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Research

Congenital myopathies and muscular dystrophies team

Our Unit has developed a scientific program of specialised analysis of the congenital myopathies and congenital muscular dystrophies. Children with congenital myopathy typical present with generalised weakness, hypotonia (low tone, which is an inability to hold against gravity) and poor muscle bulk from birth. The underlying histological feature of most congenital myopathies is a disruption of the internal contracting mechanism of muscle. In recent times, improved histology techniques and genetic testing procedures have clarified the identification of the congenital myopathies and muscular dystrophies. There are a number of specific myopathies studied by our scientists.

Nemaline myopathy

Dr Biljana Ilkovski (Postdoctoral scientist), Ana Domazetovska (PhD student), Nancy Mokbel (Honours student)

The most common form of congenital myopathy is nemaline myopathy. Nemaline myopathy was first described by a pathologist, Dr Douglas Reye at Royal Alexandra Hospital for Children (now known as The Children's Hospital at Westmead) in 1958 however; this honour was recognised only very recently. Characteristically, patients with nemaline myopathy have accumulations in their muscle cells called nemaline rods. We do not know how these accumulations occur. In recent years, genetic defects in various genes, including actin and tropomyosin have been identified to cause nemaline myopathy. The team study the causes and consequences of nemaline myopathy and have produced landmark reports influencing our understanding of this disorder. The team are now developing laboratory models to mimic this disorder in vitro. Our goal is to understand how the disruption of the internal muscle structure affects overall muscle function and determine therapies to alleviate this disorder.

Selected Publications

Corbett MA, Akkari PA, Domazetovska A, Cooper ST, North KN, Laing NG, Gunning PW, Hardeman EC. A mutation in -tropomyosinslow alters tropomyosin dimer preference in nemaline myopathy. Annals of Neurology 2005,57:42-49.

Jungbluth H, Sewry CA, Counsell S, Allsop J, Chattopadhyay A, Mercuri E, North K, Laing N, Bydder G, Pelin K, Wallgren-Pettersson C, Muntoni F. Magnetic resonance imaging of muscle in nemaline myopathy. Neuromuscul Disord. 2004 Dec;14(12):779-784.

Ilkovski B, Nowak KJ, Domazetovska A, Maxwell AL, Clement S, Davies KE, Laing NG, North KN, Cooper ST. Evidence for a dominant-negative effect in ACTA1 nemaline myopathy caused by abnormal folding, aggregation and altered polymerization of mutant actin isoforms. Human Molecular Genetics 2004:13:1727-1743.

Wallgren-Pettersson C, Pelin K, Nowak K, Muntoni F, Romero NB, Goebel HH, North K, Beggs A, Laing N. Genotype-phenotype correlations in patients with nemaline myopathy caused by mutations in the genes for nebulin and alpha-actin. Neuromuscular Disorders 2004;14:461-470.

Davis MR, Haan E, Jungbluth H, Sewry C, North KN, Muntoni F, et al. Principal mutation hotspot for central core disease and related myopathies in the C-terminal transmembrane region of the RYR1 gene. Neuromuscular Disorders 2003;13(2):151-7.

Ryan MM, Ilkovski B, Strickland CD, Schnell C, Sanoudou D, Midgett C, Dennett X, Shield LK, Iannaccone ST, Laing NG, North KN, Beggs AH. Clinical course correlates poorly with muscle pathology in nemaline myopathy. Neurology 2003;60:665-673.

Ryan MM, Schnell C, Strickland C, Shield LK, Morgan G, Iannoccone ST, Laing NG, Beggs AH, North KN. Nemaline myopathy: a clinical study of 143 cases. Annals of Neurology 2001;50:312-320.

Ilkovski B, Cooper ST, Nowak K, Ryan MM, Yang N, Schnell C, Durling HJ, Gunning P, Hardeman EC, Laing NL, North KN. Nemaline myopathy caused by mutations in the muscle alpha-skeletal actin gene. American Journal of Human Genetics 2001;68:1333-1343.

