Clinical Features.

The disorder is usually apparent in the first hours and days of life. Certain characteristics of the pregnancy often precede the neonatal disorder ( Table 33.1 ) and tend to be prominent in the most severely affected cases. Thus, spontaneous abortion or premature birth with the associated increased risk of germinal matrix/intraventricular hemorrhage occurs in the most severely affected infants. Polyhydramnios is a common characteristic of the pregnancy (see Table 33.1 ). Indeed, this sign is almost invariable in the most severely affected infants and is thought to be caused by the disturbance in swallowing. Polyhydramnios in a mother with myotonic dystrophy is a fairly reliable indicator of serious involvement of the fetus. Abnormalities of labor, which may be either prolonged or abbreviated, have been attributed to maternal uterine muscle involvement.

The clinical features in the neonatal period are usually marked and characteristic (see Table 33.1 ). In the well-established case, the most striking clinical features are facial diplegia, respiratory and feeding difficulties, arthrogryposis (especially of the lower extremities), and hypotonia. The facial diplegia imparts the characteristic tent-shaped appearance to the upper lip ( Fig. 33.1 ). The respiratory difficulties relate to weakness of respiratory muscles, impaired swallowing and handling of secretions, and occasionally diaphragmatic disturbance ( Fig. 33.2 ). At least 80% of patients require mechanical ventilation. The respiratory impairment may be so severe that the newborn infant fails to establish adequate ventilation and suffers an asphyxial episode that so dominates the clinical syndrome that the myopathic origin of the respiratory failure is overlooked. The feeding difficulties involve both sucking and swallowing and are related particularly to weakness of the facial, masticatory, and pharyngeal musculature. (A role for myotonia of pharyngeal muscles is possible. ) A disturbance of gastric motility, a manifestation of the smooth muscle involvement in this disorder, may contribute in a major way to the feeding difficulties in some infants. Arthrogryposis ( Fig. 33.3 ) is almost invariable and usually involves at least the ankles, leading to clubfoot deformity. Indeed, in one large series of arthrogryposis multiplex congenita, 50% of the patients with cases related to muscle disease had congenital myotonic dystrophy. Hypotonia is also essentially invariable, accompanied by weakness and, in approximately 90% of the cases, by areflexia or marked hyporeflexia. Atrophy is usually obvious, especially after the first days of life, when edema, which is often excessive in these infants, subsides. Clinical myotonia, elicited by percussion of such muscles as the deltoid, has been detected as early as 3 hours of age, but it is usually not readily elicited until much later in infancy.

Congenital myotonic dystrophy: facial appearance in the neonatal and infantile period.

(A) Note the facial diplegia with tent-shaped appearance of upper lip in this newborn. (B) Same affected infant at an older age; note the facial diplegia, tented upper lip, and temporalis muscle atrophy.

Congenital myotonic dystrophy: diaphragmatic involvement.

This radiograph of the chest is from a newborn with congenital myotonic dystrophy. The right hemidiaphragm is elevated and paralyzed. Note also the thin ribs, characteristic of severe congenital neuromuscular disease.

(From Sarnat HB. Neuromuscular disorders in the neonatal period. In: Korobkin R, Guilleminault C, eds. Advances in Perinatal Neurology . Vol 1. New York: Spectrum Publications; 1978.)

Congenital myotonic dystrophy: club feet.

This affected infant exhibits contractures at the ankles (club feet).

Less severely affected infants may go undetected in the newborn period. Facial weakness and hypotonia are the two most common manifestations in such patients.

The clinical course relates clearly to the severity of the disease. Neonatal mortality is generally approximately 15% to 20%, but it is as high as approximately 40% in severely affected patients. Feeding difficulties, which initially may require institution of tube feedings, usually improve, at least in reported survivors. ^a

a References .

Clinical improvement in congenital muscular dystrophy.

