Trends in Molecular Medicine
Volume 7, Issue 8, 1 August 2001, Pages 362-368
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Clinical and genetic heterogeneity in nemaline myopathy – a disease of skeletal muscle thin filaments

https://doi.org/10.1016/S1471-4914(01)02089-5Get rights and content

Abstract

The term nemaline myopathy (NM) encompasses a heterogeneous group of disorders of primary skeletal muscle weakness characterized by the presence of nemaline rods in muscles of affected individuals. Disease severity is variable and unpredictable, with prognosis ranging from neonatal death to almost normal motor function. Recent advances in the identification of NM disease genes demonstrate that NM is a disease of the skeletal muscle sarcomere and, in particular, of the thin filaments. These findings are starting to alter the approach that neurologists and geneticists take to diagnosing and counseling patients with NM, and could lead to insights into specific directed therapies in the future.

Section snippets

Clinical description

The nemaline myopathies are defined by primary proximal muscle weakness associated with a myopathic muscle biopsy, characterized by the presence of nemaline rods, and the absence of clinical or pathological findings diagnostic of other disorders. The wide range of clinical presentations represents a continuum from neonatal-lethal forms to late onset slowly progressive weakness 5. However, to facilitate further study, including potential phenotype–genotype correlation, some categorization has

Normal muscle structure

The contractile apparatus of skeletal muscle is composed of repeating units (sarcomeres) that comprise ordered arrays of actin-containing thin filaments and myosin-containing thick filaments 15 (Fig. 1). Several other associated structural and regulatory proteins are present within the sarcomere to maintain the ordered myofibrillar array and coordinate contraction.

Each sarcomere is delimited by z lines, which are electron-dense bands, perpendicular to the myofibrils, that bisect the

Muscle pathology in NM

Standard haematoxylin and eosin stained sections of skeletal muscle from patients with NM can appear normal, or can exhibit some fiber size variation, but staining of frozen sections by the Gomori trichrome method readily reveals the nemaline rods that are the hallmark of this disorder (Fig. 2). The rods vary from 1–7 μm in length and from 0.3–2 μm in width and stain dark red or purple contrasting with the pale blue-green myofibrils. They tend to cluster under the sarcolemmal membrane or around

Genetic basis of NM

As discussed below, NM is a disorder of sarcomeric thin filaments, making each thin filament or Z line protein a potential NM candidate gene. Indeed, all the NM genes identified to date encode known components of the sarcomeric thin filaments. Unfortunately however, mutations in many of these genes do not predict severity or prognosis of the clinical course (Table 1). Furthermore, this molecular variability extends to inheritance patterns, as at least some NM genes can cause sporadic cases, as

Diagnosis and treatment of NM

As with other congenital myopathies, the diagnosis of nemaline myopathy is primarily a pathological one that is made based on the observation of nemaline rods in Gomori trichrome-stained light, or electron microscopic, sections of skeletal muscle. Histological methods have been unsuccessful so far in differentiating between the different NM forms, however, there is preliminary evidence for several potential associations between morphological features and genotype or phenotype. Nuclear rods are

Conclusions

NM is a heterogeneous disorder whose etiology remained a mystery until the advent of molecular genetic studies. To date, several different, but overlapping, clinical forms of NM have been defined and defects in five distinct genes have been identified. However, there is substantial clinical variation between patients with presumed genotypic homogeneity in families with both autosomal dominant and recessive inheritance. In addition, the genetic changes do not correlate well with clinical

Outstanding questions

  • What is the molecular mechanism of rod formation and how does this relate to muscle weakness?

  • How many additional NM genes exist? Will they all encode components of sarcomeric thin filaments?

  • Will any genotype–phenotype correlations emerge from analysis of larger patient groups?

  • What are the relationships between: (1) late-onset, rapidly progressive NM cases, (2) severe lethal cases of fetal akinesia, and (3) the more typical early onset, non-progressive ones?

  • Can we use our knowledge of the

Acknowledgements

We want to thank C.Wallgren-Pettersson, N.Laing, K. North, S. Iannaccone, and the other members of the European Neuromuscular Center Consortium on Nemaline Myopathy, for many helpful discussions and ideas and to S.Watkins for the sarcomere electron micrograph. We also gratefully acknowledge the Joshua Frase Foundation, the Muscular Dystrophy Association of the USA, and National Institute of Arthritis and Musculoskeletal and Skin Diseases of NIH for ongoing support.

Glossary

Arthrogryposis
malformation of the extremities characterized by contractures of muscles and tendons and limitation of movement of the affected joints without primary osteoarticular involvement.
Congenital myopathies
A subset of primary myopathies without dystrophic, inflammatory, metabolic or mitochondrial abnormalities that are characterized instead by specific structural changes of skeletal muscle and congenital (usually) presentation of weakness and hypotonia.
Hypotonia
Lack of muscle

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