The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little ...is known so far about the clinical impact of AQP4-Ab seropositivity.
To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus.
Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%).
Seropositive patients were found to be predominantly female (p < 0.0003), to more often have signs of co-existing autoimmunity (p < 0.00001), and to experience more severe clinical attacks. A visual acuity of ≤ 0.1 during acute optic neuritis (ON) attacks was more frequent among seropositives (p < 0.002). Similarly, motor symptoms were more common in seropositive patients, the median Medical Research Council scale (MRC) grade worse, and MRC grades ≤ 2 more frequent, in particular if patients met the 2006 revised criteria (p < 0.005, p < 0.006 and p < 0.01, respectively), the total spinal cord lesion load was higher (p < 0.006), and lesions ≥ 6 vertebral segments as well as entire spinal cord involvement more frequent (p < 0.003 and p < 0.043). By contrast, bilateral ON at onset was more common in seronegatives (p < 0.007), as was simultaneous ON and myelitis (p < 0.001); accordingly, the time to diagnosis of NMO was shorter in the seronegative group (p < 0.029). The course of disease was more often monophasic in seronegatives (p < 0.008). Seropositives and seronegatives did not differ significantly with regard to age at onset, time to relapse, annualized relapse rates, outcome from relapse (complete, partial, no recovery), annualized EDSS increase, mortality rate, supratentorial brain lesions, brainstem lesions, history of carcinoma, frequency of preceding infections, oligoclonal bands, or CSF pleocytosis. Both the time to relapse and the time to diagnosis was longer if the disease started with ON (p < 0.002 and p < 0.013). Motor symptoms or tetraparesis at first myelitis and > 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome.
This study provides an overview of the clinical and paraclinical features of NMOSD in Caucasians and demonstrates a number of distinct disease characteristics in seropositive and seronegative patients.
Introduction
Lambert–Eaton myasthenic syndrome (LEMS) is characterized by autoantibodies against voltage-gated calcium channels (VGCC) at the neuromuscular junction causing proximal muscle weakness, ...decreased tendon reflexes, and autonomic changes. The European LEMS registry aimed to collate observational safety data for 3,4-diaminopyridine phosphate (3,4-DAPP) and examine long-term outcomes for patients with LEMS.
Methods
Thirty centers across four countries participated in the non-interventional European LEMS registry. Any patients diagnosed with LEMS by means of clinical assessment and abnormal neurophysiological testing, or clinical assessment and positive for VGCC antibodies were eligible to participate. Patients were monitored using standard assessments for LEMS-related clinical manifestations.
Results
Among 96 evaluable participants, 50 (52.1%) were being treated with 3,4-DAPP, 21 (21.9%) with 3,4-diaminopyridine (3,4-DAP), and 25 (26.0%) with other treatments (e.g., pyridostigmine, corticosteroids, immunoglobulins, and azathioprine); 74 participants (77.1%) were exposed to 3,4-DAPP at any time. Quantitative myasthenia gravis scores were similar across treatment groups. Muscle strength was generally good and maintained during follow-up. Cerebellar ataxia, defined as a negative Romberg’s test and at least one other positive ataxia test, was observed in 30 (56.6%) patients. Most participants had reduced reflex tone and limited functioning. Sustained or improved functioning was observed in participants administered 3,4-DAPP. Inconsistent and sporadic functional improvement and regression was observed with 3,4-DAP and other treatments. Fifty-five treatment-related adverse events (AEs) were reported by 32 (33.3%) participants. Eight (8.3%) participants reported nine treatment-related serious AEs. No new safety signals were identified.
Conclusion
No new safety signals were observed following long-term management of LEMS with 3,4-DAPP.
Neuromuscular junctions (NMJs) are synapses that transmit impulses from motor neurons to skeletal muscle fibers leading to muscle contraction. Study of hereditary disorders of neuromuscular ...transmission, termed congenital myasthenic syndromes (CMS), has helped elucidate fundamental processes influencing development and function of the nerve-muscle synapse. Using genetic linkage, we find 18 different biallelic mutations in the gene encoding glutamine-fructose-6-phosphate transaminase 1 (GFPT1) in 13 unrelated families with an autosomal recessive CMS. Consistent with these data, downregulation of the GFPT1 ortholog gfpt1 in zebrafish embryos altered muscle fiber morphology and impaired neuromuscular junction development. GFPT1 is the key enzyme of the hexosamine pathway yielding the amino sugar UDP-N-acetylglucosamine, an essential substrate for protein glycosylation. Our findings provide further impetus to study the glycobiology of NMJ and synapses in general.
Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous group of inherited disorders of the neuromuscular junction. A difficult to diagnose subgroup of CMS is characterised ...by proximal muscle weakness and fatigue while ocular and facial involvement is only minimal.
