Bulbar dysfunction: An early presentation of congenital myasthenic syndrome in three infants.

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.

Introduction

Congenital myasthenic syndromes (CMS) are inherited disorders of neuromuscular transmission caused by various genetic defects at presynaptic, synaptic, or postsynaptic levels.[1] 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 can occur, precipitated by fever or infections.[2] 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.[2] 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.

Case Reports

Case 1

Our first patient was a caucasian girl, born at term, to healthy nonconsanguineous parents. Pregnancy was uneventful. 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. Bulbar functions were impaired and she had persistent stridor. She did not have arthrogryposis, dysmorphic features, or ptosis.

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. EMG with repetitive nerve stimulation did not show a decremental response. 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. She had tracheostomy and requires nocturnal noninvasive ventilation. Motor development is delayed but social skills are relatively spared. Her clinical condition is currently stable on neostigmine and 3,4-diaminopyridine.

Case 2

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. He had difficulty in chewing, and would choke and gag on bulky food. He has had recurrent chest infections and described as being “less active” compared to other children. Motor milestones were delayed for age. There was no significant family history. No dysmorphic features were noted but he had bilateral ptosis and ophthalmoplegia. Muscle tone was reduced in all four limbs but reflexes were normal.

Barium swallow and laryngo-bronchoscopy were normal along with the MRI of the brain. Video fluoroscopy showed lack of palatal movements and pooling of secretions. AChR and MuSK antibodies were negative and EMG with repetitive nerve stimulation was normal. 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.

Case 3

This patient is the younger sibling of our second case. Parents were not keen on prenatal testing. She was born by elective caesarean section in a good condition. From day 1, there were concerns with her feeding. 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 had pooling of secretions and unsafe swallow needing nasogastric tube feeding. She was started on neostigmine with a marked improvement in her swallowing, vocalization, and activity. She looked more alert and responsive.

Discussion

CMS are currently classified based on the site of defect as presynaptic, synaptic based lamina associated, and postsynaptic, with the latter being the commonest.[1] There are 11 genes identified to date and are likely to expand in future.

RAPSN is one of the most frequently mutated genes in people of Indo-European origin.[3] Two distinct phenotypes have been described of both early and late onsets.[4] 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. These patients usually respond well to anticholinesterases. An early recognition of this genotype can prevent death in a condition, which is easily treatable with a good long-term outcome.[2]

Kinali et al. described the phenotype of 46 children with CMS.[5] 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.[1] 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 ε 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.[6] Bulbar dysfunction as a presenting feature has been rarely described in the literature.

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. The awareness of distinct phenotypes can also help to facilitate targeted genetic diagnosis.