Congenital myopathies

This review focuses on congenital myopathies, a distinct but markedly heterogeneous group of muscle disorders that present with muscle weakness and typically appear at birth or in infancy. These myopathies have characteristic histopathologic abnormalities on muscle biopsy, allowing a preliminary morphologic classification. Advances in molecular genetics have allowed a more rational classification of these disorders and have reshuffled taxonomy for some of these conditions. Here, we focus on recent research advances in specific congenital myopathies, including nemaline myopathy, myotubular myopathy, centronuclear myopathy, central core myopathy, multi-minicore myopathy, congenital fiber-type disproportion myopathy, and hyaline body myopathy. Scientific progress has not only elucidated the pathologic mechanisms of these disorders, but it has also provided the basis for therapeutic strategies.     

Congenital myopathies

The congenital myopathies encompass a group of neuromuscular disorders with characteristic morphologic abnormalities in skeletal muscle, including nemaline myopathy, central core disease, multi-minicore disease, and myotubular myopathy. Giant steps have been made in our understanding of the molecular bases of these disorders, all of which show remarkable genetic heterogeneity. This review of congenital myopathies examines progress in defining clinical diagnostic criteria and novel genetic advances that have provided important clues regarding their pathogeneses.     

Protein surplus myopathies and other rare congenital myopathies

The protein surplus myopathies have emerged as a newly recognized subgroup of morphologically defined myopathies within the spectrum of congenital myopathies because of the accumulation of protein aggregates, some of them mutant proteins. Currently, nosologic, including molecular criteria include desmin-related myopathies, actinopathies, and hereditary inclusion body myopathies, whereas hyaline body myopathy is still a putative form of protein surplus myopathy because of lack of any molecular data. The congenital myopathies (CM), foremost including nemaline and myotubular myopathies, have given evidence that, despite their epidemiologic rarity, the molecular age has dawned in CM and has even revealed surprising new nosologic features requiring reassessment and reclassification of certain CM. It is to be expected that a recently updated ENMC Consortium on "Protein surplus and other congenital myopathies" may procure important new information.     

Congenital myopathies in the new millennium

Few medical disciplines have benefited so enormously from the molecular revolution as myology. Whereas the congenital myopathies have flourished from enzyme histochemistry and electron microscopy, defining individual congenital myopathies by structural abnormalities, genetic research has only recently focused on congenital myopathies. However, a number of congenital myopathies have been molecularly elucidated: central and multiminicore diseases, nemaline myopathy, myotubular myopathy, and congenital myopathy marked by aggregation of proteins, giving rise to the concept of protein aggregate myopathies, to which now desminopathies, alpha-B crystallinopathies, selenoproteinopathy, myotilinopathy, actinopathies, and myosinopathies belong. Based on recent identification of mutations in respective genes, the principle "from morphology, that is, immunohistochemistry, to molecular analysis" through recognition of certain accrued proteins within muscle fibers and subsequent analysis of their respective genes has resulted in a wealth of genetic data and in reconsidering classification and nosologic interpretation of certain congenital myopathies. This heuristic principle needs to be further applied to other genetically still obscure congenital myopathies.     

X-linked myotubular and centronuclear myopathies

Recent work has significantly enhanced our understanding of the centronuclear myopathies and, in particular, myotubular myopathy. These myopathies share similar morphologic appearances with other diseases, namely the presence of hypotrophic myofibers with prominent internalized or centrally placed nuclei. Early workers suggested that this alteration represented an arrest in myofiber maturation, while other hypotheses implicated either failure in myofiber maturation or neurogenic causes. Despite similarities in morphology, distinct patterns of inheritance and some differences in clinical features have been recognized among cases. A severe form, known as X-linked myotubular myopathy (XLMTM), presents at or near birth. Affected males have profound global hypotonia and weakness, accompanied by respiratory difficulties that often require ventilation. Most of these patients die in infancy or early childhood, but some survive into later childhood or even adulthood. The responsible gene (MTM1) has been cloned; it encodes a phosphoinositide lipid phosphatase known as myotubularin that appears to be important in muscle maintenance. In autosomal recessive centronuclear myopathy (AR CNM), the onset of weakness typically occurs in infancy or early childhood. Some investigators have divided AR CNM into 3 subgroups: 1) an early-onset form with ophthalmoparesis, 2) an early-onset form without ophthalmoparesis, and 3) a late-onset form without ophthalmoparesis. Clinically, autosomal dominant CNM (AD CNM) is relatively mild and usually presents in adults with a diffuse weakness that is slowly progressive and may be accompanied by muscle hypertrophy. Overall, the autosomal disorders are not as clinically uniform as XLMTM, which has made their genetic characterization more difficult. Currently the responsible gene(s) remain unknown. This review will explore the historical evolution in understanding of these myopathies and give an update on their histopathologic features, genetics and pathogenesis.     

