Print version ISSN 0004-282X
Arq. Neuro-Psiquiatr. vol.67 no.2b São Paulo June 2009
Electrophysiological study in synaptic congenital myasthenic syndrome: end-plate acetylcholinesterase deficiency
Estudo eletrofisiológico na síndrome miastênica congênita sináptica: deficiência da acetilcolinesterase da placa motora
Paulo José Lorenzoni; Rosana Herminia Scola; Bianca Lamas Gervini; Cláudia Suemi Kamoi Kay; Lineu César Werneck
Neuromuscular/Neurology Division, Department of Internal Medicine, Hospital de Clínicas da Universidade Federal do Paraná (UFPR), Curitiba PR, Brazil
Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic diseases in which the safety margin of neuromuscular transmission is compromised by one or more mechanisms1,2. According to the site of the primary defect, the CMS can be classified as presynaptic, synaptic or postsynaptic1,2. In 1977, synaptic CMS was first described by Engel et al. as caused by absence of acetylcholinesterase (AChE) from synaptic space3. Although ACHE gene mutations are not able to cause end-plate AChE deficiency, recessive mutations in COLQ gene are responsible for this deficiency1,2,4-6. COLQ gene mutations are most described in synaptic CMS patients severely disabled from an early age with progressive involvement of the axial muscles which can cause severe scoliosis and restrictive ventilatory deficit2. Synaptic CMS can be confirmed by repetitive compound muscle action potential (CMAP) with decremental response on electrophysiological study and molecular analysis showing COLQ mutations; but, relatives with similar symptoms, scoliosis, slow pupillary light response, and no effect after administration of AChE inhibitors are considered as clinical clues pointing to the diagnosis1-4.
We report a patient with synaptic CMS to describe the electrophysiological findings in end-plate AChE deficiency.
A 20-year-old man presented with progressive palpebral ptosis, limited eyes movements and facial weakness in first year of life. At 7 years of age weakness was more pronounced in the proximal limb muscles and worsening his walking with frequent falls and respiratory crisis episodes. He was born at term, but had delayed motor milestones. He denied dysphagia or neck weakness. He is a second child of consanguineous parents (first cousins).
Physical examination revealed abnormal teeth implantation and scoliosis. Neurological examination showed mild mental retardation; symmetrical ptosis; bilateral slow pupillary light response; bilateral ophthalmoplegia; bilateral facial weakness; scapular winging; proximal muscular atrophy in upper and lower limbs; muscle strength grade 4 (MRC scale) in upper limbs, grade 3 in proximal and grade 4 in distal lower limbs; axial muscle weakness; generalized hyporreflexia; and waddling gait.
The symptoms and signs were thought to be consistent with dysfunction of neuromuscular transmission, and the investigation showed the following results: (1) serum creatine kinase was normal; (2) absent anti-acetylcholine receptor antibody; (3) motor nerve conduction study with repetitive CMAP (second wave) in all nerves which disappear after a brief voluntary contraction (Fig 1); (4) decremental response greater than 10% on repetitive stimulation at 3 Hz of facial, spinal accessory, median and ulnar nerves (Figs 1 and 2); (5) rapid decremental response in repetitive CMAP (second wave) at repetitive stimulation at 3 Hz in studied nerves (Figs 1 and 2); (6) needle electromyography with myopathic potentials; (7) muscle biopsy was normal; and (8) molecular analysis revealed homozygous splice-site mutation IVS2+IG>C in COLQ gene.
The patient was diagnosed as having synaptic CMS by end-plate AChE deficiency due to COLQ gene mutation (molecular findings of this and others cases were previous reported2). Administration of pyridostigmine (240 mg/day) improved his walking (less dependency and falls), but did not improve ptosis, ophthalmoplegia or weakness. He never worsened the symptoms during 10 years of follow-up, but when pyridostigmine was withdrawn his gait became worse (increasing dependence and falls). Three years ago, fluoxetine was started (20 to 30mg/day) also with mild improvement in his gait (less falls) and respiratory crisis. However, these drugs management did not improve his electrophysiological features.
All studies were carried out following informed consent.
The end-plates species of AChE is an enzyme composed of tetramers of the globular and asymmetric catalytic subunits that is attached to a triple-stranded collagen tail4-6. Asymmetric AChE is specifically localized to basal lamina at the neuromuscular junction5,6. The collagen tail anchors the AChE to the basal lamina and is composed of three subunits: N-terminal region, collagen domain and C-terminal region4-6. Thus, mutations in COLQ gene could cause a defect that binding of collagen tail subunits to AChE or the anchor of collagen tail subunits in basal lamina4-6.
