Clinical and genetic basis of congenital myasthenic syndromes

Neuromuscular junction disorders represent a wide group of neurological diseases characterized by weakness, fatigability and variable degrees of appendicular, ocular and bulbar musculature involvement. Its main group of disorders includes autoimmune conditions, such as autoimmune acquired myasthenia gravis and Lambert-Eaton syndrome. However, an important group of diseases include congenital myasthenic syndromes with a genetic and sometimes hereditary basis that resemble and mimick many of the classic myasthenia neurological manifestations, but also have different presentations, which makes them a complex clinical, therapeutic and diagnostic challenge for most clinicians. We conducted a wide review of congenital myasthenic syndromes in their clinical, genetic and therapeutic aspects.

myasthenia gravis; congenital myasthenic syndromes, genetics

Authorship

Paulo Victor Sgobbi de Souza

Universidade Federal de São Paulo, Departamento de Neurologia e Neurocicurgia, Divisão de Doenças Neuromusculares, São Paulo SP, Brasil.Universidade Federal de São PauloBrasilSão Paulo, SP, BrasilUniversidade Federal de São Paulo, Departamento de Neurologia e Neurocicurgia, Divisão de Doenças Neuromusculares, São Paulo SP, Brasil.

Gabriel Novaes de Rezende Batistella

Valéria Cavalcante Lino

Wladimir Bocca Vieira de Rezende Pinto

Marcelo Annes

Acary Souza Bulle Oliveira

Correspondence: Wladimir Bocca Vieira de Rezende Pinto; Departamento de Neurologia e Neurocicurgia, Universidade Federal de São Paulo (UNIFESP); Rua Estado de Israel, 899; 04022-002 São Paulo SP, Brasil. E-mail: wladimirbvrpinto@gmail.com

Conflict of interest: There is no conflict of interest to declare.

SCIMAGO INSTITUTIONS RANKINGS

Figures | Tables

Figures (1)
Tables (4)

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Figure
Representation of the main pathophysiological mechanisms involved in different forms of CMS: (1) acetylcholine biosynthesis defects and vesicular transport and fusion defects; (2) acetylcholinesterase deficiency; (3) acetylcholine receptor defects; (4) agrin deficiency; (5) congenital disorders of glycosylation; (6) channelopathies; (7) congenital myopathies with secondary neuromuscular transmission defects; and (8) mitochondrial dysfunction. Legends: ChAT: choline acetyltransferase; ErbBR: epidermal growth factor receptor; MASC: muscle-associated specificity component; AChE: acetylcholinesterase; Lrp4: low-density lipoprotein receptor-related protein 4; ColQ: collagen-like tail subunit or acetylcholinesterase-associated collagen; MuSK: muscle-specific tyrosine kinase receptor; Dok-7: downstream of tyrosine kinase 72,3,4.

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Table 1
Classification of congenital myasthenic syndromes (CMS) related to pattern of inheritance and molecular targets at the neuromuscular junction.

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Table 2
Main diagnostic clues to guide differential diagnosis of congenital myasthenic syndromes (CMS) subtypes.2,4

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Table 3
Therapeutic clues in the differential diagnosis of congenital myasthenic syndromes (CMS) subtypes2,4.

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Table 4
Main differential diagnosis of congenital myasthenic syndromes (CMS) of early- and late-onset presentations.

Figure Representation of the main pathophysiological mechanisms involved in different forms of CMS: (1) acetylcholine biosynthesis defects and vesicular transport and fusion defects; (2) acetylcholinesterase deficiency; (3) acetylcholine receptor defects; (4) agrin deficiency; (5) congenital disorders of glycosylation; (6) channelopathies; (7) congenital myopathies with secondary neuromuscular transmission defects; and (8) mitochondrial dysfunction. Legends: ChAT: choline acetyltransferase; ErbBR: epidermal growth factor receptor; MASC: muscle-associated specificity component; AChE: acetylcholinesterase; Lrp4: low-density lipoprotein receptor-related protein 4; ColQ: collagen-like tail subunit or acetylcholinesterase-associated collagen; MuSK: muscle-specific tyrosine kinase receptor; Dok-7: downstream of tyrosine kinase 72,3,4.

