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Now showing items 1 - 16 of 25

  • Principles and Practice of Laser-Doppler Anemometry. By F. D URST A. M ELLING and J. H. W HITELAW . Academic Press, 1976. 412 pp. £12.00. Laser Doppler Measurements. By B. M. W ATRASIEWICZ and M. R UDD . Butterworths, 1976. 167 pp. £6.90.

    Smart   A. E.  

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  • Confirmation of the type 2 myotonic dystrophy (CCTG)(n) expansion mutation in patients with proximal myotonic myopathy/proximal myotonic dystrophy of different European origins: A single shared haplotype indicates an ancestral founder effect RID A-9210-2012

    Bachinski, LL   Udd, B   Meola, G   Sansone, V   Bassez, G   Eymard, B   Thornton, CA   Moxley, RT   Harper, PS   Rogers, MT   Jurkat-Rott, K   Lehmann-Horn, F   Wieser, T   Gamez, J   Navarro, C   Bottani, A   Kohler, A   Shriver, MD   Sallinen, R   Wessman, M   Zhang, SX   Wright, FA   Krahe, R  

    Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, is a clinically and genetically heterogeneous neuromuscular disorder. DM is characterized by autosomal dominant inheritance, muscular dystrophy, myotonia, and multisystem involvement. Type 1 DM (DM1) is caused by a (CTG)(n) expansion in the 3' untranslated region of DMPK in 19q13.3. Multiple families, predominantly of German descent and with clinically variable presentation that included proximal myotonic myopathy (PROMM) and type 2 DM (DM2) but without the DM1 mutation, showed linkage to the 3q21 region and were recently shown to segregate a (CCTG)(n) expansion mutation in intron 1 of ZNF9. Here, we present linkage to 3q21 and mutational confirmation in 17 kindreds of European origin with PROMM and proximal myotonic dystrophy, from geographically distinct populations. All patients have the DM2 (CCTG)(n) expansion. To study the evolution of this mutation, we constructed a comprehensive physical map of the DM2 region around ZNF9. High-resolution haplotype analysis of disease chromosomes with five microsatellite and 22 single-nucleotide polymorphism markers around the DM2 mutation identified extensive linkage disequilibrium and a single shared haplotype of at least 132 kb among patients from the different populations. With the exception of the (CCTG)(n) expansion, the available markers indicate that the DM2 haplotype is identical to the most common haplotype in normal individuals. This situation is reminiscent of that seen in DM1. Taken together, these data suggest a single founding mutation in DM2 patients of European origin. We estimate the age of the founding haplotype and of the DM2 (CCTG) expansion mutation to be similar to200-540 generations.
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  • Laing early-onset distal myopathy in a Belgian family.

    Van den Bergh, P Y K   Martin, J J   Lecouvet, F   Udd, B   Schmedding, E  

    We report the first Belgian family with Laing early-onset distal myopathy (MPD1). The proposita started limping at age 7. Later, there was severe weakness of proximal and distal muscles, including neck flexors. Her daughter developed foot drop at age 4. Progressive weakness of distal limb extensor muscles and mild weakness of the neck flexor and proximal muscles were noted. In both patients, CK and nerve conductions were normal, but EMG showed a brief, small amplitude, abundant, polyphasic potential pattern. Heart and respiration were normal. Several muscle biopsies have been performed in each with various diagnoses, including aspecific myopathic changes, congenital fibre type disproportion, and denervation-reinnervation. Analysis of MYH7 revealed a c.4522_4524del mutation (p.Glu1508del). This appears to be a de novo mutation, which has been reported in French, Norwegian, and Finnish patients. =20
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  • Choline acetyltransferase mutations cause myasthenic syndrome associated with episodic apnea in humans RID C-2442-2009

    Ohno, K   Tsujino, A   Brengman, JM   Harper, CM   Bajzer, Z   Udd, B   Beyring, R   Robb, S   Kirkham, FJ   Engel, AG  

