This document discusses congenital myasthenic syndromes (CMS), which are rare genetic disorders characterized by compromised neuromuscular transmission. CMS are classified based on the location of the primary defect within the neuromuscular junction, including presynaptic, synaptic, and postsynaptic defects. The majority of cases involve postsynaptic defects. Over 20 genes have been identified that can cause CMS. Clinical features typically include fatigable weakness since infancy and decremental responses on electrodiagnostic testing. Treatment involves cholinesterase inhibitors and other medications depending on the specific CMS subtype. Differential diagnosis includes other neuromuscular disorders presenting in infancy. Definitive diagnosis may require genetic and other specialized testing.
2. 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
4. 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
5. 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
6. 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
7. Patients with congenital myasthenic syndrome,according to site of defect in
neuromuscular junction and molecular analysis
9. Protein products of known candidate genes for congenital myasthenic
syndromes at the neuromuscular junction
10. 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
11. 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
12. 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
13. 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
14. 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
15. 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
17. 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
18. 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
19. 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
20. 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
21. 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
22. 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
23. 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
24. Postsynaptic
Acetylcholine receptor deficiency without kinetic abnormalityPyridostigmine, 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 , 3,4DAP
Voltage-gated sodium channel- Pyridostigmine, Acetazolamide
P.J. Lorenzoni et al. / Pediatric Neurology 46 (2012) 141-148
25. 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
27. 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