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|Year : 2000 | Volume
| Issue : 3 | Page : 266-71
Congenital myasthenic syndrome : report of four cases and brief review of literature.
Khwaja GA, Chowdhury D, Gupta M
Department of Neurology, G.B. Pant Hospital, New Delhi, 110002, India.
Department of Neurology, G.B. Pant Hospital, New Delhi, 110002, India.
The term 'congenital myasthenic syndrome' (CMS) encompasses a number of heterogeneous disorders characterised by myasthenic symptoms since birth, usually with positive family history and absence of acetyl choline receptor antibodies. Recent advances in electrophysiology and ultrastructural analysis of neuromuscular junction have made it possible to identify the various defects underlying these disorders. We report four cases of CMS, with a review of literature.
|How to cite this article:|
Khwaja G A, Chowdhury D, Gupta M. Congenital myasthenic syndrome : report of four cases and brief review of literature. Neurol India 2000;48:266
Myasthenia gravis in infancy and childhood fall into two major groups i.e. acquired autoimmune and congenital. The congenital group comprises a number of phenotypically and genetically heterogeneous disorders which are familial and lack autoantibodies against acetylcholine receptors (AChR). These disorders are often described under the broad rubric of congenital myasthenic syndrome (CMS).,, Based upon clinical, routine electrophysiology, in vitro electrophysiology and ultrastructural methods of study of neuromuscular junction (NMJ), these hetereogeneous groups of CMS have recently been tentatively classified. However, in most of the centers where such advanced investigations are not possible, only the broad heading of CMS is applied. We report four cases of CMS, a family with three affected members and a single case.
Case No. 1 (Index Case) : A 6 year male child, product of consanguineous marriage, fourth in birth order, presented with delayed motor milestones, increased fatigability and weakness since infancy, bilateral ptosis and dysphagia. Patient had a normal perinatal history. There was no history of difficulty in feeding, sucking or apnoeic spells. The patient started to sit at the age of 9 months and walked around two years of age. His gait remained waddling and he could not run or walk fast and used to tire easily. At the age of 3 years, the child developed bilateral symmetrical ptosis which used to become more conspicuous as the day progressed. He had associated difficulty in swallowing and also used to take long time for chewing and eating. There was history of frequent choking while eating. The general physical examination revealed slightly elongated facies. The neurological examination revealed bilateral symmetrical ptosis with limitation of eye ball movements in all directions of gaze. The pupils were of normal size and reacted normally to light. The motor examination showed power grade 4/5 (MRC scale) at shoulder and hip joints. Increased fatigability was demonstrated by curtain sign and arm abduction tests. Deep tendon reflexes (DTR) were normal. Patient had waddling gait. There was no other skeletal deformity. Neostigmine test was unequivocally positive. The repetitive nerve stimulation (RNS) study at 3Hz showed decremental response in abductor pollicis brevis. The AChR antibody test was negative. Parents of the patient refused intercostal muscle biopsy for ultrastructural studies of NMJ. He was started on tab. pyridostigmine, 60mg, in divided doses, which was subsequently increased to 90 mg/day as he showed significant improvement in ptosis, dysphagia and motor weakness.
Case No. 2 : Elder sister of case 1, (aged 8 years) had history similar to case 1, with normal natal and perinatal events but delayed motor milestones and development of symmetrical ptosis and dysphagia at the age of 4 years. General physical examination was unremarkable except for a supernumerary left little finger. Neurological examination revealed bilateral symmetrical ptosis, limitation of extraocular movements in all directions of gaze, mild proximal weakness at shoulder and hips and preserved DTR. She also showed unequivocal positive response to neostigmine test. RNS test at 3Hz showed decremental response in abductor pollicis brevis. She was started on pyridostigmine 90mg/day and showed significant improvement. Case No. 3 : Father of cases 1 and 2, (aged 38 years) did not complain of any ptosis or weakness. On family screening, he was found to have fluctuant bilateral ptosis. The rest of the neurological examination was normal. RNS test at 3 Hz showed a normal response in abductor pollicis brevis but a decremental response in trapezius. He was not offered any treatment.
Case No. 4 (Isolated Case) : A 34 year old male, product of non consanguineous marriage, presented with history of recurrent apnoeic spells, precipitated by vigorous cry, since birth. Since the age of 4 years, such apnoeic spells disappeared but he continued to have weakness, fatigability and waddling gait. By 10 years of age, he had developed bilateral symmetrical ptosis. By 25 years of age, he was married and had two children who were normal and unaffected. During this time, per chance, he was seen by a doctor who diagnosed him as a case of myasthenia gravis and started him on neostigmine. His fatigability considerably improved on medication. Subsequently he was referred to us. The family history regarding any neuromuscular disorder was negative. On examination, he was found to have bilateral symmetrical ptosis, with mild restriction of extra ocular movements in all directions of gaze. There was proximal weakness in hip and shoulder girdle muscles (4/5 MRC scale) and increased fatigability of muscles. Edrophonium test was positive. RNS test at 3Hz showed decremental response in abductor pollicis brevis. AChR antibodies were absent. CT scan chest did not reveal any thymus enlargement. The intercostal muscle biopsy was refused by the patient. His symptoms improved on higher doses of pyridostigmine.
