When Breathing Becomes a Challenge: A Case of Congenital Myasthenia Gravis in an Indian Neonate With a DOK-7 Gene Mutation

A rare neuromuscular condition known as congenital myasthenia gravis (CMG) affects some people from birth or very soon after. It results in fatigue and muscle weakness because of genetic abnormalities that interfere with the neuromuscular junction's ability to function, where the nerves and muscles connect. Even among those who have the same genetic mutation, the severity of CMG symptoms might differ considerably. The most typical signs of CMG include eyelid drooping, breathing issues, muscle weakness and weariness, and difficulties swallowing. Clinical examinations, neurophysiologic tests, and genetic analyses are frequently combined to make the diagnosis of CMG. Although there is no known treatment for CMG, many patients may control their symptoms and lead relatively normal lives with the right care. A newborn with CMG due to a DOK-7 gene mutation is described in this article, along with its very early onset. The DOK-7 mutation is a rare variant in the Indian population that causes CMG and usually manifests as 'limb girdle' weakness. However, due to muscle weakness, the neonate in this case developed severe respiratory distress and later died despite rigorous life-saving measures.


Introduction
Myasthenia gravis is an autoimmune disease that typically presents in the third to fifth decade of life in women and the sixth to eighth decade of life in men with abnormal levels of fatigue on exertion. Paediatric myasthenia, or myasthenia affecting children under the age of 18, accounts for only about 10% of the global myasthenia burden [1]. Congenital myasthenia gravis can typically present in three main forms: transient neonatal myasthenia, where maternal antibodies directed against the acetylcholine receptor (AChR) or less often anti-muscle specific kinase (MuSK) antibodies cross over into the foetal circulation transplacentally and cause symptoms of weakness and poor feeding right after birth that can resolve spontaneously within weeks to two months of being born [2]. Congenital myasthenia syndrome (CMS) is the second mode of presentation and comprises an array of inherited disorders characterized by genetic defects that affect proteins present at the neuromuscular junction [3]. Juvenile myasthenia gravis is the third type of presentation, which is similar to adult-onset myasthenia in the clinical features and pathophysiology but presents at a much earlier age. Congenital myasthenia syndromes have been classified in many different ways based on the inheritance as autosomal recessive, which forms the majority, or autosomal dominant; as pre-synaptic, synaptic, and post-synaptic CMS; based on the function of the mutated proteins; glycosylation defects; and also based on the long term prognosis [4]. However, the overarching clinical features remain similar and are characterized by varying degrees of fatigable weakness presenting soon after birth affecting the limb, ocular, and bulbar muscles, resulting in hypotonia, ptosis, and difficulty feeding. More seriously, it can also present with periods of apnea, cyanosis, and respiratory distress precipitated by triggers such as infections [5]. CMS is characterized by the absence of anti-AChR and anti-MuSK antibodies in the serum [6]. The prognosis of CMS varies based on the genetic defect, and the treatment includes agents like pyridostigmine, a cholinergic agonist that inhibits acetylcholinesterase, adrenergic agonists such as ephedrine and albuterol, and open channel blockers of AChR such as fluoxetine, which are useful in certain subtypes of CMS [7]. In this case, we gave a trial of salbutamol, which is a beta agonist, to help relieve respiratory symptoms in the patient.
So far, 12 genes have been identified that code for proteins involved in neuromuscular transmission. Despite extensive testing, approximately half of the CMSs have yet to be identified molecularly. DOK7 mutations were first identified in recessive forms of CMS in 2006 [8]. In this case, we have diagnosed a neonate with atypical presentations of respiratory symptoms and a DOK-7 mutation in India.

Case Presentation
A full-term baby was delivered to a G4P1A2L1 mother by vacuum-assisted vaginal delivery and who cried shortly after birth with APGAR scores of 8 and 9 at one and five minutes, respectively. The baby did not require any additional help breathing and was roomed in with the mother. The mother felt normal fetal movements during her antenatal period, and it was a well-followed pregnancy with normal antenatal sonography. Within three to four hours, the baby developed a bluish discoloration of the skin and had difficulty breastfeeding, which prompted the mother to seek medical attention from a pediatrician. A physical examination revealed that the infant had central cyanosis (oxygen saturation [SpO2] of 70-83% on room air), and the child was transferred to the neonatal intensive care unit (NICU) for further treatment.
In the NICU, the baby was hypotonic, cyanosed, and had a capillary refill test of less than three seconds. The temperature was normal, and the pulses were felt very clearly in all four limbs. Respiratory findings were consistent with rhythmic and jerky breathing with intermittent subcostal retraction, air entry bilaterally equal, and a respiratory rate of 20-24 breaths per minute. A cardiac examination revealed a normal heart sound without any abnormal cardiac murmurs. Neurological status showed a hypotonic baby. The patient responded to tactile stimulation but was lethargic and drowsy. There was an absence of any active limb movement (Video 1, Video 2). The abdominal examination was normal and negative for any organomegaly. SpO2 was around 80-85% on room air, which rose to 90-100% when provided with 100% oxygen via a hood box. However, frequent desaturation occurred during episodes of apnea, so the baby was given continuous positive airway pressure (CPAP) support (Video 3). After about an hour, the baby was kept on synchronized intermittent mandatory ventilation (SIMV) ventilation due to its deteriorating condition ( Figure 1).

VIDEO 1: Neonate on admission
The neonate was lethargic and had a weak cry with an absence of any active limb movement View video here: https://youtu.be/Y5TRhMarpT0

VIDEO 2: Neonate with visible signs of respiratory distress
Respiratory findings were consistent with rhythmic and jerky breathing with intermittent subcostal retraction.

