigmine but responds well over a period of time to ephedrine38 or albuterol.37
Rapsyn concentrates and anchors acetylcholine receptors on the junctional folds39 and is required for development of the junctional folds.40 Most patients present in the first year of life.41 Joint contractures at birth and other congenital malformations occur in close to one-third.42 Intercurrent infections or fever can trigger respiratory crises that can cause brain damage due to lack of oxygen (anoxia). 43,44 The eye movements are intact in most patients.42 Multiple synaptic contacts appear on single muscle fibers. The endplate acetylcholine receptor deficiency is milder than in primary acetylcholine receptor deficiency42 and the junctional folds are not well differentiated. Most patients respond well to pyridostigmine; some derive additional benefit from ephedrine or albuterol43 and some are further improved by 3,4-DAP.
Indo-Europeans harbor a common N88K mutation in the gene that produces rapsyn, which involves replacement of an asparagine molecule (N) by a lysine molecule (K) at codon 8845 (codon: a sequence of 3 adjacent nucleotides that constitutes a genetic code for a specific amino acid). Different mutations hinder self-association of rapsyn molecules, or their binding to acetylcholine receptors, or impede agrin-MuSK-LRP4-mediated clustering of these receptors, or decrease rapsyn expression.40,46 There are no genotype-phenotype correlations (correlation between a given mutation and the clinical features) except that Near-Eastern Jewish patients with a homozygous E-box mutation (E-box: a sequence before the coding region of a gene involved in regulating gene expression) have a milder course with eyelid ptosis, a large protruding jaw, severe weakness of the masticatory and facial muscle, and hypernasal speech.47
MYASTHENIC SYNDROMES ASSOCIATED WITH CONGENITAL DEFECTS OF GLYCOSYLATION
Glycosylation is the process by which sugar ‘trees’ or residues (glycans) are created, altered and chemically attached to certain proteins or fats (lipids). When these sugar molecules are attached to proteins, they form glycoproteins; when they are attached to lipids, they form glycolipids. Glycoproteins and glycolipids have numerous important functions in all tissues and organs. Glycosylation involves many different genes, encoding many different proteins such as enzymes. A deficiency or lack of one of these enzymes can lead to a variety of symptoms potentially affecting multiple organ systems.
Glycosylation to nascent peptides increases their solubility, folding, stability, assembly, and intracellular transport. Peptides are amino acid compounds and can perform a wide range of functions in the body. O-glycosylation involves addition of sugar residues to the amino acids serine and threonine; N-glycosylation occurs in sequential steps that decorate the amino group of the amino acid asparagine.48,49
To date, defects in four enzymes subserving N-glycosylation have been shown to cause a CMS: GFPT1,50,51 DPAGT1,52,53 ALG2, and ALG14.54 Accumulation of small tubules within the muscle fibers, referred to as tubular aggregates, are a clue to the diagnosis but are not seen in all patients. Because glycosylated proteins are present at all endplate sites, the safety margin of neuromuscular transmission is likely compromised by a combination of pre- and postsynaptic defects.
GFPT1 controls the entry of glucose into the glycosylation pathway. A defect in GFPT1 predicts reduced glycosylation, and therefore defective function, of several endplate- associated proteins.50 The synaptic contacts are small and the postsynaptic regions are poorly developed .51 One patient whose mutations abolished expression of the muscle- specific exon of GFPT1 had severe facial, bulbar, and respiratory muscle weakness, and has been paralyzed since birth. She has a vacuolar myopathy, reduced quantal release evoked by nerve impulse, and low MEPP amplitude. A vacuolar myopathy is a muscle disease that is associated with the development of abnormal pockets or spaces called vacuoles within muscle tissue.
DPAGT1 catalyzes the first committed step of N-linked protein glycosylation. DPAGT1 deficiency predicts impaired asparagine glycosylation of multiple proteins distributed throughout the organism, but in the first 5 patients harboring DPAGT1 gene mutations only neuromuscular transmission was adversely affected.52 A subsequent study of two siblings and of a third patient showed the DPAGT1 deficiency associated with intellectual disability.9 The siblings respond poorly to pyridostigmine and 3,4-DAP; the third patient was partially improved by pyridostigmine and albuterol. Intercostal muscle studies showed fiber type disproportion, small tubular aggregates in some muscle fibers, and autophagic vacuoles (vacuoles that degrade and digest subcellular structures). Evoked quantal release, the MEPP amplitude, and the endplate acetylcholine receptor content were all reduced to ~50% of normal.
