Key words: Slow channel myasthenic syndrome, fluoxetine, neuromuscular junction. *Professor .... Congenital Lambert-Eaton myasthenia syndrome. 3. Paucity ...
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JIACM 2016; 17(1): 66-68
Slow channel congenital myasthenic syndrome: A case with review of congenital myasthenia gravis Kuljeet Singh Anand*, Arshad Yahya***, Jyoti Garg**, Neeraj Kumar***
Abstract Slow channel congenital myasthenic syndrome is an autosomal dominant disorder characterised by prolonged acetylcholine receptor ion-channel activation. This is a report of a family with slow channel congenital myasthenic syndrome. The index case showed good response to fluoxetine. Key words: Slow channel myasthenic syndrome, fluoxetine, neuromuscular junction.
Introduction Congenital myasthenic syndrome (CMS) is an extremely rare heterogeneous group of genetically determined and non-autoimmune disorder of neuromuscular junction which results from inherited defects in presynaptic, synaptic, or post-synaptic junctional proteins. The onset is either at birth or early childhood, but some patients do not seek treatment because symptoms are mild or not recognised. Clinical presentation includes fluctuating or progressive weakness of cranial and somatic musculature with or without muscle atrophy, often associated with high arch palate and seronegativity to anti-AchR and anti-MuSK antibodies. Acetylcholine cholinestrase inhibitors (AchE) are helpful in some but not in all other syndromes.
Case report A 22-year-old male, 5th of six siblings (Fig. 1), product of a non-consanguineous marriage, having normal birth history and early motor developmental milestones presented with fluctuating fatiguability and weakness of proximal and distal upper limbs and proximal lower limbs since seven years. There was no history of diplopia, bulbar symptoms, or respiratory involvement. He had symptoms suggestive of facial and neck muscle weakness. Family history revealed similar symptomatology in the elder and younger sister (Fig. 1). History from his maternal side was not clear. His general physical examination was unremarkable. The neurological examination revealed bilateral ptosis with limitation of ocular movements in all directions. The pupils were normal in size and reaction to light.There was wasting of bilateral temporalis muscles and bifacial weakness. The motor system examination showed power grade 4/5 (MRC scale) at the shoulder with finger extensor > flexor
weakness. The power in lower limbs was 5/5. There was neck flexor and trunkal weakness. The fatiguability tests were positive in both upper (arm abduction test) and lower limbs. He had minimal ptosis on fixed sustained upward gaze. There were no pyramidal or cerebellar signs. The routine haematological and biochemical tests were normal. On neostigmine test, there was worsening in weakness of both upper extremities with head drop and marked ptosis. The repetitive nerve stimulation test (RNST) showed decremental response in both proximal and distal muscles. The acetylcholine receptor and MuSK antibody tests was negative. The ELISA for HIV 1 and 2 was nonreactive. Computerised tomography scan of chest did not reveal any thymus enlargement.The patient was initiated on tablet fluoxetine 10 mg/day and gradually increased to 40 mg/ day. He demonstrated significant and sustained improvement in ptosis and motor weakness at one month follow-up.
Fig. 1: Pedigree diagram of the patient.
*Professor and Head, **Assistant Professor, ***Senior Resident, Department of Neurology, Post-Graduate Institute of Medical Education and Research and Dr Ram Manohar Lohia Hospital, Baba Kharak Singh Marg, New Delhi - 110 001.
Discussion Congenital myasthenic syndrome is an uncommon disorder. In 1937, Rothbart reported four brothers under the age of 2 years with myasthenic disorder; and by 1972 Sarah Bundey was able to collect 97 familial cases of myasthenia with onset before the age of 2 years4. This increasing awareness regarding congenital forms of myasthenia gravis was originally described in a paper by Engel and Lambert who succinctly described the nosology of congenital myasthenic syndrome.The ultrastructural and biochemical examination of motor end-plates, microelectrode analysis and identification of mutation have delineated a series of disorders that includes pre-synaptic, synaptic, or postsynaptic proteins including ach receptor, CoIQ part of AchE, choline acetyltransferase, rapsyn, MuSK, the NaY 1,4 sodium channel, plectin and DoK-7. CMS is classified as pre-synpatic, synaptic, and post-synaptic (Table I). Defect in function of choline acetyl transferase producing reduced reserve of acetylcholine in the presynaptic terminal, present as congenital myopathy with episodes of stress-induced apnoea10. In another type, the synaptic vesicles form poorly and are reduced in number. Both these presynaptic disorders respond to AchE inhibitors. The fast channel and slow channel syndromes are as a consequence of mutation in Ach receptor subunit that accelerates (fast channel) and slow (slow channel) the kinetics of gating of receptor channel (Croxen et al)2. Slow channel myasthenic syndrome is autosomal dominant and is caused by mutation of AChR that increases the affinity of the receptor for the acetylcholine molecule. This increases the opening time of the receptor, producing prolonged end-plate currents and excess calcium leakage into the end-plate region of the muscle fibre6. It is difficult to distinguish from acquired myasthenia because symptoms begin after infancy and as late as the third decade. Fluctuating and fatiguable ptosis, ophthalmoparesis, and trunk and extremity weakness are common. Many patients have prominent involvement of neck, forearm extensors, wrist, and finger extensor muscle. Unlike other CMS, involved and symptomatic muscles are atrophic. Muscles weakness may be asymmetrical and is worsened by pyridostigmine. Assay for AChR antibodies are negative. RNST show repetitive compound muscle action potential (CMAP) with single supra-maximal stimuli and at 2 Hz produces detrimental response7. Administration of AChE inhibitors has no effect on decrement of main CMAP but causes an increase in the amplitude and number of repetitive CMAPs. In contrast, repetitive CMAP observed in congenital AChE deficiency is unchanged by AChE inhibitors. Needle examination shows normal spontaneous activity with shortduration, low amplitude varying motor unit potentials.