VIDEO 3: Neonate on CPAP
The baby was given continuous positive airway pressure (CPAP) support to maintain oxygen saturation.

FIGURE 1: The neonate was kept on SIMV support.
Due to worsening respiratory distress, the neonate was given synchronized intermittent mandatory ventilation (SIMV) to maintain oxygen saturation.
According to the additional tests that were performed, the complete blood count, C-reactive protein (CRP), and renal function tests (RFT) were all within normal limits. The blood gas reports indicated that respiratory acidosis was present ( Table 1), and the 2D ECHO, EEG, and USG brain were all normal. Blood tests to rule out inborn metabolic errors were done along with genomic sequencing. After consulting with a neurophysician, syrup piracetam was started, considering it to be a breath-holding spell. Muscular pathology was suspected due to symptoms such as difficulty feeding, a weak cry, respiratory distress, and muscle weakness. Following additional examinations, genetic testing was agreed upon to rule out myasthenic pathology. A genetic test confirmed the suspicion of CMS due to the DOK-7 mutation ( Table 2). According to one study, oral salbutamol is well tolerated and improves muscle function in children with DOK7 CMS. Therefore, a trial of oral salbutamol (2-4 mg three times a day) was initiated.   The genomic sequence report showed likely compound heterozygous variants causative of the reported phenotype.
The patient was started on an extubation trial and weaned off to an high-flow nasal cannula (HFNC). However, soon the patient had CO2 narcosis and respiratory acidosis. Despite ventilator support, the patient's condition deteriorated, and the baby died on the 12th day.

Discussion
Congenital myasthenic syndromes are a group of rare, inherited neuromuscular disorders characterized by dysfunction of the neuromuscular junction. The onset age of CMS is highly variable, ranging from early childhood with apneic attacks and respiratory difficulties to adulthood with limb-girdle weakness and ptosis [8]. Children with CMS typically present with the condition during the first two years of life, and many of them exhibit symptoms as early as the neonatal period or early infancy. Patients may show symptoms such as hypotonia, facial weakness, swallowing difficulties, respiratory dysfunction, ptosis, and ophthalmoparesis. In this case, the presentation of symptoms was very immediate, i.e., three to four hours after birth, and respiratory symptoms were prominent. Joshi et al. [9] reported a case of a child with bilateral ptosis, a weak gag reflex, generalized hypotonia with weakness of the intercostal muscles and diaphragm, and depressed deep tendon reflexes, where the child presented with drooping of the eyelids at six months. Another case [10] was reported of a six-month-old patient who presented with episodic respiratory distress and apnea since the 10th day and was diagnosed with congenital myasthenia gravis based on electrodiagnostic findings.
The patient exhibited mutations in DOK7 (downstream of kinase), an adapter protein for MuSK, which is an important cause of congenital myasthenia. The presentation of CMS with DOK7 mutations can differ greatly, with most patients having a 'limb girdle' pattern of weakness (proximal muscles are more affected than distal muscles), and an altered waddling gait after achieving normal milestones. Ptosis may be present, but eye movements are rarely involved [16]. Fatigability may not be present or might be difficult to detect in neonates. Feeding difficulties, hypotonia, and stridor are diagnostic clues that indicate further neurological evaluation is required. In a survey of 79 CMS patients, the DOK7 mutation carriers had the worst outcomes [17]. Six of the eight ventilated, disabled individuals had the DOK7 variant [17]. Our patient presented with lethargy, hypotonia, and difficulty breathing within the first three to four hours of life. Due to the rarity of the disease and lack of sufficient research, treatment modalities for congenital myasthenia are often symptomatic [4]. Treatment with acetylcholinesterase inhibitors is futile and may often worsen symptoms. Ephedrine has been used in the treatment of CMS with DOK7 mutations. Due to the adverse alphaadrenergic effects, beta-2 agonists such as salbutamol are being used as first-line treatments. Beta-2 agonists have been shown to improve symptoms in CMS associated with DOK7 mutations. In nine infants with DOK7 congenital myasthenic syndrome (CMS), oral salbutamol administered for at least one month improved muscle function without causing significant adverse effects, with all participants reporting an increase in stamina and function [18]. Beta-2 agonists increase cAMP kinase-A activity, which compensates for the reduced signaling of MuSK due to the DOK7 mutation. The improvement in muscle function seen with salbutamol is comparable to what has been reported with ephedrine, most likely owing to the beta-2 adrenergic effects [19]. However, since ephedrine has both alpha and beta adrenergic effects, there are concerns about its cardiac and central side effects with long-term use in children. Albuterol has also been shown to significantly and persistently enhance muscle strength in patients with DOK7 congenital myasthenic syndrome [20]. Our patient was given a trial of salbutamol (2-4 mg three times a day) in an attempt to improve muscle function.
Up until now, close to 90 cases with the DOK-7 mutation CMS have been reported in the literature (  The table showcases information about the symptoms and the genetic mutation [8,14,16,21,22,23,24].

Conclusions
Based on the above-mentioned findings, CMS can present either in the neonatal period, infancy, or up to two years of age. The clinical picture of CMS can vary greatly. Typically, early-onset subgroups of the DOK-7 mutation have more severe disease manifestations. In DOK-7 CMS, oral salbutamol appears to be well tolerated and enhances muscle function. Salbutamol is preferred over ephedrine because ephedrine has central and cardiac side effects with long-term use.
submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.