Duchenne muscular dystrophy (DMD), an X-linked disorder, is the most common muscular dystrophy in children, presenting in early childhood and characterized by proximal muscle weakness and calf hypertrophy in affected boys. Patients usually become wheelchair-bound by the age of 12 years, and die of cardiorespiratory complications in their late teens to early twenties. Advances in the management of DMD, including treatment with corticosteroids and the use of intermittent positive pressure ventilation have provided improvements in function, ambulation, quality of life and life expectancy, although novel therapies still aim to provide a cure for this devastating disorder. The clinical features, investigations, and management of DMD are reviewed, as well as the latest in some of the novel therapies.

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The field of myology has undergone remarkable changes. From the period of early clinical descriptions and clinical classifications, new knowledge of these disorders has come from the developments of histopathology, enzyme histochemistry and later, immunocytochemistry and electron microscopy. These techniques have enhanced the understanding of the pathophysiology of myopathies at the cellular level. The parallel evolution of molecular genetics has taken the science further not only by way of understanding and accuracy of diagnosis, but has opened up exciting possibilities of modulation of these chronic debilitating diseases. This review gives a personal perspective of the developments in the field of myology.

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Myotonia reflects a state of muscle fiber hyperexcitability. Impaired transmembrane conductance of either chloride or sodium ions results in myotonia. Myotonic disorders include the myotonic dystrophies and nondystrophic myotonias. Mutations in the genes encoding chloride (ClC-1) or sodium (SCN4A) channels expressed exclusively in skeletal muscle cause nondystrophic myotonias. Genetic defects in the myotonic dystrophies do not involve ion channel or its regulator proteins. Recent research supports a novel RNA-mediated disease mechanism of myotonia in the myotonic dystrophies. Myotonic dystrophy Type 1 is caused by CTG repeat expansion in the 3' untranslated region in the Dystrophia Myotonica Protein Kinase (DMPK) gene. Myotonic dystrophy Type 2 is caused by CCTG repeat expansion in the first intron in Zinc Finger Protein 9 (ZNF9) gene. The expanded repeat is transcribed in RNA and forms discrete inclusions in nucleus in both types of myotonic dystrophies. Mutant RNA sequesters MBNL1, a splice regulator protein and depletes MBNL1 from the nucleoplasm. Loss of MBNL1 results in altered splicing of ClC-1 mRNA. Altered splice products do not encode functional ClC-1 protein. Subsequent loss of chloride conductance in muscle membrane causes myotonia in the myotonic dystrophies. The purpose of this review is to discuss the clinical presentation, recent advances in understanding the disease mechanism with particular emphasis on myotonic dystrophies and potential therapy options in myotonic disorders.

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Background: We present the findings from the largest hospital-based studies on myasthenia gravis from India, using data collected over a period of 43 years from the Neurology Department in a tertiary referral center in India. Objectives: To study the clinical presentation, age at onset, gender distribution, serological status and thymic pathology in patients with myasthenia gravis. Materials and Methods: A retrospective study was carried out using records of patients with myasthenia gravis from the years 1965 to 2008. Results: Of 841 patients, 836 (611 males and 225 females) had acquired myasthenia (myasthenia gravis) and five congenital myasthenia. The median age at onset was 48 years (males 53 years and females 34 years). The peak age at onset for males was in the sixth and seventh decade and in females, in the third decade. Two hundred and twenty-two (26.31%) patients had ocular and 616 (73.68%) generalized myasthenia. Serological studies were done in 281 patients with myasthenia gravis for Acetylcholine receptor (AchR) antibodies of which 238 (84.70%) were seropositive. The most common histopathology was thymoma and the second most common was thymic hyperplasia. Conclusion: Myasthenia gravis in our study was more common in males (M:F of 2.70:1). There was a single peak of age at onset (males sixth to seventh decade; females third decade). The higher prevalence of thymomas in this series is in all probability related to selection bias as patients with thymic enlargement or more severe disease underwent thymectomy. Thymoma was more common in males; hyperplasia in females.

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Electroneuromyography (ENMG) also called electrodiagnosis or at times simply (and erroneously) electromyography (EMG), has been used for the diagnosis of neuromuscular and muscle diseases. It consists of tests done serially and assessed collectively, to arrive at a diagnosis of neuromuscular weakness. The test should be treated as an extension of the clinical examination and not a replacement. When done adequately ENMG is the only test which gives information about the function of the peripheral nervous system and hence co-relates well with the clinical signs. This article reviews the role of ENMG in the evaluation of neuromuscular and muscle disease. We hope this will meet the requirements of both practicing neurologists and dedicated electromyographers.

