Antititin antibody in early- and late-onset myasthenia gravis.

OBJECTIVES: Myasthenia gravis (MG) is an autoimmune disease caused by antibodies against neuromuscular junction proteins, 85% of patients have antibodies against acetylcholine receptor (AChR-MG). Antititin antibodies are present in a subset of patients with MG. We aimed to determine the value of antititin antibodies as severity markers and thymoma predictors in early- and late-onset MG. MATERIALS & METHODS: Two-hundred and ninety-five consecutive MG patients (188 F and 107 M) aged 12-89 years (mean 50y) were included. 164 patients had early-onset (EOMG, ≤50 years of age), 131 had late-onset MG (LOMG). Twenty-six patients had thymoma. symptoms, severity graded with MGFA scale, thymus histology, medications, and treatment results were analyzed. RESULTS: Antititin antibodies were present in 81 (27%) of all patients: 54% of thymoma MG, 0.6% of non-thymomatous EOMG, and 55% of LOMG, with proportion of titin-positive patients increasing linearly from 40% in the 6th to 88% in the 9th decade of life. Titin-positive patients had more bulbar symptoms (P = 0.003). Severity of MG, need for immunosuppression, myasthenic crisis risk or treatment results were not related to its presence. Antititin antibodies had 56% sensitivity, 99% specificity, 90% positive predictive value (PPV), and 95% negative predictive value (NPV) for thymoma diagnosis in EOMG, and 50% sensitivity, 75% specificity, 71% PPV and 55% NPV in LOMG. CONCLUSIONS: Antititin antibodies have high PPV and NPV for thymoma in EOMG. In MG without thymoma, antititin antibodies can be considered as markers of LOMG, but not of a severe course in our MG cohort.

Muscle pathology in 31 patients with calpain 3 gene mutations..

BACKGROUND AND PURPOSE: At present, more than 20 different forms of limb-girdle muscular dystrophies (LGMDs) are known (at least 7 autosomal dominant and 14 autosomal recessive). Although these different forms show some typical phenotypic characteristics, the existing clinical overlap makes their differential diagnosis difficult. Limb-girdle muscular dystrophy type 2 (LGMD2A) is the most prevalent LGMD in many European as well as Brazilian communities and is caused by mutations in the gene CAPN3. Laboratory testing, such as calpain immunohistochemistry and Western-blot analysis, is not totally reliable, since up to 20% of molecularly confirmed LGMD2A show normal content of calpain 3 and a third of LGMD2A biopsies have normal calpain 3 proteo-lytic activity in the muscle. Thus, genetic testing is considered as the only reliable diagnostic criterion in LGMD2A. MATERIAL AND METHODS: In an attempt to find a correlation between genotype and muscle pathology in limb-girdle muscular dystrophy 2A we performed histopathological investigation of a group of 31 patients subdivided according to the type of pathologic CAPN3 gene mutation. RESULTS: In all biopsies typical features of muscular dystrophy such as fiber necrosis and regeneration, variation in fiber size and fibrosis were noted. Lobulated fibers were often encountered in the muscle biopsies of LGMD2A patients. Such fibers were more frequent in patients with 550delA mutation. CONCLUSIONS: These findings may be helpful in establishing diagnostic strategies in LGMD.

Lambert-Eaton myasthenic syndrome in childhood.

Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder of the neuromuscular junction. LEMS can be associated with a variety of neoplasms. Patients present with proximal muscle weakness and fatigability, often combined with areflexia. Only 5% of reported cases are children. We report a case of 11-year old boy with non-neoplastic Lambert-Eaton myasthenic syndrome. Repetitive nerve stimulation test showed 83% increment after maximal voluntary contraction, presence of antibodies against voltage-gated calcium channels confirmed the diagnosis. The boy responded well to immunosuppressive treatment with prednisone and azathioprine and remains cancer-free for 4 years.

