CONGENITAL MYASTHENIC SYNDROME

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CONGENITAL MYASTHENIC SYNDROMES:

CONGENITAL MYASTHENIC SYNDROMES Dr Prashant Makhija

INTRODUCTION:

INTRODUCTION Heterogeneous genetic disorders characterized by compromised neuromuscular transmission Rare (one in 500 000) but an important cause of seronegative myasthenia Clinical manifestations vary by congenital myasthenic syndrome subtype Present signs from birth or shortly after mild presentations, go undiagnosed until adolescence or adulthood Congenital myasthenic syndromes. Hantaı ¨ et al. Current Opinion in Neurology 2004, 17:539–551 Congenital Myasthenic Syndrome: A Brief Review. Pediatric Neurology 46 (2012) 141- 148

ACETYLCHOLINE RECEPTOR:

ACETYLCHOLINE RECEPTOR MASC = muscle-associated specificity component; MuSK =muscle-specific receptor tyrosine kinase Continuum Lifelong Learning Neurol 2009;15(1)

CLASSIFICATION:

CLASSIFICATION Depending on the location of the primary defect within the neuromuscular junction Presynaptic Synaptic Postsynaptic P.J. Lorenzoni et al. / Pediatric Neurology 46 (2012) 141- 148

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PRESYNAPTIC DEFECTS rarest, affecting an estimated 7-8% of patients 4 subtypes Episodic apnea paucity of synaptic vesicles “Lambert-Eaton-like” other presynaptic defects SYNAPTIC DEFECTS account for approximately 14-15% of patients Endplate acetylcholinesterase deficiency Abnormal laminin β2 chain P.J. Lorenzoni et al. / Pediatric Neurology 46 (2012) 141- 148

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POSTSYNAPTIC DEFECTS 75-80% of patients Acetylcholine receptor deficiency without kinetic abnormality Primary kinetic abnormality of the acetylcholine receptor Slow-channel syndrome Fast-channel syndrome Defects of acetylcholine receptor complex Rapsyn deficiency Dok-7 deficiency MuSK deficiency Voltage-gated sodium channel Agrin deficiency With tubular aggregates Other defects P.J. Lorenzoni et al. / Pediatric Neurology 46 (2012) 141- 148

Patients with congenital myasthenic syndrome,according to site of defect in neuromuscular junction and molecular analysis:

Patients with congenital myasthenic syndrome,according to site of defect in neuromuscular junction and molecular analysis

IDENTIFIED GENES OF CONGENITAL MYASTHENIC SYNDROME:

IDENTIFIED GENES OF CONGENITAL MYASTHENIC SYNDROME

Protein products of known candidate genes for congenital myasthenic syndromes at the neuromuscular junction:

Protein products of known candidate genes for congenital myasthenic syndromes at the neuromuscular junction

CLINICAL FEATURES :

CLINICAL FEATURES Generic features Fatigable weakness involving ocular, bulbar, and limb muscles since infancy or early childhood Similarly affected relative Decremental EMG response at 2- to 3-Hz stimulation, or abnormal jitter and blocking on single fiber EMG Negative tests for anti- AChR antibodies, MuSK , and P/Q type calcium channels A.G. Engel / Neuromuscular Disorders 22 (2012) 99–111

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Exceptions In some CMS the onset is delayed There may be no similarly affected relatives EMG abnormalities may not be present in all muscles, or are present only intermittently A.G. Engel / Neuromuscular Disorders 22 (2012) 99–111

CLINICAL CLUES – SPECIFIC CMS:

CLINICAL CLUES – SPECIFIC CMS Endplate acetylcholinesterase deficiency Delayed pupillary light reflex in some cases Repetitive CMAPs Refractoriness to cholinesterase inhibitors ; negative edrophonium test Absence of cholinesterase reactivity from EPs in muscle specimens A.G. Engel / Neuromuscular Disorders 22 (2012) 99–111

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Slow-channel myasthenic syndrome Cranial muscles only mildly affected ; slowly progressive course Selectively severe involvement of neck and wrist and finger extensor muscles in most cases Dominant inheritance in nearly all cases Repetitive CMAPs Worsened by long-term pyridostigmine therapy; little or no response to edrophonium A.G. Engel / Neuromuscular Disorders 22 (2012) 99–111

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Endplate choline acetyltransferase deficiency Recurrent apneic episodes , spontaneous or with fever, vomiting, or excitement No or variable myasthenic symptoms between acute episodes Rapsyn deficiency Ophthalmoparesis in 25%; strabismus relatively common Multiple congenital joint contractures or dysmorphic features in 30% Increased weakness and respiratory insufficiency precipitated by intercurrent infections A.G. Engel / Neuromuscular Disorders 22 (2012) 99–111

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Dok-7 myasthenia Predominantly limb-girdle and axial distribution of weakness , mild facial weakness, and ptosis are common, and normal ocular ductions in most patients Significant bulbar muscles involvement in some patients Can present with stridor and vocal cord paralysis in neonates and infants GFPT1 (GFAT) myasthenia Tubular aggregates in muscle in most patients Predominantly limb-girdle and axial distribution of weakness Responds to pyridostigmine A.G. Engel / Neuromuscular Disorders 22 (2012) 99–111