    Choline acetyltransferase (ChAT; EC 2.3.1.6) catalyzes the reversible synthesis of acetylcholine (ACh) from acetyl CoA and choline at cholinergic synapses. Mutations in genes encoding ChAT affecting motility exist in Caenorhabditis elegans and Drosophila, but no CHAT mutations have been observed in humans to date. Here we report that mutations in CHAT cause a congenital myasthenic syndrome associated with frequently fatal episodes of apnea (CMS-EA), Studies of the neuromuscular junction in this disease show a stimulation-dependent decrease of the amplitude of the miniature endplate potential and no deficiency of the ACh receptor. These findings point to a defect in ACh resynthesis or vesicular filling and to CHAT as one of the candidate genes. Direct sequencing of CHAT reveals 10 recessive mutations in five patients with CMS-EA, One mutation (523insCC) is a frameshifting null mutation. Three mutations (1305T, R420C, and E441K) markedly reduce ChAT expression in COS cells. Kinetic studies of nine bacterially expressed ChAT mutants demonstrate that one mutant (E441K) lacks catalytic activity, and eight mutants (L21OP, P211A, 1305T, R420C, R482G, S498L V506L and R560H) have significantly impaired catalytic efficiencies.
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  • Proximal myotonic dystrophy - A family with autosomal dominant muscular dystrophy, cataracts, hearing loss and hypogonadism: Heterogeneity of proximal myotonic syndromes?

    Udd, B   Krahe, R   WallgrenPettersson, C   Falck, B   Kalimo, H  

    We describe a family with an autosomal dominant, multisystem disorder, consisting of late-onset proximal muscular dystrophy, electrophysiological myotonia, cataracts, late-onset deafness and male hypogonadism. Four patients were available for clinical examinations. Examination of asymptomatic family members revealed another patient with bilateral cataracts but without definite muscle disorder. Five deceased members of the family had proximal muscle weakness, reportedly or confirmed in medical records. Molecular examination of genomic DNA showed no expansion of the unstable (CTG)n trinucleotide repeat on chromosome 19q13.3 associated with myotonic dystrophy (DM). Linkage to two loci implicated in other myotonic disorders, the muscle chloride channel (CLCNI) gene, and the muscle sodium channel (SCN4A) gene, was assessed and excluded. The clinical findings differ from those described in proximal myotonic myopathy (PROMM), in terms of the more severe muscle involvement with atrophy of affected muscles and the hearing loss. These findings suggest phenotypic and probably genetic heterogeneity among the proximal myotonic syndromes. (C) 1997 Elsevier Science B.V.
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  • Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin

    Hackman, P   Vihola, A   Haravuori, H   Marchand, S   Sarparanta, J   de Seze, J   Labeit, S   Witt, C   Peltonen, L   Richard, I   Udd, B  

    Tibial muscular dystrophy (TMD) is an autosomal dominant late-onset distal myopathy linked to chromosome 2q31. The linked region includes the giant TTN gene, which encodes the central sarcomeric protein, titin. We have previously shown a secondary calpain-3 defect to be associated with TMD, which further underscored that titin is the candidate. We now report the first mutations in TTN to cause a human skeletal-muscle disease, TMD. In Mex6, the last exon of TTN, a unique 11-bp deletion/insertion mutation, changing four amino acid residues, completely cosegregated with all tested 81 Finnish patients with TMD in 12 unrelated families. The mutation was not found in 216 Finnish control samples. In a French family with TMD, a Leu-->Pro mutation at position 293,357 in Mex6 was discovered. Mex6 is adjacent to the known calpain-3 binding site Mex5 of M-line titin. Immunohistochemical analysis using two exon-specific antibodies directed to the M-line region of titin demonstrated the specific loss of carboxy-terminal titin epitopes in the TMD muscle samples that we studied, thus implicating a functional defect of the M-line titin in the genesis of the TMD disease phenotype.
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  • Adult-onset ataxia and polyneuropathy caused by mitochondrial 8993T -> C mutation

    Rantamaki, MT   Soini, HK   Finnila, SM   Majamaa, K   Udd, B  

    The 8993T -> C mutation in mitochondrial DNA (mtDNA) has been described previously to be associated with infantile- or childhood-onset phenotypes, ranging from Leigh's syndrome to neurogenic weakness, ataxia, and retinitis pigmentosa syndrome. We report a kindred with adult-onset slowly progressive ataxia and polyneuropathy and with the heteroplasmic 8993T -> C mutation. Our findings suggest that the 8993T -> C mtDNA mutation should be considered in the differential diagnosis of nondominant adult-onset ataxia and axonal neuropathy.
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  • Linkage to two separate loci in a family with a novel distal myopathy phenotype (MPD3)

