| 1. |
- Arkblad, Eva L, et al.
(författare)
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Multiplex ligation-dependent probe amplification improves diagnostics in spinal muscular atrophy
- 2006
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Ingår i: Neuromuscular disorders : NMD. - : Elsevier BV. - 0960-8966 .- 1873-2364. ; 16:12, s. 830-8
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Tidskriftsartikel (refereegranskat)abstract
- Spinal muscular atrophy (SMA) is an autosomal recessive disease caused by decreased levels of survival motor neuron protein (SMN). In the majority of cases, this decrease is due to absence of the SMN1 gene. Multiplex ligation-dependent probe amplification (MLPA) is a modern quantitative molecular method. Applied in SMA cases, it improves diagnostics by simultaneously identifying the number of copies of several target sequences in the SMN1 gene and in nearby genes. Using MLPA in clinical diagnostics, we have identified a previously unreported, partial deletion of SMN1 (exons 1-6) in two apparently unrelated Swedish families. This mutation would not have been detected by conventional diagnostic methods. This paper illustrates the broad clinical and genetic spectrum of SMA and includes reports of MLPA results and clinical descriptions of a patient with homozygous absence of SMN1 and only one SMN2 (prenatal onset SMA type 1), an asymptomatic woman with five SMN2 (lacking SMN1) and representative patients with SMA types 1, 2 and 3.
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| 2. |
- Casar-Borota, Olivera, et al.
(författare)
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A novel dynamin-2 gene mutation associated with a late-onset centronuclear myopathy with necklace fibres
- 2015
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Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966 .- 1873-2364. ; 25:4, s. 345-348
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Tidskriftsartikel (refereegranskat)abstract
- Nuclear centralisation and internalisation, sarcoplasmic radiating strands and type 1 muscle fibre predominance and hypotrophy characterise dynamin-2 (DNM2) associated centronuclear myopathy, whereas necklace fibres are typically seen in late onset myotubularin-1 (MTM1)-related myopathy. We report a woman with unilateral symptoms probably related to brachial plexus neuritis. Electromyography revealed localised neuropathic and generalised myopathic abnormalities. The typical features of DNM2 centronuclear myopathy with additional necklace fibres were found in the muscle biopsy. Sequencing of the DNM2 and MTM1 genes revealed a novel heterozygous missense mutation in exon 18 of the DNM2, leading to replacement of highly conserved proline at position 647 by arginine. The muscle symptoms have not progressed during the 3-year follow-up. However, the patient has developed bilateral subtle lens opacities. Our findings support the concept that necklace fibres may occasionally be found in DNM2-related myopathy, possibly indicating a common pathogenic mechanism in DNM2 and MTM1 associated centronuclear myopathy. (C) 2015 Elsevier B.V. All rights reserved.
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| 3. |
- Darin, Niklas, 1964, et al.
(författare)
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Functional analysis of a novel POL gamma A mutation associated with a severe perinatal mitochondrial encephalomyopathy
- 2021
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Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966. ; 31:4, s. 348-358
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the mitochondrial DNA polymerase gamma catalytic subunit (POL. A) compromise the stability of mitochondrial DNA (mtDNA) by leading to mutations, deletions and depletions in mtDNA. Patients with mutations in POL gamma A often differ remarkably in disease severity and age of onset. In this work we have studied the functional consequence of POL gamma A mutations in a patient with an uncommon and a very severe disease phenotype characterized by prenatal onset with intrauterine growth restriction, lactic acidosis from birth, encephalopathy, hepatopathy, myopathy, and early death. Muscle biopsy identified scattered COX-deficient muscle fibers, respiratory chain dysfunction and mtDNA depletion. We identified a novel POL.A mutation (p.His1134Tyr) in trans with the previously identified p.Thr251Ile/Pro587Leu double mutant. Biochemical characterization of the purified recombinant POL gamma A variants showed that the p.His1134Tyr mutation caused severe polymerase dysfunction. The p.Thr251Ile/Pro587Leu mutation caused reduced polymerase function in conditions of low dNTP concentration that mimic postmitotic tissues. Critically, when p.His1134Tyr and p.Thr251Ile/Pro587Leu were combined under these conditions, mtDNA replication was severely diminished and featured prominent stalling. Our data provide a molecular explanation for the patients mtDNA depletion and clinical features, particularly in tissues such as brain and muscle that have low dNTP concentration. (c) 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
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| 4. |
- Darin, Niklas, 1964, et al.
