| 1. |
- Gurgel-Giannetti, J., et al.
(author)
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A novel complex neurological phenotype due to a homozygous mutation in FDX2
- 2018
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In: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 141, s. 2289-2298
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Journal article (peer-reviewed)abstract
- Defects in iron-sulphur [Fe-S] cluster biogenesis are increasingly recognized as causing neurological disease. Mutations in a number of genes that encode proteins involved in mitochondrial [Fe-S] protein assembly lead to complex neurological phenotypes. One class of proteins essential in the early cluster assembly are ferredoxins. FDX2 is ubiquitously expressed and is essential in the de novo formation of [2Fe-2S] clusters in humans. We describe and genetically define a novel complex neurological syndrome identified in two Brazilian families, with a novel homozygous mutation in FDX2. Patients were clinically evaluated, underwent MRI, nerve conduction studies, EMG and muscle biopsy. To define the genetic aetiology, a combination of homozygosity mapping and whole exome sequencing was performed. We identified six patients from two apparently unrelated families with autosomal recessive inheritance of a complex neurological phenotype involving optic atrophy and nystagmus developing by age 3, followed by myopathy and recurrent episodes of cramps, myalgia and muscle weakness in the first or second decade of life. Sensory-motor axonal neuropathy led to progressive distal weakness. MRI disclosed a reversible or partially reversible leukoencephalopathy. Muscle biopsy demonstrated an unusual pattern of regional succinate dehydrogenase and cytochrome c oxidase deficiency with iron accumulation. The phenotype was mapped in both families to the same homozygous missense mutation in FDX2 (c. 431C > T, p. P144L). The deleterious effect of the mutation was validated by real-time reverse transcription polymerase chain reaction and western blot analysis, which demonstrated normal expression of FDX2 mRNA but severely reduced expression of FDX2 protein in muscle tissue. This study describes a novel complex neurological phenotype with unusual MRI and muscle biopsy features, conclusively mapped to a mutation in FDX2, which encodes a ubiquitously expressed mitochondrial ferredoxin essential for early [Fe-S] cluster biogenesis.
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| 2. |
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| 3. |
- Horvath, Rita, et al.
(author)
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Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy.
- 2009
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In: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 132:Pt 11, s. 3165-74
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Journal article (peer-reviewed)abstract
- Childhood-onset mitochondrial encephalomyopathies are usually severe, relentlessly progressive conditions that have a fatal outcome. However, a puzzling infantile disorder, long known as 'benign cytochrome c oxidase deficiency myopathy' is an exception because it shows spontaneous recovery if infants survive the first months of life. Current investigations cannot distinguish those with a good prognosis from those with terminal disease, making it very difficult to decide when to continue intensive supportive care. Here we define the principal molecular basis of the disorder by identifying a maternally inherited, homoplasmic m.14674T>C mt-tRNA(Glu) mutation in 17 patients from 12 families. Our results provide functional evidence for the pathogenicity of the mutation and show that tissue-specific mechanisms downstream of tRNA(Glu) may explain the spontaneous recovery. This study provides the rationale for a simple genetic test to identify infants with mitochondrial myopathy and good prognosis.
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| 4. |
- Kollberg, Gittan, 1963, et al.
(author)
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Clinical manifestation and a new ISCU mutation in iron-sulphur cluster deficiency myopathy
- 2009
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In: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 132:8, s. 2170-2179
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Journal article (peer-reviewed)abstract
- Myopathy with deficiency of succinate dehydrogenase and aconitase is a recessively inherited disorder characterized by childhood-onset early fatigue, dyspnoea and palpitations on trivial exercise. The disease is non-progressive, but life-threatening episodes of widespread weakness, severe metabolic acidosis and rhabdomyolysis may occur. The disease has so far only been identified in northern Sweden. The clinical, histochemical and biochemical phenotype is very homogenous and the patients are homozygous for a deep intronic IVS5 382GC splicing affecting mutation in ISCU, which encodes the differently spliced cytosolic and mitochondrial ironsulphur cluster assembly protein IscU. Ironsulphur cluster containing proteins are essential for iron homeostasis and respiratory chain function, with IscU being among the most conserved proteins in evolution. We identified a shared homozygous segment of only 405 000 base pair with the deep intronic mutation in eight patients with a phenotype consistent with the original description of the disease. Two other patients, two brothers, had an identical biochemical and histochemical phenotype which is probably pathognomonic for muscle ironsulphur cluster deficiency, but they presented with a disease where the clinical phenotype was characterized by early onset of a slowly progressive severe muscle weakness, severe exercise intolerance and cardiomyopathy. The brothers were compound heterozygous for the deep intronic mutation and had a c.149 GA missense mutation in exon 3 changing a completely conserved glycine residue to a glutamate. The missense mutation was inherited from their mother who was of Finnish descent. The intronic mutation affects mRNA splicing and results in inclusion of pseudoexons in most transcripts in muscle. The pseudoexon inclusion results in a change in the reading frame and appearance of a premature stop codon. In western blot analysis of protein extracts from fibroblasts, there was no pronounced reduction of IscU in any of the patients, but the analysis revealed that the species corresponding to mitochondrial IscU migrates slower than a species present only in whole cells. In protein extracted from isolated skeletal muscle mitochondria the western blot analysis revealed a severe deficiency of IscU in the homozygous patients and appearance of a faint new fraction that could represent a truncated protein. There was only a slight reduction of mitochondrial IscU in the compound heterozygotes, despite their severe phenotype, indicating that the IscU expressed in these patients is non-functional.
