Congenital Myasthenic Syndrome in the Dog Breed Gammel Dansk Hønsehund: Clinical,Electrophysiological, Pharmacological and Immunological Comparison with Acquired Myasthenia gravis

The effect of anticholinesterase drugs on the clinical and electrophysiological features in a canine congenital myasthenic syndrome is compared with findings in acquired myasthenia gravis in dogs. Anticholinesterase treatment had no effect on muscle weakness or electrophysiological parameters in the congenital myasthenic syndrome in contrast to its effect on clinical signs and electrophysiological parameters in acquired myasthenia gravis. The lack of effect of anticholinesterase in congenital myasthenia suggests a presynaptic defect as the aetiological factor. No antibodies to acetylcholine receptors were found in the Danish dog breed Gammel Dansk Hønsehund with the myasthenic syndrome. This classifies the disease in the group of canine and human congenital myasthenic diseases.     

Molecular targets for autoimmune and genetic disorders of neuromuscular transmission.

The neuromuscular junction is the target of a variety of autoimmune, neurotoxic and genetic disorders, most of which result in muscle weakness. Most of the diseases, and many neurotoxins, target the ion channels that are essential for neuromuscular transmission. Myasthenia gravis is an acquired autoimmune disease caused in the majority of patients by antibodies to the acetylcholine receptor, a ligand-gated ion channel. The antibodies lead to loss of acetylcholine receptor, reduced efficiency of neuromuscular transmission and muscle weakness and fatigue. Placental transfer of these antibodies in women with myasthenia can cause fetal or neonatal weakness and occasionally severe deformities. Lambert Eaton myasthenic syndrome and acquired neuromyotonia are caused by antibodies to voltage-gated calcium or potassium channels, respectively. In the rare acquired neuromyotonia, reduced repolarization of the nerve terminal leads to spontaneous and repetitive muscle activity. In each of these disorders, the antibodies are detected by immunoprecipitation of the relevant ion channel labelled with radioactive neurotoxins. Genetic disorders of neuromuscular transmission are due mainly to mutations in the genes for the acetylcholine receptor. These conditions show recessive or dominant inheritance and result in either loss of receptors or altered kinetics of acetylcholine receptor channel properties. Study of these conditions has greatly increased our understanding of synaptic function and of disease aetiology.     

Mutations in DPAGT1 cause a limb-girdle congenital myasthenic syndrome with tubular aggregates

Congenital myasthenic syndromes are a heterogeneous group of inherited disorders that arise from impaired signal transmission at the neuromuscular synapse. They are characterized by fatigable muscle weakness. We performed whole-exome sequencing to determine the underlying defect in a group of individuals with an inherited limb-girdle pattern of myasthenic weakness. We identify DPAGT1 as a gene in which mutations cause a congenital myasthenic syndrome. We describe seven different mutations found in five individuals with DPAGT1 mutations. The affected individuals share a number of common clinical features, including involvement of proximal limb muscles, response to treatment with cholinesterase inhibitors and 3,4-diaminopyridine, and the presence of tubular aggregates in muscle biopsies. Analyses of motor endplates from two of the individuals demonstrate a severe reduction of endplate acetylcholine receptors. DPAGT1 is an essential enzyme catalyzing the first committed step of N-linked protein glycosylation. Our findings underscore the importance of N-linked protein glycosylation for proper functioning of the neuromuscular junction. Using the DPAGT1-specific inhibitor tunicamycin, we show that DPAGT1 is required for efficient glycosylation of acetylcholine-receptor subunits and for efficient export of acetylcholine receptors to the cell surface. We suggest that the primary pathogenic mechanism of DPAGT1 mutations is reduced levels of acetylcholine receptors at the endplate region. These individuals share clinical features similar to those of congenital myasthenic syndrome due to GFPT1 mutations, and their disorder might be part of a larger subgroup comprising the congenital myasthenic syndromes that result from defects in the N-linked glycosylation pathway and that manifest through impaired neuromuscular transmission.     

