Leigh B Waddell

University of Sydney, Sydney, New South Wales, Australia

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Publications (19)69.99 Total impact

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    ABSTRACT: Myosin myopathies comprise a group of inherited diseases caused by mutations in myosin heavy chain (MyHC) genes. Homozygous or compound heterozygous truncating MYH2 mutations have been demonstrated to cause recessive myopathy with ophthalmoplegia, mild-to-moderate muscle weakness and complete lack of type 2A muscle fibers. In this study, we describe for the first time the clinical and morphological characteristics of recessive myosin IIa myopathy associated with MYH2 missense mutations. Seven patients of five different families with a myopathy characterized by ophthalmoplegia and mild-to-moderate muscle weakness were investigated. Muscle biopsy was performed to study morphological changes and MyHC isoform expression. Five of the patients were homozygous for MYH2 missense mutations, one patient was compound heterozygous for a missense and a nonsense mutation and one patient was homozygous for a frame-shift MYH2 mutation. Muscle biopsy demonstrated small or absent type 2A muscle fibers and reduced or absent expression of the corresponding MyHC IIa transcript and protein. We conclude that mild muscle weakness and ophthalmoplegia in combination with muscle biopsy demonstrating small or absent type 2A muscle fibers are the hallmark of recessive myopathy associated with MYH2 mutations.European Journal of Human Genetics advance online publication, 6 November 2013; doi:10.1038/ejhg.2013.250.
    European journal of human genetics: EJHG 11/2013; · 3.56 Impact Factor
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    ABSTRACT: MYH7 mutations are an established cause of Laing distal myopathy, myosin storage myopathy, and cardiomyopathy, as well as additional myopathy subtypes. We report a novel MYH7 mutation (p.Leu1597Arg) that arose de novo in two unrelated probands. Proband 1 has a myopathy characterized by distal weakness and prominent contractures and histopathology typical of multi-minicore disease. Proband 2 has an axial myopathy and histopathology consistent with congenital fiber type disproportion. These cases highlight the broad spectrum of clinical and histological patterns associated with MYH7 mutations, and provide further evidence that MYH7 is likely responsible for a greater proportion of congenital myopathies than currently appreciated.
    Neuromuscular Disorders 03/2013; · 3.46 Impact Factor
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    ABSTRACT: The limb-girdle MDs (LGMDs) are characterised by predominant weakness and wasting of pelvic and shoulder girdle muscles with onset after two years of age. Recessive mutations in the TCAP gene (encoding telethonin), were first identified as the cause of LGMD2G in 2000. Only a handful of families have been reported to date. Here, we report the ninth family with LGMD2G. The proband (P1) is a 32 year old male with an affected sister, five unaffected siblings and first-cousin parents of Chinese-Cambodian descent. P1 had slowly progressive muscle weakness since his late teenage years. On examination at 27 years of age, he had bilateral Achilles contractures, mild calf hypertrophy, asymmetric scapular winging and normal facial strength except mild weakness of eye closure. There was moderate weakness of hip movements and knee extension and mild weakness of most other muscle groups, except hand and wrist movements. We performed genome-wide linkage analysis assuming autosomal recessive inheritance using Illumina 660WQ SNP platform and found positive LOD scores for the chromosomal region 17p11.2-q22, containing the TCAP gene, as well as regions on chromosomes 7, 16 and 18. Sanger sequencing of TCAP revealed a homozygous 8 base pair duplication (c.26_33dupAGGTGTCG) resulting in a frameshift and truncated protein (p.R12fsX31), predicted to abolish telethonin expression. Two other families of Chinese origin have been reported with the same homozygous mutation. A muscle MRI at 28 years of age demonstrated widespread asymmetric fatty infiltration of lower limb muscles in a pattern similar to that reported in another LGMD2G patient by CT imaging. In conclusion, LGMD2G is rare, but exists outside Brazil and our identification of a third Asian LGMD2G family with the p.R12fsX31 mutation suggests this may be a population-specific mutation. Consistency in the pattern of muscle involvement on MRI or CT in two LGMD2G patients suggests this investigation may be a useful tool for diagnosis.
    Neuromuscular Disorders 10/2012; 22(s 9–10):831–832. · 3.46 Impact Factor
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    ABSTRACT: Mutations in the gene that encodes filamin C, FLNC, represent a rare cause of a distinctive type of myofibrillar myopathy (MFM). We investigated an Italian patient by means of muscle biopsy, muscle and brain imaging and molecular analysis of MFM genes. The patient harbored a novel 7256C>T, p.Thr2419Met mutation in exon 44 of FLNC. Clinical, pathological and muscle MRI findings were similar to the previously described filaminopathy cases. This patient had, in addition, cerebellar ataxia with atrophy of cerebellum and vermis evident on brain MRI scan. Extensive screening failed to establish a cause of cerebellar atrophy. We report an Italian filaminopathy patient, with a novel mutation in a highly conserved region. This case raises the possibility that the disease spectrum caused by FLNC may include cerebellar dysfunction.