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The neuromuscular junction (NMJ) is a specialized synapse with a complex structural and functional organization. It is a target for a variety of immunological disorders and these diseases usually respond well to immunotherapies. The understanding of the immunological basis of myasthenia gravis, the most common neuromuscular junction disorder, has improved in the recent years. Most patients have antibodies to the acetylcholine receptor (AChR), but around 10% have AChR antibodies that are only identified by novel methods, and up to 5% have muscle-specific kinase antibodies which define a different subgroup of myasthenia. The spectrum of antibodies and their pathophysiological aspects are being elucidated. Even though less common, Lambert Eaton myasthenic syndrome (LEMS) is important to recognize. The abnormality in LEMS is a presynaptic failure to release enough packets of ACh, caused by antibodies to the presynaptic voltage-gated calcium channels. More than half these patients have a small cell carcinoma of lung. Acquired neuromyotonia (NMT) is a condition associated with muscle hyperactivity. Clinical features include muscle stiffness, cramps, myokymia, pseudomyotonia and weakness. The immune mechanisms of acquired NMT relate to loss of voltage-gated potassium channel function. This review will focus on the important recent developments in the immune-mediated disorders of the NMJ.

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Duchenne muscular dystrophy (DMD), the most common and serious form of childhood muscle wasting is generally caused by protein-truncating mutations in the large DMD gene. Specific removal of an exon from a defective DMD gene transcript has the potential to allow synthesis of a semi-functional dystrophin, thereby reducing the severity and presumably progression of muscle wasting. The efficacy of this treatment will vary greatly between the different mutations that preclude the synthesis of a functional dystrophin. Restoration of the reading frame from a large multi-exon genomic deletion, typically greater than 36 exons, may lead to synthesis of a protein with only partial function and limited clinical benefit, whereas excising a nonsense mutation in a redundant exon should generate a near normal dystrophin. A clinical trial has recently confirmed proof-of-principle that exclusion of Exon 51 from human dystrophin mRNAs, carrying frame-shifting deletions adjacent to this exon, results in dystrophin expression. No major side-effects after local administration of the antisense oligomer were reported. Additional trials are underway, targeting the same exon but using an oligomer of different backbone chemistry. If functional dystrophin synthesis is demonstrated, and safety issues are addressed, subsequent trials will involve systemic delivery. Great challenges are ahead, some technical; establishing an effective delivery regimen, some ethical; choosing subsequent targets for therapy, and others of an administrative and regulatory nature.

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The three major immune-mediated inflammatory myopathies, dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM), each have their own distinctive clinical features, underlying pathogenetic mechanisms and patterns of muscle gene expression. In DM a complement-dependent humoral process thought to be initiated by antibodies to endothelial cells results in a microangiopathy with secondary ischemic changes in muscles. On the other hand, in PM and IBM there is a T-cell response with invasion of muscle fibers by CD8+ lymphocytes and perforin-mediated cytotoxic necrosis. In IBM degenerative changes are also a feature and comprise autophagia with rimmed vacuole formation and inclusions containing β-amyloid and other proteins whose accumulation may be linked to impaired proteasomal function. The relationship between the inflammatory and degenerative component remains unclear, as does the basis for the selective vulnerability of certain muscles and the resistance to conventional forms of immunotherapy in most cases of IBM. Patients with DM or PM usually respond to treatment with glucocorticoids and immunosuppressive agents but their use remains largely empirical. Intravenous immunoglobulin therapy can be used to achieve disease control in patients with severe weakness or dysphagia, or in patients with immunodeficiency, but its use is limited by expense. Emerging therapies for resistant cases include TNFα inhibitors (etanercept, infliximab) and monoclonal antibodies (rituximab, alemtuzumab). However, experience with these therapies is still limited and there is a need for randomized trials to test their efficacy and establish guidelines for their use in clinical practice.

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The recent years have seen remarkable progress in the field of limb girdle muscular dystrophies (LGMDs) with the advances in immunocytochemistry and genetics. Based on this, many subgroups have emerged. Protein products and genes are getting defined and newer mechanisms of disease are being recognized. Limb girdle muscular dystrophies are common in India. The clinical material is plentiful, and from various centers in the country, phenotypes have been studied. With the help of immunocytochemistry, sarcoglycanopathies and dysferlinopathies have been studied. Genetic information on these subgroups is now beginning to emerge. The laboratory facilities are limited and available in select centers in large institutes. Establishment of genetic laboratories and sophisticated muscle pathology techniques will further elucidate the LGMDs in India.