A Novel Syndrome of Episodic Muscle Weakness Maps to Xp22.3

We describe a family with a novel disorder characterized by episodic muscle weakness and X-linked inheritance. Eight males in three generations demonstrate the characteristic features of the disorder. Episodes of severe muscle weakness are typically precipitated by febrile illness and affect the facial and extraocular musculature, as well as the trunk and limbs, and resolve spontaneously over a period of weeks to months. Younger members of the family are normal between episodes but during relapses show generalized weakness, ptosis, and fluctuations in strength. In some cases, fatigability can be demonstrated. The proband has late-onset chronic weakness and fatigability. The clinical phenotype has features suggestive both of the congenital myasthenic syndromes and of ion-channel disorders such as the periodic paralyses. We have localized the responsible gene to chromosome Xp22.3, with a maximum two-point LOD score of 4. 52 at a recombination fraction of.0, between OACA2 and DXS9985.     

Postpolio syndrome and cardiopulmonary conditioning.

Postpolio syndrome is a group of related signs and symptoms occurring in people who had paralytic poliomyelitis years earlier. New weakness, fatigue, poor endurance, pain, reduced mobility, increased breathing difficulty, intolerance to cold, and sleep disturbance in various degrees and expressions make up the syndrome. The reported incidence is between 25% and 80%. The origins are multifactorial and can be associated with underexertion, overexertion, inactivity due to intercurrent illness or injury, hypo-oxygenation, sleep apnea, deconditioning, and the failure of sprouted, compensatory large motor units. The exercise question in postpolio syndrome is related to the experience of new weakness or loss of muscle function due to overuse, which is often associated with injudicious repeated challenges to weakened musculature. Carefully prescribed exercise can be used for increasing strength and endurance and improving cardiopulmonary conditioning.     

Clinicopathological‐genetic features of congenital myasthenic syndrome from a Chinese neuromuscular centre

Congenital myasthenic syndrome (CMS) encompasses a heterogeneous group of inherited disorders affecting nerve transmission across the neuromuscular junction. The aim of this study was to characterize the clinical, physiological, pathohistological and genetic features of nine unrelated Chinese patients with CMS from a single neuromuscular centre. A total of nine patients aged from neonates to 34 years were enrolled who exhibited initial symptoms. Physical examinations revealed that all patients exhibited muscle weakness. Muscle biopsies demonstrated multiple myopathological changes, including increased fibre size variation, myofibrillar network disarray, necrosis, myofiber grouping, regeneration, fibre atrophy and angular fibres. Genetic testing revealed six different mutated genes, including AGRN (2/9), CHRNE (1/9), GFPT1 (1/9), GMPPB (1/9), PLEC (3/9) and SCN4A (1/9). In addition, patients exhibited differential responses to pharmacological treatment. Prompt utilization of genetic testing will identify novel variants and expand our understanding of the phenotype of this rare syndrome. Our findings contribute to the clinical, pathohistological and genetic spectrum of congenital myasthenic syndrome in China.     

Muscle-derived stem cells: potential for muscle regeneration

Duchenne muscular dystrophy (DMD) is a devastating X-linked muscle disease characterized by progressive muscle weakness caused by the lack of dystrophin expression at the sarcolemma of muscle fibers. Although various approaches to delivering dystrophin in dystrophic muscle have been investigated extensively (e.g., cell and gene therapy), there is still no treatment that alleviates the muscle weakness in this common inherited muscle disease. The transplantation of myoblasts can enable transient delivery of dystrophin and improve the strength of injected dystrophic muscle, but this approach has various limitations, including immune rejection, poor cellular survival rates, and the limited spread of the injected cells. The isolation of muscle cells that can overcome these limitations would enhance the success of myoblast transplantation significantly. The efficiency of cell transplantation might be improved through the use of stem cells, which display unique features, including (1) self-renewal with production of progeny, (2) appearance early in development and persistence throughout life, and (3) long-term proliferation and multipotency. For these reasons, the development of muscle stem cells for use in transplantation or gene transfer (ex vivo approach) as treatment for patients with muscle disorders has become more attractive in the past few years. In this paper, we review the current knowledge regarding the isolation and characterization of stem cells isolated from skeletal muscle by highlighting their biological features and their relationship to satellite cells as well as other populations of stem cells derived from other tissues. We also describe the remarkable ability of stem cells to regenerate skeletal muscle and their potential use to alleviate the muscle weakness associated with DMD.     

