| Objective: Hereditary motor and sensory neuropathy (HMSN), alsoknown as Charcot-Marie-Tooth disease (CMT) or peroneal muscular atrophy(PMA), is a group of peripheral neuropathies with high genetic and clinicalheterogeneity. HMSN accounts for about90%of hereditary neuropathies. Theincidence of HMSN is about10-30/100,000. Autosomal dominant (AD),autosomal recessive (AR), X-linked inheritance and sporadic cases have beendescribed for HMSN. The basic clinical manifestations of HMSN (CMT)include symmetrical, gradually aggravated muscle weakness and atrophy indistal limbs, and lack of subjective paresthesia. Patients with differentsubtypes can also be associated with one or several manifestations asfollowing: mental retardation, ataxia, ophthalmoplegia, glaucoma, cataracts,optic atrophy, hearing loss, vocal cord paralysis, respiratory impairment,autonomic nervous dysfunction, hypotonia, scoliosis, joint deformities, andpyramidal tract involvement.At present, for most HMSN patients, the diagnosis and studies can onlybe made through clinical assessments and there is certain limitation in theknowledge of HMSN, which apt to cause misdiagnosis and missed diagnosis.The intact diagnosis of HMSN requires the combination of clinicalmanifestations, inheritance mode, electrophysiological and pathologicalanalysis of sural nerve biopsy and gene sequencing. HMSN should bedifferentiated with other chronic peripheral neuropathies. Clinicians shouldfocus not only on the condition of peripheral nerve involvement (including thedistribution of involved nerves, nerve conduction velocity and myelin/axonalinvolvement), but also on the multi-organ, multi-system damage, which canprovide an important basis for the clinical classification of HMSN and guidethe direction for a targeted gene sequencing. Our study analyzed the clinical, electrophysiological features, thepathological datas of sural nerve biopsy of HMSN and their correlations. Thepurpose of this study was to improve the consciousness and level of cliniciansin diagnosis and differential diagnosis of HMSN, investigate how to establishthe diagnosis path and build a solid basis for further molecular geneticdiagnosis and therapy.Methods: According to the diagnostic criteria of HMSN (being referredto the related literatures of Swaiman KF, etc.), the datas of30patients withHMSN, from October2007to October2011, admitted into the department ofneuromuscular diseases, the Third Hospital of Hebei Medical University werecollected. All the patients received detailed electrophysiological test. Suralnerve biopsies were performed. The resin-embedded specimens with semi-thinsectioning and Toluidine blue-Safranin stain were observed under lightmicroscope and electromicroscope. Finally, the clinical, electrophysiologicalfeatures and the pathological characteristics of sural nerves under lightmicroscopy and electronmicroscopy of30HMSN patients were summarizedand comparatively analyzed.Results:1. Clinical characteristics of HMSN30HMSN patients include17males and13females. The age of30patients ranged from0.5to57and the average age was23.73years. The ageof onset altered from0to41years and the mean age was14.44years. Thecourse of disease ranged from0.5to54years and the average course is9.29years. Symptoms first appeare in infancy or adolescence for most patients andthe patients usually go to hospital because of slowly progressing dyskinesia.The basic clinical manifestations include symmetrical muscle weakness andatrophy in distal four-limbs and deformities in bones or joints (including pescavus, achilles tendon contracture, toe deformity, scoliolosis and so on). Thesymptoms of lower limbs were severe than upper limbs in the majority ofpatients. The disease affected both upper limbs and lower limbs in23casesand only affected lower limbs in7cases.7patients had paresthesia.6patients had other system involvement.12patients had an exact family history.Cerebrospinal fluid protein were detected in24patients and the results showed14cases normal,8cases slightly elevated,2cases significantly elevated(>1.0g/l). Blood creatine kinase were tested in23patients and the resultsshowed19cases normal,3cases slightly elevated,1cases significantlyelevated (>1000U/L).2. The electrophysical features of HMSNThe electrophysical exams showed:1)EMG:15/30cases showeddenervation potentials (fibrillations and positive potentials) in EMG exam and26cases showed motor unit potentials (MUP) with