Chapter 142 - Emery–Dreifuss muscular dystrophy, laminopathies, and other nuclear envelopathies
Introduction
The nuclear envelopathies are a rapidly expanding group of human hereditary diseases caused by mutations of genes that encode proteins of the nuclear envelope. The most frequent and best known form is Emery–Dreifuss muscular dystrophy (EDMD), a skeletal myopathy that typically presents between mid-childhood and the second decade of life with slowly progressive muscular weakness, joint contractures, and cardiac disease. This nosological entity is genetically heterogeneous and inheritance may be variable. An X-linked form was first studied by Emery and Dreifuss more than 45 years ago (1966), and the eponymous association (EDMD) for this condition was proposed in the late 1970s by Rowland et al., 1979 but it was not until 1994 that the gene STA, now called EMD, encoding emerin, was identified as the cause of the disease (Bione et al., 1994). In 1999, another gene linked to the nuclear envelope encoding lamins A and C, LMNA, was found to be mutated in a series of patients with the same clinical features described for the X-linked form but males and females were equally affected, showing a dominant transmission (Bonne et al., 1999). Later, mutations of LMNA were also reported in a family with an EDMD phenotype, this time inherited as a recessive autosomal trait (di Barletta et al., 2000). Since then, the spectrum of conditions has been extraordinarily enlarged, from a congenital muscular dystrophy with severe paralytic or rapidly progressive picture (Quijano-Roy et al., 2008) to a limb-girdle muscular dystrophy with adult onset and much milder weakness (Muchir et al., 2000). LMNA has also been involved in a form of isolated cardiomyopathy associated with cardiac conduction disease (Fatkin et al., 1999) and in an axonal form of hereditary neuropathy (De Sandre-Giovannoli et al., 2002). More surprising has been the identification of this gene in a number of non-neuromuscular disorders including lipodystrophy syndromes and a wide spectrum of premature aging syndromes ranging from mandibuloacral dysplasia to restrictive dermopathy (for a review see Worman and Bonne, 2007). Mutations in other genes implicated in the processing or maturation of nuclear lamins have also been found in some of these diseases. The fact that the largest spectrum of phenotypes observed in nuclear envelopathies is mostly linked to lamin A/C gene defects has led to the emergence of the more extended term laminopathies (Worman and Bonne, 2007). Intense research in the field is taking place and is currently generating huge amounts of data and revealing the extraordinary complexity of the molecular and physiopathological mechanisms in these diseases. However, it is still not clear how a single gene is responsible for such a heterogeneous spectrum of conditions. The occurrence of modifying factors or genes is highly suspected and has been occasionally proven. This and other investigations are helping in the better understanding of nuclear envelopathies, opening the possibility for the identification of new genes and the investigation of new therapeutic approaches. Work is in progress and allows the expectation of new and promising developments in these fascinating and complex conditions in the coming years.
Section snippets
The nuclear envelope
The nuclear lamina is a network of lamin polymers, a fibrous layer that is embedded in the nucleoplasmic side of the inner nuclear membrane and provides an interface between the nuclear envelope and the genetic material inside the nucleus. The lamina consists of intermediate filaments called lamins and comprises A-type (lamins A and C) and B-type (lamins B1 and B2) lamins; in humans, both A-type and B-type lamins are known to cause diseases (Worman and Bonne, 2007). Lamins interact with
Pathophysiology
It is difficult to explain how defects in nuclear membrane proteins can cause such different diseases as muscle dystrophy, cardiac or nerve diseases, as well as lipodystrophy and premature aging syndromes. For emerin (and presumably lamins A/C) to function properly, the protein must be correctly localized to the nuclear membrane. Any defect of the nuclear membrane could interfere with satellite cell function and thereby skeletal muscle regeneration, because emerin appears to be important in the
Striated muscle disorders
Globally, laminopathies affecting the striated muscles seem to constitute a continuous spectrum of successive phenotypes (Fig. 142.2). There is a strong correlation between age of onset and the resulting phenotype in single patients. Overall, it appears that early prenatal onset may be associated with lethal fetal akinesia, late prenatal onset with severe lamin-related congenital muscular dystrophy (L-CMD), onset before 1 year with dropped head L-CMD, onset in childhood or young adulthood with
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