congenital myasthenic syndromes ( cms ) are inherited disorders of neuromuscular transmission caused by various genetic defects at presynaptic , synaptic , or postsynaptic levels .
they are characterized by fatigable weakness involving ocular , bulbar , and limb muscles with the onset in the early years .
severity and progression can be variable , ranging from minimal symptoms to progressive disabling weakness . in some types of cms , sudden severe exacerbations of weakness or even acute respiratory crises
they are often misdiagnosed or the diagnosis is made quite late , as symptoms can be subtle or nonspecific in the early age and may evolve over time .
electromyogram ( emg ) reveals a decremental response on repetitive nerve stimulation or jitter and blocking with single - fiber emg .
bulbar dysfunction as an initial presentation of cms is not widely reported in the literature .
we describe three children who presented with bulbar difficulties and had either receptor - associated protein of the synapse ( rapsn ) or cholinergic receptor , nicotinic , and epsilon ( chrne ) mutations , causing postsynaptic cms .
our first patient was a caucasian girl , born at term , to healthy nonconsanguineous parents .
her first presentation was at 8 weeks of age with stridor , recurrent apneic episodes , and poor weight gain .
the apneic episodes continued needing assisted ventilation after 5 weeks . on extubation , there was marked generalized hypotonia and poor sucking reflex .
extensive neurometabolic investigations , neuroimaging , laryngo - tracheo - bronchoscopy , and muscle biopsies were all normal .
anti - acetylcholine receptor ( achr ) and muscle - specific kinase ( musk ) antibodies were absent .
the trial of neostigmine led to a marked clinical improvement with increased alertness , visual responsiveness , and stronger vocalizations .
molecular testing confirmed the presence of n88k mutation in the rapsn gene along with deletion at exon 7 , confirming postsynaptic cms .
she is currently 5 years old and continues to have recurrent apneic episodes and chest infections , though the frequency has decreased with time .
our second patient was a caucasian boy , born at term by normal delivery , to healthy nonconsanguineous parents .
he presented at 6 months of age with difficulty in swallowing , choking , and pooling of secretions .
barium swallow and laryngo - bronchoscopy were normal along with the mri of the brain .
the trial of neostigmine led to a marked clinical improvement with increased energy and stronger vocalization along with improved chewing and swallowing abilities .
molecular testing of the achr epsilon subunit chrne confirmed a homozygous mutation ( c.554_560 del ) , which resulted in achr deficiency .
currently , he is 2 years old , got a normal motor development , and is on a combination of neostigmine and ephedrine .
she took about an hour to complete a feed and this was associated with choking , spluttering , and coughing .
she developed right eye ptosis , soon followed by the involvement of the other eye .
molecular testing of the achr epsilon subunit confirmed a homozygous mutation ( c.554_560 del ) , which resulted in achr deficiency .
parents were reluctant to start her on neostigmine early , but by 5 months of age her symptoms had significantly increased .
she was started on neostigmine with a marked improvement in her swallowing , vocalization , and activity .
our first patient was a caucasian girl , born at term , to healthy nonconsanguineous parents .
her first presentation was at 8 weeks of age with stridor , recurrent apneic episodes , and poor weight gain .
the apneic episodes continued needing assisted ventilation after 5 weeks . on extubation , there was marked generalized hypotonia and poor sucking reflex .
extensive neurometabolic investigations , neuroimaging , laryngo - tracheo - bronchoscopy , and muscle biopsies were all normal .
anti - acetylcholine receptor ( achr ) and muscle - specific kinase ( musk ) antibodies were absent .
the trial of neostigmine led to a marked clinical improvement with increased alertness , visual responsiveness , and stronger vocalizations .
molecular testing confirmed the presence of n88k mutation in the rapsn gene along with deletion at exon 7 , confirming postsynaptic cms .
she is currently 5 years old and continues to have recurrent apneic episodes and chest infections , though the frequency has decreased with time .
our second patient was a caucasian boy , born at term by normal delivery , to healthy nonconsanguineous parents .
