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Congenital myasthenia

This is part of Rare diseases.

Diagnosis: Congenital myasthenia

Synonyms: --


Date of publication: 2010-12-30
Version: 1.1

ICD 10 code

G70.2

The disease

Congenital myasthenic syndromes are a group of inherited muscle disorders. “Congenital” means that the condition is present at birth and “myasthenia” refers to muscle weakness. All types of congenital myasthenia are characterized by muscle fatigability (i.e. the muscles are easily fatigued during activity) and weakness owing to impaired transmission of nerve impulses to the muscles (neuromuscular transmission). Nerve cell impulses are transmitted via synapses, the neuromuscular junction where the nerve and muscle cells communicate (see figure under “Cause”). Congenital myasthenia does not affect smooth muscle, which is the muscle tissue of inner organs and the heart.

The different types of congenital myasthenia were first described in 1937 by H.B. Rothbart, and then also by F.B. Walsh and W.F. Hoyt in 1959.

The disorders can be categorized in terms of inheritance, symptoms, the defect protein, or the site of impaired neuromuscular transmission. This information text deals with some of the main, most prevalent forms of congenital myasthenia: congenital myasthenia with episodic apnoea, acetylcholine deficiency, slow channel syndrome, fast channel syndrome, and primary acetylcholine receptor deficiency.

They are categorised according to the site of impaired neuromuscular transmission:

  • before the synapse (presynaptic), in approximately 10 per cent.
  • in the synapse (synaptic), in approximately 15 per cent.
  • after the synapse (postsynaptic), in approximately 75 per cent.
  • an abnormality in the protein responsible for synapse renewal or for preserving structure and function.

Congenital myasthenia should be differentiated from neonatal myasthenia, a condition that also involves muscle weakness but only affects newborns whose mothers have myasthenia gravis. This is an autoimmune disease in which the immune system produces antibodies that block the communication between nerve and muscle cells. In neonatal myasthenia antibodies have been transmitted to the child via the placenta. The symptoms are relieved gradually as the antibodies begin to break down. In congenital myasthenia there are no such antibodies.

Occurrence

All forms of congenital myasthenia are very rare, and the international estimated incidence is less than 1 per 100,000 population. The exact incidence in Sweden is unknown, but it is estimated that between 20 and 30 people in Sweden have one of these disorders. Because some people may not have been accurately diagnosed, a few more cases probably exist.

Cause

Congenital myasthenia is caused by a mutation in one of the genes that regulates the production of (codes for) one of the following proteins: the neurotransmitter acetylcholine, the enzyme that breaks down acetylcholine, or the acetylcholine receptor on the surface of the muscle fibre. A mutation that impairs either of these proteins obstructs the transmission of nerve impulses to muscle cells. Several hundred different mutations in one of 10 genes involved can all cause congenital myasthenia.

Figure: Neuromuscular transmission.

Figure: Neuromuscular transmission.

When a nerve impulse reaches the end of the nerve (the nerve terminal), substantial amounts of the neurotransmitter acetylcholine is released. The neurotransmitter then diffuses over the synaptic cleft (a 0.05 mm gap between the nerve and muscle cell), and binds to acetylcholine receptors on the muscle. The acetylcholine receptor consists of five different subunits (2 α, 1 ß, 1 ð and 1 ε subunit), arranged as a pore channel through which positively charged ions can flow. Acetylcholine receptors are found on the surface of the muscle fibre, in an area known as the motor end plate. When an acetylcholine molecule binds to an acetylcholine receptor the ion channel of the receptor opens, permitting passage of positively charged ions. As a result the electrical membrane potential, i.e. the difference in voltage between the interior and exterior of the muscle fibre, falls (depolarisation). When a sufficient number of acetylcholine receptors have bound acetylcholine, depolarisation reaches a critical threshold (the threshold potential). This triggers an electric signal (a nerve impulse) that sweeps down the muscle fibre and causes muscle fibre contraction. Between each impulse an enzyme known as acetylcholinesterase degrades acetylcholine in the synaptic cleft, and the electrical membrane potential returns to its resting phase.

Figure: Neuromuscular transmission.

Presynaptic defect

The CHAT gene, located on chromosome 10 (10q11.2), codes for the enzyme choline acetyltransferase, an essential component in the production of the neurotransmitter acetylcholine. A mutation in this gene results in acetylcholine deficiency in the presynaptic nerve terminals, which in turn causes congenital myasthenia with episodic apnoea.