How accurate is spirometry at predicting restrictive pulmonary impairment in children with myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction. Clinical symptoms are caused by weakness and increased fatigability of various muscle groups. Myasthenia may lead to significant respiratory dysfunction. The aim of our study was to estimate lung function in children with MG. We tested 23 non-smoking patients (18 girls and 5 boys) aged 7-18 years. Whole-body plethysmography and spirometry were performed in all patients. In 33% of the patients a decrease in VC <80% of predicted value was observed (VC = 89 +/-19%), but the analysis of TLC revealed restrictive pattern only in one patient (TLC = 102 +/-17%). In more than 75% of the children the value of RV above 120% of predicted value was found (RV = 146 +/-54%). Spirometric obstructive pattern measured by FEV1%VC <70% was not observed, although in 56% of the patients airway resistance was increased (Raw = 132 +/-44%). In 45% of the patients a decrease of PEF (76 +/-14%) was observed. In MG children true restrictive pulmonary impairment is rarely observed and a decrease in VC in these patents seems to result mainly from functional restriction provoked by an increase in RV. Spirometry is not an optimum method to assess functional changes in MG patients. The assessment of additional measures such as TLC, RV, and Raw is desirable.

IBM-type inclusions in a patient with slow-channel syndrome caused by a mutation in the AChR epsilon subunit.

We report a patient with a slow-channel congenital myasthenic syndrome who carries a novel slow-channel mutation in the epsilon subunit of the acetylcholine receptor and has tubulofilamentous inclusion bodies, in skeletal muscle of the type observed in hereditary and sporadic inclusion body myositis. Ultrastructural analysis of a muscle specimen obtained at the age of 9 years showed an endplate myopathy typical of the slow-channel syndrome. Twenty years later, a second muscle specimen again showed the endplate myopathy as well numerous nuclear and cytoplasmic tubulofilamentous inclusion bodies. Molecular genetic studies revealed a novel valine to phenylalanine mutation (epsilonV259F) in the M2 domain of the acetylcholine receptor. Coexistence of the slow-channel syndrome with a feature of IBM has not been observed before.

Autosomal recessive axonal form of Charcot-Marie-Tooth Disease caused by compound heterozygous 3'-splice site and Ser130Cys mutation in the GDAP1 gene.

A recessive demyelinating subtype of Charcot-Marie-Tooth disease called CMT4 is a heterogeneous group of disorders. A relatively frequent form of recessive CMT (CMT4 A) has been mapped to the chromosome 8 q21 and shown to be caused by mutations in the ganglioside-induced differentiation protein 1 (GDAP1) gene. Twenty mutations in the GDAP1 gene have been reported in patients suffering from the axonal and demyelinating forms of CMT disease. In this study we report two novel mutations in the GDAP1 gene in a patient suffering from CMT2 disease and whose parents were asymptomatic carriers of a Ser130Cys and 3'-splice site (311-1G > A) mutation, respectively.

Congenital myopathy with tubular aggregates and tubulofilamentous IBM-type inclusions.

We report on a 16-year-old girl with a unique neuromuscular disorder characterised by progressive proximal muscle weakness and numerous tubular aggregates, intracytoplasmic, as well as intranuclear inclusions of the IBM type in her muscle biopsy. The clinical features of the presented case, as manifested by the early childhood onset of the disease, proximal weakness, lumbar hyperlordosis, and bilateral Achilles tendon contractures, were suggestive of congenital myopathy. To the best of our knowledge, the coexistence of tubular aggregates and tubulofilamentous inclusions of the IBM type in a child has never been described.

Mild early onset axonal Charcot-Marie-Tooth disease not linked to other axonal Charcot-Marie-Tooth loci.

Autosomal dominant axonal Charcot-Marie-Tooth disease type 2 (CMT2) is a heterogeneous group of disorders with seven chromosomal loci mapped in the uncomplicated forms of CMT2. The authors report clinical, electrophysiologic, and genetic analysis of a Polish CMT2 family. Nine known CMT2 gene loci and one MPZ gene locus have been excluded. The authors' findings suggest that this family represents a novel form of CMT2 disease.