ALG2 AND ALG14 Deficiency
ALG2 catalyzes the second and third committed steps of N-glycosylation. In one family, four affected siblings had a deleterious homozygous mutation, and a third patient was homozygous for a low-expressor mutation. ALG14 forms an enzyme complex with ALG13 and DPAGT1 and also contributes to the first committed step of N-glycosylation. In one family two affected siblings carried two different recessive mutations. Endplate ultrastructure and parameters of neuromuscular transmission were not investigated.54
OTHER CONGENITAL MYASTHENIC SYNDROMES
PREPL Deletion Syndrome
The hypotonia-cystinuria syndrome is caused by recessive deletions involving the SLC3A1 and PREPL genes at chromosome 2p21. The major clinical features are cystinuria, growth hormone deficiency, muscle weakness, eyelid ptosis, and feeding problems. Cystinuria is an inherited metabolic disorder characterized by the abnormal movement (transport) in the intestines and kidneys, of certain organic chemical compounds (amino acids).
A patient with isolated PREPL deficiency had myasthenic symptoms since birth and growth hormone deficiency but no cystinuria, and responded transiently to pyridostigmine during infancy.55 She harbors a paternally inherited nonsense mutation in the PREPL gene and a maternally inherited deletion involving both PREPL and SLC3A1; therefore the PREPL deficiency determines the phenotype. PREPL expression was absent from the patient’s muscles and endplates. Endplate studies revealed decreased evoked quantal release and small MEPP amplitude despite robust endplate acetylcholine receptor expression.55 Because PREPL is an essential activator of the clathrin associated adaptor protein 1 (AP1),56 and AP1 is required by the vesicular acetylcholine transporter to fill the synaptic vesicles with acetylcholine,57 the small MEPP is attributed to a decreased vesicular content of acetylcholine.
Two patients with this syndrome have been identified to date. The first patient had abrupt episodes of respiratory and facial weakness associated with weakness of muscles required for speaking and swallowing since birth lasting from 3 to 30 minutes typical of periodic paralysis as well as a myasthenic disorder. Studies of neuromuscular transmission revealed normal amplitude EPPs that frequently failed generate muscle action potentials pointing to voltage-gated sodium channels (SCN4A gene) as the culprit. The gene for voltage-gated sodium channels (SCN4A) harbored two recessive mutations which caused the sodium channel to become inactive soon after it was activated by the EPP.58 A second patient with similar clinical findings was recently identified. In this patient two different recessive mutations in voltage-gated sodium channel caused abnormal inactivation of the sodium (Na) channel by activity.59
CMS Caused by Plectin Deficiency
Plectin, encoded by the PLEC gene, has different tissue-specific and organelle-specific forms (known as isoforms) that serve to link cytoskeletal filaments to target organelles.60-62 Organelles are a general term for any number of organized or specialized structures within a living cell.
Plectin is concentrated at sites of mechanical stress. For example, in skeletal muscle it is present under the junctional folds of the endplates, under the surface membrane of the muscle fiber, at the Z-disks (thin protein bands that mark the boundaries of adjoining contractile units), and around nuclei and mitochondria, which are found by the hundreds within virtually every cell of the body and which generate most of the cellular energy.
