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- Hedberg, Carola, 1969, et al.
(författare)
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Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy 7 is caused by a DES mutation
- 2012
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 20:9, s. 984-985
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Tidskriftsartikel (refereegranskat)abstract
- Using exome sequencing we searched for the genetic cause of autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy (ARVC) in a Swedish family. A heterozygous C-to-T transition, c.1255C>T, p.Pro419Ser in the desmin gene on chromosome 2q35, was identified. Previous studies had demonstrated linkage to chromosome 10q22.3, but no causative mutation had been found in that region. Sanger sequencing of DNA from 17 family members confirmed the heterozygous c.1255C>T desmin mutation in seven out of ten family members that had been classified as affected in the previous study. Our new results demonstrate the usefulness of next-generation sequencing, and the diagnostic difficulties with some forms of dominantly inherited muscle diseases as they can display a wide clinical and morphological variability even within a given family. European Journal of Human Genetics (2012) 20, 984-985; doi:10.1038/ejhg.2012.39; published online 7 March 2012
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- Hedberg, C., et al.
(författare)
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Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin
- 2012
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Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966 .- 1873-2364. ; 22:9-10, s. 873-873
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Hereditary myopathy with early respiratory failure (HMERF) and extensive myofibrillar lesions have been described in sporadic and familial cases and linked to various chromosomal regions. We describe the clinical manifestations, muscle histopathology and genetics in eight individuals from three apparently unrelated families with clinical and pathological features of HMERF. All patients had muscle weakness in the pelvic girdle, neck flexors, respiratory and trunk muscles, and the majority had prominent calf hypertrophy. Examination of pulmonary function showed decreased vital capacity. No signs of cardiac muscle involvement were found. Muscle histopathological features included marked muscle fibre size variation, fibre splitting, numerous internal nuclei and fatty infiltration. Frequent groups of fibres showed eosinophilic inclusions and deposits. At the ultrastructural level there were extensive myofibrillar lesions with marked Z-disc alterations. Whole exome sequencing in four individuals from one family revealed a missense mutation, g.274375, T>C; p.Cys30071Arg, in the titin gene, TTN. The mutation, which changes a highly conserved residue in the myosin binding A-band titin, was demonstrated to segregate with the disease in all three families. High density single nucleotide polymorphism arrays covering the entire genome demonstrated sharing of a 699 Mb haplotype, located in chromosome region 2q31 including TTN, indicating common ancestry of this novel and first disease-causing mutation in A-band titin associated with HMERF.
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- Lundberg, P O, et al.
(författare)
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Mitochondrial disorders
- 1996
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Ingår i: Acta Neurol Scand. ; 94
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Tidskriftsartikel (refereegranskat)
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- Luoma, Petri, et al.
(författare)
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Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study
- 2004
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Ingår i: Lancet. ; 364:9437, s. 875-82
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Mutations in the gene encoding mitochondrial DNA polymerase gamma (POLG), the enzyme that synthesises mitochondrial DNA (mtDNA), have been associated with a mitochondrial disease-autosomal dominant or recessive progressive external ophthalmoplegia-and multiple deletions of mtDNA. Mitochondrial dysfunction is also suspected to participate in the pathogenesis of Parkinson's disease. However, no primary gene defects affecting mitochondrial proteins causing mendelian transmission of parkinsonism have been characterised. We aimed to analyse the gene sequence of POLG in patients with progressive external ophthalmoplegia and their healthy relatives. METHODS: In seven families of various ethnic origins we assessed patients with progressive external ophthalmoplegia and unaffected individuals by clinical, biochemical, morphological, and molecular genetic characterisation and positron emission tomography (PET). FINDINGS: We recorded mutations in POLG in members of all seven families. Clinical assessment showed significant cosegregation of parkinsonism with POLG mutations (p<0.0001), and PET findings were consistent with dopaminergic neuron loss. Post-mortem examination in two individuals showed loss of pigmented neurons and pigment phagocytosis in substantia nigra without Lewy bodies. Furthermore, most women with progressive external ophthalmoplegia had early menopause-before age 35 years. The POLG gene defect resulted in secondary accumulation of mtDNA deletions in patients' tissues. INTERPRETATION: Dysfunction of mitochondrial POLG causes a severe progressive multisystem disorder including parkinsonism and premature menopause, which are not typical of mitochondrial disease. Cosegregation of parkinsonism and POLG mutations in our families suggests that when defective, this gene can underlie mendelian transmission of parkinsonism. RELEVANCE TO PRACTICE: Awareness that mitochondrial POLG mutations can underlie parkinsonism is important for clinicians working in diagnosis of movement disorders, as well as for studies of the genetics of Parkinson's disease. Further, progressive external ophthalmoplegia with muscle weakness and neuropathy can mask symptoms of parkinsonism, and clinicians should pay special attention to detect and treat parkinsonism in those individuals.
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- Melberg, Atle, et al.
(författare)
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Anticipation of autosomal dominant progressive external ophthalmoplegia with hypogonadism
- 1996
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Ingår i: Muscle and Nerve. - 0148-639X .- 1097-4598. ; 19:12, s. 1561-9
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Tidskriftsartikel (refereegranskat)abstract
- A large Swedish family with members affected by progressive external ophthalmoplegia with hypogonadism were followed-up and reviewed. Hypogonadism included delayed sexual maturation, primary amenorrhea, early menopause, and testicular atrophy. Cataracts, cerebellar ataxia, neuropathy, hypoacusia, pes cavus, tremor, parkinsonism, depression, and mental retardation were other features observed in this family. Muscle biopsy samples of advanced cases showed ragged-red fibers, focal cytochrome c oxidase deficiency, and multiple mtDNA deletions by Southern blot analysis. An autosomal dominant mode of inheritance was evident with anticipation in successive generations. Linkage analysis excluded the chromosome 10q23.3-q24.3 region reported as being linked to the disease in a Finnish family with autosomal dominant progressive external ophthalmoplegia. We report for the first time clinical evidence for anticipation in a family with autosomal dominant progressive external ophthalmoplegia. We hypothesize that the nuclear gene causing this enigmatic disorder may be directly influenced by an expansion of an unstable DNA sequence and that the resulting phenotype is caused by a concerted action with multiple deletions of mtDNA.
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- Melberg, Atle, et al.
(författare)
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Monozygotic twins with MELAS-like syndrome lacking ragged red fibers and lactacidaemia
- 1996
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Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314 .- 1600-0404. ; 94:4, s. 233-41
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Tidskriftsartikel (refereegranskat)abstract
- Typical cases of MELAS present a combination of clinical and neuroradiological features, lactacidaemia, and ragged red fibers (RRFs) in striated muscle. We have observed a MELAS-like syndrome in monozygotic twins. They developed seizures typically in conjunction with physical exertion, sleep deprivation or febrile episodes. Stroke-like episodes occurred usually during seizures. In twin 2 the course was fatal at age 20 years. Neuroradiological findings were typical of MELAS. Plasma lactate was normal in both. CSF lactate was normal in twin 1 and normal/elevated in twin 2. RRFs were not seen in muscle biopsies of the twins. Complex I activity was reduced in muscle in twin 1. Brain tissue removed at epilepsy surgery in twin 2 showed the presence of mitochondrial angiopathy. The commonest mitochondrial DNA mutation in MELAS, at base pair 3243, was absent. Lactacidaemia and mitochondrial myopathy with RRFs constitute part of the diagnostic criteria of MELAS. However, the absence of these features does not exclude mitochondrial disorder with the serious manifestations of MELAS (seizures and stroke-like episodes) as seen in these twins.
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