| BackgroundsMyotonic myopathies are rare neuromuscular diseases characterized by the clinical of myotonia,and include myotonic dystrophies(DM)and non-dystrophic myotonias.DM are autosomal dominant disorders characterized by progressive muscle weakness,myotonia,and early-onset cataracts,which including the myotonic dystrophy type 1(DM1)and the myotonic dystrophy type 2(DM2).DM2 is rare in Asia.DM1 is caused by the pathological expansion of CTG repeats in the 3’-untranslated region of the myotonic dystrophy protein kinase(DMPK)gene on chromosome 19q13.32.DM1 is characterized by a distinctive combination of muscular symptoms,such as facial weakness and muscular atrophy,grip myotonia,and distal muscle weakness with muscular atrophy.The classic phenotype is accompanied by extramuscular manifestations.These multisystem manifestations may present challenges to clinicians presented with these patients.Several studies have shown that the median age of death in DM1 patients is in the early fifties.The primary causes of death include arrhythmias,respiratory failure,and cancer.Prior registry data suggest that patients with DM1 take approximately 7 years to receive the appropriate diagnosis.Early recognition of the variety of organ symptoms at presentation will assist in reducing the time to diagnosis.Non-dystrophic myotonias are rare diseases caused by mutations affecting either the chloride ion channels(CLCN1)or the sodium ion channels(SCN4A)in skeletal muscle.The most common two forms of non-dystrophic myotonias are myotonia congenita(MC)caused by the CLCN1 gene mutations and paramyotonia congenita(PMC)caused by the SCN4A gene mutations.The typical characteristics of MC are that muscle stiffness is obvious at motor initation after a period of rest and improves after repeated exercise(warming phenomenon).The inheritence of MC is dominant or recessive genetic pattern with a more severe phenotype in the latter.The typical characteristics of PMC are cold or exercise induced myotonia and episodes of paralysis.Although not life limiting,patients with non-dystrophic myotonia may experience significant morbidity due to stiffness and pain related to myotonia.Distinguishing the different types of myotonia myopathies is important for diagnosis,treatment,and genetic counseling.But patients with myotonia myopathies can have complex clinical manifestations.For example,patients with DM in early stage disease with no obvious muscle weakness or muscle atrophy are difficult to differentiate with patients with non-dystrophic myotonia.In addition,although many typical features can help distinguish between SCN4A and CLCN1 mutations in non-dystrophic myotonia,there is still considerable overlap of phenotypes that is sometimes difficult to distinguish,such as,MC patients often have warm up of myotonia,but this phenomenon can also be seen in a small number of PMC patients.So that the diagnosis and classification diagnosis of myotonic myopathies should be based on the clinical data,electrophysiological,muscle MRI and genetic testing.DM1 is not well studied in the Chinese population.There is very few studies reported multisystemic impairments in Chinese patients with DM1.Several studies have described the involvement pattern of DM1 using muscle MRI worldwide.However,to our knowledge,no study to date has described the muscle involvement pattern on MRI in Chinese patients with DM1.In addition,at present,there are few reports on non-dystrophic myotonias in Chinese populations.Therefore,to explore the clinical and muscular MRI features of Chinese patients with myotonic myopathies is very helpful for improving clinicians’ understanding of the disease and follow-up study.Objective1.To investigate the manifestation and prevalence of various organs impairments in patients with DM 1.2.To analyze the muscle magnetic resonance imaging(MRI)features of lower limb muscles in DM1 patients and the correlation between clinical factors and muscle MRI data.3.To investigate the clinical,pathological features and gene mutation of patients with non-dystrophic myotonias.Methods1.We retrospectively reviewed the clinical information,muscle pathology and lower limb muscle MRI in 30 DM1 patients from different families.2.Clinical muscular impairment in DM1 was assessed using the Muscular Impairment Rating Scale(MIRS).Analysis of TI images enabled us to describe muscle fatty infiltration.The degree of fatty degeneration in each muscle was grading according to Modified Mercuri’s scale.Muscle edema was observed in the short inversion recovery images(STIR).Spearman rank correlation test was used to analyze the relationship between fatty degeneration score with age(year),age of onset(year),disease duration(year),MIRS grading and creatinine kinase(CK)level.3.The clinical,EMG,muscle MRI,muscle pathology and molecular information of 6 unrelated patients with non-dystrophic myotonias were analyzed retrospectively,3 of which had a family history.Results1.Thirty