Congenital Myasthenic Syndromes PDF

KEY POINTS CONGENITAL A Congenital myasthenic MYASTHENIC...

KEY POINTS CONGENITAL A Congenital myasthenic MYASTHENIC syndromes are caused by SYNDROMES inherited defects in molecular mechanisms of C. Michel Harper neuromuscular transmission and should be considered in ABSTRACT the differential Congenital myasthenic syndromes are produced by mutations that alter the diagnosis of expression and function of ion channels, receptors, enzymes, or other accessory seronegative molecules needed to maintain the safety margin of neuromuscular transmission. myasthenia Although rare, congenital myasthenic syndromes are an important cause of gravis, seronegative myasthenia. Rapid advances in molecular genetics and correlation of myopathies, molecular biology with microphysiology, morphologic studies, clinical electro- and other physiology, and clinical observations have led to a better understanding of the disorders of the pathophysiology of congenital myasthenic syndromes. With the current state of motor unit. knowledge, many congenital myasthenic syndromes can be diagnosed and in A Manifestations many cases given specific therapy, based on the results of clinical information and that are relatively electrodiagnostic evaluation. specific for specific Continuum Lifelong Learning Neurol 2009;15(1):63–82. congenital myasthenic syndromes are INTRODUCTION cases, causing an associated myopa- pupillary thy. Typically they manifest at birth hyporeflexia in The congenital myasthenic syndromes or in early childhood but, when clini- congenital (CMS) are a group of neuromuscular acetylcholinesterase junction diseases caused by genetic cal expression is mild and progression (AChE) deficiency, defects of endplate molecules in- gradual, they may also go unrecog- hand and neck volved in neuromuscular transmission nized until adolescence or adulthood. muscle weakness (Engel and Sine, 2005). Although rare, Proper recognition and diagnosis of in slow-channel CMS are of interest because they pro- CMS are important because many of congenital duce novel insights into the under- the syndromes are treatable with myasthenic standing of neuromuscular junction drugs that increase the availability of syndrome 63 physiology. They should be consid- acetylcholine (ACh) at the endplate (SCCMS), and ered in the differential diagnosis of or alter the kinetics of the acetylcho- a progressive line receptor (AChR). Genetic coun- myopathy in both seronegative myasthenia gravis, myop- AChE deficiency athy, peripheral neuropathy, and mo- seling is valuable in many cases as and SCCMS. tor neuron diseases affecting children well. Clinical and neurophysiologic and young adults. The CMS are ge- correlations with molecular studies netically heterogeneous but share have defined criteria that assist the common clinical manifestations by re- clinical diagnosis. Subtypes can often ducing the safety margin of neuro- be identified by clinical features, re- muscular transmission and, in some sponse to cholinesterase inhibitors, Relationship Disclosure: Dr Harper has nothing to disclose. Unlabeled Use of Products/Investigational Use Disclosure: Dr Harper discusses the unlabeled use of quinidine and fluoxetine and the investigation use of 3,4-diaminopyridine in the treatment of congenital myasthenic syndrome. Copyright # 2009, American Academy of Neurology. All rights reserved. Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.  " CONGENITAL MYASTHENIC SYNDROMES and findings on standard electrodiag- movements in the prenatal period is nostic studies. common. Affected neonates and young children exhibit generalized hypotonia CLINICAL MANIFESTATIONS and weakness of cranial, axial, and limb OF CONGENITAL musculature (Table 3-1). Various com- MYASTHENIC SYNDROMES binations of static and exertional weak- The clinical manifestations of congeni- ness are observed. Skeletal deformities tal myasthenia depend on the age at such as high-arched palate, facial dys- presentation. A history of reduced fetal morphism, arthrogryposis, and scoliosis are common. Muscles are often small and underdeveloped. Episodic respira- TABLE 3-1 Clinical Manifestations of Congenital tory crises may occur with any form Myasthenia Syndromes in Infancy and of congenital myasthenia but are par- Early Childhood ticularly common in choline acetylcho- linesterase (ChAT) deficiency. Cases " Fluctuating and Fatigable Weakness associated with respiratory crises can Crises triggered by exertion or intercurrent illness manifest CNS complications of hypoxia, " Hypotonia and Generalized Weakness and there may be a family history of sudden death in infancy. Delayed motor development When congenital myasthenia pres- Muscle hypotrophy (small underdeveloped muscles) ents during late childhood or in adult- " Cranial Muscle Weakness hood, the syndrome is difficult to differentiate clinically from autoim- Ptosis and extraocular muscle weakness (pupil mune myasthenia gravis or myopathy abnormalities in AChE deficiency) (Table 3-2). The slow-channel congeni- Facial weakness (‘‘tenting’’ of lips) tal myasthenic syndrome (SCCMS) is Chewing and feeding difficulties most likely to present at this age because High-arched palate it is the only CMS that follows an autosomal dominant pattern of inheri- " Respiratory Insufficiency tance. Thus, a family history of affected CNS signs secondary to episodic hypoxic injury relatives in other generations is com- " Skeletal Deformities mon in SCCMS, while other forms of CMS appear as sporadic cases or fol- Facial dysmorphism low an autosomal recessive pattern of Arthrogryposis multiplex inheritance. Unlike autoimmune myas- 64 thenia gravis, skeletal deformities are Scoliosis common, with scoliosis or lordosis, typ- " Family History ically worsening with standing or sitting Affected siblings in autosomal recessive disorders erect. (most common) Manifestations that are relatively spe- Generational transmission in SCCMS autosomal cific for unique CMS are pupillary dominant inheritance hyporeflexia in congenital acetylcholin- Spontaneous abortions or sudden infant esterase (AChE) deficiency, hand and death syndrome neck muscle weakness in SCCMS, and a " Benefit From AChE Inhibitors progressive myopathy in both AChE deficiency and SCCMS. Patients with All except AChE deficiency and SCCMS SCCMS or AChE deficiency are also AChE = acetylcholinesterase; CNS = central nervous system; SCCMS = unique in that they fail to improve or slow-channel congenital myasthenic syndrome. worsen with administration of acetyl- cholinesterase inhibitors (AChEIs). Continuum Lifelong Learning Neurol 2009;15(1) Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. CLASSIFICATION OF POSTSYNAPTIC DEFECTS CONGENITAL MYASTHENIC CAUSING CONGENITAL SYNDROMES MYASTHENIC SYNDROME CMS are classified by the site and Molecular Biology and molecular mechanism of the underlying Pathogenesis defect of neuromuscular transmission The AChR is a 250-kDa transmembrane (Table 3-3) (Engel et al, 2003; Engel glycoprotein ligand-gated receptor that and Sine, 2005). Postsynaptic disorders include