Corbett M, Robinson CS, Dunglison G, Yang N, Joya J, Stewart A, Schnell C, Gunning P, North KN, Hardeman E. A mutation in -tropomyosinSLOW affects muscle strength, maturation and hypertrophy in a mouse model for nemaline myopathy. Human Molecular Genetics, 2001:10:317-328.

Schnell C, Kan A, North KN. "An artefact gone awry": The first case of nemaline myopathy identified by R D.K Reye in Sydney Australia. Neuromuscular Disorders 2000;10:307-312.

Nowak KJ, Wattanasirichaigoo D, Goebel HH, Wilce M, Pelin K, Donner K, Jacob RL, Hubner C, Anderson JR, North KN, Iannaccone ST, Muller C, Nurnberg P, Muntoni F, Hughes I, Sutphen R, Lacson A, Swoboda KJ, Vigneron J, Wallgren-Petersson C, Beggs AH, Laing NG. Mutations in the skeletal muscle actin gene in patients with actin myopathy and nemaline myopathy. Nature Genetics 1999;23:208-212.

Tan P, Briner J, Boltshauser E, Davis MR, Wilton SD, North KN, Wallgren-Pettersson C, Laing NG. Homozygosity for a nonsense mutation in the alpha-tropomyosin gene TPM3 in a patient with severe infantile nemaline myopathy. Neuromusc Disord 1999;9:573-579.

Congenital fibre type disproportion

Dr Nigel Clarke (PhD student)

Muscles are composed of fast and slow muscle cells. These different cell types allow us to perform actions like sprinting (fast muscle cells) and other actions that require stamina such as standing up or running a marathon (slow muscle cells). Congenital fibre type disproportion (CFTD) describes a group of disorders that have decreased growth of slow muscle cells. Children with CFTD have muscle weakness and low tone. Relative to other congenital myopathies, the clinical patterns of disease and causes of CFTD remain poorly understood. It is now clear that type 1 fibre atrophy or hypotrophy can occur as a secondary feature in a wide range of neuromuscular conditions but there remains a group of patients who have primary CFTD. The clinical features of primary CFTD can resemble a congenital myopathy, muscular dystrophy, peripheral neuropathy, disorder of the central nervous system or multi-system disease. This clinical heterogeneity impairs the clinician's ability to predict an outcome for the patient and suggests that primary CFTD has many causes. Our aim is to better define this group of disorders and identify a range of genetic causes in our Australian population.

Selected Publications

Clarke NF, Smith R, Bahlo M, North KN. A novel X-linked form of congenital fibre type disproportion. Annals of Neurology 2005; in press.

Laing NG, Clarke NF, Dye D, Walker K, Kobayashi Y, Shimakawa S, Ogihara T, Ouvrier R, Sparrow JC, Nishino I, North KN, Nonaka I. Actin mutations are one cause of congenital fibre type disproportion. Annals of Neurology 2004, 56:689-694.

Clarke N, North KN. Congenital fiber type disproportion - pathology in search of a disease. Journal of Neuropathology and Experimental Neurology 2003;62:977-989.

Congenital muscular dystrophies

Rachel Peat (PhD student), Dr Janine Smith (Masters student)

Congenital muscular dystrophies (CMD) are a group of muscle diseases, which present during the first few months of a child's life. Children with CMD are usually weak from birth and are described as 'floppy' and may have contractures or stiffening of the joints. Muscle biopsies from children with CMD show 'dystrophic' features, which include degenerating and regenerating muscle fibres, an increase in connective tissue and increase in central nuclei. Scientists have identified several genetic defects that cause CMD including mutations in laminin -2 and collagen VI.

Our team is studying the incidence of known causes of congenital muscular dystrophies in Australia. This information is important to guide clinicians through diagnostic procedures for affected patients. In addition, researchers are examining a number of candidate proteins likely to cause these disorders in Australian patients.

Selected Publications

Baker NL, Morgelin M, Peat R, Goemans N, North KN, Bateman JF, Lamande SR. Dominant collagen VI mutations are a common cause of Ullrich congenital muscular dystrophy. Human Molecular Genetics 2005, 14:279-293.

This document was published on Tuesday, 9 August 2005.

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