Frequency and severity of musculoskeletal symptoms in humans during an outbreak of trichinellosis caused by Trichinella britovi

Musculoskeletal symptoms such as myalgia are well-known features in the course of trichinellosis; however, the characteristics of musculoskeletal findings have been described in detail in only 1 study. The present study was aimed to determine the joint and muscle symptoms in subjects diagnosed with acute trichinellosis at our rheumatology unit during a Trichinella britovi outbreak that occurred in Izmir, Turkey, in 2004. In total, 98 patients (55 females, 43 males; mean age 32.3 +/- 10.9 yr) were included in the study. A detailed history and full musculoskeletal examination were obtained in each patient. A self-administered questionnaire developed for recording the musculoskeletal symptoms was completed monthly until all the symptoms were resolved. Pain at the joints, restriction of movements (in shoulders, elbows, wrists, knees, ankles, and temporomandibular joints), myalgia, and muscle weakness (neck and shoulder girdle, muscles of the upper and forearm, back, thigh, and calf muscles) were assessed in every patient. Eosinophil counts, serum levels of creatine kinase, and lactate dehydrogenase also were analyzed. The most frequent musculoskeletal symptoms were muscle pain (86 cases [87.8%]), joint pain (83 [84.7%]), subjective muscle weakness (75 [76.5%]), and restriction of joint movements (63 [64.3%]). Calves, upper arm, neck and shoulder girdle, and forearms were the most affected muscle groups. Muscle pain was reported more frequently in the upper than in the lower extremities and during activity. The most frequent painful joints were shoulders, knees, wrists, and ankles. Upper extremity joints were affected more frequently than the lower extremity joints (77.6 vs. 70.4%). Joint pain occurred more frequently at rest. Both muscle weakness and restriction of joint movements were reported in and around the most frequently affected regions. No evidence of arthritis and objective muscle weakness was noted on physical examination in any patient. Musculoskeletal symptoms in the course of T. britovi infection are frequent but with an excellent prognosis. Joint pain in people suffering from acute trichinellosis may occur more frequently than reported previously.     

Escobar syndrome is a prenatal myasthenia caused by disruption of the acetylcholine receptor fetal gamma subunit

Escobar syndrome is a form of arthrogryposis multiplex congenita and features joint contractures, pterygia, and respiratory distress. Similar findings occur in newborns exposed to nicotinergic acetylcholine receptor (AChR) antibodies from myasthenic mothers. We performed linkage studies in families with Escobar syndrome and identified eight mutations within the gamma -subunit gene (CHRNG) of the AChR. Our functional studies show that gamma -subunit mutations prevent the correct localization of the fetal AChR in human embryonic kidney-cell membranes and that the expression pattern in prenatal mice corresponds to the human clinical phenotype. AChRs have five subunits. Two alpha, one beta, and one delta subunit are always present. By switching gamma to epsilon subunits in late fetal development, fetal AChRs are gradually replaced by adult AChRs. Fetal and adult AChRs are essential for neuromuscular signal transduction. In addition, the fetal AChRs seem to be the guide for the primary encounter of axon and muscle. Because of this important function in organogenesis, human mutations in the gamma subunit were thought to be lethal, as they are in gamma -knockout mice. In contrast, many mutations in other subunits have been found to be viable but cause postnatally persisting or beginning myasthenic syndromes. We conclude that Escobar syndrome is an inherited fetal myasthenic disease that also affects neuromuscular organogenesis. Because gamma expression is restricted to early development, patients have no myasthenic symptoms later in life. This is the major difference from mutations in the other AChR subunits and the striking parallel to the symptoms found in neonates with arthrogryposis when maternal AChR auto-antibodies crossed the placenta and caused the transient inactivation of the AChR pathway.     

Adverse effects of myasthenia gravis on rat phrenic diaphragm contractile performance.

