Distal myopathies.

The distal myopathies are a heterogeneous group of genetic disorders defined by a predominant distal weakness at onset or throughout the evolution of the disease and by pathological data supporting a myopathic process. The number of genes associated with distal myopathies continues to increase. Fourteen distinct distal myopathies are currently defined by their gene and causative mutations, compared to just five entities delineated on clinical grounds two decades ago. The known proteins affected in the distal myopathies are of many types and include a significant number of sarcomeric proteins. The useful indicators for clinicians to direct towards a correct molecular diagnosis are the mode of inheritance, the age at onset, the pattern of muscle involvement, the serum creatine kinase level and the muscle pathology findings. This review gives an overview of the clinical and genetic characteristics of the currently identified distal myopathies with emphasis on some recent findings.

The French Pompe registry. Baseline characteristics of a cohort of 126 patients with adult Pompe disease.

Pompe disease is a rare autosomal recessive muscle lysosomal glycogenosis, characterised by limb-girdle muscle weakness and frequent respiratory involvement. The French Pompe registry was created in 2004 with the initial aim of studying the natural history of French patients with adult Pompe disease. Since the marketing in 2006 of enzyme replacement therapy (alglucosidase alfa, Myozyme(®)), the French Pompe registry has also been used to prospectively gather the biological and clinical follow-up data of all adult patients currently treated in France. This report describes the main clinical and molecular features, at the time of inclusion in the French registry, of 126 patients followed up in 21 hospital-based neuromuscular or metabolic centres. Sixty-five men and 61 women have been included in the registry. Median age at inclusion was 49 years, and the median age at onset of progressive limb weakness was 35 years. Fifty-five percent of the patients were walking without assistance, 24% were using a stick or a walking frame, and 21% were using a wheelchair. Forty-six percent of the patients needed ventilatory assistance, which was non-invasive in 35% of the cases. When performed, muscle biopsies showed specific features of Pompe disease in less than two-thirds of the cases, confirming the importance of acid alpha-glucosidase enzymatic assessment to establish the diagnosis. Molecular analysis detected the common c.-32-13T>G mutation, in at least one allele, in 90% of patients. The French Pompe registry is so far the largest country-based prospective study of patients with Pompe disease, and further analysis will be performed to study the impact of enzyme replacement therapy on the progression of the disease.

Nemaline bodies as unique pathological feature in the course of treated dermatomyositis.

Dermatomyositis was diagnosed on clinical and muscle histological criteria in a 42-year-old woman. Despite treatment, the patient complained of deterioration of her muscle condition. Since her symptoms were discordant with the rest of the data, muscle biopsy was performed and disclosed rod-bearing non-atrophic fibers as the unique and predominant pathological feature. Their significance is examined in this paper.

Myopathies caused by homozygous titin mutations: limb-girdle muscular dystrophy 2J and variations of phenotype.

Limb-girdle muscular dystrophy 2J caused by mutations in C-terminal titin has so far been identified in Finnish patients only. This may in part be due to limited availability of diagnostic tests for titin defects. In this report, a French family with an autosomal-dominant late-onset distal myopathy of the tibial muscular dystrophy phenotype segregating in several members of the family was described. One deceased patient in the family proved to be homozygous for the C-terminal truncating titin mutation because of consanguinity. According to available medical records, the patient had a clearly more severe generalised muscle weakness and atrophy phenotype not recognised as a distal myopathy at the time. Autopsy findings in one of the original Finnish limb-girdle muscular dystrophy 2J patients were reported and the early phenotype in a newly identified young patient with homozygous Finnish C-terminal titin mutation (FINmaj) was detailed.

[Treatment of autoimmune myasthenia]. / Traitement de la myasthénie auto-immune.

Myasthenia gravis is the most common neuromuscular junction disorder and the best understood autoimmune disease of the nervous system. The autoimmune attack leads to decreased concentrations of the AChR and results in fatigability of skeletal muscles increasing with activity and improving with rest. The treatment of myasthenia has improved dramatically over the last few decades, with an increasing number of immunotherapies used in management although not all of them have been formally tested in double-blind, prospective trials. The principles of treatment consist in optimizing neuromuscular junction function by use of cholinesterase inhibitors, inducing an immunologic remission and then maintaining that remission by long-term immunotherapies. Prednisone and/or azathioprine are the most effective. Short-term immunotherapies, i.e. intravenous immunoglobulin or plasmapheresis, are indicated for disease exacerbation. For patients with nonthymomatous autoimmune myasthenia, the effectiveness of thymectomy remains uncertain. The overall objective of therapy is to enable patients to lead a normal life as rapidly as possible, while limiting side effects and costs if possible. Treatment should be individualized. The aggressiveness of therapy should be balanced against a number of factors including distribution of muscle involvement, rate of progression, degree of functional impairment, lifestyle choice, and coexisting disease. In all cases, adequate education, for the patient and the physician, is most helpful in facilitating management of this chronic disease.

