The European LEMS Registry: Baseline Demographics and Treatment Approaches.

INTRODUCTION: Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder affecting the neuromuscular junction, clinically characterized by proximal muscle weakness and autonomic changes. LEMS is often associated with an underlying tumor (paraneoplastic form) but also occurs in the absence of cancer (idiopathic form). Treatment consists of immunomodulation (immunosuppression), anticancer treatment when carcinoma is present, and symptomatic treatment [acetylcholinesterase inhibitors and potassium channel blockers, e.g., amifampridine (3,4-diaminopyridine, i.e., 3,4-DAP), to improve neurotransmission]. Although there has long been information from case reports, several randomized controlled trials, and treatment guidelines, population data are still scarce. METHODS: The LEMS patient registry was launched in the European community in mid-2010 as a voluntary, multinational, observational, non-interventional program to collect structured empirical data on clinical course, treatment utilization, and safety and efficacy from the use of LEMS-specific treatments. RESULTS: Sixty-nine patients have been enrolled [36 males, 32 females, 1 gender not reported; mean age 61.5 (27-84) years]. Eighteen patients (26%) were diagnosed with an associated carcinoma. At the time of enrollment, the majority of patients (65%) were receiving amifampridine [either compounded 3,4-DAP (22%) or 3,4-DAP phosphate, Firdapse(®) (43%)]. At enrollment, most patients demonstrate a profile of mild-to-moderate deficits in daily functioning but generally have good muscle strength, albeit with reduced deep tendon reflexes, frequent ataxia during walking, and signs of autonomic dysfunction including dry mouth, bladder dysfunction, and constipation. CONCLUSION: The LEMS European Union registry will continue to enroll patients and periodically report the accrued longitudinal data obtained on clinical assessments and laboratory findings, treatment practices, the safety and efficacy of treatment approaches, and long-term clinical outcomes. FUNDING: BioMarin Pharmaceutical Inc., Novato, CA, USA.

Myasthenia gravis: emerging new therapy options.

Myasthenia gravis is probably the most thoroughly understood of all human autoimmune diseases. The basic mechanism of the disease is an antibody-mediated autoimmune attack that decreases the acetylcholine receptor density at the neuromuscular junction. Current therapies aim to restore the available acetylcholine receptors, deplete the autoantibodies or suppress the immune system. Prolonged drug treatment is required, but this carries a potential risk of severe adverse effects. Therefore, the ideal treatment for myasthenia would eliminate the abnormal autoimmune response without interfering with the immune system.

Novel truncating RAPSN mutations causing congenital myasthenic syndrome responsive to 3,4-diaminopyridine.

Rapsyn is essential for clustering the acetylcholine receptor at the postsynaptic membrane of the neuromuscular junction. Direct sequencing of RAPSN in two children with congenital myasthenic syndromes with no mutation in any of the AChR subunits identified two heterozygous recessive mutations in each: a previously characterized N88K mutation in both, and a second frameshifting mutation in Patient (Pt) 1 and a nonsense mutation in Pt 2. An intercostal muscle biopsy in Pt 1 revealed decreased AChRs per endplate and decreased amplitude of the miniature endplate potential, predicted consequences of rapsyn deficiency. Clinically, both children manifested with hypomotility in utero, fatigable ocular and limb weakness since birth, decreased strength during viral illness, decremental response on electromyography, and absence of AChR antibodies. Pt 1, however, had a more severe clinical course with recurrent episodes of respiratory failure, contractures, and craniofacial malformations. In both patients, treatment with pyridostigmine was of some benefit, but the addition of 3,4-diaminopyridine led to significant clinical improvement. Thus, rapsyn deficiency predicting similar consequences at the cellular level can result in phenotypes with marked differences in severity of symptoms, risk of respiratory failure, and presence of contractures and craniofacial malformations.

Congenital myasthenic syndrome with episodic apnea in patients homozygous for a CHAT missense mutation.

BACKGROUND: The syndrome of congenital myasthenia with episodic apnea (CMS-EA) was previously found to be due to mutations in the choline acetyltransferase gene (CHAT). OBJECTIVE: To identify the mutations underlying CMS-EA in a Turkish multiplex family. DESIGN: Direct sequencing of the CHAT gene. PATIENTS: A consanguineous Turkish family with 2 siblings affected by muscular weakness and episodic respiratory distress. RESULTS: The sequencing of CHAT coding exons identified a previously unknown missense mutation that affected a highly conserved amino acid residue (I336T). The mutation was absent in 164 control chromosomes. CONCLUSIONS: The high degree of conservation in different species strongly suggests that I336T is a functionally important amino acid residue. The absence of I336T from a large control sample further supports the pathogenic role of I336T in CMS-EA. This is the second report of CHAT mutations causing presynaptic CMS.

Iatrogenic and toxic myopathies.

There has been increasing awareness of the adverse effects of therapeutic agents and exogenous toxins on the structure and function of muscle. The resulting clinical syndrome varies from one characterized by muscle pain to profound myalgia, paralysis, and myoglobinuria. Because toxic myopathies are potentially reversible, their prompt recognition may reduce their damaging effects or prevent a fatal outcome. Interest in the toxic myopathies, however, derives not only from their clinical importance but also from the fact that they serve as useful experimental models in muscle research. Morphological and biochemical studies have increased our understanding of the basic cellular mechanisms of myotoxicity. Toxins may produce, for instance, necrotizing, lysosomal-related, inflammatory, anti-microtubular, mitochondrial, hypokalemia-related, or protein synthesis-related muscle damage.

Congenital myasthenic syndromes.

Congenital myasthenic syndromes (CMS) constitute a heterogenous group of inherited disorders in which neuromuscular transmission is compromised by one or more specific mechanisms. Clinical evidence for the diagnosis of a CMS includes a history of increased fatigable weakness since infancy or early childhood, a decremental EMG response, and the absence of acetylcholine receptor (AChR) antibodies. There has been rapid progress in understanding of the molecular basis of CMS. Mutation analysis of the AChR subunits has revealed numerous disease-associated mutations. These mutations alter the response to acetylcholine. It is decreased in the fast-channel syndromes and in primary AChR deficiency; and it is increased in the slow-channel syndrome due to prolonged open-time of the AChR. Acetylcholinesterase deficiency is associated with mutations in the gene encoding the collagenic tail subunit of the enzyme. Mutations in the gene encoding for choline acetyltransferase causes the CMS associated with episodic apnea.