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1.
Lancet Neurol ; 13(11): 1092-1099, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25297016

ABSTRACT

BACKGROUND: In human beings, 5-HT6 receptors are almost exclusively expressed in the brain, particularly in areas relevant for cognition, such as the hippocampus and frontal cortex. We assessed the effect on cognitive performance of Lu AE58054 (idalopirdine), a selective 5-HT6 receptor antagonist, in donepezil-treated patients with moderate Alzheimer's disease. METHODS: For this randomised, double-blind, placebo-controlled phase 2 trial (LADDER), we recruited patients from 48 outpatient clinical sites in seven countries. Patients were 50 years or older, had moderate Alzheimer's disease (a mini-mental state examination score of 12-19), and had been stably treated with donepezil 10 mg per day for 3 or more months. Using a computer-generated sequence, we randomly assigned patients (1:1, stratified by site) to receive either idalopirdine 90 mg per day (30 mg thrice daily) or placebo. The primary endpoint was change from baseline in the 11-item Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) at week 24. We analysed all efficacy endpoints in the full-analysis set (modified intention-to-treat analysis). This trial is registered with ClinicalTrials.gov, number NCT01019421. FINDINGS: Between Dec 8, 2009, and Dec 23, 2011, we randomly allocated 278 patients to treatment: 133 to placebo and 145 to idalopirdine. 132 patients in the placebo group and 140 in the experimental group were included in the final analysis. At week 24, the change from baseline in ADAS-cog total score was +1·38 (SD 0·53) in the placebo group and -0·77 (0·55) in the idalopirdine group (treatment difference of -2·16 points, 95% CI -3·62 to -0·69; p=0·0040). 25 patients (seven taking placebo and 18 taking idalopirdine) discontinued treatment because of adverse events, the difference between groups being mainly due to asymptomatic transient increases in transaminase concentrations in some idalopirdine-treated patients. The most common adverse events (occurring in >3% of patients) were increased γ-glutamyltransferase (14 [10%] patients in the idalopirdine group vs two [2%] in the placebo group), diarrhoea (six [4%] vs nine [7%]), urinary tract infection (three [2%] vs nine [7%]), fall (three [2%] vs eight [6%]), increased alanine aminotransferase (nine [6%] vs none), and benign prostatic hyperplasia (two [5%] vs none). Serious adverse events were reported by 14 (10%) patients in the idalopirdine group and 13 (10%) patients in the placebo group. One death occurred in each treatment group, neither were regarded as being related to treatment. INTERPRETATION: Idalopirdine improved cognitive function in donepezil-treated patients with moderate Alzheimer's disease. Larger studies in a broader population of patients are ongoing to substantiate the effects reported here. FUNDING: H Lundbeck A/S.


Subject(s)
Alzheimer Disease/diagnosis , Alzheimer Disease/drug therapy , Benzylamines/adverse effects , Indoles/adverse effects , Receptors, Serotonin , Serotonin Antagonists/adverse effects , Aged , Aged, 80 and over , Alzheimer Disease/psychology , Benzylamines/therapeutic use , Cognition Disorders/diagnosis , Cognition Disorders/drug therapy , Cognition Disorders/psychology , Donepezil , Double-Blind Method , Female , Follow-Up Studies , Humans , Indans/adverse effects , Indans/therapeutic use , Indoles/therapeutic use , Male , Nootropic Agents/adverse effects , Nootropic Agents/therapeutic use , Piperidines/adverse effects , Piperidines/therapeutic use , Receptors, Serotonin/physiology , Serotonin Antagonists/therapeutic use , Treatment Outcome
2.
Muscle Nerve ; 47(3): 409-15, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23169601

ABSTRACT

INTRODUCTION: The pathogenesis of muscle involvement in patients with myotonic dystrophy type 1 (DM1) is not well understood. In this study, we characterized the muscle phenotype in patients with confirmed DM1. METHODS: In 38 patients, muscle strength was tested by hand-held dynamometry. Myotonia was evaluated by a handgrip test and by analyzing the decrement of the compound muscle action potential. Muscle biopsies were assessed for morphological changes and Na(+)-K(+) pump content. RESULTS: Muscle strength correlated with a decline in Na(+)-K(+) pump content (r = 0.60, P < 0.001) and with CTG expansion. CTG expansion did not correlate with severity of myotonia, proximal histopathological changes, or Na(+)-K(+) pump content. Histopathologically, we found few centrally placed nuclei (range 0.2-6.9%). CONCLUSIONS: The main findings of this study are that muscle weakness correlated inversely with CTG expansion and that central nuclei are not a prominent feature of proximal muscles in DM1.