In skin, it is associated with hemidesmosomes (peg-like structures that link epithelial cells to the underlying basement membrane). Alone or in combination, mutations in plectin can result in a blistering skin disease known as epidermolysis bullosa simplex (EBS), in progressive muscular dystrophy, and sometimes in a myasthenic syndrome. The two patients investigated by the author had EBS, a myasthenic syndrome due to low amplitude MEPPs caused by degenerating junctional folds, as well as muscular dystrophy associated with dislocation of the muscle fiber nuclei, mitochondria and myofibrils (basic rod-like units of muscle cells) as well as defects in the muscle fiber surface membrane causing calcium overloading and degeneration of the muscle fibers.63
CMS Associated with Defects in the Mitochondrial Citrate Synthase Carrier SLC25A1
The SLC25A1 gene encodes a transporter protein that is responsible for the movement of citrate across the inner membranes of mitochondria. Mutations in the SLC25A1 gene interfere with brain, eye, and psychomotor development.64
Two siblings born to consanguineous parents had a CMS associated with intellectual disability and whole exome sequencing revealed they carried a homozygous mutation in SLC25A1. Subsequent studies showed that the mutation impairs the transport activity of the enzyme, and that knockdown of the gene equivalent to SLC25A1 in zebra fish hindered motor axons from innervating muscle fibers.65 A third patient who harbored two recessive mutations in SLC25A1 had myasthenic symptoms as well underdeveloped optical nerves, undeveloped corpus callosum (a structure connecting the two cerebral hemispheres), and excessive urinary excretion of 2-hydroxyglutaric acid.64
CMS Associated with Centronuclear Myopathies
Eyelid ptosis, weakness of the external ocular and facial muscles, exercise intolerance, a decremental EMG study, and response to pyridostigmine have been documented in patients with centronuclear myopathies (CNM) caused by mutations in amphiphysin (BIN1),66 myotubularin (MTM1),67 and dynamin 2 (DNM2)68 as well as in other CNM patients with no identified mutations.69
Congenital myasthenic syndromes are caused by alterations (mutations) in specific genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
Approximately 30 different genes are known to cause CMS. These genes contain instructions for proteins that are essential for the proper function or health of the neuromuscular junction and the motor endplate. Some of these proteins are found in other areas of the body and, in those subtypes, other areas of the body in addition to the neuromuscular junction can be affected.
In some individuals with CMS, no altered gene has been found indicating that additional, as-yet-unidentified genes exist that can cause a congenital myasthenic syndrome.
In most subtypes, CMS are inherited as autosomal recessive traits. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Specific CMS subtypes, specifically SNAP25, synaptotagmin 2, and the slow-channel-myasthenic syndrome are transmitted by autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
A generic diagnosis of a CMS can be made on clinical grounds from a history of fatigable weakness involving ocular muscles, bulbar muscles (muscles of the face, and muscles used for speaking and swallowing), and limb muscles since infancy or early childhood, a history of similarly affected relatives, and a variety of tests.
Such tests include a decremental electromyographic (EMG) response, and negative tests for antibodies against the acetylcholine receptor (AChR) and the muscle specific receptor tyrosine kinase (MuSK). However, in many CMS patients the family history is negative; in others the onset is delayed, the EMG abnormalities are not present in all muscles or are present only intermittently, and the weakness has a restricted distribution.
An electromyography or EMG test records electrical activity in skeletal (voluntary) muscles at rest and during muscle contraction. The decremental EMG response is measured by stimulation of a motor nerve to muscle at a rate of 2 to 3 times per second; the evoked electrical responses from muscle, known as compound muscle action potentials, or CMAPs, are recorded by electrodes placed on skin overlying the stimulated muscle. The response is abnormal if the fourth evoked CMAP is more than 10% smaller than the first evoked CMAP. Single fiber EMG is a more sensitive but less specific test for a myasthenic disorder. In this test, single intramuscular nerve fibers are stimulated repetitively and the evoked single fiber action potentials are recorded simultaneously from 2 to 4 muscle fibers at a time. An abnormally increased variability in the time-locked firing of individual action potentials is an early indicator of a defect in neuromuscular transmission.1
A specific diagnosis of a CMS depends on identifying the disease gene and the pathologic mutations in that gene. Commercially available studies can readily detect mutations in previously identified types of CMS. Mutations in previously unrecognized types of CMS can be detected by whole exome sequencing or whole genome sequencing but the bioinformatic analysis of the obtained result remains challenging. Genetic diagnosis of the CMS is important because therapy that benefits one type CMS can worsen another type.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the CMS overall and that fact that certain subtypes have only been identified in a handful or fewer individuals, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with CMS.
As stated above, it is critically important to identify the specific subtype in each individual as medications that prove effective for one type of CMS may be ineffective or even harmful in another. More detailed treatment information for specific subtypes of CMS is discussed in the “Signs and Symptoms” section above under each individual subtype listing.
Current therapies for CMS include medications known as cholinergic agonists such as pyridostigmine or amifampridine (3,4-diaminopyridine), long-lived open channel blockers of acetylcholine receptor ion channel fluoxetine and quinidine, and adrenergic agonists such as salbutamol and ephedrine.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, in the main, contact:
For more information about clinical trials conducted in Europe, contact:
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