Table 1 Classification of congenital myasthenic syndromes (CMS) related to pattern of inheritance and molecular targets at the neuromuscular junction.

I. Pattern of inheritance
Autosomal dominant (gain-of-function)	Slow-channel syndrome, SNAP25B, SYT2
Autosomal recessive (loss-of-function)	All other subtypes
II. Site of defect and molecular targets at the neuromuscular junction
Presynaptic defects	ChAT deficiency, SNAP25B deficiency, synaptotagmin-2 deficiency
Acetylcholine receptor defects	Primary deficiency, slow-channel syndrome (CHRNA1, CHRNB, CHRND, CHRNE, CHRNG), fast-channel syndrome (CHRNA, CHRND, CHRNE)
Synaptic basal lamina defects	Acetylcholinesterase deficiency (ColQ), β2-laminin deficiency
Endplate development and maintenance congenital defects	Agrin deficiency, MuSK deficiency, LRP4 deficiency, Dok-7 deficiency, rapsyn deficiency, COL13A1 mutations
Metabolic and mitochondrial disorders	Congenital disorders of glycosylation, SLC25A1 gene mutations
Others	Congenital myopathies with secondary neuromuscular transmission compromise (MTM1, RYR1, DNM2, TPM3, BIN1); PREPL deletion; plectin deficiency

*extremely rare presentations.

Table 2 Main diagnostic clues to guide differential diagnosis of congenital myasthenic syndromes (CMS) subtypes.2,4

I. Clinical clues of CMS subtypes
Early-onset phenotypes (neonatal, lactancy, early infancy)	ChAT deficiency, synaptotagmin-2 deficiency, acetylcholinesterase, slow-channel syndrome, fast-channel syndrome, agrin deficiency, LRP4 deficiency, MuSK deficiency, Dok-7 deficiency, rapsyn deficiency, GFPT1, ALG2, ALG14, GMPPB, PREPL deficiency, plectin deficiency, SCN4A, COL13A1
Late-onset phenotypes (late infancy, adolescence, juvenile, adult)	Acetylcholinesterase deficiency (variants), slow-channel syndrome, agrin deficiency, SCN4A
LGMD-like phenotype	GFPT1, LRP4 deficiency, plectin deficiency
Apneic episodes	ChAT deficiency, SCN4A
Laryngeal stridor and vocal cord palsy	Dok-7 deficiency
Epilepsy with intellectual disability	DPAGT1 deficiency
Cerebellar ataxia	SNAP25B
Pupillary defects	ColQ mutations
Ptosis	Primary AChR deficiency, Dok-7 deficiency, SNAP25B, agrin deficiency, MuSK deficiency, rapsyn deficiency, PREPL, congenital myopathies, COL13A1
Ophthalmoparesis (± strabismus)	Rapsyn deficiency, primary AChR deficiency, MuSK deficiency, Dok-7 deficiency, congenital myopathies
Facial palsy	Agrin deficiency, MuSK deficiency, Dok-7 deficiency, rapsyn deficiency, PREPL, congenital myopathies
Cervical weakness	Slow-channel syndrome, Dok-7 deficiency, COL13A1
Arthrogryposis multiplex congenital-like phenotype and early-onset joint contractures	Rapsyn deficiency, ChAT deficiency, AChR deficiency (CHRND, CHRNG), SNAP25B, synaptotagmin-2
Dysmorphic features	Rapsyn deficiency, β2-laminin deficiency, COL13A1
Congenital malformations	Pierson syndrome (β2-laminin: ocular malformation, congenital nephrosis); rapsyn deficiency; GFPT1 deficiency; SLC25A1 (optic nerve hypoplasia, corpus callosum agenesis)
Anoxic encephalopathy-like phenotype	Rapsyn deficiency, SCN4A
Epidermolysis bullosa simplex	Plectin deficiency
II. Histopathological clues of CMS subtypes
Tubular aggregates in the sarcoplasmic reticulum	GFPT1, DPAGT1 and ALG2-related CMS subtypes
Vacuolar autophagic myopathy	GFPT1 and DPAGT1-related subtypes

LMGD: limb-girdle muscular dystrophy.