Late-onset cervicoscapular muscle atrophy and weakness after radiotherapy for Hodgkin disease: a case series.

Patients with cervical or mediastinal Hodgkin disease (HD) classically underwent chemotherapy plus extended-field radiation therapy. We report six patients who gradually developed severe atrophy and weakness of cervical paraspinal and shoulder girdle muscles 5-30 years after mantle irradiation for HD. Although clinical presentation was uniform, including a dropped head syndrome, electrophysiological and pathological findings were rather heterogeneous. Either neurogenic or myogenic processes may be involved and sometimes combined. We discuss the pathophysiological mechanisms underlying these cervicoscapular motor complications of mantle irradiation in HD.

Contraception and screening for cervical and breast cancer in neuromuscular disease: a retrospective study of 50 patients monitored at a clinical reference centre.

OBJECTIVE: To analyse contraceptive methods and the extent of screening for breast and cervical cancer in women with neuromuscular disease, compare these results with data and guidelines for the general population and determine the environmental and attitudinal barriers encountered. PATIENTS AND METHODS: A retrospective, descriptive study in a population of female neuromuscular disease patients (aged 20 to 74) monitored at a clinical reference centre. RESULTS: Complete datasets were available for 49 patients. Seventy percent used contraception (hormonal contraception in most cases). Sixty-eight percent had undergone screening for cervical cancer at some time in the previous 3 years and 100% of the patients over 50 had undergone a mammography. Architectural accessibility and practical problems were the most common barriers to care and were more frequently encountered by wheelchair-bound, ventilated patients. CONCLUSIONS: In general, the patients had good access to contraceptive care and cervical and breast cancer screening. However, specific measures may be useful for the most severely disabled patients.

[Cutaneous EBV-associated lymphoproliferative disorder in a dermatomyositis treated with immunosuppressive agents]. / Syndrome lymphoprolifératif cutané lié à l'EBV au cours d'une dermatomyosite traitée par immunosuppresseurs.

We report a case of Epstein Barr virus-associated large B cell lymphoproliferative disorder, with an abdominal cutaneous localization, in an adult treated for 10 years with immunosuppressive agents for a dermatomyositis. This is the third case of immunosuppressive induced lymphoproliferative disorder localized to skin in a patient with dermatomyositis. Diagnosis was unexpectedly obtained by the histologic examination of surgical samples of skin necrosis possibly induced by edetate calcium disodium subcutaneous injections in calcinosis cutis.

[Ocular disturbances in neuromuscular disorders]. / Manifestations oculaires des maladies du muscle et de la jonction neuromusculaire.

Compared with other skeletal muscles, extraocular muscles have fundamentally distinct properties that make them selectively vulnerable to certain neuromuscular disorders. When the oculomotor signs are predominant, their temporal progression allows the clinician to make the distinction between a muscular disease (mitochondrial disorder, oculopharyngeal muscular dystrophy...) and a disorder of the neuromuscular junction (myasthenia gravis, botulism...). In other instances, such as myotonic dystrophy or facioscapulohumeral dystrophy, the ocular signs are not in the forefront but must be recognized by the ophthalmologist as hallmarks of a muscular disorder. In all cases, the collaboration between the neurologist and the ophthalmologist is fruitful.

Dehydroepiandrosterone for myotonic dystrophy type 1.

BACKGROUND: Myotonic dystrophy type 1 may be associated with low circulating dehydroepiandrosterone (DHEA) levels. This study was aimed at investigating the efficacy and safety of DHEA in myotonic dystrophy type 1 patients. METHODS: This was a prospective, multicenter, randomized, double-blind, placebo-controlled trial conducted from February 2005 to January 2006 at 10 university-affiliated neuromuscular disease centers in France. Seventy-five ambulatory adults with myotonic dystrophy type 1 received an oral replacement dose (100 mg/d) or a pharmacologic dose (400 mg/d) of DHEA, or placebo. The primary endpoint was the relative change in the manual muscle testing (MMT) score from baseline to week 12. Secondary outcome measures included changes from baseline to week 12 in quantitative muscle testing and timed functional testing, respiratory and cardiac function, and quality of life. This study was registered with ClinicalTrials.gov identifier NCT00167609. RESULTS: The median (1st, 3rd quartile) relative changes in MMT score from baseline to week 12 after randomization were 3.1 (-0.9, 6.7), 1.9 (-2.7, 3.5), and 2.2 (0, 7.9), in the DHEA 100 mg, DHEA 400 mg, and placebo groups, respectively. There were no differences between placebo and combined DHEA groups (p = 0.34), placebo and DHEA 100 mg (p = 0.86), or placebo and DHEA 400 mg (p = 0.15). There were also no evidence for a difference between groups for the changes from baseline to week 12 in any secondary outcome. CONCLUSIONS: There is no evidence that a 12-week treatment with replacement or pharmacologic doses of dehydroepiandrosterone improves muscle strength in ambulatory myotonic dystrophy type 1 patients.