    Muscle & Nerve 08/2012; 46(2):275-82. · 2.31 Impact Factor
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    ABSTRACT: The main diagnostic feature of congenital fibre type disproportion is that type 1 fibres are consistently smaller than type 2 fibres in the absence of other histological abnormalities. Mutations in the TPM3, RYR1 and ACTA1 genes are the most common established genetic causes. There has been one previous report of congenital fibre type disproportion due to a mutation in TPM2, although some atypical histological features were present. We present two cases in which novel de novo missense mutations in TPM2 are associated with marked fibre size disproportion. The finding of typical histological changes of congenital fibre type disproportion in association with a p.Ser61Pro mutation confirms that TPM2 can cause typical congenital fibre type disproportion. Although not seen on light microscopy studies, protein inclusions typical of small 'caps' were found on electron microscopy in a second patient with a p.Ala155Val mutation in TPM2. This case emphasises the importance of electron microscopy in patients with presumed congenital fibre type disproportion, to exclude the presence of caps, nemaline bodies or minicores, which, if present, may be very helpful in guiding genetic analysis.
    Neuromuscular Disorders 07/2012; · 3.46 Impact Factor
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    ABSTRACT: To identify the most useful clinical and histologic markers that facilitate early diagnosis in LMNA-related muscular dystrophy and to assess the usefulness of Western blotting (WB) for lamin A/C. We analyzed the clinical and histologic features and WB results of all patients with laminopathies diagnosed in a research-based diagnostic service over 8 years. Although patients with congenital muscular dystrophy (MDCL) (n = 5) and Emery-Dreifuss muscular dystrophy (EDMD) (n = 5) had distinctive early clinical features, the lack of a suggestive clinical phenotype significantly delayed diagnosis in 2 of 3 patients with limb-girdle muscular dystrophy (LGMD) (n = 3). In addition, 6 of 20 muscle biopsy samples were considered nondystrophic, which contributed to delays in diagnosis in some patients. Neck extensor involvement (weakness or contractures) was the most consistent clinical sign, present in all patients. Reduced lamin A/C levels on WB were seen in 5 of 9 patients with laminopathies. Clinical features provide the best clues for diagnosing MDCL and EDMD early in the disease, and we urge clinicians to become familiar with those phenotypes. WB for lamin A/C may contribute to diagnosis but requires technical expertise, and results are normal in many individuals with LMNA mutations. Because of the survival benefit of early diagnosis and treatment, we recommend that LMNA gene sequencing be performed in all patients with undiagnosed congenital muscular dystrophy and neck extensor weakness, all patients with genetically undiagnosed LGMD, and those with suggestive clinical signs and nonspecific histologic abnormalities.
    Neurology 04/2012; 78(16):1258-63. · 8.25 Impact Factor
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    ABSTRACT: Description of 8 new ANO5 mutations and significant expansion of the clinical phenotype spectrum associated with previously known and unknown mutations to improve diagnostic accuracy. DNA samples of 101 patients in 95 kindreds at our quaternary referral center in Finland, who had undetermined limb-girdle muscular dystrophy (LGMD), calf distal myopathy, or creatine kinase (CK) elevations of more than 2,000 IU/L, were selected for ANO5 genetic evaluation, and the clinical findings of patients with mutations were retrospectively analyzed. A total of 25 patients with muscular dystrophy caused by 11 different recessive mutations in the ANO5 gene were identified. The vast majority of mutations, 8 of 11, proved to be previously unknown new mutations. The most frequent mutation, c.2272C>T (p.R758C), was present in 20 patients. The phenotypes associated with this and the common European mutation, c.191dupA, varied from nearly asymptomatic high hyperCKemia to severe LGMD with consistently milder phenotypes in female patients. Mutations in ANO5 are a frequent cause of undetermined muscular dystrophy, with both distal and proximal presentation. Other types include high hyperCKemia, myalgia, or calf hypertrophy over decades without significant weakness, especially in female patients. Mutations are distributed all over the gene, indicating that muscular dystrophy caused by ANO5 can be expected to occur in all populations.