Myotubular/centronuclear myopathy and central core disease

The term congenital myopathy is applied to muscle disorders presenting with generalized muscle weakness and hypotonia from early infancy with delayed developmental milestones. The congenital myopathies have been classified into various categories based on morphological findings on muscle biopsy. Although the clinical symptoms may seem homogenous, the genetic basis is remarkably variable. This review will focus on myotubular myopathy, centronuclear myopathy, central core disease, and congenital neuromuscular disease with uniform Type 1 fiber, myopathies that are subjects of our ongoing examinations.     

Congenital myopathies

Several dozen congenital myopathies are defined by clinical and morphological criteria. The application of the current generation of scientific techniques including immunohistochemistry and molecular genetics has resulted in the expansion of our knowledge and understanding of the well-established conditions including central core myopathy and centronuclear/myotubular myopathy and allowed greater understanding of the interrelationships of some of the less common or less wellestablished conditions. In the near future molecular genetics may allow the identification of the specific gene defect in many of these diseases. This article reviews the major congenital myopathies and presents some of the information gained by application of new technology to these conditions. © 1994 John Wiley & Sons, Inc.     

X-linked myotubular myopathy: report of a case with novel mutation

Myotubular myopathy is a well-defined entity within the centronuclear myopathy subgroup of congenital myopathies. The authors present a patient with the most severe X-linked recessive type (XLMTM). A baby boy presented at birth with severe hypotonia, weak spontaneous movements, arthrogryposis, and respiratory insufficiency. Muscle biopsy showed features of myotubular myopathy. The diagnosis was confirmed and further specified by genetic analysis, revealing a novel frameshift mutation (1314-1315insT) of the myotubularin-coding MTM1 gene. This case underlines the importance of interdisciplinary analysis of congenital muscle diseases, including histomorphological and genetic investigations.     

X-linked myotubular myopathy due to a complex rearrangement involving a duplication of MTM1 exon 10

X-linked myotubular myopathy is a predominantly severe congenital myopathy with central nuclei on muscle biopsy due to mutations in the MTM1 gene encoding myotubularin. We report a boy with typical features of X-linked myotubular myopathy. Sequencing of the MTM1 gene did not reveal any causative mutations. Subsequent MLPA analysis identified a duplication of MTM1 exon 10 both in the patient and his mother. Additional quantitative fluorescent PCR and long-range PCR revealed an additional large deletion (2536bp) within intron 10, 143bp downstream of exon 10, and confirmed the duplication of exon 10. Our findings suggest that complex rearrangements have to be considered in typically affected males with X-linked myotubular myopathy.     

Distal myopathies

Distal myopathies are a heterogeneous group of genetic disorders characterized clinically by progressive muscular weakness and atrophy beginning in the hands or feet, and pathologically by myopathic changes in skeletal muscles. Five distinct distal myopathies are identified, among them four have been recently defined by their gene and causative mutations. They are classified according to age at onset, mode of inheritance, and muscle groups initially involved into the following: Laing myopathy (infancy onset, autosomal dominant inheritance, onset in anterior compartment of legs) caused by mutations in a myosin gene (MYH7) on chromosome 14q; Nonaka myopathy (early adult onset, autosomal recessive inheritance, onset in anterior compartment of legs), identical to quadriceps-sparing familial inclusion myopathy, caused by mutations in the GNE gene on chromosome 9p-q; Miyoshi myopathy (early adult onset, autosomal recessive inheritance, onset in posterior compartment of legs) caused by mutations in the dysferlin gene on chromosome 2p; Welander myopathy (late adult onset, autosomal dominant inheritance, onset in hands) linked to chromosome 2p; Udd/Markesbery-Griggs myopathy (late adult onset, autosomal dominant inheritance, onset in anterior compartment of legs) caused by mutations in the titin gene on chromosome 2q. Except for Miyoshi myopathy, which has a striking elevated serum creatine kinase level and the typical findings of muscular dystrophy, most of the distal myopathies have normal or midly elevated creatine kinase levels and share the common pathologic feature of rimmed vacuoles.     

