Myasthenic Syndromes, Congenital, Including AChR Deficiency

Clinical Characteristics
Ocular Features: 

The congenital myasthenic syndromes are genetically and clinically heterogeneous.  Ptosis is the outstanding ocular sign and virtually always present.  Strabismus and ophthalmoplegia are less common.  These signs are not helpful in the differential diagnosis of the many types of congenital myasthenia.

Some degree of ptosis is usually evident during the first 6 months of life.  By about 2 years of age strabismus and ophthalmoparesis are apparent but this sequence is highly variable.

Systemic Features: 

This is a group of nonprogressive disorders most often associated with acetylcholine receptor (AChR) defects at the neuromuscular junction.  An early sign may be decreased fetal movements.  Generalized weakness, a weak cry, and hypotonia are evident at birth.  Easy fatigability and limb weakness are noted in early childhood and affected children have difficulty running. Facial weakness, dysarthria, weakness of the tongue, and dysphagia are often present and many patients have respiratory difficulties. Motor development can be delayed.  Acute illnesses may exacerbate muscle weakness.

Genetics

This is the most common form of the congenital myasthenic syndromes. It is an autosomal recessive disorder of the postsynaptic type, so called because the mutations occur in genes that encode the subunits of acetylcholine receptors: CHRNE(17P13.2), and CHRNB1(17p13.1).  A similar phenotype results from mutations in MUSK (9p31.3) which is critical for synaptic differentiation.

Mutations in RAPSN(11p11.2), whose protein product is important for stabilization of the acetylcholine receptors at the endplate, may result in a similar phenotype but may also produce the fetal akinesia deformation sequence.  This lethal condition is often associated with severe respiratory disease and dysmorphism including limb contractures, micrognathia, and feeding difficulties.  Nothing is known about the ocular signs.

Another autosomal recessive congenital myasthenic syndrome (610542), CMSTA1, has a somewhat later onset (adolescence) and weakness in a limb girdle distribution but no ptosis or oculomotor problems.  Tubular aggregates of muscle fibers can be seen on biopsy.

Presynaptic autosomal recessive forms of congenital myasthenia such as CMS20 (617143) caused by mutations in SLC5A7 (2q12) and CMS21 (617239) secondary to mutations in SLC18A3 (10q11.23) with severe episodic apnea and ocular signs of ptosis and ophthalmoparesis have been reported.

Other postsynaptic forms of congenital myasthenia are the fast-channel type (FCCNS) (608930) and the slow channel type (SCCMS) (601462).  Ophthalmoparesis occurs early in both types.

The classification of congenital myasthenia syndromes is under construction.  In the case of many types only a single or very few families have been reported.   While the clinical manifestations involve alterations in the neuromuscular junnction, some result from heterozygous mutations while others are due to homozygous changes.  The defect may reside in presynaptic, synaptic, or postsynaptic mechanisms.  For a discussion and comprehensive listing of the various types see 601462.

Treatment
Treatment Options: 

Cholinesterase inhibitor drugs can be highly beneficial in some forms of the disease but genotyping is necessary before attempting pharmacological therapy.  Frequent ventilation and enteric feeding may be helpful for selected individuals.  Individuals should be protected from acute illnesses, especially respiratory infections.

References
Article Title: 

Impaired Presynaptic High-Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea

Bauche S, O'Regan S, Azuma Y, Laffargue F, McMacken G, Sternberg D, Brochier G, Buon C, Bouzidi N, Topf A, Lacene E, Remerand G, Beaufrere AM, Pebrel-Richard C, Thevenon J, El Chehadeh-Djebbar S, Faivre L, Duffourd Y, Ricci F, Mongini T, Fiorillo C, Astrea G, Burloiu CM, Butoianu N, Sandu C, Servais L, Bonne G, Nelson I, Desguerre I, Nougues MC, Boeuf B, Romero N, Laporte J, Boland A, Lechner D, Deleuze JF, Fontaine B, Strochlic L, Lochmuller H, Eymard B, Mayer M, Nicole S. Impaired Presynaptic High-Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea. Am J Hum Genet. 2016 Sep 1;99(3):753-61.

PubMed ID: 
27569547

Congenital myasthenic syndromes

Hanta?O D, Richard P, Koenig J, Eymard B. Congenital myasthenic syndromes. Curr Opin Neurol. 2004 Oct;17(5):539-51. Review.

PubMed ID: 
15367858

References

Bauche S, O'Regan S, Azuma Y, Laffargue F, McMacken G, Sternberg D, Brochier G, Buon C, Bouzidi N, Topf A, Lacene E, Remerand G, Beaufrere AM, Pebrel-Richard C, Thevenon J, El Chehadeh-Djebbar S, Faivre L, Duffourd Y, Ricci F, Mongini T, Fiorillo C, Astrea G, Burloiu CM, Butoianu N, Sandu C, Servais L, Bonne G, Nelson I, Desguerre I, Nougues MC, Boeuf B, Romero N, Laporte J, Boland A, Lechner D, Deleuze JF, Fontaine B, Strochlic L, Lochmuller H, Eymard B, Mayer M, Nicole S. Impaired Presynaptic High-Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea. Am J Hum Genet. 2016 Sep 1;99(3):753-61.

PubMedID: 27569547

Hanta?O D, Richard P, Koenig J, Eymard B. Congenital myasthenic syndromes. Curr Opin Neurol. 2004 Oct;17(5):539-51. Review.

PubMedID: 15367858

M?oller JS, Mihaylova V, Abicht A, Lochm?oller H. Congenital myasthenic syndromes: spotlight on genetic defects of neuromuscular transmission. Expert Rev Mol Med. 2007 Aug 9;9(22):1-20. Review.

PubMedID: 17686188