    Neurology 03/2012; 78(12):897-903. · 8.25 Impact Factor
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    ABSTRACT: Large muscle genes are often sequenced using complementary DNA (cDNA) made from muscle messenger RNA (mRNA) to reduce the cost and workload associated with sequencing from genomic DNA. Two potential barriers are the availability of a frozen muscle biopsy, and difficulties in detecting nonsense mutations due to nonsense-mediated mRNA decay (NMD). We present patient examples showing that use of MyoD-transduced fibroblasts as a source of muscle-specific mRNA overcomes these potential difficulties in sequencing large muscle-related genes.
    Muscle & Nerve 08/2011; 44(2):280-2. · 2.31 Impact Factor
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    ABSTRACT: Epidermolysis bullosa associated with muscular dystrophy is a rare, autosomal recessive form of epidermolysis bullosa simplex caused by mutations in the plectin gene, PLEC1. We describe a phenotypically mild case due to compound heterozygous mutations in PLEC1 (2677_2685del and the novel mutation Q1644X). Clinical features included mild skin blistering since birth, slowly progressive and late-onset upper limb-predominant weakness, facial weakness, ptosis, incomplete ophthalmoplegia, and paroxysmal atrial fibrillation.
    Muscle & Nerve 07/2011; 44(1):135-41. · 2.31 Impact Factor
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    ABSTRACT: FHL1, BAG3, MATR3 and PTRF are recently identified myopathy genes associated with phenotypes that overlap muscular dystrophy. TCAP is a rare reported cause of muscular dystrophy not routinely screened in most centres. We hypothesised that these genes may account for patients with undiagnosed forms of muscular dystrophy in Australia. We screened a large cohort of muscular dystrophy patients for abnormalities in FHL1 (n=102) and TCAP (n=100) and selected patients whose clinical features overlapped the phenotypes previously described for BAG3 (n=9), MATR3 (n=15) and PTRF (n=7). We found one FHL1 mutation (c.311G>A, p.C104Y) in a boy with rapidly progressive muscle weakness and reducing body myopathy who was initially diagnosed with muscular dystrophy. We identified no pathogenic mutations in BAG3, MATR3, PTRF or TCAP. In conclusion, we have excluded these five genes as common causes of muscular dystrophy in Australia. Patients with reducing body myopathy may be initially diagnosed as muscular dystrophy.
    Neuromuscular Disorders 06/2011; 21(11):776-81. · 3.46 Impact Factor
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    ABSTRACT: Mutations in dysferlin cause an inherited muscular dystrophy because of defective membrane repair. Three interacting partners of dysferlin are also implicated in membrane resealing: caveolin-3 (in limb girdle muscular dystrophy type 1C), annexin A1, and the newly identified protein mitsugumin 53 (MG53). Mitsugumin 53 accumulates at sites of membrane damage, and MG53-knockout mice display a progressive muscular dystrophy. This study explored the expression and localization of MG53 in human skeletal muscle, how membrane repair proteins are modulated in various forms of muscular dystrophy, and whether MG53 is a primary cause of human muscle disease. Mitsugumin 53 showed variable sarcolemmal and/or cytoplasmic immunolabeling in control human muscle and elevated levels in dystrophic patients. No pathogenic MG53 mutations were identified in 50 muscular dystrophy patients, suggesting that MG53 is unlikely to be a common cause of muscular dystrophy in Australia. Western blot analysis confirmed upregulation of MG53, as well as of dysferlin, annexin A1, and caveolin-3 to different degrees, in different muscular dystrophies. Importantly, MG53, annexin A1, and dysferlin localize to the t-tubule network and show enriched labeling at longitudinal tubules of the t-system in overstretch. Our results suggest that longitudinal tubules of the t-system may represent sites of physiological membrane damage targeted by this membrane repair complex.
    Journal of Neuropathology and Experimental Neurology 03/2011; 70(4):302-13. · 4.35 Impact Factor
  • L. Waddell, K. N. North, N. F. Clarke
    Neuromuscular Disorders - NEUROMUSCULAR DISORD. 01/2011; 21(9):743-743.
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    ABSTRACT: Congenital heart disease (CHD) represents one of the most common birth defects, but the genetic causes remain largely unknown. Mutations in GATA4, encoding a zinc finger transcription factor with a pivotal role in heart development, have been associated with CHD in several familial cases and a small subset of sporadic patients. To estimate the pathogenetic role of GATA4 in CHD, we screened for mutations in 357 unrelated patients with different congenital heart malformations. In addition to nine synonymous changes, we identified two known (A411V and D425N) and two novel putative mutations (G69D and P163R) in five patients with atrial or ventricular septal defects that were not seen in control subjects. The four mutations did not show altered GATA4 transcriptional activity in synergy with the transcription factors NKX2-5 and TBX20. Our data expand the spectrum of mutations associated with cardiac septal defects but do not support GATA4 mutations as a common cause of CHD.
