MUSCLE INVOLVEMENT
Recommended panel testing at Breda Genetics for this condition:
Clinical description
Congenital myasthenic syndromes are a heterogeneous group of inherited disorders that result from impaired neuromuscular transmission, caused by mutations in genes encoding proteins that are involved in presynaptic, synaptic and postsynaptic transmission at the motor endplate and in forming and maintaining the structural integrity of neuromuscular junctions.
The condition is characterized by muscle weakness (myasthenia) that typically worsens with physical exertion. Onset varies from childhood to the adult age and the clinical course is highly variable. As congenital myasthenic syndromes may affect all muscles, clinical symptoms include almost all possible muscular manifestations at variable grades (difficulty in walking, crawling, feeding, chewing, swallowing, moving the eyes). Congenital myasthenic syndromes may also fit in the chapter of congenital respiratory diseases, since infections and fever may trigger difficulty in breathing in some patients.
Molecular genetics
Heredity of congenital myasthenic syndromes is most commonly autosomal recessive, but also instances of autosomal dominant transmission are described.
Choline acetyltransferase (CHAT) gene mutations cause a rare presynaptic congenital myasthenic syndrome due to impaired acetylcholine re-synthesis.
RAPSN mutations are a common cause of postsynaptic congenital myasthenic syndromes.
Signs of congenital myasthenic syndrome and periodic paralysis can be found in patients harbouring mutations in the SCN4A gene.
DOK7 causes congenital myasthenic syndrome which often presents with limb-girdle muscle weakness, and can be treated successfully with ephedrine, salbutamol, and albuterol (a molecule often used in bronchial asthma).
Homozygous loss-of-function mutations have been identified also in the COL13A1 gene.
SYT2 mutations cause a complex presynaptic congenital myasthenic syndrome characterized by motor neuropathy causing lower limb wasting and foot deformities, with reflex potentiation following exercise and a uniquely prolonged period of posttetanic potentiation.
GFPT1 mutations lead to a distinct sub-class of congenital myasthenic syndromes called limb-girdle congenital myasthenic syndromes with tubular aggregates (CMS12).
CHRNE mutations cause a postsynaptic congenital myasthenic syndrome with mild to moderate fatigable weakness involving ocular, bulbar and limb muscles. Onset is early, usually within the first years of life. The transmission can be autosomal recessive or autosomal dominant.
Other congenital myasthenic syndrome genes include: CHRNB1, CHRND, COLQ, AGRN, MUSK, DPAGT1, ALG2, ALG14, LRP4, and SNAP25.
Whole exome and whole genome sequencing will certainly help in identifying other as-yet-unknown genes of which mutations associate with congenital myasthenic syndromes.
Recommended panel testing at Breda Genetics for this condition:
References:
Congenital myasthenic syndrome due to novel CHAT mutations in an ethnic kadazandusun family. Tan JS, Ambang T, Ahmad-Annuar A, Rajahram GS, Wong KT, Goh KJ. Muscle Nerve. 2016 May;53(5):822-6. PMID: 26789281
Long-term follow-up in patients with congenital myasthenic syndrome due to RAPSN mutations. Natera-de Benito D, Bestué M, Vilchez JJ, Evangelista T, Töpf A, García-Ribes A, Trujillo-Tiebas MJ, García-Hoyos M, Ortez C, Camacho A, Jiménez E, Dusl M, Abicht A, Lochmüller H, Colomer J, Nascimento A. Neuromuscul Disord. 2016 Feb;26(2):153-9. PMID: 26782015
A recessive Nav1.4 mutation underlies congenital myasthenic syndrome with periodic paralysis. Habbout K, Poulin H, Rivier F, Giuliano S, Sternberg D, Fontaine B, Eymard B, Morales RJ, Echenne B, King L, Hanna MG, Männikkö R, Chahine M, Nicole S, Bendahhou S. Neurology. 2016 Jan 12;86(2):161-9. PMID: 26659129
Congenital Myasthenic Syndrome Type 19 Is Caused by Mutations in COL13A1, Encoding the Atypical Non-fibrillar Collagen Type XIII α1 Chain. Logan CV, Cossins J, Rodríguez Cruz PM, Parry DA, Maxwell S, Martínez-Martínez P, Riepsaame J, Abdelhamed ZA, Lake AV, Moran M, Robb S, Chow G, Sewry C, Hopkins PM, Sheridan E, Jayawant S, Palace J, Johnson CA, Beeson D. Am J Hum Genet. 2015 Dec 3;97(6):878-85. PMID: 26626625
Effective Treatment With Albuterol in DOK7 Congenital Myasthenic Syndrome in Children. Tsao CY. Pediatr Neurol. 2016 Jan;54:85-7. PMID: 26552645
Electrophysiologic features of SYT2 mutations causing a treatable neuromuscular syndrome. Whittaker RG, Herrmann DN, Bansagi B, Hasan BA, Lofra RM, Logigian EL, Sowden JE, Almodovar JL, Littleton JT, Zuchner S, Horvath R, Lochmüller H. Neurology. 2015 Dec 1;85(22):1964-71. PMID: 26519543
Global N-linked Glycosylation is Not Significantly Impaired in Myoblasts in Congenital Myasthenic Syndromes Caused by Defective Glutamine-Fructose-6-Phosphate Transaminase 1 (GFPT1). Chen Q, Müller JS, Pang PC, Laval SH, Haslam SM, Lochmüller H, Dell A. Biomolecules. 2015 Oct 16;5(4):2758-81. PMID: 26501342
Congenital myasthenic syndrome due to mutation in CHRNE gene with clinical worsening and thymic hyperplasia attributed to association with autoimmune-myasthenia gravis. Santos E, Moreira I, Coutinho E, Gonçalves G, Lopes C, Lopes Lima J, Leite MI. Neuromuscul Disord. 2015 Dec;25(12):928-31. PMID: 26363966
http://ghr.nlm.nih.gov/condition/congenital-myasthenic-syndrome
