Efficacy of terbutaline in familial limb girdle myasthenia: Case report and review of literature.

Congenital myasthenic syndromes (CMS) are frequently misdiagnosed due to their wide clinical heterogeneity. Molecular defects in various end-plate associated proteins are being identified. Better understanding of the molecular pathogenesis and genotype-phenotype correlations can help evolve newer therapeutic targets. We present a report of two siblings with familial limb girdle myasthenia who showed significant objective clinical improvement after initiation of terbutaline. The possible mechanism of action and utility of terbutaline in the setting of CMS are described. Terbutaline is a potential treatment option in certain subtypes of CMS refractory to conventional medicines. However, long-term follow-up is required to determine the overall efficacy and safety profile.

Introduction

Congenital myasthenic syndromes (CMS) include a heterogeneous spectrum of treatable disorders with varied clinical manifestations. Molecular defects in various end-plate associated proteins are being identified. Optimal choice of drugs depends on the underlying molecular defect. Considering the limited availability of diagnostic genetic testing in resource crunch settings, correlation of the phenotype with most likely underlying gene defect is paramount to selection of appropriate medications. In this case report, the diagnostic considerations and management in two siblings with limb girdle myasthenia are described. The therapeutic potential of terbutaline in the setting of CMS will also be highlighted.

Case Reports

Case 1

A 28-year-old lady, born to non-consanguineous parents presented with a history of weakness of all four limbs since the age of 6 years. Antenatal period was uneventful with fetal movements being reportedly normal. She had a normal cry at birth and attained developmental milestones normally. Symptoms were noted at 6 years of age. There were recurrent episodes of fall with buckling of knees as well as difficulty in climbing stairs. There was difficulty in lifting objects affecting both upper limbs since 10 years of age. There was history of intermittent mild nasal twang to speech and nasal regurgitation since the last 5 years. There was no drooping of eyelids or diplopia. There was history of fatigability, significant fluctuation of the symptoms with worsening toward the evening. There was episodic worsening of her limb weakness lasting for a few days. She also noted worsening during her menstrual cycles. There was similar illness in her younger sister as mentioned below.

On examination, she had short stature (height 140 cm). No other skeletal deformities were noted. There was no ptosis, extraocular movements and pupils were normal. Bifacial weakness was present and the lower cranial nerves were normal. Axial muscles were moderately weak. She had bilateral symmetric weakness in a limb girdle distribution. Deltoid was Medical Research Council (MRC) grade 3/5, biceps and triceps grade 4/5, mild distal hand grip weakness, iliopsoas grade 2/5, quadriceps, glutei, and hip adductors grade 3/5. Deep tendon reflexes were normal (++). Sensory examination was normal.

Case 2

The younger sister, 25-year-old, had weakness mainly involving the proximal lower limbs with difficulty in getting up from squat noted since the age of 10 years. There was history of episodic worsening as mentioned in the earlier case. On examination, she only had mild weakness with iliopsoas power grade 4+/5, rest of the muscles were normal but fatigable. Cranial nerves, deep tendon reflexes, and sensory examination were normal.

Diagnosis of familial limb girdle myasthenia was considered. Routine nerve conductions were normal. Repetitive nerve stimulation (RNS) at 3 Hz showed significant decremental response from right abductor pollicis brevis (APB) (11%), right trapezius (16%), and left trapezius (21%) [Figure 1]. There were no repetitive compound motor action potentials (R-CMAPs). Single fiber electromyography (EMG) from left frontalis showed abnormal jitter (mean consecutive difference-69 μs) with increased blocking (percentage of recordings with block-95%). There was noticeable improvement in motor power (by MRC grade 1) following a neostigmine challenge test (1 mg of neostigmine). RNS in the sister (Case 2) showed decremental response from right APB (16%), right trapezius (14%), and left trapezius (16%) [Figure 2].

Figure 1

Repetitive nerve stimulation from right trapezius showing decremental response (Case 1)

Figure 2

Repetitive nerve stimulation from right abductor pollicis brevis showing decremental response (Case 2)

Treatment for the elder sibling was started with oral cholinesterase inhibitors (Neostigmine 15 mg twice daily). However, there was worsening of motor power after initiation of the same and subsequently it was stopped. Considering the clinical phenotype and variable response to cholinesterase inhibitors, the possibility of CMS due to mutations in Dok-7 protein was considered most likely. Meanwhile, she also reported subjective improvement after ingestion of a cough syrup (containing terbutaline) prescribed incidentally for a lower respiratory tract infection. Ephedrine was considered as an option, however it was not available. Hence, it was decided to give a therapeutic trial with terbutaline (terbutaline sulphate 2.5 mg twice daily) after obtaining informed consent from both the patients.