(författare)
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Mitochondrial myopathy with exercise intolerance and retinal dystrophy in a sporadic patient with a G583A mutation in the mt tRNA(phe) gene
- 2006
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Ingår i: Neuromuscular disorders : NMD. - : Elsevier BV. - 0960-8966 .- 1873-2364. ; 16:8, s. 504-6
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Tidskriftsartikel (refereegranskat)abstract
- We describe a second patient with the 583G>A mutation in the tRNA(phe) gene of mitochondrial DNA (mtDNA). This 17-year-old girl had a mitochondrial myopathy with exercise intolerance and an asymptomatic retinopathy. Muscle investigations showed occasional ragged red fibers, 30% cytochrome c oxidase (COX)-negative fibers, and reduced activities of complex I+IV in the respiratory chain. The mutation was heteroplasmic (79%) in muscle but undetectable in other tissues. Analysis of single muscle fibers revealed a significantly higher level of mutated mtDNA in COX-negative fibers. Our study indicates that the 583G>A mutation is pathogenic and expands the clinical spectrum of this mutation.
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| 5. |
- Garmendia, Joana, et al.
(författare)
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A validated WAIS-IV short-form to estimate intellectual functioning in myotonic dystrophy type 1
- 2022
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Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966 .- 1873-2364. ; 32:9, s. 749-753
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Tidskriftsartikel (refereegranskat)abstract
- Currently, no rapid and specific instrument is available to briefly estimate intelligence in patients with myotonic dystrophy type 1 (DM1), a multisystemic disease that involves the CNS and is associated with cognitive deficits and low intellectual functioning. This study aimed to develop a DM1-specific and valid short-form of the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) to estimate intellectual functioning in this population. Thirty non-congenital DM1 patients (10 female; mean age=46.77; SD= 9.76) were assessed with the WAIS-IV. Data were analyzed following two independent strategies: A) multiple linear regression with the aim of maintaining the scale's factorial structure; and B) correlational analyses between scores on all WAIS-IV subtests and Full-Scale IQ (FSIQ). Validity of the resulting short-forms was also analyzed. Three short-forms were developed: Proposal A from strategy A (Vocabulary, Block Design, Arithmetic and Symbol Search), Proposal B1 (Vocabulary, Block Design, Digit Span and Visual Puzzles) and Proposal B2 (Vocabulary and Block Design), from strategy B. All three short-forms showed a strong and significant correlation with the FSIQ and were considered psychometrically acceptable. Arguments in favor of Proposal B1 are discussed. Assessing FSIQ with these short-forms will be useful for avoiding long assessment procedures in a population characterized by high fatigability.
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| 6. |
- Hammarén, Elisabet, et al.
(författare)
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Factors of importance for dynamic balance impairment and frequency of falls in individuals with myotonic dystrophy type 1 - A cross-sectional study - Including reference values of Timed Up & Go, 10m walk and step test
- 2014
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Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966 .- 1873-2364. ; 24:3, s. 207-215
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Tidskriftsartikel (refereegranskat)abstract
- Patients with myotonic dystrophy type 1 suffer from gait difficulties including stumbles and falls. To identify factors of importance for balance impairment and fall-risk a mapping of functional balance was performed, in a cross-sectional study of 51 adults. Walking, balance, falls and muscle force were self-assessed and measured. Reference values of balance were established through measurements of 220 healthy subjects. Falls were more frequently observed in the patients who were more severely affected of muscle weakness than in mildly affected patients, p= 0.014. The number of falls showed negative correlation with balance confidence ( rs= -0.516, p<. 0.001). The ankle dorsiflexor force together with the time difference between comfortable and maximum speed in 10. m-walk proved to be significant factors for fall frequency. A ten Newton muscle force decrease showed 15% increase in odds ratio for frequent falls. One-second increase in time difference between comfortable and maximum walking speed showed 42% increase in odds ratio for frequent falls. In conclusion, assessing the ankle muscle force and the time difference in different walking speeds is important to detect risk of falling. The activities-specific balance confidence score reflects the consequences of the muscle force decrease. Certain patient strategies to diminish risk of falling could be due. © 2013 Elsevier B.V.
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| 7. |
- Hammarén, Elisabet, et al.
(författare)
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Muscle force, balance and falls in muscular impaired individuals with myotonic dystrophy type 1: A five-year prospective cohort study
- 2015
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Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966. ; 25:2, s. 141-148
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Tidskriftsartikel (refereegranskat)abstract
- Individuals with myotonic dystrophy type 1 (DM1) have progressive muscle weakness with gait and balance impairments. We explored prospectively the natural history of muscle force, gait, balance, balance confidence and walking ability in muscular affected individuals with DM1. After five years data from 43 individuals (m/f:18/25) were analysed. All measures of balance showed statistically significant deterioration (p < 0.001) with averaged yearly loss of function by 3–4%. In the group as a whole, loss of muscle force was statistically significant in all lower limb muscles measured after five years: changes relative to baseline force were median −6% to −18%. For males muscle force loss was statistically significant in all leg muscles, but only in hip flexors for women. After five years 100% of the men had fallen during the previous year and 67% three times or more, in contrast only 60% of the women had fallen in the previous year and 36% three times or more. The proportion of individuals seeking medical care the previous year, after falling, was more than doubled after five years, albeit the number of falls had not changed.Awareness of this increased risk of falls is important for caregivers and patients.