DOK7
mutations have been identified as causing the disorder in about half of the cases. More recently, using classical positional cloning, we have identified mutations in a previously unrecognised CMS gene,
GFPT1
, in a series of
DOK7
-negative cases. However, detailed description of clinical features of
GFPT1
patients has not been reported yet. Here we describe the clinical picture of 24 limb-girdle CMS (LG-CMS) patients and pathological findings of 18 of them, all carrying
GFPT1
mutations. Additional patients with CMS, but without tubular aggregates, and patients with non-fatigable weakness with tubular aggregates were also screened. In most patients with
GFPT1
mutations, onset of the disease occurs in the first decade of life with characteristic limb-girdle weakness and fatigue. A common feature was beneficial and sustained response to acetylcholinesterase inhibitor treatment. Most of the patients who had a muscle biopsy showed tubular aggregates in myofibers. Analysis of endplate morphology in one of the patients revealed unspecific abnormalities. Our study delineates the phenotype of CMS associated with
GFPT1
mutations and expands the understanding of neuromuscular junction disorders. As tubular aggregates in context of a neuromuscular transmission defect appear to be highly indicative, we suggest calling this condition congenital myasthenic syndrome with tubular aggregates (CMS-TA).
To elucidate the genetic defect in four previously reported related Brahman calves with severe myasthenic weakness, we determined the genomic structure of the gene encoding the bovine epsilon-subunit ...(bovCHRNE) of the acetylcholine receptor (AChR). Amplification of DNA isolated from paraplast-embedded tissue samples from one of the myasthenic calves and subsequent sequencing of all bovCHRNE exons revealed a homozygous 20-bp deletion within exon 5 (470del20). The deletion causes a frame shift followed by a premature stop codon in the predicted bovCHRNE protein. Thus, the 470del20 mutation reported here leads to a non-functional allele, explaining the impairment of neuromuscular transmission observed in the affected Brahman calves. With a survival time limited to only several months, the effect on neuromuscular transmission was more pronounced in the calves than that observed in humans homozygous for truncating CHRNE mutations. This may be due to a different capacity to express the fetal-type AChR after birth.
Congenital myasthenic syndromes (CMS) are inborn disorders due to presynaptic, synaptic, or postsynaptic defects of neuromuscular transmission. Some previously described kinships with typical signs ...of CMS showed a marked deficiency of acetylcholine receptors (AChR) and utrophin at the neuromuscular junctions. Additionally, the end-plate ultrastructure was immature, with reduced enfolding of the postsynaptic membrane. In two such families, we found truncating mutations of the epsilon-AChR subunit. In family 1, both affected siblings were heteroallelic for a epsilon911delT and a epsilonIVS4+1G-->A mutation within the AChR epsilon-subunit gene (CHRNE). In the affected member of family 2, a epsilon1030delC mutation and a previously described epsilonR64X mutation were found. These deleterious epsilonAChR mutations not only result in AChR deficiency, but also affect end-plate maturation, including the formation of secondary synaptic clefts during ontogenesis.
The quinoline derivatives quinine, its stereoisomer quinidine, and chloroquine may worsen or provoke disorders of neuromuscular transmission. In this study, we investigate effects of these drugs on ...neuromuscular transmission by conventional microelectrode as well as patch-clamp techniques. At 5 X 10
−5 M, quinine, quinidine, and chloroquine reduced the quantal content of the end-plate potential by 37–45%. Between 10
−6 and 10
−4 M, all 3 drugs progressively decreased the amplitude and decay time constant of miniature end-plate potential (MEPP) and miniature end-plate current (MEPC); at 5 X 10
−3 M, the MEPP became undetectable. The effect on the MEPP was not reversed by 1 μg/ml neostigmine. Single-channel patch-clamp analysis of the effects of quinine showed that this agent causes a long-lived open-channel as well as a closed-channel block of AChR. Tests for competitive inhibition or desensitization of the acetylcholine receptor (AChR) by quinine in concentrations that had a marked effect on the MEPC and on single-channel open and closed intervals were negative. Because quinoline drugs adversely affect both presynaptic and postsynaptic aspects of neuromuscular transmission at concentrations close to those employed in clinical practice, they should not be used, or used with caution, in disorders that compromise the safety margin of neuromuscular transmission.
In Germany approximately one percent of the population suffers from clinically relevant restless legs syndrome (RLS). Three non-ergoline dopamine agonists and levodopa/benserazide are now ...specifically licensed for RLS in Germany. Augmentation is the main complication of long-term dopaminergic treatment of RLS. Augmentation is defined as a paradoxical worsening of the symptoms during long-term dopaminergic treatment with increasing dose. According to a recent study this occurs in up to 60% of RLS patients during the first 6 months of treatment. Augmentation emerges less frequently during dopamine agonist treatment. The dopamine agonist doses required for the treatment of RLS patients is far below the dose range in Parkinson therapy. However, severe complications of dopamine agonist treatment can occur even in this dose range, like compulsive behaviours. A considerable number of RLS patients needs non-dopaminergic treatment for RLS. Most of them receive opioids as one of the second-line options in RLS therapy.
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