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Laminin-b2 myasthenia Nephrotic syndrome, ocular abnormalities ( Pierson syndrome) Refractoriness to cholinesterase inhibitors Plectin deficiency myasthenia Epidermolysis bullosa simplex Myasthenic syndrome associated with centronuclear myopathy Muscle histology A.G. Engel / Neuromuscular Disorders 22 (2012) 99–111

DIFFERENTIAL DIAGNOSIS:

DIFFERENTIAL DIAGNOSIS Vs Neonatal transient Myasthenia + ve h/o MG in mother (affects 10-20% of newborns whose mothers have autoimmune MG) Transient symptoms (usually last < 2wks but may occur upto 12 wks) Vs Infantile Botulism Suggestive history ( 4mths of age, infants fed with honey) Rapidity of symptom progression Prominent involvement of ocular & bulbar musculature ( pupillary invovement seen in ~ 50% ) Bradley’s Neurology in Clinical Practice. 6 th edition

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Vs Juvenile MG (<18 yrs) Almost never occurs <1 year of age ( CMS- birth) Association with other autoimmune disorders (diabetes, thyroid dx and JRA, Thymoma rare) Seropositivity for AChR Ab (~20% of JMG & ~ 50% those with prepubertal onset are seronegative ) + ve response to immunomodulatory therapy Spontaneous remission Skeletal deformities(scoliosis, lordosis )- favours CMS Bradley’s Neurology in Clinical Practice. 6 th edition

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Vs SMA (neonatal & infantile onset) neonatal form – diffuse weakness of limb & trunk muscles, facial sparing or mild involvement , arthrogryposis Infantile form- weakness in first 6 mths of life, proximal> distal, lower> distal Relative preservation of diaphragmatic muscle as compared to abdominal & chest musculature Needle EMG- denervation Genetic testing- SMN (survival motor neuron gene) Bradley’s Neurology in Clinical Practice. 6 th edition

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Vs Congenital myopathies Autosomal recessive or X-linked pattern of inheritance Diffuse weakness & hypotonia , weakness may be severe but is typically static or slowly progressive Midly elevated CK EMG- myopaathic Histopathology- type I predominance Bradley’s Neurology in Clinical Practice. 6 th edition

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Vs Congenital Muscular dystrophies diffuse weakness and hypotonia significant elevations in serum CK subcortical white matter abnormalities may be seen on brain MRI , cognition is usually normal Epilepsy may occur Supportive EMG, Histopatholgy , genetic analysis is confirmatory Bradley’s Neurology in Clinical Practice. 6 th edition

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Vs Congenital Myotonic dystophy type 1 myotonic dystrophy (~25% of infants born to mothers with myotonic dystrophy) hypotonia and weakness of the face and limbs in infancy global developmental delay - intellectual impairment and motor disability Later develop myotonia and other characteristic symptoms Electrphysiology & Genetic analysis Bradley’s Neurology in Clinical Practice. 6 th edition

TREATMENT:

TREATMENT Presynaptic Pyridostigmine - 1 mg/kg every 4 hours (maximal, 7 mg/kg/day, divided into 5-6 doses 3,4-DAP- 1 mg/kg/day, divided into 3-4 doses Synaptic Ephedrine-1 mg/kg/day and slowly increased to a maximum of 3 mg/kg/day, divided into three doses per day Albuterol - 0.1 mg/kg/day (maximum, 2 mg/dose) divided into three doses for children at 2-6 years of age, and 2 mg/dose 2-3 times daily for children between 6-12 years of age P.J. Lorenzoni et al. / Pediatric Neurology 46 (2012) 141- 148

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Postsynaptic Acetylcholine receptor deficiency without kinetic abnormality- Pyridostigmine , 3,4-DAP Primary kinetic abnormality of the acetylcholine receptor Slow-channel syndrome- Quinidine (15-60 mg/kg/day, divided into 4-6 doses), Fluoxetine (No standard dose) Fast-channel syndrome- Pyridostigmine , 3,4-DAP Defects of acetylcholine receptor complex- Pyridostigmine , 3,4-DAP Voltage-gated sodium channel- Pyridostigmine , Acetazolamide P.J. Lorenzoni et al. / Pediatric Neurology 46 (2012) 141-148

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Agrin deficiency- Ephedrine, 3,4-DAP With tubular aggregates- Pyridostigmine Other defects( Plectin , With centronuclear myopathy )- 3,4-DAP, Pyridostigmine P.J. Lorenzoni et al. / Pediatric Neurology 46 (2012) 141- 148

TREATMENT:

TREATMENT

CONCLUSION:

CONCLUSION CMS should be suspected in any patient with fatigable ocular, bulbar, or limb weakness presenting in infancy or early childhood In older patients who are anti- AChR and anti– MuSK -antibody negative and fail to respond to immunosuppressant medications Certain clinical features, such as a delayed pupillary light reflex, prominent weakness of finger/wrist extensors, scoliosis, or a repetitive CMAP, may aid in making a diagnosis in certain cases Definitive diagnosis in many cases requires detailed morphologic, microphysiologic , and genetic studies

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