Subject(s)
Muscle, Skeletal/pathology , Myotonic Dystrophy/genetics , Myotonic Dystrophy/pathology , Adolescent , Adult , Aged , Aging/physiology , Binding Sites , Biopsy , Electromyography , Female , Hand Strength/physiology , Humans , Male , Middle Aged , Muscle Strength , Muscle Strength Dynamometer , Muscle Weakness/pathology , Myotonia/pathology , Ouabain/metabolism , Sodium-Potassium-Exchanging ATPase/genetics , Sodium-Potassium-Exchanging ATPase/metabolism , Trinucleotide Repeats , Young Adult
3.
Ugeskr Laeger ; 171(5): 331-3, 2009 Jan 26.
Article in Danish | MEDLINE | ID: mdl-19176172

ABSTRACT

Two patients with progressive multifocal sensory symptoms and signs are described. The sensory disturbances were bilateral, and mainly arose in the territory of the radial nerves. Stretching or touching the wrist elicited electrical sensations in the fingers. The diagnosis of Wartenberg's migrant sensory neuritis (WMSN) was suggested. Nerve conduction studies confirmed the presence of peripheral nerve affection, and the electrophysiological abnormalities corresponded to the pattern and progression of clinical abnormalities.


Subject(s)
Neuritis , Adult , Female , Fingers/innervation , Humans , Male , Middle Aged , Neuritis/diagnosis , Neuritis/physiopathology , Paresthesia/diagnosis , Paresthesia/physiopathology , Radial Nerve/physiopathology , Wrist/innervation
4.
Neuromuscul Disord ; 18(4): 306-9, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18396044

ABSTRACT

The Twinkle gene product is important for mtDNA replication. Only a few reports have investigated the clinically effect of mutations in this gene. We describe a new de novo mutation (1110C>A) in the PEO1 gene in a mother and her two sons. The mother had progressive ophthalmoplegia, limb weakness, sensory neuropathy, elevated resting plasma lactate, glucose intolerance and impaired VO2max while her sons only had mild ptosis. In accordance with the clinical presentation, abnormal morphological findings in muscle and multiple deletions and depletion of mtDNA in muscle were more pronounced in the proband than in her sons.


Subject(s)
DNA Helicases/genetics , Family Health , Mutation , Ophthalmoplegia, Chronic Progressive External/genetics , Phenotype , Adult , DNA Mutational Analysis/methods , Female , Humans , Male , Middle Aged , Mitochondrial Proteins , Ophthalmoplegia, Chronic Progressive External/pathology , Ophthalmoplegia, Chronic Progressive External/physiopathology
6.
Neurology ; 67(1): 153-5, 2006 Jul 11.
Article in English | MEDLINE | ID: mdl-16832098

ABSTRACT

Myotonia permanens is associated with a G1306E mutation in the SCN4A gene. Two sporadic patients have been reported, but the clinical phenotype has not been fully characterized. The authors report a family in which the disease is autosomal dominantly inherited. The patients have severe myotonia, but the clinical picture is not qualitatively different from that seen in other nondystrophic myotonias.


Subject(s)
Mutation , Myotonia Congenita/genetics , Myotonia/genetics , Sodium Channels/genetics , Child , DNA Mutational Analysis , Electromyography/methods , Family Health , Glutamic Acid/genetics , Glycine/genetics , Humans , Male , Middle Aged , Myotonia/pathology , Myotonia/physiopathology , Myotonia Congenita/pathology , Myotonia Congenita/physiopathology , NAV1.4 Voltage-Gated Sodium Channel
8.
Muscle Nerve ; 32(1): 19-34, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15786415

ABSTRACT

Myotonia congenita is a hereditary chloride channel disorder characterized by delayed relaxation of skeletal muscle (myotonia). It is caused by mutations in the skeletal muscle chloride channel gene CLCN1 on chromosome 7. The phenotypic spectrum of myotonia congenita ranges from mild myotonia disclosed only by clinical examination to severe and disabling myotonia with transient weakness and myopathy. The most severe phenotypes are seen in patients with two mutated alleles. Heterozygotes are often asymptomatic but for some mutations heterozygosity is sufficient to cause pronounced myotonia, although without weakness and myopathy. Thus, the phenotype depends on the mutation type to some extent, but this does not explain the fact that severity varies greatly between heterozygous family members and may even vary with time in the individual patient. In this review, existing knowledge about phenotypic variability is summarized, and the possible contributing factors are discussed.