Synaptic defect

The COLQ-gene (collagenic tail subunit of the acetylcholinesterase) codes for the enzyme acetylcholinesterase, specifically the connective tissue (collagen) tail which binds the enzyme to the motor end plate. Acetylcholinesterase deficiency in the motor end plate inhibits acetylcholine degradation in the synaptic space. This causes over-stimulation of the end plate and the nerve impulse is blocked.

Postsynaptic defects

The most common cause of a postsynaptic defect is a mutation in one of the genes CHRNA1, CHRNB1, CHRND and CHRNE. Each of these genes regulates the production of one of the acetylcholine receptor subunits α, ß, ð and ε. Different gene mutations result in different receptor defects: prolonged ion channel opening (slow channel syndrome), shortened ion channel opening (fast channel syndrome), or acetylcholine receptor deficiency.

Other defects

Researchers have recently identified several mutations in genes coding for proteins that are necessary to maintain normal synapse structure. One example is a mutation in the RAPSN gene that codes for rapsyn, a protein required for clustering acetylcholine receptors in the motor end plate. DOK7 is another gene that affects clustering of the receptors. This gene in turn activates MUSK, a gene that codes for the muscle-specific receptor tyrosine kinase. Congenital myasthenia can also be caused by a number of mutations in the skeletal muscle sodium channel gene, SCN4A, all affecting the inflow of sodium ions.

Heredity

The inheritance pattern of congenital myasthenic syndromes is usually autosomal recessive. This means that both parents are healthy carriers of a mutated gene. When two healthy carriers have a child, there is a 25 per cent risk that the child will inherit the mutated genes (one from each parent) in which case he or she will have the disease. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene.

Figure: Autosomal recessive inheritance

A person with an inherited autosomal recessive disease has two mutated genes. If this person has a child with a person who is not a carrier of the mutated gene, all the children will inherit the mutated gene but they will not have the disorder. If a person with an inherited autosomal recessive disease has children with a healthy carrier of the mutated gene (who has one mutated gene) there is a 50 per cent risk of the child having the disorder, and a 50 per cent risk of the child being a healthy carrier of the mutated gene.

The inheritance pattern may also be autosomal dominant, especially in slow channel syndrome. This means that one of the parents has the disease, and so has one normal gene and one mutated gene. Sons and daughters of this parent have a 50 per cent risk of inheriting the disease. Children who do not inherit the mutated gene do not have the disorder and do not pass it down.

Figure: Autosomal dominant inheritance

The disorders with dominant inheritance can also be caused by a new mutation. This means that the genetic mutation occurs in an individual for the first time and is not inherited from either parent. Consequently, parents with a child with a new mutation generally do not have an increased risk of having another child with the disorder. However, the new genetic mutation will be hereditary and an adult with this mutation risks passing on the mutated gene to his/her children.

Symptoms

People with congenital myasthenia have abnormal muscle fatigability and muscle weakness. The condition presents in infancy, usually in the first two years of life. Sometimes muscle weakness is present in newborns, causing sucking difficulties, choking, and respiratory problems. In rare cases the onset of symptoms does not occur until between the ages of 20 and 30. The severity of muscle weakness varies widely, and an infection will often worsen the condition temporarily. Common symptoms include drooping eyelids (ptosis), double vision, nasal speech, swallowing difficulties and problems climbing stairs or running.

Presynaptic defect

The onset of the least common type, congenital myasthenia with episodic apnoea, usually occurs during the first year of life or in infancy. The condition is associated with episodes of suspended breathing (apnoea), presenting in newborns and infants. These children may also have sucking difficulties and reduced crying ability. The apnoeas present acutely, without previous warning. In most cases the onset is associated with fever, vomiting, tension or excitement, but sometimes there is no evident trigger. The apnoeas may last for anything from minutes to hours or even days, in which case the condition is life-threatening. In some cases these children may need to use a respiratory aid for a week or longer. As even brief apnoeas are potentially fatal, carers and family need to know how to provide rescue breathing. As the child grows the episodes will occur less frequently. Apart from the apnoea episodes these children have no symptoms, or only mild signs of the disorder such as drooping eyelids or generalised muscle weakness.

Synaptic defect

Acetylcholinesterase deficiency is the second most common form of congenital myasthenia. Symptoms appear before the age of two, and are sometimes noticeable even in newborns, who may be affected by muscle weakness, drooping eyelids, sucking difficulties and reduced crying ability. Motor development is delayed, and these children learn to sit and walk later that normal. Eye movement is significantly restricted, and pupil contraction in response to light is minimal. Later, often between the ages of 8 and 12, muscle function deteriorates, causing problems with walking. They may also develop an abnormal curvature of the spine (scoliosis), and respiratory failure.

