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


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


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


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


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


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


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


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


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)


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


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


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


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


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


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

THANK YOU

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