Subject(s)
Chloride Channels/genetics , Genetic Variation , Myotonia Congenita/genetics , Myotonia Congenita/physiopathology , Humans , Pedigree , Phenotype
10.
Eur J Hum Genet ; 12(9): 738-43, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15162127

ABSTRACT

Mutations in the CLCN1 gene, encoding a muscle-specific chloride channel, can cause either recessive or dominant myotonia congenita (MC). The recessive form, Becker's myotonia, is believed to be caused by two loss-of-function mutations, whereas the dominant form, Thomsen's myotonia, is assumed to be a consequence of a dominant-negative effect. However, a subset of CLCN1 mutations can cause both recessive and dominant MC. We have identified two recessive and two dominant MC families segregating the common R894X mutation. Real-time quantitative RT-PCR did not reveal any obvious association between the total CLCN1 mRNA level in muscle and the mode of inheritance, but the dominant family with the most severe phenotype expressed twice the expected amount of the R894X mRNA allele. Variation in allelic expression has not previously been described for CLCN1, and our finding suggests that allelic variation may be an important modifier of disease progression in myotonia congenita.


Subject(s)
Alleles , Chloride Channels/genetics , Gene Expression , Mutation/genetics , Myotonia Congenita/genetics , DNA Primers , Humans , Inheritance Patterns/genetics , Muscle, Skeletal/metabolism , Pedigree , Reverse Transcriptase Polymerase Chain Reaction
11.
Muscle Nerve ; 28(6): 722-32, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14639587

ABSTRACT

Voltage-gated ClC-1 chloride channels encoded by the CLCN1 gene have a major role in setting the membrane potential in skeletal muscle. More than 60 CLCN1 mutations have been associated with myotonia congenita. These mutations are traditionally classified as recessive (Becker's disease) or dominant (Thomsen's disease). In this study, we have electrophysiologically characterized two new dominant ClC-1 mutations, thereby elucidating the observed phenotype in patients. The two ClC-1 mutants M128V and E193K were identified, and the DNA was isolated from patients and subsequently expressed in Xenopus laevis oocytes for electrophysiological characterization. Both ClC-1 mutants, M128V and E193K, showed a large rightward shift in the current-voltage relationship. In addition, the activation kinetics were slowed in the ClC-1 M128V mutant, as compared to the wild-type ClC-1. Interestingly, ClC-1 E193K revealed a change in reversal potential compared to wild-type channels. This finding supports the notion that the E193 amino acid is an important determinant in the selectivity filter of the human ClC-1 channel. The electrophysiological behavior of both mutants demonstrates a severe reduction in ClC-1 channel conductance under physiologically relevant membrane potentials. These studies thereby explain the molecular background for the observed myotonia in patients.


Subject(s)
Chloride Channels/genetics , Mutation/genetics , Myotonia/genetics , Adult , Amino Acid Sequence , Animals , Child , Electrophysiology , Female , Genes, Dominant/genetics , Genetic Vectors , Humans , Ion Channel Gating/genetics , Ion Channel Gating/physiology , Male , Molecular Sequence Data , Mutation/physiology , Myotonia/physiopathology , Oocytes/metabolism , Patch-Clamp Techniques , Pedigree , Transcription, Genetic , Xenopus laevis
12.
Muscle Nerve ; 27(4): 449-55, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12661046

ABSTRACT

Decrement of the compound muscle action potential (CMAP) during 10-HZ repetitive nerve stimulation is thought to be an unusual finding in dominant myotonia congenita, and has not previously been reported in patients with the genetically verified disorder. It was the purpose of the present study to elucidate the relation between decrement and CLCN1 mutation type in myotonia congenita. Decrement and genotypes were studied in eight Danish families with myotonia congenita. Six patients with the known dominant mutation P480L had decrements of 30-84%. Patients heterozygous for the R894X mutation had decrements of 20-47%. Three novel CLCN1 mutations (two dominant and one recessive) were found segregating with the Thomsen/Becker phenotypes. In families with the novel dominant mutations M128V and E193K, decrement was absent in all family members tested. In conclusion, CMAP decrement may be pronounced in dominant myotonia congenita, and the presence of decrement is related to mutation type.


Subject(s)
Action Potentials/genetics , Action Potentials/physiology , Muscle, Skeletal/physiopathology , Mutation/genetics , Mutation/physiology , Myotonia Congenita/genetics , Myotonia Congenita/physiopathology , Adult , Age Factors , Aged , Chloride Channels/genetics , DNA Mutational Analysis , Denmark , Electric Stimulation , Female , Humans , Male , Middle Aged , Muscle Contraction/genetics , Muscle Contraction/physiology , Muscle Weakness/genetics , Muscle Weakness/physiopathology , Pedigree , Sex Factors
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