A novel MPZ gene mutation in congenital neuropathy with hypomyelination.

Congenital hypomyelinating neuropathy (CHN; MIM# 605253) is a severe neuropathy with early infancy onset inherited as an autosomal dominant or recessive trait. Sural nerve biopsy shows a characteristic picture of nonmyelinated and poorly myelinated axons with basal lamina onion bulbs and lack of myelin breakdown products. Several mutations in the MTMR2, PMP22, EGR2, and MPZ genes have been found in patients with CHN. The authors describe the clinical and morphologic features of a patient with CHN and the identification of a novel Thr124Lys mutation in the MPZ gene.

[The role of molecular genetics in diagnosis of hereditary motor-sensory neuropathy]. / Miejsce genetyki molekularnej w diagnostyce dziedzicznych neuropatii ruchowo-czuciowych.

Hereditary motor-sensory neuropathies (HMSN) are a heterogeneous group of disorders of peripheral nervous system. Four genes in HMSN have been characterized so far i.e.: PMP22, MPZ, Cx32 and EGR-2. The advent of molecular genetic techniques over the past few years has provided identification of molecular defects in a few forms of HMSN. The present study describes the application of modern molecular genetic methods, which are used in the studies of HMSN. Southern blot hybridisation, Fluorescence in situ hybridisation (FISH), Short Tandem Repeat analysis (STR), Semiquantitative PCR analysis (SQ-PCR), Single Strand Conformation Polymorphism method (SSCP), Heteroduplex analysis (HD) and finally DNA automated sequencing are described in the present paper. In the conclusions the advantages and limits of mentioned methods of DNA analysis in HMSN have been described.

[Genotype-phenotype correlation in hereditary motor-sensory neuropathy type IA associated with duplication in chromosome 17p11.2-12]. / Korelacja genotypowo-fenotypowa w dziedzicznej neuropatii ruchowo-czuciowej typu I A zwiazanej z duplikacja w chromosomie 17p11.2-12.

Results of clinical, electrophysiological and morphological examination, were presented in 19 patients from 8 families with hereditary motor-sensory neuropathy type I (HMSN type I) with 17p11.2-12 duplication (i.e. CMT IA). The course of the disease was rather mild, slowly progressive. Generalized demyelinating lesion of peripheral nerves was found on EMG examination, with median nerve conduction velocity between 10-20 m/s and very prolonged F wave latency. Sural nerve biopsy was characteristic of chronic demyelinating process. Phenotypic characteristics of our HMSN type I patients shows clinical, electrophysiological and morphological homogeneity, however there are some data from literature indicating possibility of intrafamilial and interfamilial variability.

[Is there true remission in myasthenia gravis? Long-term clinical and electrophysiological studies]. / Czy istnieja prawdziwe remisje w miastenii? Wieloletnia katamneza kliniczna i elektrofizjologiczna.

Twenty myasthenic patients were followed up who had in the years 1981-1982 full clinical remission (no drugs, no symptoms), lasting at that time at least several years. However, in 19 of them neuromuscular transmission defects were then found by single fibre electromyography (SFEMG). We then concluded that true remissions did not exist in myasthenia (J. Neurol., 1985, 231, 331). Recently, we were able to evaluate those patients. One patient, who had full long lasting remission after thymomectomy, died at the age of 69 of myocardial infarction in the course of a myasthenic relapse. Another patient had a relapse, 20 years after thymoma extirpation. Two patients had recurrent fluctuating relapses of myasthenia. One patient, who had undergone thymectomy in his childhood, developed immune thrombocytopenic syndrome. SFEMG done in 12 patients showed abnormalities in 5 cases only (mean jitter elongation, increased percentage of potential pairs with blocking and jitter elongation more than 55 microseconds). In 7 remaining patients the catamnesis covering more than 14 years revealed full clinical and electrophysiological remission. Thus, repeated analysis of the group of myasthenic patients with remission has lead us to revise our former opinion that there are no true remissions, clinical and electrophysiological, in myasthenia. They certainly occur but in some patients normalization of the electrophysiological pattern appears only several years after they have become clinically asymptomatic.