congenital AChR deficiency, congenital myasthenia associated with TABLE 3-2 Clinical Manifestations of Congenital Dok-7 deficiency, and sodium-channel Myasthenic Syndromes in Late myasthenia. AChR mutations account for Childhood and Adults about 75% to 80% of CMS cases (Engel et al, 2003; Engel and Sine, 2005). Some " Fluctuating and Fatigable Weakness AChR mutations primarily alter channel Crises triggered by exertion or intercurrent illness kinetics, while others reduce AChR ex- " Generalized Weakness pression. Reduced AChR expression is also caused by mutations in the genes May have selected distribution (eg, neck, wrist, and digit extensors in SCCMS) for rapsyn and muscle-specific receptor tyrosine kinase (MuSK), molecules pro- Muscle hypotrophy or progressive atrophy duced by muscle that are important for " Cranial Muscle Weakness AChR aggregation (Muller et al, 2006). Ptosis and extraocular muscle weakness, Mutations in DOK-7, which codes for a (pupil abnormalities in acetylcholinesterase deficiency) ‘‘downstream of kinase’’ Dok-7 cytoplas- mic protein that interacts with MuSK, Facial weakness have been identified as the major cause Dysphagia, dysarthria, and jaw weakness of limb-girdle myasthenia, characterized " Respiratory Insufficiency by proximal shoulder and hip girdle weak- ness and small nerve terminals (Palace May be subtle such as desaturation with exercise or sleep et al, 2007). One patient has been described with AChR deficiency in the " Skeletal Deformities setting of a myopathy associated with Facial dysmorphism plectin deficiency (Banwell et al, 1999). High-arched palate Congenital AChE deficiency is sy- naptic, being localized to the basal lam- Scoliosis and lordosis (increase with standing) ina on the muscle surface. Congenital " Personal History of Neuromuscular Problems in 65 AChE deficiency, caused by mutations in Infancy or Early Childhood COLQ coding for the collagen-like tail of " Family History the AChE molecule, is the second most Affected siblings in autosomal recessive disorders common CMS, accounting for about (most common) 15% of cases. Presynaptic disorders in- clude a disease of infants that physiolog- Generational transmission in SCCMS autosomal dominant inheritance ically resembles Lambert-Eaton myas- thenic syndrome, a disorder associated Spontaneous abortions or sudden infant with a paucity of synaptic vesicles on death syndrome morphologic studies, and ChAT defi- " Benefit From Acetylcholinesterase Inhibitors ciency. Mutations of CHAT produce the All except acetylcholinesterase deficiency and SCCMS CMS associated with ChAT deficiency, SCCMS = slow-channel congenital myasthenic syndrome. the rate-limiting enzyme in the synthesis of ACh. Continuum Lifelong Learning Neurol 2009;15(1) Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.  " CONGENITAL MYASTHENIC SYNDROMES KEY POINT has five subunits and is anchored to (Figure 3-2). The extracellular por- A Mutations of the the muscle membrane and cytoskele- tion contains specific sites at or near acetylcholine receptor and ton by rapsyn (Ramarao et al, 2001). the 190-192 position for ACh binding other Agrin, a growth factor released by and a variety of epitopes that are postsynaptic the nerve terminal, reacts with muscle- recognized by AChR antibodies in molecules associated specificity component (MASC) patients with myasthenia gravis. Muta- account for and MuSK. MuSK then promotes tions of the AChR produce a variety approximately AChR aggregation through an interac- of CMS secondary to reduced ex- 80% of tion with rapsyn. Rapsyn further links pression of AChR or alteration of re- congenital the AChR to the cytoskeleton by bind- ceptor gating, or both. All of the AChR myasthenic ing with b-dystroglycan and utrophin subunits share the same basic struc- syndromes. (Figure 3-1). ture (Figure 3-2). The N-terminus The adult isoform of AChR is forms the large extracellular domain, composed of two a, one b-, one -, which, in the a-subunit, contains the and one e-subunits. The e-subunit is binding site for ACh. There are four replaced by the g-subunit in the fetal transmembrane domains (M1 to M4), isoform. Each a-subunit contains four with the M2 domain forming the transmembrane domains, with the M2 major channel-lining segment. The domain lining the pore of the channel large cytoplasmic loop between M3 and M4 contains peptide segments that link AChR to rapsyn. TABLE 3-3 Classification of Congenital Mutations that Reduce Myasthenic Syndromes (Based on 271 Index Cases Evaluated at Mayo Clinic) Acetylcholine Receptor Expression " Postsynaptic Defects (79%) Acetylcholine receptor subunit mu- Reduced AChR expression (with or without minor AChR tations. Autosomal recessive muta- kinetic abnormality) tions in the genes that code for subunits of the AChR are the most AChR mutations (isolated or with plectin deficiency) common cause of congenital myasthe- Rapsyn mutations nia. Over 60 pathogenic null, frame DOK-7 mutations (formerly limb–girdle myasthenia) shift, missense, nonsense, and splice- AChR kinetic abnormality (some with mild reduced site mutations affecting all four adult AChR expression) receptor subunits have been discov- ered (Engel and Sine, 2005). These 66 Slow-channel syndrome mutations reduce AChR density on the Fast-channel syndrome postsynaptic membrane of muscle by Sodium-channel mutations impairing synthesis or assembly of the affected subunit or by inhibition of " Synaptic Defect (Basal Lamina) (14%) AChR clustering (Muller et al, 2006). Endplate acetylcholinesterase deficiency Some mutations produce minor ki- " Presynaptic Defects (7%) netic abnormalities of the receptor, Choline acetyltransferase deficiency but these changes are overshadowed by the marked reduction in recep- Paucity of synaptic vesicles tor expression on the postsynaptic Congenital Lambert-Eaton–like syndrome membrane of the neuromuscular junc- Other unclassified presynaptic defects tion. Mutations of the e-subunit are most common and tend to be suble- AChR = acetylcholine receptor. thal because this subunit can be re- placed by the g-subunit, resulting in Continuum Lifelong Learning Neurol 2009;15(1) Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.  