    Haravuori, H   Siitonen, HA   Mahjneh, I   Hackman, P   Lahti, L   Somer, H   Peltonen, L   Kestila, M   Udd, B  

    We recently described a new type of adult onset distal myopathy (MPD3) with autosomal dominant inheritance. The onset of symptoms is around the age of 30 and the characteristic first symptoms include clumsiness of the hands and stumbling. The thenar and hypothenar muscles are involved at the onset. The disease progressed to the intrinsic muscles of the hands, both anterior and posterior muscle compartments of the lower legs, the forearm muscles, and later to the proximal muscles. Dystrophic changes with rimmed vacuoles were observed in the muscle biopsy. We have performed a genome wide scan here in order to identify the MPD3 locus. Unexpectedly, markers on two distinct chromosomal regions 8p22-q11 and 12q13-q22, provided significant evidence for linkage in this family. Multipoint linkage analyses produced equal maximum multipoint LOD score of 3.01 for both chromosomal regions and haplotype analysis showed a specific haplotype segregating with the disease for both loci. It is thus impossible to distinguish between two loci without additional family material. Two obvious regional candidate genes, encoding muscular proteins became subjects for sequence analyses, the gene for myosin light chain 1 slow-twitch muscle A on 12q13 and the muscle specific exons of ankyrin 1 on 8p11. No mutations were identified in the coding sequence. (C) Elsevier B.V. All rights reserved.
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  • Congenital myasthenic syndrome associated with episodic apnea and sudden infant death

    Byring, RF   Pihko, H   Tsujino, A   Shen, XM   Gustafsson, B   Hackman, P   Ohno, K   Engel, AG   Udd, B  

    The sudden infant death syndrome has multiple etiologies. Some congenital myasthenic syndromes can cause sudden infant death syndrome by apnea, but the frequency of this etiology is unknown. We report here a young patient with sudden respiratory crises culminating in apnea followed by recovery, against a background of no or variable myasthenic symptoms without dyspnea. One sib without myasthenic symptoms and one sib who only had mild ptosis died previously during febrile episodes. Studies reported by us elsewhere traced the proband's illness to mutations in choline acetyltransferase. Here, we describe in detail the morphologic investigations and electrophysiologic findings, which point to a presynaptic defect in acetylcholine resynthesis or vesicular tilling, in the proband. Analysis of DNA from a sib who previously died of sudden infant death syndrome revealed the same choline acetyltransferase mutation. Thus, mutations in choline acetyltransferase may be a cause of sudden infant death syndrome as, theoretically, could other presynaptic myasthenic disorders. (C) 2002 Elsevier Science B.V. All rights reserved.
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  • Principles and Practice of Laser-Doppler Anemometry. By F. D URST A. M ELLING and J. H. W HITELAW . Academic Press, 1976. 412 pp. £12.00. Laser Doppler Measurements. By B. M. W ATRASIEWICZ and M. R UDD . Butterworths, 1976. 167 pp. £6.90.

    Smart, A. E.  

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  • Muscular dystrophy with separate clinical phenotypes in a large family.

    Udd, B   Kaarianen, H   Somer, H  

    This report describes a large consanguineous family with muscular dystrophy in 23 patients showing intrafamilial variation of clinical expression. One main variant appeared in the first decade with proximal muscle weakness progressing over the next 20 years to wheelchair confinement, and appeared compatible with classical limb-girdle muscular dystrophy. The other main variant showed onset of distal muscle weakness in lower limbs in the third or fourth decade, progressing very slowly without greater disability throughout the lifetime. Tibial muscle weakness and wasting were clinical landmarks in this variant, but computed tomography of skeletal muscle revealed focal areas of fatty degeneration also in truncal, pelvifemoral, and distal leg muscles in a way not previously reported in distal myopathy. The overall difference in clinical findings between these main variants would suggest 2 separate genetic entities, genealogical data makes a common genetic background possible.
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  • Muscle magnetic resonance imaging shows distinct diagnostic patterns in Welander and tibial muscular dystrophy

    Mahjneh, I   Lamminen, AE   Udd, B   Paetau, AE   Hackman, P   Korhola, OA   Somer, HVK  