Myasthenia gravis has variable effects on the respiratory system, ranging from no abnormalities to life-threatening respiratory failure. Studies characterized diaphragm muscle contractile performance in rat autoimmune myasthenia gravis. Rats received monoclonal antibody that recognizes acetylcholine receptor determinants (or inactive antibody); 3 days later, phrenic nerve and diaphragm were studied in vitro. Myasthenic rats segregated into two groups, those with normal vs. impaired limb muscle function when tested in intact animals ("mild" and "severe" myasthenic). Baseline diaphragm twitch force was reduced for both severe (P < 0.01) and mild (P < 0.05) myasthenic compared with control animals (twitch force: normal 1,352 +/- 140, mild myasthenic 672 +/- 99, severe myasthenic 687 +/- 74 g/cm2). However, only severe myasthenic diaphragm had impaired diaphragm endurance, based on significantly (P < 0.05) accelerated rate of peak force decline during the initial period of stimulation (0.02 + 0.02, 0.03 +/- 0.01, and 0.09 +/- 0.01%/pulse for normal, mild myasthenic, and severe myasthenic, respectively, during continuous stimulation) and intratrain fatigue (up to 30.5 +/- 7.4% intratrain force drop in severe myasthenic vs. none in normal and mild myasthenic, P < 0.01). Furthermore, compared with continuous stimulation, intermittent stimulation had a protective effect on force of severe myasthenic diaphragm (force after 2,000 pulses was 31.4 +/- 2.0% of initial during intermittent stimulation vs. 13.0 +/- 2.1% of initial during continuous stimulation, P < 0.01) but not on normal diaphragm. These data indicate that baseline force and fatigue may be affected to different extents by varying severity of myasthenia gravis and furthermore provide a mechanism by which alterations in breathing pattern may worsen respiratory muscle function in neuromuscular diseases.     

Effect of fluoxetine on neuromuscular function in acetylcholinesterase (AChE) knockout mice

Congenital myasthenic syndromes (CMS) are a heterogeneous group of diseases caused by genetic defects affecting neuromuscular transmission. The causal mutations have been described in number of cases. The slow channel myasthenic syndrome (slow-channel-CMS) results in a marked prolongation of channel opening in stimulated receptors (nAChR) and the end plate acetylcholinesterase (AChE) deficiency congenital myasthenic syndrome (ColQ-CMS) results in an increased action of acetylcholine (ACh) at the synapse. Anticholinesterase medication is detrimental in these cases. The successful treatment of slow-channel-CMS patients with the antidepressant serotonin re-uptake inhibitor fluoxetine has been reported. At high concentration it has a non-depolarizing effect on nicotinic receptors. This led us to the idea that fluoxetine could protect AChR from a relative excess of ACh. We investigated the possible use of fluoxetine as treatment in the AChE KO mouse. Treatment at 6mg/kg from 3 weeks to 2 months increased slightly the daily weight gain but not the final weight at 2 months in AChE-/- mice. Isometric force production of Tibialis anterior in response to electric nerve stimulation was measured in situ in AChE-/- and wild type mice treated or not by fluoxetine. The results show that the maximum twitch force in response to a single nerve stimulation, the maximal tetanic force (P0) in response to repetitive nerve stimulation and the tetanic fade are not changed in AChE-/- mice treated with fluoxetine versus control AChE-/- mice.     

Ion channels-related diseases

There are many diseases related to ion channels. Mutations in muscle voltage-gated sodium, potassium, calcium and chloride channels, and acetylcholine-gated channel may lead to such physiological disorders as hyper- and hypokalemic periodic paralysis, myotonias, long QT syndrome, Brugada syndrome, malignant hyperthermia and myasthenia. Neuronal disorders, e.g., epilepsy, episodic ataxia, familial hemiplegic migraine, Lambert-Eaton myasthenic syndrome, Alzheimer's disease, Parkinson's disease, schizophrenia, hyperekplexia may result from dysfunction of voltage-gated sodium, potassium and calcium channels, or acetylcholine- and glycine-gated channels. Some kidney disorders, e.g., Bartter's syndrome, policystic kidney disease and Dent's disease, secretion disorders, e.g., hyperinsulinemic hypoglycemia of infancy and cystic fibrosis, vision disorders, e.g., congenital stationary night blindness and total colour-blindness may also be linked to mutations in ion channels.     

Islet-cell Carcinoma (Zollinger—Ellison Syndrome) with Fulminating Adrenocortical Hyperfunction and Hypokalemia

The production of ACTH-like material by tumours arising in non-endocrine tissue may initiate severe adrenocortical hyperfunction. The pathogenesis and clinical and laboratory features of Cushing''s syndrome associated with such tumours are characteristic. The autonomous production by the tumour of ACTH-like material cannot be suppressed by exogenous corticoids. The onset of clinical symptoms is rapid; muscle wasting, general weakness, thirst and peripheral edema predominate, and the classical signs of Cushing''s syndrome may be absent. High levels of plasma 17-hydroxycorticosteroids and urinary 17-hydroxycorticosteroids and 17-ketosteroids, usually with normal levels of urinary aldosterone, commonly occur. Hypokalemic alkalosis unresponsive to replacement therapy may cause death. In the case reported herein, the intriguing possibility exists that two hormone-like substances were produced by the primary growth and its metastases: one, ACTH-like, to account for the adrenal hyperplasia and Cushing''s syndrome; and another, gastrin-like, giving rise to the ulcerogenic diathesis.     