FIGURE 3-1 Graphic representation of the adult acetylcholine receptor isoform in skeletal muscle. MASC = muscle-associated specificity component; MuSK = muscle-specific receptor tyrosine kinase; M2 = second transmembrane segment of a-subunit. overexpression of fetal receptors. Fetal plasmic loop of the AChR subunits, receptors have less efficient channel a RING-H2 domain that binds to b- kinetics with prolonged open times and dystroglycan and other subsarcolemmal reduced currents compared with adult proteins, and a serine phosphorylation receptors, adding to the mild abnor- site (Figure 3-3). mality of channel kinetics observed in The RAPSN mutation most com- patients with e-subunit mutations. No monly associated with CMS is the N88K cases with null mutations of the a-, mutation in the TPR3 domain (Dunne b-, or -subunits have been described, and Maselli, 2003; Ohno et al, 2002). This presumably because these mutations prevent assembly of functioning re- ceptors, which would be incompatible with life. Escobar syndrome (arthrogry- posis multiplex, pterygia, and respira- tory distress) has been associated with mutations of the g-subunit (Hoffman 67 et al, 2006). Rapsyn mutations. Rapsyn (receptor- associated protein at synapse) is a 43 kDa protein synthesized by muscle that mediates agrin and MuSK-induced clustering of AChRs on the crests of the postsynaptic folds of the neuromus- cular junction (Ramarao et al, 2001). The primary structure of rapsyn reveals a myristoylated amino terminal needed for membrane targeting, seven tetra- tricopeptide repeats (TPR) that are FIGURE 3-2 Schematic diagram of the a-subunit of the acetylcholine receptor. The sequence important for self-association, a coiled- 190-192 indicates acetylcholine-binding site. coil domain that binds to the cyto- Continuum Lifelong Learning Neurol 2009;15(1) Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.  " CONGENITAL MYASTHENIC SYNDROMES is symptomatic as a homozygous muta- weakness producing Gower sign and tion or when heteroallelic with several skeletal anomalies such as high-arched other mutations. Patients usually pres- palate and other facial dysmorphism. ent in the neonatal period, but varia- Milder cases present in late childhood ble expression is common. Genotype or adulthood but frequently have a analysis of the region of chromosome 11 history of mild neuromuscular symp- close to the RAPSN gene suggests that toms dating back to the infantile pe- the N88K allele is derived from a com- riod. Common cranial manifestations in- mon European ancestor (Muller et al clude variable ptosis, ophthalmoparesis, 2003; Richard et al, 2003). Studies in dysphagia, dysarthria, and chewing diffi- knockout mice and expression studies in culties. In some cases, respiratory infec- vitro demonstrate AChR deficiency, tions, other illnesses, or stress produces reduced self-aggregation of AChR, or episodes of generalized weakness, which impaired co-clustering of rapsyn with may include respiratory insufficiency. In the AChR. Truncating mutations have others, ambulation and activities of daily been associated with neonatal onset living, including participation in sports, and arthrogryposis (Burke et al, 2003; are minimally affected. The disorder Engel and Sine, 2005). Asymptomatic tends to be relatively nonprogressive relatives with the homozygous N88K and may even improve slightly with age. genotype have been described, suggest- Patients with E-BOX mutations in the ing that other factors play a role in the promoter region of RAPSN have myas- clinical phenotype of rapsyn deficiency. thenic symptoms from birth, character- Homozygous recessive mutations in ized by variable degrees of ptosis, the E-box of the RAPSN promoter pro- dysarthria, and masticatory muscle weak- duce a unique CMS thus far confined to ness (Ohno et al, 2003). Limb muscles Middle Eastern Jewish kindreds (Ohno are relatively spared. Facial deformities et al, 2003). such as mandibular prognathism and Clinical manifestations of acetyl- malocclusion are common in these choline receptor subunit and rapsyn cases. mutations. The severity of congenital Diagnosis. Congenital AChR defi- myasthenia secondary to AChR defi- ciency should be suspected in infants ciency varies considerably within and with hypotonia, arthrogryposis multi- between affected kindreds. This is true plex, skeletal deformities, ptosis, weak for cases associated with either re- cry, cough, feeding difficulties, and res- ceptor subunit or rapsyn mutations. piratory insufficiency. In this setting the 68 Mutations of the a-, b-, and -subunits differential diagnosis includes congeni- that reduce receptor expression tend tal myopathy or dystrophy, motor neu- to produce severe phenotypes, while ron disease, inherited neuropathies, e-subunit mutations produce milder and CNS disorders. Episodic crises, symptoms. Homozygous N88K and com- fluctuating ptosis and ophthalmopare- pound heterozygous rapsyn mutations sis, and improvement with AChEIs favor are associated with either mild or se- the diagnosis of congenital myasthenia vere manifestations. Severe cases pres- over other neuromuscular disorders. ent in early infancy with hypotonia, The findings on nerve conduction generalized limb weakness, ptosis, feed- studies and needle EMG also help dif- ing difficulties, and respiratory compro- ferentiate congenital myasthenia from mise. These patients have underdevel- myopathies and other neurologic dis- oped muscles and demonstrate delays orders. The findings on clinical electro- in motor milestones. Some have arthro- diagnostic studies in congenital AChR gryposis multiplex. They may have fixed deficiency are variable and depend Continuum Lifelong Learning Neurol 2009;15(1) Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. FIGURE 3-3 Schematic diagram of rapsyn polypeptide. The coiled-coil domain binds to acetylcholine receptor (AChR), and the RING-H2P domain binds to b-dystroglycan. Reprinted with permission from Harper CM. Congenital myasthenic syndromes. Semin Neurol 2004;24(1):111–123. primarily on the severity and distribu- synaptic disorder of neuromuscular tion of weakness (Harper, 2002). Re- transmission. Channel kinetics are rel- petitive stimulation at slow rates (2 Hz atively normal, although mild slow- to 3 Hz) demonstrates a decrement of channel or fast-channel characteristics the compound muscle action potential can be observed (see section on ki- (CMAP) in most patients (Figure 3-4), netic defects below). In summary, CMS but the decrement may be absent or caused by AChR deficiency may be restricted to facial muscles in mild cases. difficult to differentiate clinically and The decrement is partially repaired electrodiagnostically from seronegative with either cholinesterase inhibitors or autoimmune myasthenia gravis. If pres- 3,4-diaminopyridine (Engel, 2007). In ent, onset of manifestations from birth moderate to severe cases, the decrement or early childhood, skeletal deformi- frequently worsens with higher rates of ties, decrement at higher rates of re- repetitive stimulation (10 Hz to 50 Hz). petitive stimulation, and a history of The findings on standard needle EMG and single fiber EMG in congen- ital AChR deficiency are nonspecific. Small motor unit potentials with rapid recruitment and motor unit potential amplitude variation without fibrillation potentials are observed on standard needle EMG. Single fiber EMG dem- onstrates increased jitter and blocking. 