he presented at 6 months of age with difficulty in swallowing , choking , and pooling of secretions .
barium swallow and laryngo - bronchoscopy were normal along with the mri of the brain .
the trial of neostigmine led to a marked clinical improvement with increased energy and stronger vocalization along with improved chewing and swallowing abilities .
molecular testing of the achr epsilon subunit chrne confirmed a homozygous mutation ( c.554_560 del ) , which resulted in achr deficiency .
currently , he is 2 years old , got a normal motor development , and is on a combination of neostigmine and ephedrine .
this patient is the younger sibling of our second case . parents were not keen on prenatal testing .
she took about an hour to complete a feed and this was associated with choking , spluttering , and coughing .
she developed right eye ptosis , soon followed by the involvement of the other eye .
molecular testing of the achr epsilon subunit confirmed a homozygous mutation ( c.554_560 del ) , which resulted in achr deficiency .
parents were reluctant to start her on neostigmine early , but by 5 months of age her symptoms had significantly increased .
she was started on neostigmine with a marked improvement in her swallowing , vocalization , and activity .
cms are currently classified based on the site of defect as presynaptic , synaptic based lamina associated , and postsynaptic , with the latter being the commonest .
rapsn is one of the most frequently mutated genes in people of indo - european origin .
children usually present with episodes of generalized muscle weakness , hypotonia , and respiratory insufficiency , though the phenotypic expression can be highly variable .
it is often associated with arthrogryposis multiplex congenita and structural abnormalities of the jaw and palate .
an early recognition of this genotype can prevent death in a condition , which is easily treatable with a good long - term outcome .
their cohort had six children with stridor , which included four with docking protein 7 ( dok7 ) and one with choline acetyltransferase ( chat ) mutation .
stridor , which was an early feature in our patient , has not been reported so far with rapsn mutation .
achr deficiency is the most common form of cms and frequently results from mutations in chrne , the gene encoding the achr epsilon subunit .
more than 80 subunit mutations have been reported including nonsense , splice site , or frameshift mutations .
our second child and his younger sibling had a homozygous mutation ( c.554_560 del ) , which resulted in a frameshift , causing a premature termination of the translational chain and achr deficiency ( postsynaptic cms ) .
this mutation , although rare ( compared to the common chrne 1267delg of the  achr subunit gene found in the eastern european population ) , has been described in a 31-year - old female .
she had poor suck and ptosis in the neonatal period and bulbar dysfunction at 4 months of age .
the current therapy of cms is primarily symptomatic and includes various pharmaceutical drugs and other supportive measures .
the management of these children should be undertaken by a specialized multidisciplinary team comprising a pediatrician / pediatric neurologist , physiotherapist , occupational therapist , speech therapist , and a dietician .
the specialist services of a pediatric gastroenterologist may be required as children with bulbar symptoms may have significant dysphagia , which may require nasogastric tube or gastrostomy feeding . in children with severe weakness of respiratory muscles , nocturnal or 24-h noninvasive ventilation may be required . for children with cms , specific molecular diagnosis can help to determine the prognosis along with genetic counseling for the families . although rare , cms are an important and expanding group of disorders involving neuromuscular junction , often requiring a high index of clinical suspicion .
these three cases highlight the fact that in any infant or young child with unexplained swallowing difficulties , the possibility of a myasthenic disorder warrants consideration . with the availability of molecular genetics these conditions
can now be diagnosed early and specific treatment initiated , thus preventing morbidity and mortality .
 congenital myasthenic syndromes are a group of rare genetic disorders affecting neuromuscular transmission . 
 a high index of suspicion is required as clinical manifestations can be variable and nonspecific . 
 clinical phenotype includes arthrogryposis , respiratory crises , facial deformities , and weakness . with the availability of molecular genetics 
 , this group of conditions can now be more clearly delineated and targeted treatment can be initiated . 
 we describe three children who presented with bulbar difficulties and had cholinergic receptor , nicotinic , and epsilon or receptor associated protein of the synapse mutations . 