Bilateral Thoracic Outlet Syndrome from Anomalous 8th Cervical Vertebrae Ribs

Thoracic outlet syndrome (TOS) is a group of diverse disorders resulting from compression of neurovascular structures as they pass from the lower neck to upper limb. Neurological symptoms, such as pain, weakness, or paraesthesia, are much more common than vascular symptoms such as pallor or venous congestion. Anatomical abnormalities can contribute to this condition. Thirty percent of patients with TOS can have a cervical rib, arising from the transverse process of the 7th cervical vertebra, compared with 1% of the general population. We report the first case in the literature of neurogenic TOS from a cervical rib arising from a supernumerary 8th cervical vertebra. This patient had immediate improvement in TOS symptoms following scalene muscle surgery and resection of cervical and first thoracic ribs.     

Ectopic production of ACTH and corticotropin-releasing hormone (CRH).

The most common ectopic production of a pituitary hormone is the one of ACTH leading to Cushing's syndrome. Ectopic ACTH-hypersecretion is the cause of Cushing's syndrome in 10-15% of all cases. The ACTH-secreting tumours are often oat-cell carcinomas of the lung, less frequently pancreatic cancers, hypernephromas, or C-cell carcinomas of the thyroid. Some of these tumours may be benign or semi-benign as the rare carcinoid tumours and cause great problems in the differential diagnosis of ACTH-dependent hypercortisolism. Out of 173 of our patients with Cushing's syndrome observed in the last 12 years 21 were caused by ectopic ACTH-production. Of these 21 patients 13 have a small cell carcinoma of the lung. The ectopic ACTH-syndrome often has typical clinical features caused by the levels of ACTH and cortisol leading to hypocalcemic alkalosis with muscle weakness and wasting, carbohydrate intolerance, and hypertension with oedema. The survival time in many of these patients is not long enough to allow them to develop typical signs of Cushing's syndrome though they are often highly pigmented. These patients are easily diagnosed. However, patients with small tumours which do not cause very elevated ACTH-levels and who have the more typical clinical signs of full-blown Cushing's syndrome are difficult to recognize. For the differential diagnosis of ACTH-dependent Cushing's syndrome the corticotropin-releasing hormone (CRH) stimulation test and dexamethasone suppression test with high doses are helpful. In special cases the venous sampling procedure for ACTH-measurements is necessary, also CT or NMR is helpful. Ectopic CRH-production is a rare cause of ACTH-dependent Cushing's syndrome. Patients with ectopic CRH-production and consecutive ACTH-hypersecretion from the pituitary have not been studied extensively. There are especially no well documented results of the use of the CRH-stimulation test in vivo in this group of patients with Cushing's syndrome. On the other hand, in the documented cases, not only CRH-, but also ACTH-production was found in the tumours. So far, this rare cause of ACTH-dependent Cushing's syndrome has to be excluded or confirmed by the measurement of endogenous CRH-levels. But until now we have not been able to detect one single case of ectopic CRH-production using a sensitive homologous CRH-radioimmunoassay over a period of more than 8 years in which we have seen nearly 120 newly diagnosed patients with ACTH-dependent Cushing's syndrome. Only in the plasma and tumour tissue of two patients of other groups have we found high CRH-levels.     

Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases

Limited neural input results in muscle weakness in neuromuscular disease because of a reduction in the density of muscle innervation, the rate of neuromuscular junction activation or the efficiency of synaptic transmission. We developed a small-molecule fast-skeletal-troponin activator, CK-2017357, as a means to increase muscle strength by amplifying the response of muscle when neural input is otherwise diminished secondary to neuromuscular disease. Binding selectively to the fast-skeletal-troponin complex, CK-2017357 slows the rate of calcium release from troponin C and sensitizes muscle to calcium. As a consequence, the force-calcium relationship of muscle fibers shifts leftwards, as does the force-frequency relationship of a nerve-muscle pair, so that CK-2017357 increases the production of muscle force in situ at sub-maximal nerve stimulation rates. Notably, we show that sensitization of the fast-skeletal-troponin complex to calcium improves muscle force and grip strength immediately after administration of single doses of CK-2017357 in a model of the neuromuscular disease myasthenia gravis. Troponin activation may provide a new therapeutic approach to improve physical activity in diseases where neuromuscular function is compromised.     

