Bases clínicas e genéticas das síndromes miastênicas congênitas

Distúrbios da junção neuromuscular representam um grupo amplo de doenças neruológicas caracterizadas por fraqueza, fadigabilidade e graus variados de envolvimento das musculaturas apendicular, ocular e bulbar. Os principais grupos de doenças deste grupo incluem condições auto-imunes, como a miastenia gravis auto-imune adquirida e a síndrome de Lambert-Eaton. Entretanto, um outro grupo importante de doenças incluem as sindromes miastênicas congênitas com uma base genética e eventualmente hereditária que lembra e mimetiza muitas das manifestações neurológicas clássicas das miastenias, mas também se apresentam de diferentes formas tornando um desafio clínico, terapêutico e diagnóstico complexo para a maioria dos clínicos. Realizamos ampla revisão sobre as síndromes miastênicas congênitas em seus aspectos clínicos, genéticos e terapêuticos.

miastenia gravis; síndromes miastênicas congênitas, genética

Autoria

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.

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Figuras | Tabelas

Figuras (1)
Tabelas (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