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| 8. |
- Hammarén, Elisabet, et al.
(författare)
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Quantification of mobility impairment and self-assessment of stiffness in patients with myotonia congenita by the physiotherapist.
- 2005
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Ingår i: Neuromuscular disorders : NMD. - : Elsevier BV. - 0960-8966. ; 15:9-10, s. 610-7
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Tidskriftsartikel (refereegranskat)abstract
- We investigated test-retest reliability and responsiveness in two functional measuring instruments, Timed Up&Go (TUG) and Timed-Stands Test (TST), and in three self-assessment scales, Visual Analogue Scale (VAS), Borg's Category-Ratio Scale (BorgCR10) and Myotonia Behaviour Scale (MBS) when quantifying myotonic stiffness and mobility impairment. These methods were used in the assessment of treatment efficacy of mexiletine. Six male patients with myotonia congenita followed a standardised protocol with time scoring and rest on two occasions, with and without mexiletine. Time scoring of TUG and TST and self-assessments of stiffness were performed. A 14-day stiffness diary was used at home. Timed Up&Go and TST showed very good test-retest agreement (ICC=0.87-0.95) and significant to change (P=0.005 and 0.001, respectively). All self-assessment scales revealed excellent responsiveness and good test-retest reliability. The measurement instruments possess great capacity to detect functional impairment in the myotonia congenita patient group, and sensibility to identify true changes due to treatment. When considering the results, three instruments are favoured; Timed Up&Go and BorgCR10 for short, and MBS for long-term evaluations.
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| 9. |
- Hedberg, Carola, 1969, et al.
(författare)
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Hereditary myopathy with early respiratory failure is associated with misfolding of the titin fibronectin III 119 subdomain
- 2014
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Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966. ; 24:5, s. 373-379
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Tidskriftsartikel (refereegranskat)abstract
- Hereditary myopathy with early respiratory failure is a rare disease with muscle weakness and respiratory failure as early symptoms. Muscle pathology is characterized by the presence of multiple cytoplasmic bodies and other protein aggregates in muscle fibers. The disease is associated with mutations in the titin gene (TTN). All patients harbor mutations located in exon 343 in the TTN gene that codes for the fibronectin III domain 119 (FN3 119) in the 10th motif of the 11-element motif A-band super-repeat. We investigated how such disease-causing mutations affect the biochemical behavior of this titin domain. All five disease-causing amino acid changes analyzed by us (p.P30068R, p.C30071R, p.W30088R, p.W30088C and p.P30091L) resulted in impaired FN3 119 domain solubility. In contrast, amino acid changes associated with common SNPs (p.V30076I, p.R30107C and p.S30125F) did not have this effect. In silica analyses further support the notion that disease-causing mutations impair proper folding of the FN3 119 domain. The results suggest that hereditary myopathy with early respiratory failure is caused by defective protein folding. (C) 2014 Elsevier B.V. All rights reserved.
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| 10. |
- Hedberg, Carola, 1969, et al.
(författare)
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Myopathy in a woman and her daughter associated with a novel splice site MTM1 mutation.
- 2012
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Ingår i: Neuromuscular disorders : NMD. - : Elsevier BV. - 1873-2364 .- 0960-8966. ; 22:3, s. 244-51
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Tidskriftsartikel (refereegranskat)abstract
- We have investigated a woman and her daughter with an early onset, slowly progressive myopathy. Muscle biopsy showed in both cases severe atrophy with marked fatty replacement. Frequent fibers with internalized nuclei were present but no typical features of centronuclear myopathy. There were also many fibers with deep invaginations of the plasma membrane. The presence of necklace fibers provided clue to correct genetic diagnosis. Both patients had a novel heterozygous splice site mutation in the myotubularin gene, MTM1 (c.867+1G>T). Analysis of MTM1 cDNA revealed that the mutation resulted in aberrant splicing with variable exon skipping. The expression of normal transcripts was markedly reduced and there was reduced expression of myotubularin protein. Although the expression of the allele without the mutation was reduced we did not obtain evidence of skewed X-chromosome inactivation. Other factors than skewed X-inactivation may cause allele inactivation and manifestation of severe myopathy in heterozygous carriers of pathogenic MTM1 mutations.
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