Congenital myasthenic syndrome
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Transcript of Congenital myasthenic syndrome
CONGENITAL MYASTHENIC SYNDROMES
Dr Prashant Makhija
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
MASC = muscle-associated specificity component; MuSK =muscle-specific receptor tyrosine kinase
Continuum Lifelong Learning Neurol 2009;15(1)
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
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
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 defectsP.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
IDENTIFIED GENES OF CONGENITAL MYASTHENIC SYNDROME
Protein products of known candidate genes for congenital myasthenic syndromes at the neuromuscular junction
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
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
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
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
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
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
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
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. 6th edition
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. 6th edition
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. 6th edition
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. 6th edition
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. 6th edition
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. 6th edition
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
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, AcetazolamideP.J. Lorenzoni et al. / Pediatric Neurology 46 (2012) 141-148
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
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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