    Objectives This is a report on a retrospective muscle magnetic resonance imaging (MRI) study on 11 patients affected by Welander distal myopathy (WDM) and 22 patients with tibial muscular dystrophy (TMD) carried out in order to define the pattern and characteristics of muscle involvement. Results - WDM patients showed involvement of gastrocnemius, soleus, tibial anterior (TA) and extensor digitorum longus (EDL), as well as hamstrings and hip adductor muscles. TMD patients showed involvement of the TA and EDL muscles, and in some patients also hamstring and posterior compartment muscles of the legs. Some patients showed asymmetry of muscle involvement. Conclusion - We conclude that muscle MRI examination proved to be very useful in the determination of the exact pattern of muscle involvement in WDM and TMD. Clinical testing using the Medical Research Council scale is not sensitive enough to establish the pattern of muscle involvement in focal muscle diseases.
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  • Proximal myotonic myopathy (PROMM) and other proximal myotonic syndromes

    Moxley, RT   Udd, B   Ricker, K  

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  • Multiple founder effects in spinal and bulbar muscular atrophy (SBMA, Kennedy disease) around the world

    Lund, A   Udd, B   Juvonen, V   Andersen, PM   Cederquist, K   Davis, M   Gellera, C   Kolmel, C   Ronnevi, LO   Sperfeld, AD   Sorensen, SA   Tranebjaerg, L   Van Maldergem, L   Watanabe, M   Weber, M   Yeung, L   Savontaus, ML  

    SBMA (spinal and bulbar muscular atrophy), also called Kennedy disease, is an X-chromosomal recessive adult-onset neurodegenerative disorder caused by death of the spinal and bulbar motor neurones and dorsal root ganglia. Patients may also show signs of partial androgen insensitivity. SBMA is caused by a CAG repeat expansion in the first exon of the androgen receptor (AR) gene on the X-chromosome. Our previous study suggested that all the Nordic patients with SBMA originated from an ancient Nordic founder mutation, but the new intragenic SNP marker ARd12 revealed that the Danish patients derive their disease chromosome from another ancestor. In search of relationships between patients from different countries, we haplotyped altogether 123 SBMA families from different parts of the world for two intragenic markers and 16 microsatellites spanning 25 cM around the AR gene. The fact that different SBMA founder haplotypes were found in patients from around the world implies that the CAG repeat expansion mutation has not been a unique event. No expansion-prone haplotype could be detected. Trinucleotide diseases often show correlation between the repeat length and the severity and earlier onset of the disease. The longer the repeat, the more severe the symptoms are and the onset of the disease is earlier. A negative correlation between the CAG repeat length and the age of onset was found in the 95 SBMA patients with defined ages at onset.
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  • Assignment of the tibial muscular dystrophy locus to chromosome 2q31.

    Haravuori, H   Makela-Bengs, P   Udd, B   Partanen, J   Pulkkinen, L   Somer, H   Peltonen, L  

    Tibial muscular dystrophy (TMD) is a rare autosomal dominant distal myopathy with late adult onset. The phenotype is relatively mild: muscle weakness manifests in the patient's early 40s and remains confined to the tibial anterior muscles. Histopathological changes in muscle are compatible with muscular dystrophy, with the exception that rimmed vacuoles are a rather common finding. We performed a genomewide scan, with 279 highly polymorphic Cooperative Human Linkage Center microsatellite markers, on 11 affected individuals of one Finnish TMD family. The only evidence for linkage emerged from markers in a 43-cM region on chromosome 2q. In further linkage analyses, which included three other Finnish TMD families and which used a denser set of markers, a maximum two-point LOD score of 10.14 (recombination fraction of .05) was obtained with marker D2S364. Multipoint likelihood calculations, combined with the haplotype and recombination analyses, restricted the TMD locus to an approximately 1-cM critical chromosomal region without any evidence of heterogeneity. Since all the affecteds share one core haplotype, the dominance of one ancestor mutation is obvious in the Finnish TMD families. The disease locus that was found represents a novel muscular dystrophy locus, providing evidence for the involvement of one additional gene in the distal myopathy group of muscle disorders.
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  • 104th European Neuromuscular Centre (ENMC) International Workshop: distal myopathies, 8-10th March 2002 in Naarden, The Netherlands.

    Udd, B   Bushby, K   Nonaka, I   Griggs, R  

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