Transcriptional explorations of CAPN3 identify novel splicing mutations, a large-sized genomic deletion and evidence for messenger RNA decay.

Mutations in the gene encoding calpain-3 (CAPN3) cause autosomal recessive limb-girdle muscular dystrophy type 2A (LGMD2A) and idiopathic eosinophilic myositis. Accurate diagnosis and genetic counselling are based on the identification of disease-causing mutations on both alleles of CAPN3 in the patients. In the present study, we used transcriptional analysis as a complementary approach for patients suspected of being affected with LGMD2A, in whom initial denaturing high-performance liquid chromatography genomic mutation screening evidenced no or only one CAPN3 mutation obviously considered as disease causing. This allowed to identify and characterize cDNA deletions. Further genomic analysis allowed to determine the origin of these deletions, either as splicing defects caused by intronic mutations or as an internal multi-exonic deletion. In particular, we report two novel CAPN3 mutations (c.1745 + 4_1745 + 7delAGTG in IVS13 and c.2185-16A>G in IVS20) and a recurrent large-sized genomic deletion including exons 2-8 for which genomic breakpoints have been characterized. In addition, our results indicate nonsense-mediated messenger RNA decay as a mechanism for under-expression of CAPN3 associated to some specific variations.

[Autosomal dominant limb-girdle muscular dystrophy associated with conduction defects (LGMD1B): a description of 8 new families with the LMNA gene mutations]. / La dystrophie musculaire des ceintures autosomique dominante associée à des troubles de la conduction cardiaque (LGMD1B). Description de 8 nouvelles familles avec mutations du gène LMNA.

INTRODUCTION: Limb girdle muscular dystrophy type 1b (LGMD1B), due to LMNA gene mutations, is a relatively rare form of LGMD characterized by proximal muscle involvement associated with heart involvement comprising atrio-ventricular conduction blocks and dilated cardiomyopathy. Its clinical and genetic diagnosis is crucial for cardiac management and genetic counselling. Seven LMNA mutations have been previously reported to be responsible for LGMD1B. PATIENTS AND METHODS: We describe the neurological and cardiologic features of 14 patients belonging to 8 families in whom we identified 6 different LMNA mutations, 4 of them having never been reported. Results. Eleven patients had an LGMD1B phenotype with scapulohumeral and pelvic-femoral involvement. Thirteen patients had cardiac disease associating conduction defects (12 patients) or arrhythmias (9 patients). Seven patients needed cardiac device (pacemaker or implantable cardiac defibrillator) and two had heart transplantation. CONCLUSION: This study allowed us to specify the clinical characteristics of this entity and to outline the first phenotype/genotype relations resulting from these observations.

[Distal myopathies]. / Myopathies distales.

Distal myopathies are a heterogeneous group of genetic disorders characterized clinically by progressive muscular weakness and atrophy beginning in the hands or feet, and pathologically by myopathic changes in skeletal muscles. Five distinct distal myopathies are identified, among them four have been recently defined by their gene and causative mutations. They are classified according to age at onset, mode of inheritance, and muscle groups initially involved into the following: Laing myopathy (infancy onset, autosomal dominant inheritance, onset in anterior compartment of legs) caused by mutations in a myosin gene (MYH7) on chromosome 14q; Nonaka myopathy (early adult onset, autosomal recessive inheritance, onset in anterior compartment of legs), identical to quadriceps-sparing familial inclusion myopathy, caused by mutations in the GNE gene on chromosome 9p-q; Miyoshi myopathy (early adult onset, autosomal recessive inheritance, onset in posterior compartment of legs) caused by mutations in the dysferlin gene on chromosome 2p; Welander myopathy (late adult onset, autosomal dominant inheritance, onset in hands) linked to chromosome 2p; Udd/Markesbery-Griggs myopathy (late adult onset, autosomal dominant inheritance, onset in anterior compartment of legs) caused by mutations in the titin gene on chromosome 2q. Except for Miyoshi myopathy, which has a striking elevated serum creatine kinase level and the typical findings of muscular dystrophy, most of the distal myopathies have normal or midly elevated creatine kinase levels and share the common pathologic feature of rimmed vacuoles.

[Cardiac manifestations of laminopathies]. / Manifestations cardiaques des laminopathies.

