| 41. |
- Conceicao, I., et al.
(författare)
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Phase 2 open-label extension study of patisiran, an investigational siRNA agent for hereditary ATTR amyloidosis with polyneuropathy (hATTR-PN)
- 2016
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Ingår i: Neuromuscular Disorders. - : Elsevier. - 0960-8966 .- 1873-2364. ; 26, s. S142-S142
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Hereditary ATTR amyloidosis with polyneuropathy (hATTR-PN), also known as familial amyloidotic polyneuropathy (FAP), is an inherited, progressive disease that can cause sensory, motor, and autonomic dysfunction, resulting in significant disability and death. Patisiran is an investigational, systemically administered small interfering RNA (siRNA) targeting wild-type and mutant TTR. A recently completed multi-center, multi-dose Phase 2 trial of patisiran in hATTR-PN patients (N = 29) showed >80% sustained mean knockdown of serum TTR when administered at a dose of 0.3 mg/kg every 3 weeks with a generally favorable safety profile. Phase 2 open label (OLE) study to evaluate patisiran's safety effect on serum TTR levels, impact on neuropathy impairment scores and QOL. Twenty-seven patients with hATTR-PN were enrolled; median age 64 years (range: 29–77 years). Patisiran was well tolerated throughout the23-months of follow-up. Five patients experienced SAEs (unrelated) including one discontinuation and subsequent death (gastroesophageal cancer). Flushing (25.9%) and infusion-related reactions (18.5%) were mild AEs; and did not result in any discontinuations. Approximately 80% sustained mean serum TTR lowering was obtained with a mean nadir of up to 93% between doses. Among the 20 evaluable patients, neuropathy impairment scores were stable with a mean change in mNIS+7 and NIS of 1.7 and 4.2 points, respectively. This compares favorably to 17–26 point mNIS+7/NIS increase at 18-months from prior hATTR-PN studies. Stabilization of quality of life (QOL) measures and significant improvement of distal thigh sweat gland nerve fiber density was observed. Long-term (>18 months) patisiran administration was generally well tolerated, resulted in sustained mean serum TTR lowering; supporting the hypothesis that TTR knockdown potentially halts neuropathy progression. As of March 2016, dosing continues; updated results will be presented.
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| 42. |
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| 43. |
- Cuisset, J. M., et al.
(författare)
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'Cap myopathy' : case report of a family
- 2006
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Ingår i: Neuromuscular Disorders. - : Institute of Information Science. - 0960-8966 .- 1873-2364. ; 16:4, s. 277-281
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Tidskriftsartikel (refereegranskat)abstract
- We report the observation of an 18-year-old girl, whose clinical presentation was very suggestive of a congenital myopathy with neonatal onset. A congenital myopathy had been already diagnosed in her brother and in addition her half-cousin died diagnosed with a severe nemaline myopathy at age 4 years. A muscle biopsy performed on both siblings revealed histological and ultrastructural features of 'cap myopathy'. This case report suggests that 'cap myopathy' and some cases of nemaline myopathy with neonatal onset might be two phenotypic expressions of the same genetic disorder. These two entities could therefore, perhaps, be regarded as 'Z-line disorders' possibly caused by defective myofibrillogenesis.
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| 44. |
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| 45. |
- Danielsson, Olof, et al.
(författare)
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Expression of apoptosis related proteins in normal and diseased muscle : A possible role for Bcl-2 in protection of striated muscle
- 2009
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Ingår i: NEUROMUSCULAR DISORDERS. - : Elsevier BV. - 0960-8966. ; 19:6, s. 412-417
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Tidskriftsartikel (refereegranskat)abstract
- The unique absence of major histocompatibility complex class I antigen (MHC-I) expression in normal muscle is one possible mechanism protecting striated muscle. In order to define their possible involvement in protection of normal muscle. we investigated the expression of molecules involved in muscle fibre death and survival mechanisms (Bcl-2, Fas, Fas-ligand and TRAIL), focusing on disorders with possible involvement of cytotoxic T cells. We studied muscle biopsies from 20 healthy volunteers, from 10 patients affected by polymyositis and 10 by Duchenne muscular dystrophy. By using immunohistochemistry, Western blot and real-time PCR we detected a constitutional expression of Bcl-2 in healthy muscle, whereas the expression was weaker in disease processes. Fas-L and TRAIL were not detected in muscle fibres, and Fas only in muscle affected by disease. Our findings indicate that the major apoptotic protein Bcl-2 might have a hitherto unrecognized role in the protection of normal muscle.
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| 46. |
- 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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| 47. |
- 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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| 48. |
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| 49. |
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| 50. |
- Ehrstedt, Christoffer, et al.
(författare)
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Novel pathogenic ALG2 mutation causing congenital myasthenic syndrome : A case report
- 2022
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Ingår i: Neuromuscular Disorders. - : Elsevier. - 0960-8966 .- 1873-2364. ; 32:1, s. 80-83
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Tidskriftsartikel (refereegranskat)abstract
- ALG2 mutations are extremely rare causes of congenital myasthenic syndromes (CMS). The clinical phenotype and treatment response is therefore not well described. We present the case of a baby who immediately after birth presented with pronounced truncal hypotonia, proximal muscle weakness and feeding difficulties. Single fibre electromyography showed neuromuscular transmission failure and salbutamol and ephedrine treatment improved both muscle weakness and neuromuscular transmission. Genetic analysis revealed a likely pathogenic variant c.1040del, p.(Gly347Valfs*27) in exon 2 and a variant of uncertain significance, c.239G>A, p.(Gly80Asp) in exon 1 of the ALG2 gene. Western blot in whole cell lysates of HEK293 cells transfected with p.Gly80Asp, or p.Gly347Valfs*27 expression constructs indicated that p.Gly347Valfs*27 is likely a null allele and p.Gly80Asp is pathogenic through marked reduction of ALG2 expression. This case highlights the utility of functional studies in clarifying variants of unknown significance, in suspected cases of CMS. (C) 2021 The Author(s). Published by Elsevier B.V.
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