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| 5. |
- Kärppä, Mikko, et al.
(author)
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Spectrum of myopathic findings in 50 patients with the 3243A>G mutation in mitochondrial DNA
- 2005
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In: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 128:Pt 8, s. 1861-9
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Journal article (peer-reviewed)abstract
- Myopathy is a typical clinical finding among patients with the 3243A>G mutation in mitochondrial DNA (mtDNA), but the variability in such findings has not been properly established. We have previously determined the prevalence of patients with 3243A>G in a defined population in northern Finland and characterized a group of patients who represent a good approximation to a population-based cohort. We report here on examinations performed on patients belonging to this cohort in order to determine the frequency of myopathy and to evaluate the clinical, histological, ultrastructural and single fibre mtDNA variability in muscle involvement. Fifty patients with 3243A>G underwent a thorough structured interview and clinical examination. Muscle histology, ultrastructure and single fibre analysis were examined in a subset of patients. A clinical diagnosis of myopathy was made in 50% of cases [95% confidence interval (CI), 36-64] and abnormalities in muscle histology were found in 72% (95% CI, 55-86). Moderate limb weakness leading to functional impairment was the most common myopathic sign, but mild weakness, ptosis and external ophthalmoplegia could also be found. The presence of intramitochondrial crystals and cytochrome c oxidase (COX)-negative fibres and variation in mitochondrial size and shape were more common in the muscles of the myopathic patients. Longitudinal variations in mutation heteroplasmy were examined in single muscle fibres from two severely affected patients. Although the total variation in mutation heteroplasmy along four ragged red fibres (RRFs) was small, the mutation heteroplasmy in five 10 microm segments was clearly lower (median 68%, range 64-74%) than that in the neighbouring segments. There were also segments with deviant mutation load in histologically normal fibres in one patient. The highest incidence of myopathy was in the fifth decade of life, but, apart from age, no other clinical variables such as gender, muscle heteroplasmy, physical inactivity or diabetes were associated with an increased risk of myopathy. The clinical presentation of myopathy is highly variable in patients with 3243A>G.
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| 6. |
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| 7. |
- Ohlsson, Monica, et al.
(author)
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Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin
- 2012
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In: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 135:6, s. 1682-1694
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Journal article (peer-reviewed)abstract
- Hereditary myopathy with early respiratory failure and extensive myofibrillar lesions has been described in sporadic and familial cases and linked to various chromosomal regions. The mutated gene is unknown in most cases. We studied eight individuals, from three apparently unrelated families, with clinical and pathological features of hereditary myopathy with early respiratory failure. The investigations included clinical examination, muscle histopathology and genetic analysis by whole exome sequencing and single nucleotide polymorphism arrays. All patients had adult onset 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.274375T > 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 6.99 Mb haplotype, located in chromosome region 2q31 including TTN, indicating common ancestry. Our results demonstrate a novel and the first disease-causing mutation in A-band titin associated with hereditary myopathy with early respiratory failure. The typical histopathological features with prominent myofibrillar lesions and inclusions in muscle and respiratory failure early in the clinical course should be incentives for analysis of TTN mutations.
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| 8. |
- Oldfors Hedberg, Carola, 1969, et al.