69 The findings on standard muscle bi- opsy are also nonspecific in congenital AChR deficiency with type II fiber atrophy as the predominant feature (Engel et al, 2003). Histochemical stud- Typical findings on electrodiagnostic studies FIGURE 3-4 ies show a loss of a-bungarotoxin- in congenital myasthenic syndromes secondary to reduced expression of the binding sites and poor development acetylcholine receptor. Traces on the right represent CMAPs of the postsynaptic membrane. Micro- in response to a train of four repetitive stimuli at 2 Hz electrode studies on intercostal or before and after exercise. NCS = nerve conduction studies; CMAP = compound muscle anconeus muscle preparations show action potential; R-CMAP = repetitive CMAP; RS = repetitive decreased miniature endplate potential stimulation; AChEI = acetylcholinesterase inhibitors; amplitudes and currents, with normal 3,4-DAP = 3,4-diaminopyridine; MUP = motor unit potential; SFEMG = single fiber EMG; ex = exercise; 10 = 1 minute; miniature endplate potential frequency 1500 = 15 seconds. and quantal content, suggesting a post- Continuum Lifelong Learning Neurol 2009;15(1) Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.  " CONGENITAL MYASTHENIC SYNDROMES KEY POINTS a similar disease or fetal/infantile mor- AChR deficiency (Selcen et al, 2007). A Congenital tality of siblings are helpful differen- The disorder typically presents in the myasthenic syndrome tiating features. Ultimately, intercostal first 5 years of life. The spectrum of caused by muscle biopsy or experimental genetic manifestations includes reduced fetal acetylcholine analysis may be required to make a movements in utero; static and fatigable receptor specific diagnosis. weakness of cranial, respiratory, and deficiency may Natural history and treatment. The limb muscles; and a gradually progres- be difficult to CMS associated with AChR deficiency sive course. The findings on electro- distinguish from tends to be relatively nonprogressive diagnostic studies are indistinguishable seronegative and may even improve slightly as the from patients with other causes of autoimmune patient ages. The disorder typically re- congenital AChR deficiency (Selcen myasthenia et al, 2007). Response to AChEIs is sponds to symptomatic therapy with pyr- gravis. Onset idostigmine and/or 3,4-diaminopyridine variable, with some patients improving early in life, (Engel, 2007). Ephedrine produces ben- but many demonstrating no response. skeletal deformities, efit in some cases (Engel, 2007). Immu- Ephedrine and 3,4-diaminopyridine decrement at notherapy has no effect. produce modest benefits (Muller et al, high rates of 2007; Selcen et al, 2007). repetitive DOK-7 Mutations stimulation, Dok-7 is a muscle cytoplasmic protein Mutations that Produce Kinetic and sibling that activates MuSK and is therefore Abnormalities of the involvement critical in endplate development and Acetylcholine Receptor are helpful AChR aggregation (Muller et al, 2007). Slow-channel congenital myasthenic differentiating syndrome. Pathogenesis. SCCMS is Mutations in the DOK-7 gene reduce features. the most common CMS caused by a phosphorylation and clustering of AChR A Congenital in cultured myotubes while innervated kinetic abnormality of the AChR (Engel myasthenic muscle fibers demonstrate small end- and Sine, 2005). Slow-channel muta- syndrome plates but normal AChR density per tions increase the rate of channel open- associated endplate (Selcen et al, 2007). Morpho- ing, slow the rate of closure, or increase with Dok-7 the affinity of the receptor for ACh. The logic studies in patients with CMS deficiency was net effect is a gain-of-function mutation associated with DOK-7 mutations (in- formerly known cluding expression of these mutations that prolongs channel-opening events, as limb–girdle in HEK cells) demonstrate simplifica- slows the decay of endplate currents, myasthenia because the tion, destruction, and reduced over- and permits cationic overload of the most common all size of neuromuscular endplates synaptic region of the muscle fiber. The (Muller et al, 2007; Selcen et al, 2007). majority of slow-channel mutations are 70 phenotype demonstrates Physiologic correlates of these changes autosomal dominant, although reces- prominent include reduced quantal release of ACh sive mutations have also been described proximal limb and reduced quantal response to ACh (Croxen et al, 2002; Engel et al, 1996). weakness with (Selcen et al, 2007). Miniature endplate The autosomal dominant mutations relative sparing potential and endplate potential ampli- demonstrate variable penetrance and of cranial tudes are reduced and account for the expression, which may give the appear- musculature. ance of a sporadic or recessive disorder. impaired safety margin of neuromuscu- lar transmission in patients with Dok-7 Prolonged channel opening and de- deficiency. Although initially thought to layed decay of endplate currents lead to have a distinctive clinical phenotype of depolarization block, producing weak- relatively isolated proximal limb weak- ness with exertion. Cationic overload ness (ie, limb-girdle myasthenia), the leads to an endplate myopathy charac- clinical manifestations of CMS asso- terized by degeneration of the post- ciated with DOK-7 mutations are largely synaptic region and static weakness indistinguishable from patients with (Croxen et al, 2002; Engel et al, 1996; Continuum Lifelong Learning Neurol 2009;15(1) Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.  KEY POINT Gomez et al, 1997). More than 20 the seventh decade. Characteristically, A SCCMS involves dominant slow-channel mutations af- the weakness in SCCMS involves mus- prominent fecting all four AChR subunits have cles of the neck and distal regions of the weakness of been reported (Engel and Sine, 2005) upper limbs more prominently than neck muscles, (Figure 3-5). other regions. In particular, intrinsic intrinsic hand Most slow-channel mutations are lo- hand muscles and digit extensors are muscle, and cated in the channel-lining M-2 trans- weak and atrophic. Ptosis, ophthalmo- extensors of the membrane segment of each subunit, paresis, dysarthria, dysphagia, proximal wrist and digits. although mutations also affect the limb weakness, and respiratory insuffi- M-1 segment of the a- and b-subunits ciency also occur in selected cases. and the extracellular domain of the Nocturnal hypoxemia may contribute a-subunit. Two autosomal recessive to the fatigue and weakness associated mutations in the e-subunit (eP245L and with SCCMS and other forms of con- eL78P) also lead to the SCCMS. Muta- genital myasthenia. tions of the transmembrane segments Diagnosis. SCCMS should be con- tend to produce a more severe phe- sidered in patients of any age with a notype than those of the extracellular history of chronic fatigable and static domain. weakness affecting cranial, axial, and Clinical manifestations. Variable ex- limb musculature. The differential di- pression results in a wide spectrum of agnosis includes congenital myopathy, clinical manifestations and severity in muscular dystrophy, mitochondrial kindreds of SCCMS. Severe cases pres- and other metabolic myopathies, auto- ent in infancy or early childhood. Mild immune myasthenia gravis, and other cases present in adulthood, even into forms of congenital myasthenia. The 71 FIGURE 3-5 Acetylcholine (ACh) receptor subunit mutations (black circles) associated with the slow-channel congenital myasthenic syndrome. Continuum Lifelong Learning Neurol 2009;15(1) Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.  " CONGENITAL MYASTHENIC SYNDROMES KEY POINTS prominent involvement of neck, wrist the main motor response that worsens A SCCMS and and digit extensors, and intrinsic with increasing rates of stimulation congenital myasthenic hand muscles should raise suspicion (Figure 3-7) (Harper, 2002). This phe- syndrome of SCCMS, especially in the setting of nomenon is likely the result of depo- caused by fatigable ptosis and ophthalmoparesis. larization block and is observed in some acetylcholinesterase Worsening of the symptoms with ad- other CMS (cholinesterase deficiency deficiency are ministration of cholinesterase inhibitors and some cases of AChR deficiency), typically made helps differentiate SCCMS from autoim- but not typically in autoimmune myas- worse by mune myasthenia gravis and other CMS thenia gravis. acetylcholinesterase (except congenital AChE deficiency). Needle EMG findings (standard or inhibitors. Standard motor nerve conduction single fiber EMG) are identical to those A SCCMS is studies reveal repetitive CMAPs when observed in other disorders of neuro- distinguished by single supramaximal stimuli are ap- muscular transmission (ie, normal inser- an autosomal plied (Harper, 2002). Repetitive CMAPs tional activity, small varying motor unit dominant pattern (R-CMAPs) are also observed in congen- potentials on routine EMG, increased of inheritance, ital AChE deficiency or pharmacologic jitter and blocking on single fiber EMG). unique inhibition of AChE. R-CMAPs result from Because congenital SCCMS is typi- distribution of prolonged endplate currents. Adminis- cally autosomal dominant, clinical and clinical weakness, tration of a cholinesterase inhibitor electrodiagnostic examination of first- worsening of typically increases the number and degree relatives may reveal characteris- symptoms with acetylcholinesterase size of repetitive potentials in SCCMS tic features of slow-channel syndrome. inhibitors, the but not in congenital AChE defi- Mutational analysis is available at se- appearance ciency (Figure 3-6). Repetitive nerve lected academic medical centers (Engel of repetitive stimulation reveals a decrement of and Sine, 2005). Muscle biopsy shows compound degeneration of the postsynaptic folds muscle action and subsarcoplasmic regions of the potentials, and a muscle fiber in the endplate region rate-dependent (Engel et al, 2003). The endplate my- decrement on opathy is often associated with a repetitive nerve secondary deficiency of AChRs. Micro- stimulation electrode studies show prolonged end- studies. plate currents secondary to prolonged opening events of individual receptors. The prolonged opening events are caused by increased affinity of receptor 72 for ACh, stabilization of the open state, or destabilization of the closed state of the receptor (Engel et al, 2003). Natural history and treatment. Without treatment, the condition wor- sens over years as the endplate myopa- thy progresses. Cholinesterase inhibitors typically worsen symptoms by prolong- FIGURE 3-6 Repetitive stimulation of ulnar nerve at 2 Hz before ing endplate currents and promoting and after administration further desensitization of the receptor. of a cholinesterase inhibitor (prostigmine) in slow-channel congenital myasthenic Quinidine and fluoxetine, which reduce syndrome. The number and size of the the duration of AChR channel openings, repetitive compound muscle action are both effective treatments for SCCMS potentials is increased after administration of prostigmine. (Harper et al, 2003; Harper and Engel, 1998). Quinidine administered at 200 mg Continuum Lifelong Learning Neurol 2009;15(1) Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. 2 to 3 times daily, producing serum levels Diagnosis. Fast-channel syndrome of 1 g/mL to 2.5 g/mL, reduces pro- should be considered in children with longed AChR openings and produces features of seronegative myasthenia short-term, as well as gradual long-term, gravis. Electrodiagnostic studies reveal improvement of weakness and nerve a decrement with slow rates of repetitive conduction abnormalities. Fluoxetine, stimulation and repair of the decrement which like quinidine is a long-lived open with exercise, high-frequency stimula- channel blocker, produces similar bene- tion, cholinesterase inhibitors, and 3,4- fit as quinidine (often with fewer side diaminopyridine (Harper, 2002). No effects) at doses ranging from 80 mg/d repetitive CMAPs are observed. Needle to 160 mg/d. examination shows small varying motor Congenital fast-channel myas- unit potentials with increased jitter and thenic syndrome. Pathogenesis. The blocking on single fiber studies. In very fast-channel syndrome is the mirror mild cases, the decrement on repetitive image of the slow-channel syndrome. stimulation can be missed, especially Instead of prolonging opening events, when it is confined to facial muscles. In fast-channel mutations shorten the du- this setting normal creatine kinase levels ration of AChR channel openings by and findings confined to type II fiber decreasing the receptor’s affinity for atrophy on standard muscle biopsy ACh, impairing channel-gating effi- help differentiate fast-channel syndrome ciency or destabilizing channel kinetics from a myopathy. Ultrastructural studies (Brownlow et al, 2001; Ohno et al, 1996; are typically normal or show a reduc- Shen et al, 2002). Destabilization of the tion in the density of AChRs on the channel open state results in faster postsynaptic membrane (Engel and decay of endplate currents than normal, thereby reducing the safety margin of neuromuscular transmission. In order for the recessive fast-channel mutations to be expressed, they must be com- bined with allelic missense or null mutations in the gene for the same subunit, making it less common than the slow-channel syndrome. Clinical manifestations. The con- genital fast-channel myasthenic syn- drome presents in infancy or early 73 childhood with ptosis, ophthalmopa- resis, dysphagia, dysarthria, difficulty chewing, and exertional weakness of axial and limb muscles. Mild cases are difficult to differentiate from congenital or metabolic myopathies. More severe cases have prominent cranial and res- piratory involvement or arthrogryposis multiplex (Engel and Sine, 2005). The clinical history and examination findings FIGURE 3-7 Rate-dependent decrement. Decrement are similar to autoimmune myasthenia gets more severe with increasing rates of repetitive stimulation in slow-channel gravis. The weakness responds favor- congenital myasthenic syndrome. ably to cholinesterase inhibitors and Stim = stimulus. 3,4-diaminopyridine (Engel, 2007). Continuum Lifelong Learning Neurol 2009;15(1) Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.  " CONGENITAL MYASTHENIC SYNDROMES KEY POINT Sine, 2005). Microelectrode studies re- induce the decrement and the rapidity A Fast-channel veal reduced amplitude and rapid decay of repair after the repetitive stimulation syndrome responds of endplate currents. is discontinued. An intercostal muscle well to a Natural history and treatment. The biopsy performed on this patient re- combination of fast-channel CMS tends to be static or vealed normal ultrastructure and micro- acetylcholinesterase slowly progressive but usually very re- electrode studies except for elevation inhibitors sponsive to combination therapy with of the endplate currents required to and 3,4- 3,4-diaminopyridine (enhances release bring the muscle to threshold. Expres- diaminopyridine of ACh) and pyridostigmine (reduces sion of the V1442E mutation in human because the metabolism of ACh) (Engel, 2007). embryonic kidney cells reproduced this kinetic defect Cases of pure kinetic abnormalities abnormality and demonstrated the al- raises the terations in Nav1.4 activation described and relatively normal expression AChRs threshold of respond best to therapy. above. acetylcholinesterase receptor Sodium-channel congenital my- desensitization asthenic syndrome. A single case of SYNAPTIC BASAL in the presence sodium-channel myasthenic syndrome LAMINA-ASSOCIATED DEFECTS of acetylcholine. has been described associated with two recessive mutations in the skeletal mus- Congenital cle sodium-channel gene SCN4A (S246L Acetylcholinesterase in the cytoplasmic linker between S4 Deficiency and S5, and V1442E in the S3-S4 extra- Pathogenesis. Endplate AChE defi- cellular linking segment) (Tsujino, 2003). ciency is caused by recessive muta- The disorder of perijunctional sodium tions of COLQ, the gene responsible channels decreases the safety margin of for synthesis of ColQ, the triple- neuromuscular transmission by increas- stranded collagenous tail of the het- ing the size of the endplate potential eromeric AChE molecule at the motor required to reach threshold for muscle endplate (Ohno et al, 2000). ColQ is action potential generation. responsible for anchoring the globular The patient was symptomatic from catalytic subunits of AChE to the basal birth with ptosis, bulbar and general- lamina of the postsynaptic membrane ized fatigable weakness, and recurrent (Figure 3-8). acute episodes of worsening bulbar The proline-rich N-terminal domain weakness and respiratory insufficiency attaches ColQ to the catalytic subunits. through childhood into early adult The central triple-helix domain links the life. The episodes typically lasted sev- N-terminal to the C-terminal, which is 74 eral minutes but no longer than 30 responsible for attaching ColQ to the minutes and recurred several times basement membrane. Mutations have per month. Nerve conduction studies been described in each of the three (Tsujino, 2003) were normal when domains, producing partial or com- brief trains of repetitive stimulation plete AChE deficiency at the endplate. were delivered at 2 Hz and 50 Hz. No N-terminal mutations prevent attach- change was noted after brief exercise. ment of the catalytic subunits, while The amplitude of the CMAP did de- mutations in the central or C-terminal crease significantly when repetitive produce truncation of ColQ, which stimulation at either 10 Hz or 50 Hz impairs the insertion of the enzyme was continued for 1 or more minutes into the basal lamina. Absence or dys- but recovered within 2 to 3 minutes af- function of endplate AChE prolongs ter stimulation was discontinued. This the exposure of ACh to its receptor, pattern differs from ChAT deficiency in leading to prolongation of endplate the duration of stimulation required to currents, receptor desensitization, and Continuum Lifelong Learning Neurol 2009;15(1) Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.  KEY POINT depolarization block of the muscle terase inhibitors has no effect because A The number membrane at physiologic rates of con- there is little or no cholinesterase to and size of the traction. Like SCCMS, the prolonged inhibit. In contrast, cholinesterase in- repetitive endplate currents lead to cationic over- hibitors increase the number and size of compound load and an endplate myopathy. repetitive CMAPs in SCCMS. Like SCCMS muscle action Clinical manifestations. Patients and some forms of AChR deficiency, potentials is with endplate AChE deficiency usually congenital AChE deficiency is associated increased after present in infancy or early childhood with a decrement of the CMAP at low administration of with generalized weakness, underde- rates of repetitive stimulation that wors- acetylcholinesterase velopment of muscles, slowed pupil- ens at higher rates and fails to repair with inhibitors in lary responses to light, and either no edrophonium. slow-channel congenital response or clinical worsening with The findings on needle EMG in myasthenic cholinesterase inhibitors (Hutchinson congenital AChE deficiency are nonspe- syndrome but et al, 1993). Skeletal deformities, in- cific and consistent with a disorder of not in congenital cluding lordosis or scoliosis, which neuromuscular transmission and an acetylcholinesterase worsens with prolonged standing, are associated endplate myopathy. Abnor- deficiency. common. Ptosis, ophthalmoparesis, dys- mal insertional activity is rare, but motor phagia, dysarthria, and chronic respi- unit potentials are typically small and ratory and limb weakness are common. polyphasic with rapid recruitment. Mo- Generally, complete deficiency of the tor unit potential amplitude variation is enzyme produces more severe mani- observed on concentric needle EMG festations than partial deficiency, but and increased jitter with blocking on phenotypic variability within kindreds single fiber EMG. The amount of block- with the same homozygous mutation ing is less than expected, presumably has been described (Hutchinson et al, because the rise time of the endplate 1993). Infants present with hypotonia, potential is affected more than the severe generalized weakness, small overall amplitude. Standard muscle bi- muscles, feeding difficulties, weak cry, opsy reveals type II fiber atrophy. and respiratory insufficiency. Diagnosis. Even though myopathies and other forms of myasthenia (con- genital and autoimmune) can be con- fused with congenital AChE deficiency, the diagnosis is fairly easy to confirm on the basis of characteristic clinical fea- tures and findings on electrodiagnostic 75 studies (Harper, 2002). Infantile onset, underdeveloped muscles, delayed pu- pillary light responses, and unrespon- siveness to cholinesterase inhibitors suggest the diagnosis. Nerve conduc- tion studies reveal one or more repet- itive CMAPs with single stimuli. SCCMS is the only other congenital disorder associated with repetitive CMAPs and The structure of endplate acetylcholinesterase. FIGURE 3-8 can be differentiated from cholinester- ColQ is the collagenous tail that anchors globular catalytic subunits into the basal ase deficiency by observing the effect of lamina over the surface of the muscle fiber. IV edrophonium or prostigmine on the Reprinted with permission from Harper CM. Congenital myasthenic number and size of repetitive potentials syndromes. Semin Neurol 2004;24(1):111–123. (Case 3-1). Administration of cholines- Continuum Lifelong Learning Neurol 2009;15(1) Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.  " CONGENITAL MYASTHENIC SYNDROMES Case 3-1 An 8-year-old girl presented with generalized weakness, dysarthria, and dysphagia. In the infantile period she had required multiple hospitalizations for generalized hypotonia, feeding difficulties, and respiratory stridor. Major motor developmental milestones were delayed, but intelligence was normal. With ambulation she exhibited an exaggerated lumbar lordosis and thoracic scoliosis. A previous sibling died of a similar illness in infancy, but no other family history was relevant. Examination revealed moderately severe generalized weakness with small, poorly developed muscles. There was bilateral asymmetric fatigable ptosis, ophthalmoparesis, bifacial weakness, and a high-arched palate. A flaccid dysarthria was noted. Administration of a trial of pyridostigmine caused the symptoms to worsen. Nerve conduction studies showed an R-CMAP in multiple muscles. Repetitive stimulation elicited a 30% to 50% decrement that worsened during higher rates of stimulation. Needle examination showed small motor unit potentials with prominent instability (motor unit variation). Administration of IV edrophonium failed to repair the decrement or significantly alter the number or severity of the repetitive R-CMAP. Mutational analysis revealed a previously described pathogenic point mutation in COLQ, which codes for the collagenouslike tail of the AChE molecule. Comment. This patient did not require an intercostal muscle biopsy. The diagnosis of congenital AChE deficiency was made based on characteristic clinic and electrodiagnostic findings. The only other CMS that displays R-CMAPs is the SCCMS. The R-CMAPs increase in size and number following administration of edrophonium in SCCMS but not in AChE deficiency. In addition, AChE deficiency is autosomal recessive, while SCCMS follows an autosomal dominant pattern of inheritance. Although rarely required for diagnosis, AChR by intermittent administration of intercostal or anconeus biopsy reveals a controlled infusion of a short-acting ultrastructural changes of an endplate neuromuscular blocking agent pro- myopathy, small nerve terminals with duced temporary benefit (Breningstall insinuation of Schwann cell processes et al, 1996). Ephedrine produces sub- into the synaptic space, reduced or ab- jective benefit in some patients (Engel, 76 sent histochemical staining for endplate 2007; Milone and Engel, 1996). AChE, and prolonged endplate currents (Hutchinson et al, 1993; Kohara et al, PRESYNAPTIC DEFECTS 2002). CAUSING CONGENITAL Natural history and treatment. MYASTHENIC SYNDROME Infantile cases are typically quite se- vere, and mild to moderately severe Congenital Choline cases tend to progress over time as Acetyltransferase Deficiency the endplate myopathy worsens. No Pathogenesis. Initially described as effective long-term treatment has familial infantile myasthenia (Conomy been described for congenital end- et al, 1975) and later as congenital plate AChE deficiency. Cholinesterase myasthenic syndrome with episodic inhibitors do not help and may make apnea (Kraner et al, 2003), this congen- symptoms worse. In one severe case, ital myasthenia is now known to be counteracting desensitization of the caused by mutations in the CHAT gene, Continuum Lifelong Learning Neurol 2009;15(1) Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. which codes for endplate ChAT, the teristically, the early course of the rate-limiting enzyme in the resynthesis disease is punctuated by sudden epi- of ACh from acetyl-CoA (coenzyme A) sodes of severe bulbar and generalized and choline within the nerve terminal weakness, with respiratory insufficiency (Kraner et al, 2003; Schmidt et al, 2003). triggered by infections or stress. These Recessive null and missense CHAT episodes resolve over days to weeks, mutations have been described that depending on their initial severity and lead to either reduced expression or precipitating cause. The delay in recov- catalytic activity of ChAT at the neuro- ery may reflect the additional time re- muscular junction. Absence or impaired quired to replenish presynaptic reserves function of ChAT leads to reduced ACh of ACh. A family history of ‘‘sudden infant release with eventual failure of neuro- death syndrome,’’ particularly affecting muscular transmission. In severe cases previously born siblings, is fairly com- (usually during infancy and early child- mon. Phenotypic variability within kin- hood), ACh is depleted rapidly, pro- dreds is also observed. ducing characteristic sudden crises of Diagnosis. Episodic acute prolonged generalized weakness, dysphagia, and crises are characteristic, but not diagnostic, respiratory insufficiency. Manifestations of congenital endplate ChAT deficiency. tend to lessen in adolescence and Other forms of congenital myasthenia, adulthood, when the disease resembles autoimmune myasthenia, neuropathies, mild autoimmune myasthenia gravis or a and myopathies can be associated with congenital myopathy. In milder cases, one or more crises in infancy or child- prolonged exercise or continuous re- hood. A reduction in the number and petitive stimulation at moderate rates severity of crises with age, documenta- (eg, 10 Hz to 15 Hz) may be required to tion of a decremental response on re- elicit neuromuscular transmission failure petitive stimulation during a crisis, and (Harper, 2002; Tsujino et al, 2003). partial improvement with cholinesterase Clinical manifestations. When inhibitors are clues to the diagnosis. the disorder presents in infancy, major During a crisis or when clear evi- features are generalized hypotonia, dence of weakness is present on clinical ptosis, and feeding difficulties. Charac- examination, electrodiagnostic studies TABLE 3-4 Findings on Routine Nerve Conduction Studies and Repetitive Stimulation at Various Frequencies in Choline Acetylcholinesterase Deficiency 77 Nerve Conduction Study During Crisis Between Crises Routine Normal to low-amplitude CMAP Normal to low-amplitude CMAP No R-CMAP No R-CMAP Repetitive stimulation: 2-Hz Decrement Normal or mild decrement to 3-Hz train of four to Repair with exercise, tetanic Repair with exercise, tetanic five stimuli stimulation, or AChEI stimulation, or AChEI 10 Hz Continuous for Profound early and sustained Decrement begins after 1 to 5 minutes decrement 4 minutes Slow recovery over 15 minutes Slow recovery over 15 minutes 20 Hz to 50 Hz for 1 to Decrement more severe with Decrement more severe with 2 seconds increasing rates increasing rates CMAP = compound muscle action potential; R-CMAP = repetitive CMAP; AChEI = acetylcholinesterase inhibitor. Continuum Lifelong Learning Neurol 2009;15(1) Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.  " CONGENITAL MYASTHENIC SYNDROMES KEY POINT demonstrate a pattern that is similar to Natural history and treatment. If A Congenital autoimmune myasthenia gravis. Nerve patients with endplate ChAT defi- myasthenic syndrome conduction studies show a decrement ciency survive infancy and childhood, caused by of the CMAP that repairs with brief the symptoms generally improve grad- choline exercise but decreases further with ually with age. Adults are often mini- acetylcholinesterase prolonged exercise or continuous re- mally disabled by their symptoms and deficiency is petitive stimulation at 10 Hz for 3 to 5 respond modestly to pyridostigmine characterized by minutes (Table 3-4). (Engel, 2007). 