Congenital myopathies at their molecular dawning.

The introduction and application of molecular techniques have commenced to influence and alter the nosology of congenital myopathies. Long-known entities such as nemaline myopathies, core diseases, and desmin-related myopathies have now been found to be caused by unequivocal mutations. Several of these mutations and their genes have been identified by analyzing aggregates of proteins within muscle fibers as a morphological hallmark as in desminopathy and actinopathy, the latter a subtype among the nemaline myopathies. Immunohistochemistry has played a crucial role in recognizing this new group of protein aggregate myopathies within the spectrum of congenital myopathies. It is to be expected that other congenital myopathies marked by inclusion bodies may turn out to be such protein aggregate myopathies, depending on analysis of individual proteins within these protein aggregates and their association with putative gene mutations.     

Early onset myopathy with a novel mutation in the Selenoprotein N gene (SEPN1)

Mutations in SEPN1 have been associated with three autosomal recessive congenital myopathies, including rigid spine muscular dystrophy, multiminicore disease and desmin-related myopathy with Mallory body-like inclusions. These disorders constitute the SEPN1 related myopathies (SEPN-RM). On the basis of clinical and laboratory features compatible with SEPN-RM, we performed mutation analysis of SEPN1 in 11 unrelated patients and found one case with pathogenic mutations. He showed early onset axial muscle weakness and developed scoliosis with respiratory insufficiency. Muscle biopsy showed increased variability of fiber size and slight, focal increase of connective tissue. A few fibers showed mini-core changes. SEPN1 mutation analysis revealed that the patient was a compound heterozygote: a previously described insertion (713-714 insA), and a novel nonsense mutation (R439stop).     

Early and severe presentation of X-linked myotubular myopathy in a girl with skewed X-inactivation

X-linked myotubular myopathy is a severe congenital myopathy in males, caused by mutations in the myotubularin (MTM1) gene on chromosome Xq28. In heterozygous carriers of MTM1 mutations, clinical symptoms are usually absent or only mild.We report a 6-year-old girl presenting at birth with marked hypotonia and associated feeding and respiratory difficulties. A muscle biopsy performed at 5 months suggested a diagnosis of myotubular myopathy. On examination at 6 years she had marked facial weakness with bilateral ptosis and external ophthalmoplegia, severe axial and proximal weakness and a mild scoliosis. Muscle magnetic resonance imaging showed a distinctive pattern of muscle involvement.Molecular genetic investigation of the MTM1 gene identified a heterozygous mutation in exon 12. X-inactivation studies in lymphocytes showed an extremely skewed pattern (97:3).This case emphasizes that investigation of the MTM1 gene and X-inactivation studies are indicated in isolated females with histopathological and clinical findings suggestive of myotubular myopathy.     

Predisposition to subdural hemorrhage in X-linked myotubular myopathy

X-linked myotubular myopathy is a severe congenital myopathy that can involve multiple organs. We report on a 10-month-old boy who manifested X-linked myotubular myopathy with subdural hemorrhage. The diagnosis of X-linked myotubular myopathy was based on typical muscle pathology and MTM1 missense mutation. The patient had undergone no traumatic episodes or bleeding diathesis. Axial growth acceleration is known to occur in X-linked myotubular myopathy, potentially leading to dolichocephaly. In our patient, an enlarged subdural space apparently stretched the bridging veins, increasing susceptibility to subdural hemorrhage. Patients who manifest X-linked myotubular myopathy with typical dolichocephaly are at increased risk for subdural hemorrhage.     