    Genetic Testing and Molecular Biomarkers 12/2010; 14(6):797-802. · 1.44 Impact Factor
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    ABSTRACT: The main histological abnormality in congenital fiber type disproportion (CFTD) is hypotrophy of type 1 (slow twitch) fibers compared to type 2 (fast twitch) fibers. To investigate whether mutations in RYR1 are a cause of CFTD we sequenced RYR1 in seven CFTD families in whom the other known causes of CFTD had been excluded. We identified compound heterozygous changes in the RYR1 gene in four families (five patients), consistent with autosomal recessive inheritance. Three out of five patients had ophthalmoplegia, which may be the most specific clinical indication of mutations in RYR1. Type 1 fibers were at least 50% smaller, on average, than type 2 fibers in all biopsies. Recessive mutations in RYR1 are a relatively common cause of CFTD and can be associated with extreme fiber size disproportion.
    Human Mutation 07/2010; 31(7):E1544-50. · 5.21 Impact Factor
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    ABSTRACT: We report a third patient with typical cap myopathy due to a heterozygous TPM3 mutation, confirming the importance of this causal association. The p.R168C TPM3 mutation we identified has been reported in two previous patients. The histological changes associated with this mutation vary widely from typical cap myopathy with near complete type 1 predominance (two patients), to typical congenital fibre-type disproportion without protein inclusions (one patient). We performed 2D-gel electrophoresis using muscle biopsies from two patients with the p.R168C mutation and show that mutant protein accounts for around 50% of alpha-tropomyosin(slow) in sarcomeres, consistent with a dominant negative mechanism of disease pathogenesis.
    Neuromuscular Disorders 07/2010; 20(7):464-6. · 3.46 Impact Factor
  • Neuromuscular Disorders - NEUROMUSCULAR DISORD. 01/2010; 20(9):615-615.
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    ABSTRACT: Cap disease or cap myopathy is a form of congenital myopathy in which peripheral, well-demarcated 'caps' of disorganised thin filaments are seen in muscle fibres. Mutation of the TPM2 gene, that encodes beta-tropomyosin, is the first reported genetic cause. In this paper, we describe a further case of cap disease due to a mutation in TPM2, confirming the importance of this genetic association. This is the first report of cardiac dysfunction due to a mutation in TPM2. Our patient has an identical TPM2 mutation to the first genetically diagnosed cap disease patient, a denovo heterozygous three base pair deletion that removes glutamic acid 139 from the centre of beta-tropomyosin (p.E139del). 2D-gel electrophoresis studies show that the shortened mutant protein incorporates into sarcomeric structures, where it likely imposes a dominant-negative effect to cause muscle weakness.
    Neuromuscular Disorders 05/2009; 19(5):348-51. · 3.46 Impact Factor
  • Neuromuscular Disorders - NEUROMUSCULAR DISORD. 01/2009; 19(8):557-557.
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    ABSTRACT: The T-box family transcription factor gene TBX20 acts in a conserved regulatory network, guiding heart formation and patterning in diverse species. Mouse Tbx20 is expressed in cardiac progenitor cells, differentiating cardiomyocytes, and developing valvular tissue, and its deletion or RNA interference-mediated knockdown is catastrophic for heart development. TBX20 interacts physically, functionally, and genetically with other cardiac transcription factors, including NKX2-5, GATA4, and TBX5, mutations of which cause congenital heart disease (CHD). Here, we report nonsense (Q195X) and missense (I152M) germline mutations within the T-box DNA-binding domain of human TBX20 that were associated with a family history of CHD and a complex spectrum of developmental anomalies, including defects in septation, chamber growth, and valvulogenesis. Biophysical characterization of wild-type and mutant proteins indicated how the missense mutation disrupts the structure and function of the TBX20 T-box. Dilated cardiomyopathy was a feature of the TBX20 mutant phenotype in humans and mice, suggesting that mutations in developmental transcription factors can provide a sensitized template for adult-onset heart disease. Our findings are the first to link TBX20 mutations to human pathology. They provide insights into how mutation of different genes in an interactive regulatory circuit lead to diverse clinical phenotypes, with implications for diagnosis, genetic screening, and patient follow-up.
    The American Journal of Human Genetics 09/2007; 81(2):280-91. · 11.20 Impact Factor

Publication Stats

179 Citations
69.99 Total Impact Points


  • 2009–2012
    • University of Sydney
      • Discipline of Paediatrics and Child Health
      Sydney, New South Wales, Australia
  • 2007–2012
    • Children's Hospital at Westmead
      • • Institute of Neuroscience and Muscle Research
      • • Kids Heart Research Unit
      Sydney, New South Wales, Australia