DM1 patients(21 males and 9 females),aged 21～55 years old,and the disease duration was 1～25 year.Half of the patients had a positive family history,and most of the patients had limb myotonia and/or weakness as the first symptoms.Among the 30 patients,all patients had myotonia and facial weakness,86.7%of patients had limb weakness,and 80.0%of patients had muscle atrophy.2.Among the 30 patients with DM1,93.3%of patients had extramuscular involved.In the 30 patients,frontal baldness or hair lose and cataract were respectively found in 46.7%of patients,daytime sleepiness,ventilatory functional disturbance and fatty liver were respectively found in 30.0%of patients,electrocardiogram abnormalities were found in 26.7%of patients,and digestive system symptoms were found in 23.3%of patients.26 patients underwent brain MRI,of which,24 had white matter abnormities.About 33.3%of the 21 male patients had hypogonadism.3.In the 30 DM1 patients,muscular pathology revealed that dystrophic changes was found in 80.0%of patients,all including internal nuclei,pyknotic nuclear clump and sarcoplasmic mass,and type I fibers predominate in 43.3%of patients.20.0%of the patients showed a mild myopathic change.4.Among the 30 DM1 patients,fatty infiltration was found in 93.3%of patients and 36.7%of patients were asymmetrically affected.The medial gastrocnemius was the most involved muscle,followed by soleus and tibialis anterior muscles in distal lower limbs.Regarding thighs,the anterior compartment(especially vastus medialis and vastus intermedius)was usually the most affected region with the rectus femoris relatively spared.80.0%of DM1 patients had edema in lower limb muscles.5.The total mean score of fatty degeneration of the DM1 patients correlated with MIRS grading and age but did not correlate with disease duration,the age of onset or CK level.6.Onset of the disease of the 6 patients with non-dystrophic myotonias started at infancy or early adolescence.The 4 patients with myotonia congenita(MC)all complained of muscle stiffness,which appeared upon initiating movement following a period of rest and improved after repetitive muscle contractions(warm-up phenomenon).2 of the 4 MC patients also complained of muscle stiffness after long running.The lower limb muscles were involved in the 4 patients with MC,whereas,the upper limb muscles in 3 patients,and the facial and eyelid muscles in 2 patients.Stiffness was aggravated in winter in 3 patients and was aggravated by fatigue and nervous tension in 1 patient.CK and lower limb muscle MRI in the 4 patients with MC were all normal.The other 2 patients(patient 5 and patient 6)with paramyotonia congenita(PMC)had the main symptoms of cold-induced myotonia and episodic weakness.While,the other affected family members of the patient 5 all presented with pure cold-induced myotonia,without episodic weakness.2 patients with PMC all showed four limbs,face,eyelid and neck stiffness,and trunk muscles,tongue,throat,and extraocular muscles stiffness were presented only in 1 patient.Episodic weakness could induced by cold,repeated activities or application of hormones.CK level was slightly increased between attacks of weakness of the 2 patients with PMC,and was significantly increased(>10000 U/L)in the episodes of weakness in patient 6.In patient 6,lower limb muscle MRI revealed edema in the bilateral medial gastrocnemius.7.EMG showed myotonia discharges in all the 6 patients with non-dystrophic myotonias,4 of whom also had myogenic damage.In 5 of the 6 patients,skeletal muscle pathology showed mild myopathic changes,and the other 1 patient showed no abnormalities.8.Genetic testing found 6 mutations of CLCN1 in the 4 patients with MC and 2 mutations in the 2 patients with PMC,of which,the p.C254W and p.M470V mutations in the CLCN1 gene and R1448G mutation in the SCN4A gene may be three new missense mutations.Conclusion1.Myotonia,muscle weakness and atrophy are the characteristics of DM1 patients and extramuscular manifestations are found in most patients.Muscular pathology of DM1 patients usually reveals dystrophic changes,including internal nuclei,pyknotic nuclear clump and sarcoplasmic mass.Muscle MRI reveals that fatty degeneration is observed in most DM1 patients with a selective muscle involvement pattern.2.Muscle stiffness at motor initiation and improved with repetitive movement are the classic characteristics of MC,and cold-induced myotonia with episodic weakness are the classic characteristics of PMC.Muscular pathology of non-dystrophic myotonias lacks specificity,and muscle MRI usually has no abnormality.The p.C254W and p.M470V mutations in the CLCN1 gene and R1448G mutation in the SCN4A gene may be three new missense mutations.3.A combination of clinical data,muscular pathology and muscle MRI can distinguish DM1 from non-dystrophic myotonias,but further genetic testing is needed to confirm the classification diagnosis. |
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