widened-duration andincreased-amplitude. Significantly reduced recruitment order can be seen in30/30patients.2) Nerve conduction analysis:26/30cases had abnormal nerveconduction function in both upper and lower limbs.1/30cases had normalnerve conduction function in upper limbs and abnormal nerve conductionfunction in lower limbs.3/30cases only received nerve conduction tests inlower limbs and the results were abnormal. Among these patients, compoundmuscle action potentials (CMAP) could not be evoked in5cases but could beevoked in25cases (including21cases with reduced amplitude,13cases withmotor conduction velocity (MCV)<38m/s,6cases with MCV between39and43m/s and8cases normal.) Sensory nerve action potentials (SNAP) could notbe evoked in19cases but could be evoked in11cases (including8cases withreduced SNAP amplitude and8cases with decreased SCV).Electrophysiological examinations of all the patients showed simultaneouslyinvolved sensory and motor nerves.3) Distribution of the involved nerves:30/30cases of HMSN had lower limbs involvement.27/30cases had upperlimb involvement.18/30cases who received electrophysiological detection infour limbs showed symmetrical limb involvement.3. The pathological analysis of sural nerve biopsy under light microscopySural nerve biopsy was performed in28HMSN patients, whoseresin-embedded specimens semi-thin section and Toluidine blue-Safranin stainwere observed under optical microscopy and analyzed pathologically.28cases showed decreased myelinated fiber density and myelin changes were the mainfindings. Myelin changes included thinner myelin in25cases, sporadicthickened myelin in17cases, the separating lamellar structure of myelin in9cases, myelin fold in20cases, naked axon in15cases, onion bulb formationin21cases. Axonal degeneration could be seen in16cases. Small-diameternerve fibers hyperplasia in stackes were occasionally observed in4cases.Phagocytes were visible in5cases (differentiated from CIDP). Mast cellswere visible in13cases. Small vessels between and in nerve bundles arenormal (differentiated from vasculitic peripheral neuropathy and diabeticperipheral neuropathy), and there is no amyloid deposition or other specialstructures in visual field (differentiated from amyloidotic peripheralneuropathy and giant axonal neuropathy).4. The ultrastructural pathologic changes under transmission electronSural nerve ultrastructure of14patients were analyzed by electronmicroscope, which showed the following pathological changes:1) the changesin myelin of myelinated fibers: thinner or thickened myelin, myelin fold, theseparating lamellar structure of myelin, naked axons, sausage-like fibers;2)axonal degeneration: the loose arrangement of microfilaments andmicrotubules within axons, swelling mitochondria with membrane-cristafusion and vacuolation;3) other changes: small-diameter nerve fiber cluster,foamy phagocytes and mast cells.Conclusions:1. The clinical features of HMSN include insidious onset in childhood oradolescence, AD, AR, X-linked inheritance or being sporadic cases, slowlyprogressed course, abnormal gait, foot deformity, symmetrical weakness andatrophy in lower limbs or four limbs, and the appearance of "crane-like legs"in severe cases. Most patients have no complaint of paresthesia. Some patientsmay complicate with tissues and organs involvement beyond peripheralnervous system.2. The electrophysiological examination is a significant method for thediagnosis of HMSN. Nerve conduction examination can distinguish HMSN subtypes and investigate the extent of axonal or myelin involvement.Sub-clinical symptoms (motor and sensory involvement) can be find outthrough the electrophysical detection, so symmetrical electrophysiologicalexamination of four limbs are recommended to the suspected patients.3. The most common pathological change of sural nerve biopsy ismarkedly reduced density of myelinated fibers, especially the changes inmyelin. Massive onion bulb formation usually prompt HMSN diagnosis.Pathological analysis can provide an objective basis for the diagnosis, theclassification of HMSN and the differential diagnosis of HMSN with othertypes of neuropathy (CIDP, amyloidosis, etc.).The entire diagnosis path of HMSN should cover the following points:the clinical and electrophysical analysis, pathological manifestation of suralnerve biopsy, gene chip analysis of HMSN and virulence gene sequencing. |
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