3,4-Diaminopyridine may episodic severe This progressive pattern of decre- produce transient benefit but then crises during ment can be seen in autoimmune worsen the symptoms with time as ACh infancy that myasthenia gravis and in congenital stores are depleted. Supportive treat- improve with AChR deficiency but is usually much ment in infancy includes close monitor- age and by a more severe and recovers more slowly ing for early signs of crisis, aggressive progressive decrement of (over 10 to 15 minutes) in cases of treatment of infections, and judicious the compound ChAT deficiency (Case 3-2). When use of respiratory and nutritional sup- muscle action clinical manifestations are mild (ie, port during crises. potential with older patients or between crises) and Muscle biopsy is normal or shows repetitive there is a lack of objective weakness, only type II fiber atrophy. Microelec- stimulation routine repetitive stimulation studies trode studies show the quantal content at 10 Hz for are normal, but prolonged exercise or to be normal at rest but steadily decline 5 minutes. repetitive stimulation will induce a dec- with prolonged repetitive stimulation at rement with slow recovery over 10 to 15 10 Hz (Tsujino, 2003). This indicates a minutes (Figure 3-9). Standard needle gradual reduction in the number of EMG may be normal or show small quanta available for ready release and varying motor unit potentials. Single fi- mirrors the pattern of findings on ber EMG is generally abnormal even in clinical electrodiagnostic studies. mild cases. Incompletely Characterized Presynaptic Defects Paucity of vesicles. The molecular genetic basis for this disorder remains unknown. In the only reported case, manifestations began in infancy with generalized hypotonia and feeding dif- ficulties (Mora et al, 1987). Fatigable 78 ptosis and bulbar and limb weakness developed during childhood. The symp- toms responded modestly to pyridostig- mine. The patient was studied at 23 years of age. Serum assays for antibodies to the AChR were negative. Nerve con- duction studies showed a decrement of the CMAP with slow rates of repetitive Prolonged continuous repetitive stimulation stimulation and partial repair with exer- FIGURE 3-9 in a patient with ChAT deficiency. Baseline cise, brief high-frequency stimulation, train of four stimuli produces no decrement (top insert), but continuous stimulation at 10 Hz for 5 minutes and edrophonium. Needle examination produces a progressive decrement (middle insert). A train revealed small, rapidly recruited varying of four stimuli at 2 Hz continued to produce a decrement motor unit potentials that were simple for up to 15 minutes after continuous stimulation was discontinued (lower insert). in configuration. Single fiber EMG was not done. Continuum Lifelong Learning Neurol 2009;15(1) Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.  Case 3-2 A 5-year-old boy presented with a history of generalized weakness. He was hypotonic at birth and required multiple hospitalizations for episodic crises during the first year of life. During these episodes he experienced feeding and respiratory difficulties in addition to worsening of the generalized hypotonia. Between episodes he exhibited only mild bilateral ptosis and mild generalized weakness. His motor milestones were delayed, but intelligence was normal. Examination showed a waddling gait with Gower sign, bilateral ptosis, and mild facial weakness. A muscle biopsy performed at age 4 showed type II fiber atrophy as the only abnormality. On electrodiagnostic testing, no decrement was noted with repetitive stimulation at rest, but when performed under sedation, a severe decrement occurred in response to 10 minutes of continuous stimulation at 5 Hz. The decrement recovered gradually over 30 minutes. Needle EMG showed small unstable motor unit potentials, and single fiber EMG showed gross blocking and increased jitter in all areas tested. Comment. This patient has the characteristic clinical and electrodiagnostic findings for congenital ChAT deficiency. This is an autosomal recessive disorder that is characterized by episodic crises early in life and gradual improvement during later childhood. When examined between crises or later in life, routine repetitive stimulation may be normal, but prolonged stimulation at moderate rates (or prolonged exercise) causes a significant decrement that is slow to repair after discontinuation of the stimulation. This phenomenon is related to depletion and slow resynthesis and uptake of the ACh due to the deficiency of ChAT, the rate-limiting enzyme in the synthesis of ACh. An intercostal muscle biopsy revealed usually requiring chronic mechanical an 80% reduction in the density of ventilation. Electrodiagnostic studies synaptic vesicles in the motor nerve show a low-amplitude baseline CMAP, terminal. Microelectrode studies showed a decrement with low rates of repetitive a marked decrease in the quantal content stimulation, and facilitation of 200% or of the endplate potential due to reduc- more with high-frequency stimulation. tion in the number of readily releasable Needle examination shows small vary- quanta, suggesting impaired synthesis or ing motor unit potentials. Single fiber recycling of synaptic vesicles. EMG reveals increased jitter and block- 79 Lambert-Eaton–like congenital my- ing that may improve with increas- asthenic syndrome. Several incom- ing rates of stimulation. Morphologic pletely characterized patients have pre- studies have been essentially nor- sented in infancy with a severe disorder mal, and microelectrode studies mimic that has similar features to Lambert- the results observed in autoimmune Eaton myasthenic syndrome on electro- Lambert-Eaton syndrome. The ampli- physiologic studies (Bady et al, 1987; tude of the miniature endplate poten- Engel and Sine, 2005; Maselli et al, tial is normal, and the quantal content 2001). The pathogenesis of these cases of the endplate potential is reduced is poorly understood. Assays for cal- due to a decreased probability of quan- cium channel antibodies are negative. tal release. Attempts to identify a muta- Reported cases have invariably been tion in Cav2.1 have been unsuccessful. severely affected infants with hypo- Defects in other components of the tonia and respiratory insufficiency, synaptic vesicle release complex could Continuum Lifelong Learning Neurol 2009;15(1) Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.  " CONGENITAL MYASTHENIC SYNDROMES produce the same type of defect as senting in infancy or early childhood, or a calcium channel mutation. Cholines- in older patients who are anti-AChR and terase inhibitors, guanidine, and 3,4- anti–MuSK-antibody negative and fail to diaminopyridine have been used for respond to immunosuppressant medi- treatment with variable improvement. cations. 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