(author)
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Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles
- 2020
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In: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 143:8, s. 2406-2420
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Journal article (peer-reviewed)abstract
- The muscle specific isoform of the supervillin protein (SV2), encoded by the SVIL gene, is a large sarcolemmal myosin II- and F-actin-binding protein. Supervillin (SV2) binds and co-localizes with costameric dystrophin and binds nebulin, potentially attaching the sarcolemma to myofibrillar Z-lines. Despite its important role in muscle cell physiology suggested by various in vitro studies, there are so far no reports of any human disease caused by SVIL mutations. We here report four patients from two unrelated, consanguineous families with a childhood/adolescence onset of a myopathy associated with homozygous loss-of-function mutations in SVIL. Wide neck, anteverted shoulders and prominent trapezius muscles together with variable contractures were characteristic features. All patients showed increased levels of serum creatine kinase but no or minor muscle weakness. Mild cardiac manifestations were observed. Muscle biopsies showed complete loss of large supervillin isoforms in muscle fibres by western blot and immunohistochemical analyses. Light and electron microscopic investigations revealed a structural myopathy with numerous lobulated muscle fibres and considerable myofibrillar alterations with a coarse and irregular intermyofibrillar network. Autophagic vacuoles, as well as frequent and extensive deposits of lipoproteins, including immature lipofuscin, were observed. Several sarcolemma-associated proteins, including dystrophin and sarcoglycans, were partially mis-localized. The results demonstrate the importance of the supervillin (SV2) protein for the structural integrity of muscle fibres in humans and show that recessive loss-of-function mutations in SVIL cause a distinctive and novel myopathy
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| 9. |
- Olsen, Rikke K J, et al.
(author)
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ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency.
- 2007
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In: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 130:Pt 8, s. 2045-54
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Journal article (peer-reviewed)abstract
- Multiple acyl-CoA dehydrogenation deficiency (MADD) is a disorder of fatty acid, amino acid and choline metabolism that can result from defects in two flavoproteins, electron transfer flavoprotein (ETF) or ETF: ubiquinone oxidoreductase (ETF:QO). Some patients respond to pharmacological doses of riboflavin. It is unknown whether these patients have defects in the flavoproteins themselves or defects in the formation of the cofactor, FAD, from riboflavin. We report 15 patients from 11 pedigrees. All the index cases presented with encephalopathy or muscle weakness or a combination of these symptoms; several had previously suffered cyclical vomiting. Urine organic acid and plasma acyl-carnitine profiles indicated MADD. Clinical and biochemical parameters were either totally or partly corrected after riboflavin treatment. All patients had mutations in the gene for ETF:QO. In one patient, we show that the ETF:QO mutations are associated with a riboflavin-sensitive impairment of ETF:QO activity. This patient also had partial deficiencies of flavin-dependent acyl-CoA dehydrogenases and respiratory chain complexes, most of which were restored to control levels after riboflavin treatment. Low activities of mitochondrial flavoproteins or respiratory chain complexes have been reported previously in two of our patients with ETF:QO mutations. We postulate that riboflavin-responsive MADD may result from defects of ETF:QO combined with general mitochondrial dysfunction. This is the largest collection of riboflavin-responsive MADD patients ever reported, and the first demonstration of the molecular genetic basis for the disorder.
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| 10. |
- Tajsharghi, Homa, 1968, et al.
(author)
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Human disease caused by loss of fast IIa myosin heavy chain due to recessive MYH2 mutations.
- 2010
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In: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 133:Pt 5, s. 1451-9
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Journal article (peer-reviewed)abstract
- Striated muscle myosin heavy chain is a molecular motor protein that converts chemical energy into mechanical force. It is a major determinant of the physiological properties of each of the three muscle fibre types that make up the skeletal muscles. Heterozygous dominant missense mutations in myosin heavy chain genes cause various types of cardiomyopathy and skeletal myopathy, but the effects of myosin heavy chain null mutations in humans have not previously been reported. We have identified the first patients lacking fast type 2A muscle fibres, caused by total absence of fast myosin heavy chain IIa protein due to truncating mutations of the corresponding gene MYH2. Five adult patients, two males and three females, from three unrelated families in UK and Finland were clinically assessed and muscle biopsy was performed in one patient from each family. MYH2 was sequenced and the expression of the corresponding transcripts and protein was analysed in muscle tissue. The patients had early-onset symptoms characterized by mild generalized muscle weakness, extraocular muscle involvement and relatively favourable prognosis. Muscle biopsy revealed myopathic changes including variability of fibre size, internalized nuclei, and increased interstitial connective and adipose tissue. No muscle fibres expressing type IIa myosin heavy chain were identified and the MYH2 transcripts were markedly reduced. All patients were compound heterozygous for truncating mutations in MYH2. The parents were unaffected, consistent with recessive mutations. Our findings show that null mutations in the fast myosin heavy chain IIa gene cause early onset myopathy and demonstrate that this isoform is necessary for normal muscle development and function. The relatively mild phenotype is interesting in relation to the more severe phenotypes generally seen in relation to recessive null mutations in sarcomeric proteins.
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