Postsynaptic defect

Primary acetylcholine receptor deficiency is the most prevalent form of congenital myasthenia, representing approximately half of all cases. Different mutations cause different receptor defects, meaning that symptoms vary. There are thus mild, intermediate and severe forms of the disease.

In the severe form of the disease symptoms present in newborns. Symptoms include drooping eyelids, restricted eye movement, and generalised muscle weakness that causes swallowing difficulties and respiratory problems. Motor development is delayed and these children often have breathing problems. They may require respiratory support (via a ventilator). Facial bone abnormalities may occur and can cause misalignment of the bite. Some children develop scoliosis.

In the intermediate form symptoms are usually not apparent until around the age of one, when muscle weakness begins to restrict eye movements and the eyelids drop. Symptoms of muscle weakness and fatigability are relatively mild, and do not cause any major disability.

The mild form of the disorder is not associated with motor delay, although these children may appear clumsy and find running a bit difficult.

The prognosis of primary acetylcholine receptor deficiency depends on the severity of the condition. All types are stationary, meaning that the condition remains stable, neither improving nor deteriorating over time.

The onset and severity of slow channel syndrome varies. Symptoms may present in newborns, while others remain asymptomatic until the age of 50. Early onset muscle weakness is associated with a more severe form of the disease. Face, neck, trunk and limb muscles may be affected. Respiratory musculature may also be involved. Muscle weakness is most pronounced in the neck and the underarm muscles that stretch the wrists and fingers. Muscle strength and endurance decrease successively with age.

Other defects

Mutations in the DOK7 gene usually give rise to symptoms in childhood or early adulthood, including hip and leg weakness that causes walking difficulties. Drooping eyelids and breathing problems are also common. The condition is progressive, but the degree of muscle weakness varies considerably from case to case. The symptoms can be mistaken for a variant of limb-girdle muscle dystrophy.

Symptoms of fast channel syndrome are often present at birth or appear during the first or second year of life. The severity of muscle weakness and fatigability varies, but eye, face, neck, trunk and limb muscles are usually affected. Some individuals have congenital multiple joint contractures (arthrogryposis).

Diagnosis

Congenital myasthenia disorders are diagnosed on the basis of characteristic symptoms, age of onset and the results of neurophysiological tests, particularly repetitive nerve stimulation (RNS). In an RNS test a fast series of electric impulses stimulate a motor nerve. The muscle controlled by the nerve will respond electrically and mechanically (by contracting). This response is measured and neuromuscular transmission abnormalities can be detected.

  • Congenital myasthenia with episodic apnoea: Decreased muscle response to RNS, but only after prolonged nerve stimulation or following active muscle work.
  • Acetylcholinesterase deficiency: Even a single nerve impulse causes a series of minor muscle contractions. RNS causes decreased muscle response.
  • Primary acetylcholine receptor deficiency: Rapidly decreased muscle response to RNS.
  • Mutation in the DOK7 gene: Rapidly decreased muscle response to RNS.
  • Slow channel syndrome: Muscle response to RNS decreases rapidly, and single nerve stimulation results in repeated minor muscle contractions.
  • Fast channel syndrome: RNS results in rapidly decreased muscle response.

Three other tests are usually performed to distinguish congenital myasthenia from other disorders involving impaired neuromuscular transmission. They are also used to identify the specific type. Single Fibre EMG, in which a thin needle electrode is inserted into the muscle, is used to measure the efficiency of neuromuscular transmission. Autoimmune myasthenia gravis is excluded by testing for the presence of antibodies against the acetylcholine receptor. In the third test a substance blocking acetylcholine degradation is injected into the muscle and the effect on muscle strength is measured.

DNA-based diagnostic testing is often possible. It is important that the condition is accurately diagnosed in order to assure that the genetic information is correct and also because some forms of congenital myasthenia can be treated medically.

Prenatal diagnosis is possible if the mutation causing the disease has been identified.

Treatment/interventions

All forms of congenital myasthenia are associated with muscle weakness and abnormal fatigability. As some forms of the disorder are associated with other symptoms and the severity varies it is not possible to predict how disabling the condition will be. Treatment should be adapted to the needs of the individual and aims to compensate for disabilities.

Medical treatment

In Congenital myasthenia with episodic apnoea muscle strength and endurance can be improved by medical treatment that blocks the breakdown of acetylcholine (an acetylcholinesterase inhibitor). A breathing monitor with a warning signal is used to detect episodes of sleep apnoea in these children, and respiratory aids (a ventilator and balloon) should be kept close at hand. As the child grows these episodes become less frequent and eventually cease.