Distal myopathies

PURPOSE OF REVIEW: The distal myopathies are a heterogeneous group of disorders that pose a challenge to both the clinician and geneticist. This article summarizes the findings of recent clinical, genetic and molecular studies and the current diagnostic approach to this group of patients. RECENT FINDINGS: Publications over the past 5 years describe a number of new clinical phenotypes and genetic loci and further emphasize the overlap in clinical phenotype between a number of these disorders and between the distal and limb girdle myopathies and hereditary inclusion body myopathies. Recent studies have led to the identification of the genes and mutations responsible for early onset (Laing) myopathy and tibial (Udd) myopathy, and for distal myopathy with rimmed vacuoles (Nonaka), which has been shown to be allelic with quadriceps sparing hereditary inclusion body myopathy (IBM2), and have elucidated the underlying pathogenetic mechanisms in these conditions. New diagnostic approaches using magnetic resonance imaging, and a blood-based assay for dysferlin deficiency, have also been reported. SUMMARY: These findings have important implications for future genetic linkage and gene expression studies and for the diagnostic approach to patients with a distal myopathy phenotype. They also hold promise for the eventual development of therapies for this group of disorders.     

Congenital myotubular myopathy with a novel MTM1 gene mutation in a premature infant presenting with ventilator dependency and intrahepatic cholestasis

Myotubular myopathy is a rare congenital disease characterized by hypotonia and respiratory compromise at birth in affected males. It causes high neonatal mortality. Most surviving newborns need prolonged ventilation and have significantly delayed motor development. Although all patients with congenital myotubular myopathy have respiratory problems such as atelectasis and recurrent lung infections, concurrent neonatal intrahepatic cholestasis is rare. We report a newborn with a myotubular myopathy, ventilator dependency, recurrent lung infections and pleural effusion, facial diplegia, ophthalmoplegia, and progressive intrahepatic cholestasis. A genetic study showed a novel mutation of the MTM1gene: c.1142 G>A (R381Q). We suggest that physicians consider probable concurrent disorders of other organs in neonates with congenital myotubular myopathy.     

Congenital Myopathies: An Update

Congenital myopathy is a clinicopathological concept of characteristic histopathological findings on muscle biopsy in a patient with early-onset weakness. Three main categories are recognized within the classical congenital myopathies: nemaline myopathy, core myopathy, and centronuclear myopathy. Recent evidence of overlapping clinical and histological features between the classical forms and their different genetic entities suggests that there may be shared pathomechanisms between the congenital myopathies. Animal models, especially mouse and zebrafish, have been especially helpful in elucidating such pathomechanisms associated with the congenital myopathies and provide models in which future therapies can be investigated.     

Actin-related myopathy without any missense mutation in the ACTA1 gene

Actinopathies are defined by missense mutations in the ACTA1 gene coding for sarcomeric actin, of which some 70 families have, so far, been identified. Often, but not always, muscle fibers carry large patches of actin filaments. Many such patients also have nemaline myopathy, qualifying actinopathies as a subgroup of nemaline myopathies. This article concerns a then newborn, now 2 1/2-year-old boy, the first and single child of nonconsanguineous parents, who was born floppy, requiring immediate postnatal assisted ventilation. A quadriceps muscle biopsy revealed large patches of thin myofilaments reacting at light and electron microscopic levels with antibodies against actin but only a few sarcoplasmic rods and no intranuclear rods. DNA analysis of the patient's and both parents' blood did not reveal any missense mutation in the ACTA1 gene. Thus, this congenital myopathy can be caused by a new type of ACTA1 gene mutation, a new non-ACTA1 gene mutation, or no mutation at all, designating it as an actin-related myopathy, perhaps a new type of congenital myopathy and a new member of protein aggregate myopathies marked by aggregation of proteins within muscle fibers, among them desminopathies, alpha-beta crystallinopathies, other desmin-related myopathies (also termed myofibrillar myopathies), actinopathies and, now, actin-related myopathies.     

Reducing body myopathy and other FHL1-related muscular disorders

During the past 2 years, considerable progress in the field of four and a half LIM domain protein 1 (FHL1)-related myopathies has led to the identification of a growing number of FHL1 mutations. This genetic progress has uncovered crucial pathophysiological concepts, thus redefining clinical phenotypes. Important new characterizations include 4 distinct human myopathies: reducing body myopathy, X-linked myopathy with postural muscle atrophy, Emery-Dreifuss muscular dystrophy, and scapuloperoneal myopathy. Additionally, FHL1 mutations have been discovered in rigid spine syndrome and in a single family with contractures, rigid spine, and cardiomyopathy. In this review, we focus on the clinical phenotypes, which we correlate with the novel genetic and histological findings encountered within FHL1-related myopathies. This correlation will frequently lead to a considerably expanded clinical spectrum associated with a given FHL1 mutation.