Neuromuscular transmission in some hindlimb muscles of piglets with congenital myofibrillar hypoplasia (splayleg).

Seventeen new-born piglets of hybrid stock were tested for defects of neuromuscular transmission by stimulation electromyography (EMG). Nine of these displayed extreme symptoms of muscle weakness (splayleg), while the others were their clinically normal littermates. Muscles from four different functional groups were investigated, including the gastrocnemius, tibialis anterior, knee flexors and thigh adductors. Repetitive stimulation of muscle nerves at 3 Hz gave comparable peak-to-peak amplitudes of the EMG response in splayleg and control piglets (mean values from 5 to 10 mV). The lowest mean EMG response values at this stimulation frequency were found in splayleg adductor muscles of the thigh which were not, however significantly different from the controls. Higher frequencies of stimulation (30, 50 and 100 Hz), in general, led to a less pronounced decrease of EMG amplitude in splayleg piglet muscles than in the controls, with the exception of knee flexors. Neither splayleg nor control muscles exhibited post-activation exhaustion or post-tetanic potentiation. It is being concluded from these results that congenital myofibrillar hypoplasia is not primarily a myasthenia-like syndrome, but that either excitation-contraction coupling or the contractile mechanism itself are primarily affected.     

Rheumatic symptoms after cardiac surgery: a prospective study.

The incidence of different types of shoulder pain after open heart surgery was studied prospectively. Of 101 patients studied, 45 developed rheumatic symptoms during the first six weeks after the operation. Thirty eight patients reported pain in the region of the shoulder girdle with no loss of shoulder function (postpericardiotomy rheumatism). Three of these patients also had features compatible with the postpericardiotomy syndrome (fever, malaise, or pleuritic chest pain), and seven developed the syndrome without pain in the shoulder girdle. Of these 10 patients, one had generalised myalgia. Postpericardiotomy rheumatism alone was not associated with increased inflammation (measured by the erythrocyte sedimentation rate and concentration of C reactive protein); immunological tests including measurement of antibodies to cardiac muscle yielded inconclusive results. Replies to a postal questionnaire showed that symptoms of postpericardiotomy rheumatism were present for over three months in 18 patients and for six months or longer in 14. In view of the large number of patients now having open heart surgery postpericardiotomy rheumatism should be considered when patients report pain around the shoulders so that it is not misdiagnosed as angina.     

Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders

Impaired fetal movement causes malformations, summarized as fetal akinesia deformation sequence (FADS), and is triggered by environmental and genetic factors. Acetylcholine receptor (AChR) components are suspects because mutations in the fetally expressed gamma subunit (CHRNG) of AChR were found in two FADS disorders, lethal multiple pterygium syndrome (LMPS) and Escobar syndrome. Other AChR subunits alpha1, beta1, and delta (CHRNA1, CHRNB1, CHRND) as well as receptor-associated protein of the synapse (RAPSN) previously revealed missense or compound nonsense-missense mutations in viable congenital myasthenic syndrome; lethality of homozygous null mutations was predicted but never shown. We provide the first report to our knowledge of homozygous nonsense mutations in CHRNA1 and CHRND and show that they were lethal, whereas novel recessive missense mutations in RAPSN caused a severe but not necessarily lethal phenotype. To elucidate disease-associated malformations such as frequent abortions, fetal edema, cystic hygroma, or cardiac defects, we studied Chrna1, Chrnb1, Chrnd, Chrng, and Rapsn in mouse embryos and found expression in skeletal muscles but also in early somite development. This indicates that early developmental defects might be due to somite expression in addition to solely muscle-specific effects. We conclude that complete or severe functional disruption of fetal AChR causes lethal multiple pterygium syndrome whereas milder alterations result in fetal hypokinesia with inborn contractures or a myasthenic syndrome later in life.