Table 3 Therapeutic clues in the differential diagnosis of congenital myasthenic syndromes (CMS) subtypes2,4.

Quinidine-responsive phenotype	Slow-channel syndrome
Fluoxetine-responsive phenotype	Slow-channel syndrome
Acetazolamide-responsive phenotype	Sodium channel
Amifampridine-responsive phenotype (3,4-diaminopyridine)	Primary AChR deficiency, SNAP25, fast channel syndrome, MuSK, rapsyn, ALG2, ALG14, GFPT1, DPAGT1, COL13A1
Albuterol-responsive phenotype	Dok-7, Primary AChR deficiency, MuSK (partial), acetylcholinesterase deficiency
Salbutamol-responsive phenotype	Rapsyn, acetylcholinesterase, primary AChR deficiency, MuSK, DPAGT1 (partial), COL13A1
Ephedrine-responsive phenotype	Laminin-β2 deficiency, agrin, acetylcholinesterase, Dok-7
Pyridostigmine-responsive phenotype	GFPT1, sodium channel (SCN4A), centronuclear congenital myopathy, ChAT deficiency, fast-channel syndrome, AChR deficiency, paucity of synaptic vesicles and reduced quantal release (partial), congenital myopathies (partial: centronuclear myopathy), PREPL (transient)
Pyridostigmine-avoidance phenotype (clinical worsen)	Acetylcholinesterase deficiency, Laminin-β2 deficiency, slow-channel syndrome, LRP4, Dok-7 and MuSK deficiencies; agrin deficiency
Amifampridine-avoidance phenotype (clinical worsen)	Acetylcholinesterase deficiency, slow channel syndrome, LRP4 mutations
Fluoxetine-avoidance phenotype (clinical worsen)	Fast channel syndrome
Quinidine-avoidance phenotype (clinical worsen)	Fast channel syndrome
Clinical refractory phenotype	Plectin deficiency (pyridostigmine, amifampridine), laminin-β2, plectin, acetylcolinesterase (pyridostigmine), DPAGT1 (partial), GMPPB

Table 4 Main differential diagnosis of congenital myasthenic syndromes (CMS) of early- and late-onset presentations.

I. Early-onset (neonatal, infant)

Motor neuron disease: spinal muscular atrophy (types I-III)

Congenital muscular dystrophy, infantile myotonic dystrophy type I, congenital myopathies (central core disease, centronuclear, nemaline, myotubular, congenital fiber-type disproportion)

Neonatal myasthenia gravis, seropositive and seronegative acquired autoimmune myasthenia gravis, infantile botulism

Mitochondrial myopathies

Toxic exogenous poisoning

Miscellaneous: Möbius syndrome, brainstem anomalies, congenital fibrosis of extraocular muscles

II. Late-onset (teenager, young adult)

Motor neuron Disease

Metabolic myopathies: mitochondrial myopathies, muscle lipidosis

LGMDs, FSHD, congenital myopathies

Seropositive and seronegative acquired autoimmune myasthenia gravis

Toxic exogenous poisoning

Chronic fatigue syndrome

FSHD: facioscapulohumeral muscular dystrophy; LGMD: limb-girdle muscular dystrophy^2,4.

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[1] Correspondence: Wladimir Bocca Vieira de Rezende Pinto; Departamento de Neurologia e Neurocicurgia, Universidade Federal de São Paulo (UNIFESP); Rua Estado de Israel, 899; 04022-002 São Paulo SP, Brasil. E-mail: wladimirbvrpinto@gmail.com