CMS includes a heterogeneous group of disorders, characterized by dysfunction of NMJ transmission, which are present since birth and are genetically inherited. Although cases of myasthenia gravis during infancy and childhood have been described in the literature since 1960,,, the distinction between acquired autoimmune form and congenital forms has been increasingly recognized and emphasized.,,,,,,,,,,, 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. Engel classified CMS into broad groups of pre synaptic defects, post synaptic defects and partially characterised syndromes. The current thrust of research is naturally directed towards elucidation of molecular basis of such disorders.,,,,, Two major features distinguish CMS from acquired autoimmune myasthenia gravis (MG), namely, a positive family history and absence of AChR antibodies. While a positive family history is consistent with the diagnosis of CMS, a negative family history does not exclude autosomal recessive inheritance, an incompletely penetrant autosomal dominant gene in one parent, or a new mutation. Furthermore, while most cases of acquired autoimmune childhood MG are sporadic, familial aggregates have been observed which may be due to inheritance of HLA haplotypes that predispose to sensitisation of acetylcholine receptor (AChR). On the other hand, while a positive AChR antibody test excludes the diagnosis of CMS, but a negative test in a sporadic case does not necessarily imply a diagnosis of CMS because a high proportion of juvenile patients with autoimmune MG are also sero negative.
The clinical features common to most of the cases of CMS are described in table II. It is also important to note that though many patients of CMS have historical evidence of fatigability and weakness since early age, some may present in adult age, for example, those with slow channel syndrome and familial limb girdle myasthenia.,, Ocular muscle involvement may be absent or minimal in cases of NMJ AChE deficiency, slow channel syndrome and familial limb girdle myasthenia. At the other end of the severity spectrum, there may be arthrogryposis at birth, with or without history of reduced foetal movements in utero., The response to anticholinesterase drugs varies among the various groups. In general, patients who suffer from AChR deficiency without a significantly prolonged open time of AChR channel, those who release insufficient number of ACh quanta but do not have AChE deficiency or those in whom quantal size is reduced, benefit from these drugs. Patients with slow channel syndrome either respond transiently or not at all and those with end plate AChE deficiency are refractory., It is important to note here that correct differentiation of CMS from autoimmune MG is also important therapeutically, as CMS patients do not respond to immunosuppressive therapy or plasma exchange and thymectomy. The analysis of inheritance pattern of various types of CMS suggests that almost all of them follow autosomal recessive (AR) mode of inheritance except the classic slow channel syndrome which follows autosomal dominant (AD) inheritance.
Routine electrophysiology showing the myasthenic decremental response in weak muscles, though common, may not be universally seen. In a large proportion of such negative cases, single fibre EMG (SFEMG) additionally confirms the defect in NMJ transmission. Demonstration of repetitive compound muscle action potential (CMAP) on single stimulation in a completely resting muscle and without any effect of anticholinesterase medication is diagnostically useful in CMS, as it is seen in two varieties, namely congenital absence of endplate AChE and slow channel syndrome. This is explained by prolonged end plate potential (EPP) seen in these conditions. Certain putative mechanisms have been proposed to explain the various defects, based on invitro electrophysiology and detailed analysis of ultrastructure of NMJ in patients of CMS. These investigations thus form the corner stone for confirming the site(s) of NMJ transmission defect and elucidating the nature of such defects. For this purpose, a muscle sample of the patient from its origin to insertion is required. External intercostal muscle or anconeus is commonly used for this purpose. The various parameters which are studied have been highlighted in [Table III].
Electrophysiologically measurable parameters of quantal release by conventional microelectrode techniques rely on the equation m = np for interpreting the defect in NMJ transmission. Here, m signifies the number of ACh quanta released by a nerve impulse; n, number of readily releasable ACh quanta and p, the probability of quantal release.,, Identifying these parameters provides important clues regarding the diagnosis e.g., in both Lambert Eaton myasthenic syndrome (LEMS) and paucity of synaptic vesicles and reduced quantal release variety of CMS, m is reduced. However, it is due to reduced p in the former but reduced n in the latter syndrome. Similarly, the miniature end plate potential (MEPP) amplitude in resting state is normal in the syndrome of defect in ACh resynthesis and packaging (unlike in autoimmune MG where it is decreased at rest). Upon stimulation at 10Hz for 5 minutes, MEPP amplitude decreases abnormally thus suggesting a progressive decrease in ACh content of the synaptic vesicle and confirming the diagnosis. More recent advances employing noise analysis for channel kinetics and single channel patch clamp recordings have further pinpointed the various congenital defects in NMJ transmission. For example, prolonged decay phases in EPP and MEPP which get further prolonged on addition of prostigmin in the bath, together with prolonged channel open time and normal conductance constitute the chief characteristics of classic slow channel syndrome. This contrasts with large MEPP and EPP with short decay time, increased conductance and decreased channel open time seen in high conductance fast channel syndrome. Thus, it is evident that both morphological analysis of NMJ and in vitro electrophysiology studies complement each other in delineating the nature of CMS.
The analysis of our patients in the family suggests vertical transmission indicating autosomal dominant inheritance with variable expression. As detailed evaluation of in vitro electrophysiological studies and morphological analysis of NMJ had not been done, definite subcategorisation of CMS in our patients is not possible. However, based on the various differential features, following observations can be made regarding our cases.
Familial Cases : A very good response to pyridostigmine virtually rules out end plate ACh deficiency; AD inheritance with variable expressivity favours slow channel syndrome but selective involvement of cervical, scapular and finger extensions are lacking in our cases. Furthermore, no repetitive CMAPs on single stimulation were obtained. No feeding or sucking difficulties and no apnoeic spells in infancy point against resynthesis/packaging defect. Considering together the picture of fatigability and weakness since birth with variable severity and good response to therapy, paucity of synaptic vesicles and reduced quantal release remain a possibility. Only a few cases have been described in the literature so far and autosomal dominant mode of inheritance may not be ruled out.
Single Case : This case fits classically with defect in acetyl choline resynthesis or packaging. The early onset of life threatening apnoeic spells which got ameliorated with increasing age as seen in our case is quite classical of this syndrome. Furthermore, the patient responded very well to anticholinesterases, as commonly occurs in this group.
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