Quantitative myasthenia gravis (QMG)[1] score for disease severity was used for objective assessment of therapeutic response before and after administration of the medication (minimum score-0, maximum score for severe weakness-39). Components of QMG score, which were impaired included: Arm raise time, head lift time, leg raise time, and eye lid closure (facial muscles). Composite QMG scores pretreatment, post treatment at 48 h and post treatment at 3 months were 14, 11, and 8 respectively. Corresponding QMG scores in the younger sister (Case 2) with terbutaline were 10, 6, and 5 respectively. Both the siblings were able to lift their arms, get up from low-lying squat and walk unaided during the follow-up at 3 months.

Discussion

Molecular defects in acetylcholine receptor (AChR) sub-units, rapsyn, Collagen Q (ColQ) sub-unit of acetylcholinesterase, Dok-7, choline acetyltransferase deficiency, agrin, Glutamine fructose-6-phosphate amidotransferase (GFPT1) have already been identified in CMS.[2] Limb girdle presentation can be usually seen with Dok-7, agrin-related and GFPT1. Cholinesterase inhibitors are usually ineffective[3] in slow channel syndromes and CMS related to defects in Dok-7, ColQ (related end-plate acetyl cholinesterase deficiency), agrin and laminin beta 2. R-CMAPs are seen in slow channel syndromes and end-plate AchE (acetyl cholinesterase) deficiency.

The familial limb girdle presentation with episodic worsening, relative sparing of extraocular muscles, absence of repetitive CMAPs, and variable response to cholinesterase inhibitors make the possibility of CMS related to Dok-7 mutation a likely possibility in our case. The initial positive response to neostigmine challenge test had prompted us to give a trial with cholinesterase inhibitors and had delayed the start of appropriate therapy. This again emphasizes the utility of appropriate genetic testing and need for definitive diagnosis considering the clinical heterogeneity and possible overlap between the various CMS subtypes.

This variable response to cholinesterase inhibitors has been previously reported in literature. Slater et al. had observed some patients with “limb girdle myasthenia” who showed initial motor strength improvement following initiation of pyridostigmine with subsequent secondary deterioration seen after a few days to weeks while on treatment.[4] A reduced quantal release of acetylcholine (ACh) in addition to altered structural integrity of the neuromuscular junction has been proposed to be the reason for impaired neuromuscular transmission in limb girdle myasthenia. The initial response to neostigmine can be attributed to the increased availability of ACh at the synaptic cleft, which diffuses and interacts with the postsynaptic AChRs. The possible reasons for secondary deterioration are discussed in the section below.

Ephedrine has been reported to be an effective treatment for CMS associated with Dok-7, agrin, and ColQ.[5] However, the non-availability of ephedrine has prompted search for newer therapies with similar mechanism of action. There have also been reports of benefits of albuterol in CMS with Dok-7 and epsilon sub-unit mutations.[67] The efficacy and safety of terbutaline has also been described in myasthenia gravis.[8] With newer insights in to the molecular pathogenesis of Dok-7, the likely explanation for the therapeutic benefits of ephedrine and other beta 2 stimulants have also been elucidated. An adaptor protein encoded by Dok-7 is essential for neuromuscular junction synaptogenesis and differentiation by inducing phosphorylation of muscle specific tyrosine kinase (MuSK).[9] Agrin released in to synaptic space by presynaptic neurons also activates MuSK (extrinsic indirect activation).[10] Beta 2 agonists act by activating the cAMP-protein kinase A that feeds in to the MuSK signaling pathway, compensating for the mutant MuSK and enhancing the integrity and stability of the neuromuscular junction.[5] Muscle “anabolic” actions are also reported, which counteract the myopathic effects secondary to muscle fiber necrosis due to postsynaptic membrane instability. Possible effects on quantal release of ACh or receptor kinetics are also being implicated.[5] The muscle “anabolic” effects could explain the beneficial effects and progressive improvement over a longer time period as seen in our case. This feature has also been mentioned in literature.[5] The poor long-term response and secondary worsening to cholinesterase inhibitors in this subset of CMS could be attributed by overstimulation of postsynaptic receptors in the setting of impaired integrity and stability of neuromuscular junction with secondary myopathic changes as mentioned earlier.

Common side-effects to terbutaline like tachycardia or tremors were not noted in either of the patients. Terbutaline and salbutamol are available as oral slow release tablets, syrups, and intravenous preparations. Oral bioavailability of terbutaline (25-80%) is lesser compared to salbutamol[11] and the plasma half-life (2.5-5 h) of both drugs are similar though the terminal half-life of terbutaline is much longer (14-18 h), hence the duration of action may be prolonged.[11]

Conclusions

Genotype-phenotype correlations are paramount to optimal therapeutic management in CMS. Considering the beneficial effects on neuromuscular junction, terbutaline can be considered as the first line therapy in some subtypes of CMS and as an effective add on therapy in other subtypes with suboptimal response to conventional agents. However, the efficacy and safety profile over a prolonged period of time will need to be ascertained with long-term follow-up studies using large sample size.