Dilated cardiomyopathy (DCM) of genetic origin represents about 25% of all so-called primary DCM. Cases due to mutation of the gene which codes the lamins A and C (LMNA) carry a poor prognosis with a high risk of sudden death. The finding of primary DCM in a young person associated with conduction defects or arrhythmias should lead to investigation for mutation of the gene of lamins A and C, even in the absence of a suggestive family history. The authors report 5 cases of DCM, with and without associated skeletal muscular disease, due to laminopathies.

[Multiple sclerosis and Leber's hereditary optic neuropathy mitochondrial DNA mutations]. / Sclérose en plaques et mutations de l'ADN mitochondrial associées à la maladie de Leber.

Multiple sclerosis (MS) has long been known to be associated with Leber's hereditary optic neuropathy (LHON), a disease caused by mitochondrial DNA (mtDNA) mutations. We have investigated the possible involvement of LHON mtDNA point mutations in MS. The study covered a group of 75 unrelated Caucasian patients, with the relapse-remitting or primary progressive form of MS, and a control group of 75 volunteers (matched for age, gender and ethnic origin). Mitochondrial DNA from each subject was examined for 4 primary LHON mutations (at nucleotide positions 3460, 4160, 11778 and 14484) and 7 secondary LHON mutations (at nucleotide positions 4216, 4917, 5244, 7444, 13708, 15257 and 15812) by means of restriction site polymorphism and sequencing techniques. None of the primary LHON mutations were detected in the MS patients or in the controls, whereas the proportion of individuals with secondary LHON mutations was identical (27 p. cent) in the two groups. A combination of 2 or 3 homoplasmic mutations, defining mtDNA haplogroups, was found in the majority of cases. Haplogroups J, T and X were not particularly associated with MS. The frequency of the 13708 mutation alone (haplogroup X), or associated with the 4216 mutation (haplogroup J), was somewhat higher (p=0.059) in the subgroup of MS patients with optic neuritis (ON). ON was the initial symptom in all but one of the patients with haplogroups J or X. No other correlation was found between MS phenotypes and mtDNA genotypes. Our observations confirm previous reports that neither primary nor secondary LHON mutations are involved in the development of MS. However, MS patients with haplogroups J or X appear to have a moderately higher risk of developing optic neuritis. Thus, a specific mtDNA background may be a predisposing genetic factor for optic nerve damage in MS patients.

[Trismus, pseudobulbar syndrome and cerebral deep venous thrombosis]. / Trismus, syndrome pseudobulbaire et thrombose veineuse profonde cérébrale.

We report a case of cerebral deep venous thrombosis that manifested clinically by a pseudobulbar syndrome with major trismus, abnormal movements and static cerebellar syndrome. To our knowledge, only three other cases of deep cerebral venous thrombosis associated with cerebellar or pseudobulbar syndrome have been published since 1985. The relatively good prognosis in our patient could be explained by the partially intact internal cerebral veins as well as use of early anticoagulant therapy. There was a spontaneous hyperdensity of the falx cerebri and the tentorium cerebelli on the brain CT scan, an aspect highly contributive to diagnosis. This hyperdensity of the falx cerebri was found in 19 out of 22 cases of deep venous thrombosis detailed in the literature.

Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene.

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contractures of the elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and life-threatening cardiomyopathy with conduction blocks. We recently identified LMNA encoding two nuclear envelope proteins, lamins A and C, to be implicated in the autosomal dominant form of EDMD. Here, we report on the variability of the phenotype and spectrum of LMNA mutations in 53 autosomal dominant EDMD patients (36 members of 6 families and 17 sporadic cases). Twelve of the 53 patients showed cardiac involvement exclusively, although the remaining 41 all showed muscle weakness and contractures. We were able to identify a common phenotype among the patients with skeletal muscle involvement, consisting of humeroperoneal wasting and weakness, scapular winging, rigidity of the spine, and elbow and Achilles tendon contractures. The disease course was generally slow, but we observed either a milder phenotype characterized by late onset and a mild degree of weakness and contractures or a more severe phenotype with early presentation and a rapidly progressive course in a few cases. Mutation analysis identified 18 mutations in LMNA (i.e., 1 nonsense mutation, 2 deletions of a codon, and 15 missense mutations). All the mutations were distributed between exons 1 and 9 in the region of LMNA that is common to lamins A and C. LMNA mutations arose de novo in 76% of the cases; 2 of these de novo mutations were typical hot spots, and 2 others were identified in 2 unrelated cases. There was no clear correlation between the phenotype and type or localization of the mutations within the gene. Moreover, a marked inter- and intra-familial variability in the clinical expression of LMNA mutations exists, ranging from patients expressing the full clinical picture of EDMD to those characterized only by cardiac involvement, which points toward a significant role of possible modifier genes in the course of this disease. In conclusion, the high proportion of de novo mutations together with the large spectrum of both LMNA mutations and the expression of the disease should now prompt screening for LMNA in familial and sporadic cases of both EDMD and dilated cardiomyopathy associated with conduction system disease.