Congenital Myasthenic Syndrome:Clinical,Pathological,Electrophysiological And Genetic Analysis Of 10 Patients

Objective:In this research,10 congenital myasthenic syndromes(CMS)cases which were diagnosed in Qilu hospital during 2012-2018 will be retrospectively reviewed.The clinical,muscular pathological,electrophysiological and genetic features will be analyzed,summarized and compared to that of the cases reported in literatures,thus,to provide clinical data as a reference for the diagnosis and treatment of CMS.Materials and methods:All the 10 cases were clinically diagnosed with CMS in Qilu hospital during 2012～2018.Detailed medical history collection and neurological physical examination were perfonned and the patients underwent serology,electrophysiology,muscle pathology and gene screening.The course and treatment outcomes of the 10 patients were followed up.Outcomes:In this group,10 patients included 2 cases of slow channel syndrome,1 case of DOK7 deficiency,2 cases of cholinesterase deficiency caused by COLQ mutation,1 case of DPAGT1 deficiency,and 4 cases of GMPPB deficiency(3 cases were from the same family).Of the 10 patients,6 were male and 4 were female,and the ratio of male to female was 3:2.The age of onset was 0-28 years:8 patients were presented with weakness and fatigue at an early age from infancy while the onsets of the 2 slow channel syndrome patients were in their youth(28 and 22 years old,respectively).The interval between onset and diagnosis was 3-36 years,and the average was 22.1±10.7 years.The symptom of all the 10 patients showed inconspicuous onset and was characterized by varying degrees of muscle weakness and fatigue.Of the 10 patients,limb-girdle muscles of 8 patients were mainly involved(8/10),while 2 patients with slow channel syndrome had principal involvement of extensor muscle of fingers and wrists(2/10).Extraocular muscle involvement(4/10)was found in 4 patients,among which 2 patients presented with ophthalmoplegia only,1 patient had symmetrical bilateral blepharoptosis only,while 1 patient exhibited both.All the 10 patients had normal pupil light reflex.Four patients had facial muscle involvement(4/10),presenting as weakness of eye-closing and cheek-bulging.Respiratory muscle involvement was found in 3 patients(3/10),among which 1 patient exhibited pneumonia after upper respiratory infection and respiratory failure after taking diazepam;1 patient exhibited sudden dyspnea after fatigue;and 1 patient exhibited chronic dyspnea and could not lie supine at night.All the 10 patients in this group had clinical manifestations of fatigue(10/10)and 8 patients had fluctuation(8/10):7 patients had diurnal fluctuation that the morning light sunset to reduce weight,4 patients had seasonal fluctuation,among which 3 had a light weight in winter and 1 had a light weight in summer.The serum creatine kinase(CK)was tested in 8 patients.Serum CK level was significantly elevated in 2 patients of GMPPB deficiency(2/8)and was normal in other 6 patients.Muscle MRI was performed in 4 patients,among which 2 patients showed no obvious abnormality,and 2 patients of GMPPB deficiency CMS exhibited muscle steatosis mainly in the posterior group of thighs.Electromyography was performed in 8 patients and repetitive nerve stimulation(RNS)at a low frequency(3Hz)demonstrated a decrement in amplitude of compound muscle action potential(CMAP)in all the patient(8/8).Repetitive compound muscle action potential(R-CMAP)was found in 4 patients,including 2 cases of slow channel syndrome(case 1,2)and 2 cases of cholinesterase deficiency CMS(case 4,5),7 patients had no obvious abnormalities in motor nerve conduction examination(7/8),and electromyography of the needle electromyography showed myogenic lesions,while 1 patient exhibited mild neurogenic lesions in both conduction examination and needle electromyography(case 6).Muscle biopsy was performed in 7 patients and all the muscle specimens were taken from the left biceps brachii.The average age of muscle biopsy was 21 years old.The result of frozen section staining showed myogenic lesions in 6 patients(6/7)and mild neurogenic lesions in 1 patient(1/7).Among the patients with myogenic lesions,2 patients of GMPPB deficiency exhibited muscular dystrophy-like lesions and other 4 patients exhibited non-specific mild myogenic lesions.The result of muscle biopsy was consistent with that of electromyography.Immunohistochemistry demonstrated a decreased activity of a-dystroglycan in 2 patients with GMPPB deficiency.9 patients accepted standard treatment(9/10):1 patient of slow channel syndrome was treated with fluoxetine;1 patient of DOK7 deficiency and 2 patients of cholinesterase deficiency were treated with salbutamol;5 patients with CMS of glycosylation disorder CMS were treated with pyridostigmine.All the 9 patients had varying degrees of improvement and exhibited no significant side effects.In addition,1 case of slow channel syndrome,1 case of DOK7 deficiency and 2 cases of AChE deficiency was once treated with pyridostigmine before the diagnosis was made,and the symptoms were aggravated to different degrees.Conclusions:1.In this group,the onset ages of CMS were usually in infancy and some were in youth.The major clinical manifestation was muscle weakness and fatigue,and subtypes with different gene mutations exhibited clinical heterogeneity.2.Electrophysiologically,CMS cases exhibited a decrement in amplitude of CMAP in RNS.Slow channel syndrome and cholinesterase deficiency CMS might exhibit R-CMAP,which was of great significance for diagnosis.3.The muscle pathology in most cases were manifested as non-specific myogenic damage,and in cases of GMPPB deficiency could be manifested as muscular dystrophy.4.CMS were treatable congenital diseases and the selection of medicines should be linked with genetic mutations.Cholinesterase inhibitors should be avoided in cases clinically suspected as slow-channel syndrome,cholinesterase deficiency and DOK7 deficiency.