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Dysferlinopathies encompass a large variety of neuromuscular diseases characterized by the absence of dysferlin in skeletal muscle and an autosomal recessive mode of inheritance. So far, three main phenotypes have been reported: Miyoshi myopathy (MM), limb girdle muscular dystrophy type 2B (LGMD 2B), and distal myopathy with anterior tibial onset (DMAT). A growing number of clinical variants have recently been described with a much wider range of symptoms and onset. Although rare, dysferlinopathies can account for up to 30% of progressive recessive muscular dystrophies in certain geographical areas, notably in the Middle East and the Indian subcontinent. Dysferlin is a large protein involved in membrane repair and vesicle trafficking and interacts probably with important immunological pathways. New insights in its pathophysiology may result in innovative therapies in the near future.

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The application of molecular diagnostic techniques has greatly improved the diagnosis, carrier detection, prenatal testing and genetic counseling for families with Duchenne and Becker muscular dystrophy (D/BMD) in India. The prediction of Duchenne muscular dystrophy (DMD) patients to have out-framed deletions and Becker's muscular dystrophy (BMD) patients to have in-frame deletions of dystrophin gene holds well in the vast majority of cases. Mutation detection is obviously critical for diagnosis but it may also be important for future therapeutic purposes. These factors underscore the need for earlier referral, genetic counseling and provision of support and rehabilitation services which are the main priorities for psychosocial assessment and intervention at medical and social levels.

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Distal myopathies are a group of heterogeneous disorders classified into one broad category due to the presentation of weakness involving the distal skeletal muscles. The recent years have witnessed increasing efforts to identify the causative genes for distal myopathies. The identification of few causative genes made the broad classification of these diseases under "distal myopathies" disputable and added some enigma to why distal muscles are preferentially affected. Nevertheless, with the clarification of the molecular basis of specific conditions, additional clues have been uncovered to understand the mechanism of each condition. This review will give a synopsis of the common distal myopathies, presenting salient facts regarding the clinical, pathological, and molecular aspects of each disease. Distal myopathy with rimmed vacuoles, or Nonaka myopathy, will be discussed in more detail.

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The increasing knowledge about limb girdle muscular dystrophy (LGMD) has clarified many aspects of this extensive group of neuromuscular conditions and has moreover proven their wide clinical and genetic heterogeneity. For these reasons, achieving a precise diagnosis of a particular type of LGMD may be still difficult and requires a comprehensive approach, which includes epidemiology, medical history, clinical examination, laboratory and genetic tests. All of the LGMDs are individually rare and their population frequency is highly variable. The prevalence of the different forms of LGMD in different populations has to be considered for the differential diagnosis. Some characteristic clinical features may help to distinguish subtypes of LGMD however protein analysis on muscle biopsy and genetic testing still represent the gold standard in the diagnosis of these muscular dystrophies. Reaching a precise diagnosis in all patients is important to allow genetic counseling to be properly applied and to direct appropriate medical management with a potential positive impact on the length and quality of life. Moreover, new specific therapeutic approaches, including limited local gene therapy, have been emerging over the last few years and require a precise genetic definition of the conditions. This article will concentrate on the diagnostic process by which these disorders can be defined and the implications of making these diagnoses.

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Background: Miyoshi myopathy (MM) and limb girdle muscular dystrophy (LGMD2B) are distinct clinical entities because different muscle groups are involved at the onset. We describe the clinical features in 28 patients with dysferlin deficiency confirmed by muscle immunohistochemistry (IHC). Settings and Design: A case series from a tertiary national referral center for neurological disorders. Materials and Methods: Patients with classical phenotype of MM and LGMD2B underwent a thorough phenotypic characterization followed by muscle histopathological study including IHC for dysferlin deficiency. Results: There were 28 patients (20 men and eight women) presenting with manifestations of distal myopathy or LGMD2B and had absence of dysferlin staining on IHC. Patients presented predominantly with distal myopathy of Miyoshi type (MM) or proximal LGMD type and were diagnosed to have dysferlinopathy on IHC. Two patients had the proximodistal form and two had onset as tibial muscular dystrophy. The main clinical features in these patients were onset in late adolescence or early adulthood (mean age of onset for MM was 22.0 ± 6.7 years and for LGMD2B 19.4 ± 5.1 years). There was early and predominant involvement of the posterior compartment muscles of the leg or proximal pelvic girdle muscles, dystrophic features with necrotic regeneration pattern without vacuoles on muscle biopsy and markedly elevated serum creatine kinase values with mean of 10033.8 ± 9283 IU/l (range 402-27460). Consanguinity was reported in 46.4%. The mean duration of illness was 6.4 ± 4.2 years. Dysferlinopathies formed nearly one-fourth of our patients with LGMD. Conclusion: In our experience dysferlinopathies was not an uncommon form of LGMD.

