Developmental Disorders of Muscle

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Chapter 600 Developmental Disorders of Muscle

Harvey B. Sarnat

A heterogeneous group of congenital neuromuscular disorders is known as the congenital myopathies, but in some of these disorders, the assumption that the pathogenesis is primarily myopathic is unjustified. Most congenital myopathies are nonprogressive conditions, but some patients show slow clinical deterioration accompanied by additional changes in their muscle histology. Most of the diseases in the category of congenital myopathies are hereditary; others are sporadic. Although clinical features, including phenotype, can raise a strong suspicion of a congenital myopathy, the definitive diagnosis is determined by the histopathologic findings in the muscle biopsy specimen. In conditions for which the defective gene has been identified, the diagnosis may be established by the specific molecular analysis of the suspected gene expressed in lymphocytes. The morphologic and histochemical abnormalities differ considerably from those of the muscular dystrophies, spinal muscular atrophies, and neuropathies. Many are reminiscent of the embryologic development of muscle, thus suggesting possible defects in the genetic regulation of muscle development.

Myogenic Regulatory Genes and Genetic Loci of Inherited Diseases of Muscle

A family of four myogenic regulatory genes shares encoding transcription factors of “basic helix-loop-helix” (bHLH) proteins associated with common DNA nucleotide sequences (Table 600-1). These genes direct the differentiation of striated muscle from any undifferentiated mesodermal cell. The earliest bHLH gene to program the differentiation of myoblasts is myogenic factor 5 (Myf5). The second gene, myogenin, promotes fusion of myoblasts to form myotubes. Herculin (also known as MYF6) and MYOD1 are the other two myogenic genes. Myf5 cannot support myogenic differentiation without myogenin, MyoD, and MYF6. Each of these four genes can activate the expression of at least one other and, under certain circumstances, can autoactivate as well. The expression of MYF5 and of herculin is transient in early ontogenesis but returns later in fetal life and persists into adult life. The human locus of the MYOD1 gene is on chromosome 11, very near to the domain associated with embryonal rhabdomyosarcoma. The genes encoding Myf5 and herculin are on chromosome 12 and that for myogenin is on chromosome 1.

Table 600-1 INHERITANCE PATTERNS AND CHROMOSOMAL OR MITOCHONDRIAL LOCI OF NEUROMUSCULAR DISEASES AFFECTING THE PEDIATRIC AGE GROUP

DISEASE TRANSMISSION LOCUS
Duchenne and Becker muscular dystrophy XR Xp21.2
Emery-Dreifuss muscular dystrophy XR Xq28
Myotonic muscular dystrophy (Steinert) AD 19q13
Facioscapulohumeral muscular dystrophy AD 4q35
Limb-girdle muscular dystrophy AD 5q
Limb-girdle muscular dystrophy AR 15q
Congenital muscular dystrophy with merosin deficiency AR 6q2
Congenital muscular dystrophy (Fukuyama) AR 8q31-33
Myotubular myopathy XR Xq28
Myotubular myopathy AR Unknown
Nemaline rod myopathy (NEM1) AD 1q21-q23
Nemaline rod myopathy (NEM2) AR 2q21.2-q22
Nemaline rod myopathy (NEM3) AD, AR 1q42.1
Nemaline rod myopathy (NEM4) AD 9q13
Nemaline rod myopathy (NEM5) AR 19q13
Congenital muscle fiber-type disproportion AR, X-linked R 19p13.2, Xp23.12-p11.4, Xq13.1-q22.1; t(10; 17); sporadic
Central core disease AD 19q13.1
Myotonia congenita (Thomsen) AD 7q35
Myotonia congenita (Becker) AR 7q35
Paramyotonia congenita AD 17q13.1-13.3
Hyperkalemic periodic paralysis AD 17q13.1-13.3
Hyperkalemic periodic paralysis AD 1q31-q32
Glycogenosis II (Pompe; acid maltase deficiency) AR 17q23
Glycogenosis V (McArdle; myophosphorylase deficiency) AR 11q13
Glycogenosis VII (Tarui; phosphofructokinase deficiency) AR 1cenq32
Glycogenosis IX (phosphoglycerate kinase deficiency) XR Xq13
Glycogenosis X (phosphoglycerate mutase deficiency) AR 7p12-p13
Glycogenosis XI (lactate dehydrogenase deficiency) AR 11p15.4
Muscle carnitine deficiency AR Unknown
Muscle carnitine palmityltransferase deficiency 2 AR 1p32
Spinal muscular atrophy (Werdnig-Hoffmann; Kugelberg-Welander) AR 5q11-q13
Familial dysautonomia (Riley-Day) AR 9q31-33
Hereditary motor-sensory neuropathy (Charcot-Marie-Tooth; Dejerine-Sottas) AD 17p11.2
Hereditary motor-sensory neuropathy (axonal type) AD 1p35-p36
Hereditary motor-sensory neuropathy (Charcot-Marie-Tooth-X) XR Xq13.1
Mitochondrial myopathy (Kearns-Sayre) Maternal; sporadic Single large mtDNA deletion
Mitochondrial myopathy (MERRF) Maternal tRNA point mutation at position 8344
Mitochondrial myopathy (MELAS) Maternal tRNA point mutation at positions 3243 and 3271

AD, autosomal dominant; AR, autosomal recessive; MELAS, mitochondrial encephalopathy lactic acidosis, and stroke; MERRF, myoclonic epilepsy with ragged-red fibers; mtDNA, mitochondrial deoxyribonucleic acid; tRNA, transfer ribonucleic acid; XR, X-linked recessive.