Individuals with acetylcholinesterase deficiency sometimes require respiratory support (a ventilator). An acetylcholinesterase inhibitor will not improve the condition and may even exacerbate the symptoms. Scoliosis should be regularly monitored and treated. A corset may be very helpful, but surgery is sometimes necessary.

Slow channel syndrome is treated medically with a substance (quinidine) that decreases the number of after-discharges in the muscles. This treatment improves muscle strength and endurance. The degree of improvement varies from person to person, and the risk of adverse reactions is relatively high. Fluoxetine, a drug that inhibits the reuptake of serotonin into the nerve terminal, also improves muscle function in slow channel syndrome. Acetylcholinesterase inhibitor treatment may exacerbate the condition.

The treatment for fast channel syndrome includes a combination of 3.4 diaminopyridine (DAP, a drug which increases the release of acetylcholine from the nerve terminals) and acetylcholinesterase inhibitors. The treatment improves muscle strength and endurance.

The symptoms of primary acetylcholine receptor deficiency are usually relieved using the same drug combination as in fast channel syndrome. In cases of congenital myasthenia caused by a mutation in the DOK7 gene ephedrine chloride is an effective drug, sometimes used in combination with an acetylcholinesterase inhibitor.

Several drugs may exacerbate the symptoms of congenital myasthenia. They include ciprofloxacin, chloroquine, lithium, phenytoin, and beta-blockers.

Other Interventions

It is important that preschool and school staff are informed about suitable physical activities and that all activities are adapted to the capacities of the individual. For example, when the child’s timetable is drawn up it is important to ensure that breaks can be taken when needed and that the walking distance between different activities is reasonable. The child and family may also require early contact with a habilitation team, which includes professionals with special expertise in disabilities and their impact on health, development and everyday life. The team provides medical, educational, psychological, technical and social support and treatment. Treatment and support are planned according to individual needs in close cooperation with the child’s social network.

It is helpful to be well informed about the causes of the condition, both for realising one’s own potentials and for dealing with other people’s expectations of what one can and can’t do. Knowledge about the disorder also facilitates choices about education and suitable career paths, as well as what types of leisure activities to participate in.

Depending on the degree of disability, new routines, assistive devices, and individualized adaptations may facilitate activities of daily living. Aided by an assistive technology consultant, an occupational therapist and physical therapist will determine what measures need to be taken. If necessary the home, car and workplace can all be adapted to individual needs.

There is evidence to support the safety and potential benefit of low-intensive physiotherapy for improving muscle function. Examples of suitable physical activities include swimming, particularly backstroke, and water exercise/play.

Practical advice

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National and regional resources in Sweden

Children and adults with muscle disorders are normally evaluated at university hospital neurology clinics. Those who are diagnosed with congenital myasthenia should be referred to a neurologist with special expertise in neuromuscular disorders.

Regional habilitation centres and regional/county council specialist teams have special resources for assessment and training.

Resource personnel

For adults

Associate Professor Håkan Askmark, Neurocenter, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 23 03.

Associate Professor Christopher Lindberg, Neuromuscular Center, Sahlgrenska University Hospital, SE-431 80 Göteborg, Sweden. Tel: +46 31 343 69 10, email: christopher.lindberg@vgregion.se.

Associate Professor Ritva Matell, Myasthenia Gravis Center at the Neurology Clinic, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 51 77 47 02, fax: +46 8 51 77 37 57, email: ritva.matell@karolinska.se.

For children

Associate professor Niklas Darin, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00, email: niklas.darin@vgregion.se.

Professor Thomas Sejersen, Neuropaediatric Clinic, Astrid Lindgren Children’s Hospital, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 00.

Courses, exchanges of experience, recreation

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Organizations for the disabled/patient associations

NHR, The Swedish Association for Persons with Neurological Disabilities, St Eriksgatan 44, Stockholm. Mailing address: Box 490 84, SE-100 28 Stockholm, Sweden. Tel: +46 8 677 70 10, fax: +46 8 24 13 15, email: nhr@nhr.se, www.nhr.se.

RBU, The Swedish National Association for Disabled Children and Young People, St Eriksgatan 44, Stockholm. Mailing address: Box 8026, SE-104 20 Stockholm, Sweden. Tel: +46 8 677 73 00, fax: +46 8 677 73 09, email: info@riks.rbu.se, www.rbu.se.