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Background: Proximal spinal muscular atrophy (SMA) is a genetically heterogeneous disease with paresis and muscle atrophy due to loss of anterior horn cell function. The survival of motor neuron gene (SMN) and neuronal apoptosis inhibitory protein (NAIP) play a primary role. Both the gene homologues exist as inverted duplications on Chromosome 5q. The telomeric/functional (SMN1) and the centromeric (SMN2) copies differ from each other in eight nucleotides. The C→T transition (at Codon 280) within Exon 7 of SMN2 causes disruption of an exonic splicing enhancer (ESE) and/or creates an exonic splicing silencer (ESS) leading to abnormal splicing and a truncated protein. Objective: To determine the molecular genetics of SMN1 and NAIP genes in SMA from southern India. Materials and Methods: In the present study, 37 patients from the neuromuscular disorders clinic of National Institute of Mental Health and Neurosciences were assayed for the deletions in the SMN1 and NAIP genes using PCR-RFLP methods. Results: Among the SMA Type I patients, 43% showed deletions of SMN1 and NAIP. In patients Type II SMA, 57% showed deletions of the SMN1 exons. Conclusion: Thus, deletions were found to occur in 47.8% of the Type I and II patients. Lower sensitivity of gene deletion study in clinically suspected SMA needs further study as clinical diagnosis of SMA is not gold standard. However, the results do correlate with other studies conducted in India.

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The term congenital myopathy is applied to muscle disorders presenting with generalized muscle weakness and hypotonia from early infancy with delayed developmental milestones. The congenital myopathies have been classified into various categories based on morphological findings on muscle biopsy. Although the clinical symptoms may seem homogenous, the genetic basis is remarkably variable. This review will focus on myotubular myopathy, centronuclear myopathy, central core disease, and congenital neuromuscular disease with uniform Type 1 fiber, myopathies that are subjects of our ongoing examinations.

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Treatment of the genetic metabolic myopathies remains generally unsatisfactory with the exception of a select few. Multiple Acyl Co-A Dehydrogenase Deficiency (Glutaric Aciduria type II), in particular, has been shown to respond well to riboflavin supplementation. Recently, studies have also confirmed the effectiveness of recombinant enzyme replacement therapy for Acid Maltase Deficiency (Pompe's Disease). Accurate and early diagnosis of these diseases is vital to prevent serious complications and impaired recovery following delayed treatment.

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Background: Becker muscular dystrophy (BMD) is caused by mutations in the dystrophin gene with variable phenotypes. Becker muscular dystrophy patients have low levels of nearly full-length dystrophin and carry in-frame mutations, which allow partial functioning of the protein. Aim: To study the deletion patterns of BMD and to correlate the same with reading frame rule and different phenotypes. Setting: A tertiary care teaching hospital. Design: This is a prospective hospital-based study. Materials and Methods: Thirty-two exons spanning different "hot spot" regions using Multiplex PCR techniques were studied in 347 patients. Two hundred and twenty-two showed deletions in one or more of the 32 exons. Out of these, 46 diagnosed as BMD patients were analyzed. Results: Forty-six BMD patients showed deletions in both regions of the dystrophin gene. Out of these 89.1% (41/46) were in-frame deletions. Deletions starting with Exon 45 were found in 76.1% (35/46) of the cases. Mutations in the majority of cases i.e. 39/46 (84.8%) were seen in 3' downstream region (Exon 45-55, distal rod domain). Few, i.e. 5/46 (10.8%) showed deletions in 5' upstream region (Exons 3-20, N-terminus and proximal rod domain) of the gene, while in 2/46 (4.4%) large mutations (>40 bp) spanning both regions (Exons 3-55) were detected. Conclusion: This significant gene deletion analysis has been carried out for BMD patients particularly from Western India using 32 exons.

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We describe the clinical presentation, course and pathologic findings found in three adult patients with lipid storage myopathy. Excessive lipid storage was found in Type 1 fibers of muscle. Clinical improvement on oral levo-carnitine therapy suggests the possibility of carnitine deficiency as the most likely etiology in two of the patients and one had mitochondrial myopathy confirmed on genetic analysis.