Journal, Indian Academy of Clinical Medicine
Quinidine which shortens the prolonged opening and fluoxetine may improve strength (Harper et al 2003)8. Table I: Classification of congenital myasthenic syndrome1. Pre-synaptic defects 1. Congenital myasthenic syndrome with episodic apnoea 2. Congenital Lambert-Eaton myasthenia syndrome 3. Paucity of synaptic vesicles Synaptic defects 1. Congenital end-plate acetylcholinesterase deficiency Post-synaptic defects 1. Primary kinetic abnormality with or without acetylcholine receptor deficiency a. Slow channel syndrome b. Fast channel syndrome 2. Primary acetylcholine receptor deficiency without or with only minor kinetic abnormality a. Myasthenic syndrome with plectin deficiency A fast channel syndrome with impaired response to acetylcholine has been reported in rare patients with mutation of e-subunit. Another mutation in the same subunit leads to abnormal kinetics of Ach receptor activation so that the channel opens more slowly and closes more rapidly than normal. The 38 known mutations of e-subunit are inherited recessively and result in severe lack of Ach receptors in the end-plate. One syndrome results from mutation in the college tail subunit of Ach receptor, creating a deficiency of enzyme (Engel)5. Another variety of CMS having an early and late onset (as late as 48 years) has been associated with mutation in the end-plate clustering protein “rapsyn” which plays a role in maintaining integrity of the post-synaptic membrane (Burke et al, 2003)9. These receptor mutations cause congenital ophthalmoparesis, bulbar symptoms and limb weakness. The early onset present, with arthrogryposis and lifethreatening crisis, whereas late onset resemble, seronegative myasthenia. A well characterised inherited childhood onset limb girdle (proximal weakness) myasthenia with absence of oculobulbar features is due to mutation of DoK-7 protein important for maintaining normal neuromuscular junction structure (Beeson et al 2006)9. The disorders affecting post-synaptic structures (the fast channel, AchR deficiency, rapsyn and plectin mutation associated myasthenia) also respond to AchE inhibitors and 3,4 DAP although both agents are hazardous in slow channel syndrome.
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Table II: Features of various congenital myasthenic syndromes (CMS)3,11. Myasthenic syndromes Causal agent or Onset NCS Treatment gene defect decade Pre-synaptic Episodic apnoea Choline 1st Amplitude of baseline CMAP is AchE inhibitors acetyltansferase normal; no repetitive CMAP Paucity of synaptic vesicle
Clinical features
Mild episode of weakness; recurrent apnoea; Ptosis common
Unknown
1st
Normal CMAP amplitude at rest decrement at 2 HZ
AchE inhibitors
Recurrent, sometimes pronounced weakness
AChE collagen tail for AChE
1st
Repetitive CMAP
None available Avoid AchE Inhibitors
Diffuse weakness; ptosis, delayed papillary response to light
Post-synaptic Slow channel
AchR subunit
1st-6th
Repetitive CMAP stimulation at 2 Hz Produces decrem. Of CMAP; worsen on higher rate of stimulation.
Quinidine, AchE inhibitors Avoid 3,4 DAP atrophy of dorsal forearm;
Fast channel
AchR subunit
1st
3,4 DAP
Prim. AchR deficiency
AchR subunit
1st
Resemble those of autoimmune MG decrement at low frequency, partial repair after exercise Same as autoimmune MG
Ptosis, diffuse weakness, delayed motor milestone; often shows selective weakness of cervical and distal upper limb extensor muscles. Ptosis, recurrent weakness, motor developmental delay
Rapsyn deficiency Pectin deficiency
Rapsyn Pectin
1st 1st
Synaptic AChE deficiency
References
AchE inhibitors, 3,4 DAP AchE inhibitors, 3,4 DAP 3,4 DAP
Ptosis, recurrent weakness, motor developmental delay Ptosis, recurrent weakness Myasthenic features, epidermolysis bullosa
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Harper CM, Engel AG. Quinidine sulphate therapy for slow channel congenital myesthenic syndrome. Ann Neurol 1998; 43: 480-4.
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Hutchison DO, Engel AG, Walls TJ et al. The spectrum of congenital end-plate acetylcholine receptor deficiency. Ann NY Acad Sci 1993; 681: 469-86.
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Engel AG, Ohno K, Sine SM. Congenital Myasthenic Syndrome; Approach to disease of the neuro muscular junction part II ed: page 251-3. Engel AG, Lambert EH, Gomez MR. A new myasthenic syndrome with end-plate acetylcholinesterase deficiency, small nerve terminals, and reduced acetylcholine release. Ann Neurol 1977; 1: 315-30.
10. Ohno K, Tsujino A, Brengman J et al. Choline acetyl transferase mutations cause myesthenic syndrome associated with episodic apnoea in humans. Proc Natl Acad Sci USA 2001; 98: 2017-22. 11. Khwaja GA, Chowdhury D, Gupta M. Case report Congenital Myasthenic Syndrome: Report of Four Cases and Brief Review of Literature. Neurol India 2000; 48: 266-71.
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