Courses, exchanges of experience for personnel

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Research and development (R&D)

The main researcher in the field of congenital myasthenia is Professor Andrew Engel at the Mayo Clinic, Rochester, Minnesota, USA. In Europe, research is carried out at the Genzentrum und Friedrich-Baur-Institute, Ludwig-Maximilians-Universität, München, Germany (Professor Hans Lochmüller), and by the Neurosciences group, Weatherall Institute of Molecular Medicine, The John Radcliffe Hospital, Headington, Oxford, Great Britain (Professor D. Beeson).

Information material

An information leaflet on Congenital myasthenia that summarises the information in this database text is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2010-4-15). Address: SE-120 88 Stockholm, Sweden. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se. Postage will be charged for bulk orders.

Literature

Beeson D, Hantai D, Lochmüller H, Engel A. 126th International Workshop: Congenital myasthenic syndromes, 24-26 September 2004, Naarden, The Netherlands. Neuromusc Disord 2005; 15: 498-512.

Engel AG, Lambert EH, Mulder D, Torres C, Sahashi K, Bertorini T et al. A newly recognised congenital myasthenic syndrome attributed to a prolonged open time of the acetylcholine-induced ion channel. Ann Neurol 1982; 11: 553-569.

Engel AG, Ohno K, Shen X-M, Sine SM. Congenital myasthenic syndromes: multiple molecular targets at the neuromuscular junction. Ann NY Acad Sci 2003; 998: 138-160.

Engel AG, Sine SM. Current understanding of congenital myasthenic syndromes. Cur Opin Pharmacol 2005; 5: 308-321.

Harper CM, Engel AG. Quinidine sulfate therapy for the slow-channel congenital myasthenic syndrome. Ann Neurol 1998; 43: 480-484.

Harper CM. Congenital myasthenic syndromes. Semin Neurol 2004; 24: 111-123.

Kinali M, Beeson D, Pitt MC, Jungbluth H, Simonds AK, Aloysius A et al. Congenital myasthenic syndromes in childhood: Diagnostic and management challenges. J Neuroimmunol 2008; 201-202: 6-12.

Müller JS, Herczeqfalvi A, Vilchez JJ, Colomer J, Bachinski LL, Mihaylova V et al. Phenotypical spectrum of DOK7 mutations in congenital myasthenic syndromes. Brain 2007; 130: 1497-1506.

Ohno K, Engel AG, Shen X-M, Selcen D, Brengman J, Harper CM et al. Rapsyn mutations in humans cause endplate acetylcholine-receptor deficiency and myasthenic syndrome. Am J Hum Genet 2002; 70: 875-885.

Palace J, Lashley D, Newsom-Davis J, Cossins J, Maxwell S, Kennett R et al. Clinical features of the DOK7 neuromuscular junction synaptopathy. Brain 2007; 130: 1507-1515.

Parr JR, Jaywant S. Childhood myasthenia: clinical subtypes and practical management. Dev Med Child Neurol 2007; 49: 629-635.

Pitt M. Neurophysiological strategies for the diagnosis of disorders of the neuromuscular junction in children. Dev Med Child Neurol 2008; 50: 328-333.

Rothbart HB. Myasthenia gravis in children: its familial incidence. JAMA 1937; 108: 715-717.

Schara U, Barisic N, Deschauer M, Lindberg C, Straub V, Strigl-Pill N et al. Ephedrine therapy in eight patients with congenital myasthenic syndrome due to DOK7 mutations. Neuromuscul Disord 2009; 12: 828-832.

Slater CR, Fawcett PRW, Walls TJ, Lyons PR, Bailey SJ, Beeson D et al. Pre- and post-synaptic abnormalities associated with impaired neuromuscular transmission in a group of patients with ‘limb-girdle myasthenia’. Brain 2006; 129: 2061-2076.

Walsh FB, Hoyt WF. External ophtalmoplegia as part of congenital myasthenia in siblings: myasthenia gravis in children: report of family showing congenital myasthenia. Am J Ophtal 1959; 47: 28-34.

Walton JM, Nattrass FJ. On the classification, natural history and treatment of the myopathies. Brain 1954; 77: 169-184.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: myasthenic syndrome, congenital

GeneReviews (University of Washington)
www.genetests.org (select GeneReviews, then “Titles”)
Search: congenital myasthenic syndromes

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Assistant Professor Christopher Lindberg, Sahlgrenska University Hospital, Sweden.

Associate Professor Göran Solders, Karolinska University Hospital, Sweden, contributed to the revised version.

The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Date of publication: 2010-12-30
Version: 1.1
Publication date of the Swedish version: 2010-09-14

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden. Tel +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

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