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Background: Idiopathic inflammatory myopathies (IIMs) form important treatable myopathies, hence it is important to recognize and categorize them. In some cases, the differential diagnosis between IIM and muscular dystrophies can be difficult. Aim: To study the clinical and laboratory features of patients with IIMs and compare and contrast this group with limb girdle muscular dystrophies (LGMDs). Setting and Design: A prospective study for the period of five years [1999-2004] was undertaken at a tertiary neuromuscular center. Materials and Methods: Bohan and Peter criteria were used for the diagnosis of IIM and Bushby criteria were used for the diagnosis of LGMD. Patients underwent history, clinical examination, hematological tests, electrophysiological studies and muscle biopsy. The biopsies were studied for histology and immunocytochemistry. A clinical scoring system was evolved to differentiate IIM from LGMD and was validated in a blinded manner. Receiver operator curves were used as the statistical method to analyze the sensitivity and specificity. Results and Conclusions: In the IIM group, dermatomyositis was most common, followed by polymyositis, occurring in young females. Overlap group was less common. In patients with polymyositis, onset in upper girdle was associated with adverse outcome. The scoring system helped to differentiate IIM from LGMD, mainly using clinical pointers. This was particularly valuable in chronic cases.

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Aim: Utility of major histocompatibility complex (MHC) Class I antigen immunostaining was studied to differentiate idiopathic inflammatory myopathies from dystrophies. Materials and Methods: Forty muscle biopsies including seven dermatomyositis (DM), six polymyositis (PM), two sporadic inclusion body myositis (sIBM), 20 dystrophies (one Duchenne, three Becker's, four alpha, one gamma sarcoglycanopathy, nine limb girdle, one myotonic and one fascioscapulohumeral muscular dystrophy) and five controls were stained with antibody for MHC Class I antigen (Novocastra clone W6/32 HL 1:100 dilution). Results: Polymyositis and sIBM showed MHC class I antigen positivity along sarcolemma of single and small groups of muscle fibers. The regenerating fibers in the perifascicular area in DM showed intense cytoplasmic positivity of MHC class I antigen. Muscle fibers in all dystrophies except regenerating fibers and control normal muscle were negative for MHC. Capillaries and lymphocytes were positive controls. There were no false positives in the study. Conclusion: MHC Class I immunostaining can be used as a complementary diagnostic tool for the diagnosis of idiopathic inflammatory myopathies.

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Background: Brachial monomelic amyotrophy (BMMA) is known to affect the central cervical cord gray matter resulting in single upper limb atrophy and weakness. Settings and Design: Case series of BMMA patients who underwent somatosensory evoked potentials (SEP) studies at a tertiary referral center. Aims: We proposed to record Multichannel Somatosensory Evoked Potentials (MCSSEP) from median and ulnar nerves with neck in neutral and neck fully flexed position in 17 patients with classical BMMA seen over three years. Materials and Methods: Recordings were done from both median (MN) and ulnar nerves (UN). N9, P9, N13, N20 potentials were recorded and amplitudes measured. SSEPs were performed in 22 age-matched healthy men. Amplitudes of cervical response were calculated by N13/P9 ratio and compared in both positions. Results: Among the controls N13 amplitude was always normal {MN: mean N13/P9 - 0.96 in neutral; 0.95 in flexed}{UN: mean N13/P9 - 0.82 in neutral; 0.83 in flexed}, and mean amplitudes did not reveal any difference in both conditions ( P >0.05). Among 17 patients N9, P9 and N20 responses were normal in neutral position. Flexion showed no change in latency or amplitude of N9 and N20 responses ( P -0.63) whereas the N13 response was abnormal in at least one tested nerve in the affected limb (MN: P <0.01; UN: P <0.01). During flexion, N13 response was abnormal in 14 (82%) patients after MN stimulation and in all 17(100%) after UN stimulation {MN: mean N13/P9 - 0.62 in neutral; 0.38 in flexed}{UN: mean N13/P9 - 0.55 in neutral; 0.31 in flexed}. Conclusion: MCSSEP in BMMA with neck flexion caused a significant reduction of the cervical N13 response indicating segmental cervical cord dysfunction.

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Long-term observations over a period of 22 years in an Indian family with primary dysferlinopathy are recorded, defining phenotypic variability. In the propositus, the dystrophy began distally in the tibialis anterior muscles, before involving the gastrocnemius. Transient painful calf hypertrophy, followed by calf wasting was observed. The proximal lower and upper limbs weakened after three to four years. The younger sibling presented with the proximo-distal phenotype. Both patients showed very high creatine kinase values early into the illness. Disease progression was slow. The younger sibling lost ambulation 14 years after onset, while the elder one remains ambulatory 22 years into the illness. Muscle biopsy showed dystrophic features and absence of dysferlin. Monocyte western blotting confirmed absence of dysferlin. Genetic analysis detected a heterozygous mutation in Exon 54 [c.6124C>T] in the DYSF gene. This is the first family with a diagnosis of dysferlinopathy supported by genetic data, reported from India.

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