Diagnostic value of satellite potentials in clinical EMG.

Complex motor unit potentials (CMUPs) with satellites were recorded and analysed in 231 electromyograms of patients with spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD) and a healthy control group. In the control adult group only few CMUPs with satellites were found; no CMUP were found in children. In SMA and DMD patients the CMUPs were present with similar frequency but their morphology, i.e. shape, duration, amplitude of the main and satellite spike components and number of satellites was different. In ALS patients a significant difference between severely involved interosseous muscle and proximal muscles was found. The pathomechanism of CMUPs with satellites is different in myopathic and neurogenic processes, in both however they reflect remodelling of the motor unit. In myopathy they reflect muscle fiber diameter variability and distribution of preserved muscle fibers within the motor unit under study. In neurogenic lesion the CMUPs with satellites are the result of increasing desynchronisation during progressive de- and reinnervation.

A new familial congenital myopathy in children with desmin and dystrophin reacting plaques.

In 5 children with a progressive congenital myopathy representing 3 different families, unusual histological, immunohistochemical and ultrastructural changes in skeletal muscle have been found. Histologically, this myopathy was characterized by the presence of fine hyaline plaques devoid of oxidative as well as ATPase enzyme activities. At the ultrastructural level plaques were composed of helical filaments and amorphous dense material. Helical filament storage corresponded to strong desmin as well as ubiquitin immunoreactivity. In addition they were also dystrophin positive. The exclusive appearance of desmin, ubiquitin and dystrophin positive plaques in muscle specimens from 5 children emphasize the uniqueness of these plaques as well as this special form of a congenital myopathy.

An X:autosome translocation stabilizes truncated dystrophin: implications for lack of truncated dystrophins in Duchenne muscular dystrophy.

We report a 5-year-old girl with clinical symptoms of typical Duchenne muscular dystrophy in males. The girl showed dramatic elevations of serum creatine kinase, and muscle biopsy histopathology consistent with a severe dystrophic myopathy. Cytogenetic analysis revealed an X:22 translocation (46,X,t [X;22] [p21.2;11.2]). Dystrophin immunofluoresence studies showed strong membrane immunostaining of dystrophin with antibodies directed against the amino terminus of the protein, but vastly reduced immunostaining with carboxyl-terminal antibodies. Immunoblot studies showed a major immunoreactive protein of approximately 350 kDa at approximately 20% levels. Nested RT-PCR analysis of the dystrophin mRNA in the patient's muscle showed the RNA to be positive for primers covering the first 85% of the dystrophin coding sequence, and negative for the carboxyl-terminal 15%. Taken together, our data suggests that the translocation breakpoint occurs towards the 3' end of the gene. The translocated dystrophin gene is still expressed into a truncated dystrophin protein associated with the plasma membrane. Our results are consistent with the translocation resulting in a more stable abnormal dystrophin mRNA.

Treatment of myotonia with antiarrhythmic drugs.

The effects of disopyramide, phenytoin, mexiletine, and tocainide were compared in 30 patients with myotonic disorders. The severity of myotonia was assessed by clinical and electromyographic criteria at the end of each treatment phase lasting four weeks. Mexiletine (MXT) and tocainide (TCD) were found to be the most potent antimyotonic agents. The antimyotonic efficacy of MXT and TCD is explained by their fast-blocking effect on voltage-dependent sodium channels in the muscle membrane. The benefits of myotonia control with pharmacological agents must be weight against the risk of therapy in the individual patient. Because of the risks of hematologic problems, TCD is not recommended by us for the treatment of myotonia.