The myogenic genes are activated during muscle regeneration, recapitulating the developmental process; MyoD in particular is required for myogenic stem cell (satellite cell) activation in adult muscle. PAX3 and PAX7 genes also play an important role in myogenesis and interact with each of the four basic genes mentioned above. Another gene, myostatin, is a negative regulator of muscle development by preventing myocytes from differentiating. The precise role of the myogenic genes in developmental myopathies is not yet fully defined.

Satellite cells in mature muscle that mediate regeneration have the same somitic origin as embryonic muscle progenitor cells, but the genes that regulate them differ. Pax3 and Pax7 mediate the migration of primitive myoblast progenitors from the myotomes of the somites to their peripheral muscle sites in the embryo, but only one of two Pax7 genes continues to act postnatally for satellite cell survival. Then it, too, no longer is required after the juvenile period for muscle satellite (i.e., stem) cells to become activated for muscle regeneration.

600.1 Myotubular Myopathy

Harvey B. Sarnat

The term myotubular myopathy implies a maturational arrest of fetal muscle during the myotubular stage of development at 8-15 wk of gestation. It is based on the morphologic appearance of myofibers: A row of central nuclei lies within a core of cytoplasm; contractile myofibrils form a cylinder around this core (Fig. 600-1). Many challenge this interpretation and use the more neutral term centronuclear myopathy when referring to this myopathy. This term is nonspecific because internal nuclei occur in many unrelated myopathies.

image

Figure 600-1 Cross section of muscle from a 14 wk old human fetus (A), a normal full-term neonate (B), and a term neonate with X-linked recessive myotubular myopathy (C). Myofibers have large central nuclei in the fetus and in myotubular myopathy, and nuclei are at the periphery of the muscle fiber in the term neonate as in the adult (H&E, ×500).

Pathogenesis

The molecular mechanism appears similar in the X-linked recessive and autosomal recessive forms of myotubular myopathy. The common pathogenesis involves loss of myotubularin protein, leading to structural and functional abnormalities in the organization of T-tubules and sarcoplasmic reticulum and defective excitation-contraction coupling. This pathogenesis also provides a link to central core and multicore and minicore myopathies to at least partially explain the clinical and histopathologic similarities of these different congenital myopathies.

Persistently high fetal concentrations of vimentin and desmin are demonstrated in myofibers of infants with myotubular myopathy, although not reproduced in cultured myocytes of patients. These intermediate filament proteins serve as cytoskeletal elements in fetal myotubes, attaching nuclei and mitochondria to the sarcolemmal membranes to preserve their central positions. As intracellular organization changes with maturation, the nuclei move to the periphery and mitochondria are redistributed between myofibrils. At the same time, vimentin and desmin diminish. Vimentin disappears altogether by term, and desmin remains only in trace amounts. Persistent fetal vimentin and desmin in muscle fibers may be one mechanism of “maturational arrest.” A secondary myasthenia-like defect in neuromuscular transmission also occurs in some infants with myotubular myopathy. Myocytes of patients co-cultured with nerve in vitro develop normal innervation and mature normally, not reproducing the in vivo pathologic changes.

The defective gene of the X-linked form and 3 genes of the autosomal recessive form are known.

Clinical Manifestations

Fetal movements can decrease in late gestation. Polyhydramnios is a common complication because of pharyngeal weakness of the fetus and inability to swallow amniotic fluid.

At birth, affected infants have a thin muscle mass involving axial, limb girdle, and distal muscles; severe generalized hypotonia; and diffuse weakness. Respiratory efforts may be ineffective, requiring ventilatory support. Gavage feeding may be required because of weakness of the muscles of sucking and deglutition. The testes are often undescended. Facial muscles may be weak, but infants do not have the characteristic facies of myotonic dystrophy. Ptosis may be a prominent feature. Ophthalmoplegia is observed in a few cases. The palate may be high. The tongue is thin, but fasciculations are not seen. Tendon stretch reflexes are weak or absent.

Myotubular myopathy is not associated with cardiomyopathy (mature cardiac muscle fibers normally have central nuclei), but one report describes complete AV block without cardiomyopathy in a patient with confirmed X-linked myotubular myopathy. Congenital anomalies of the central nervous system or of other systems are not associated. A single patient with progressive dementia was reported, who had a mutation removing the start signal of exon 2.

Older children and adults can develop centronuclear myopathy with variable weakness. The relation of this disorder to the severe neonatal disease is uncertain.

Laboratory Findings

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