Synaptic CMS demonstrated absence of AChE from end-plate by histochemical, immunocytochemical, and electron cytochemical criteria4. AChE is the enzyme responsible for rapid hydrolysis of acetylcholine (ACh) release at cholinergic synapses4,5. At the normal end-plate, AChE limits the number of collisions between ACh and its receptor (AChR) determining the duration of the synaptic response5. Therefore, AChE inhibition results in prolonged exposure of AChR to ACh because more ACh remains in the synaptic cleft for a longer period before diffusing away4,5,7,8. Normally, activation of AChR by ACh evokes an end-plate potential (EPP) to propagate an action potential5. In vitro microelectrode studies in synaptic CMS revealed prolonged miniature end-plate potential and EPP outlast the muscle' refractory period7,8. Thus, EPP remains above threshold beyond the refractory period and produces one or more additional action potentials7,8.
Electron microscopy studies of the end-plate reveal abnormally small nerve terminals, often by Schwann cell processes, which extend into the synaptic cleft, partially or totally isolating the postsynaptic region3-5. This occurs to restrict the number of ACh quanta that can be released by a nerve impulse4. Despite this protective mechanism, many end-plates display focal degeneration of the junctional folds with loss of AChR4,5. AChE inhibition also produces desensitization of AChR and depolarization block at physiological rates of stimulation4.
Repetitive stimulation reveals decremental response at low rates (2-3 Hz) in clinically affected muscles7,8. Therefore, single nerve stimulation evoke repetitive CMAP, with two or more small waves separated by 6-10 ms which also decrements at repetitive stimulation7,8. Repetitive CMAP are smaller than the preceding one, and disappear more rapidly than the main CMAP after a brief voluntary contraction or repetitive stimulation at rates between 0.2 and 2 Hz, similar our case7-9. However, repetitive CMAP also can occur in slow-channel syndrome, pharmacological inhibition of AChE and rarely in normal people8-10. The repetitive CMAP with single stimulation may be absent in young infants and in severely affected patients with congenital AChE deficiency, but can be easily observed after administration of AChE inhibitors2,8. This may be result of severe restriction in the ACh quantal content to form EPP, which could overshadow the effect of the prolonged EPP duration8.
Electromyographic findings vary according to the time when the study is performed and the severity of the disease8. In early cases electromyography can be normal, whereas in those patients in late stages of the disease an electromyography study can show abnormalities suggestive of myopathic pattern8. This finding can be found when this CMS is associated with end-plate myopathy, with abnormal motor unit potentials with reduced amplitude and duration, an increase in the density of short polyphasic potentials and increased motor unit recruitment7,8. AChE inhibition cause an endplate myopathy with loss of AChR owing to cationic overloading of the postsynaptic region, by toxic effects of calcium, which enters the end-plate region in excess due to prolonged duration of the miniature end-plate current4,8.
Acknowledgment - We are grateful to Drs Violeta Mihaylova and Hanns Lochmuller (Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University, Munich, Germany) for their collaboration.
1. Donger C, Krejci E, Serradell AP, et al. Mutation in the human acetylcholinesterase-associated collagen gene, COLQ, is responsible for congenital myasthenic syndrome with end-plate acetylcholinesterase deficiency (type Ic). Am J Hum Genet 1998;63:967-975. [ Links ]
2. Mihaylova V, Muller JS, Vilchez JJ, et al. Clinical and molecular genetic findings in COLQ -mutant congenital myasthenic syndromes. Brain 2008;131:747-759. [ Links ]
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;1:315-330. [ Links ]
4. Engel AG, Ohno K, Sine SM. Congenital myasthenic syndromes: progress over the past decade. Muscle Nerve 2003; 27:4-25. [ Links ]
5. Aldunate R, Casar JC, Brandan E, Inestrosa NC. Structural and functional organization of synaptic acetylcholinesterase. Brain Res Rev 2004;47:96-104. [ Links ]
6. Engel AG, Ohno K, Sine SM. Congenital myasthenic syndromes: recent advances. Arch Neurol 1999;56:163-167. [ Links ]
7. Amato AA, Dumitru D. Neuromuscular junction disorders. In Dumitru D, Amato AA, Zwarts MJ (Eds). Electrodiagnostic medicine, second edition. Philadelphia: Hanley & Belfus, 2002:1196-1197. [ Links ]
8. Harper CM. Neuromuscular transmission disorders in childhood. In Jones HR, Bolton CF, Harper CM (Eds). Pediatric clinical electromyography. Philadelphia: Lippincott-Raven, 1996:368-372. [ Links ]
9. Van Dijk JG, Lammers GJ, Witzen AR, Molenaar PC. Repetitive CMAPs: mechanisms of neural and synaptic genesis. Muscle Nerve 1996;19:1127-1133. [ Links ]
10. Lorenzoni PJ, Kay CSK, Arruda WO, Scola RH, Werneck LC. Neurophysiological study in slow-channel congenital myasthenic syndrome: case report. Arq Neuropsiquiatr 2006;64:318-321. [ Links ]
Received 29 September 2008, received in final form 13 January 2009.
Accepted 4 April 2009.
Dra. Rosana Herminia Scola - Serviço de Doenças Neuromusculares / Hospital de Clínicas da UFPR - Rua General Carneiro 181 / 3º andar - 80060-900 Curitiba PR - Brasil. E-mail: firstname.lastname@example.org