(A) A 9-month-old boy with weakness and hypotonia from birth. Note the marked head lag with pull to sit. The infant cannot sit without support or support his body weight on his legs. (B and C) The same child at 2 years of age. He can sit without support and can bear considerable weight when standing with support.

(From Dubowitz V. Muscle Disorders in Childhood . Philadelphia: Saunders; 1978.)

Clinical myotonia in an 11-month-old infant.

(A) Blinking was precipitated by a bright flash of light. (B) This photograph was taken approximately 15 seconds later. Note the persisting partial closure of the eyelids caused by myotonia of the orbicularis oculi muscles and also the temporal hollowing, suggesting atrophy.

(From Dodge PR, Gamstorp I, Byers RK, Russell P. Myotonic dystrophy in infancy and childhood. Pediatrics . 1965;35:3–19.)

Impairment of motor and intellectual development is apparent in the first weeks of life (see Table 33.1 ). Intellectual disability is essentially invariable in infants with congenital myotonic dystrophy who survive the neonatal period. Intelligence quotient (IQ) scores in the 50 to 65 range have generally been observed. The disturbance of intellectual development is nonprogressive. The only available data on relatively long-term follow-up (i.e., ≈10–30 years) indicated that only 2 of 42 patients managed normal education , and only one was gainfully employed . Some improvement in motor function occurs in late infancy and childhood.

Transmission of myotonic dystrophy in patients with the neonatal form of the disease is essentially always through the mother (see Table 33.1 ). Only approximately seven cases of congenital myotonic dystrophy transmitted through an affected father have been reported. At any rate, it is critical for the physician to be cognizant of the disorder as it appears in adults. Indeed, it is common for the mother with an affected infant to be unaware that she has the disease. Most helpful in recognition of the disease in the mother is the typical facies of myotonic dystrophy ( Fig. 33.6 ), characterized by atrophy of the masseter and temporalis muscles, ptosis, and a straight, stiff smile. Myotonia is prominent and readily elicited. Thus active myotonia is seen in the affected woman when she closes her eyes tightly and then is unable to open them fully for several seconds or more, or when she clenches her fist tightly and then cannot extend her fingers immediately on command. Passive myotonia is demonstrable by percussion of such muscles as the deltoid, thenar eminence, and tongue and by observation of the prolonged dimpling caused by sustained muscle contraction (Videos 33.1 to33.4 ). Other characteristics (e.g., cataracts, disturbance of intellect, and cardiac abnormality) may also be present. The essential point is that the physician should examine the mother when this diagnosis is considered in a newborn.

Congenital myotonic dystrophy: infant and mother.

The mother exhibits some of the typical facial features of myotonic dystrophy, as described in the text. Note also in the affected infant the facial diparesis with a tent-shaped upper lip. Additional features of congenital myotonic dystrophy may be seen inVideos 33.1 to33.4 .

Laboratory Studies.

Serum creatine kinase (CK) level, cerebrospinal fluid (CSF) protein concentration, and nerve conduction studies are normal. Slender ribs are commonly observed on chest radiographs (see Fig. 33.2 ) and may suggest the diagnosis in an infant thought initially to have primary asphyxia. This finding can be observed with other congenital myopathic disorders as well as with Werdnig-Hoffmann disease.

The diagnosis is supported particularly by demonstrating myotonic discharges on the electromyogram (EMG). These discharges are difficult to elicit in the neonatal period, although they have been observed as early as 5 days of age. Electrical myotonia is elicited by movement of the recording needle or by direct percussion of the recorded muscle; this procedure results in repetitive electrical potentials of up to 100/second that wax and wane in frequency and amplitude ( Fig. 33.7 ). These potentials produce the characteristic dive bomber sound. Later in infancy, particularly after the age of 2 to 3 years, myotonia is elicited more easily, and small-amplitude, short-duration, and polyphasic potentials, typical of myopathic disease, can also be demonstrated. Fibrillation potentials may also be observed.

Electromyogram from an infant with congenital myotonic dystrophy at 5 days of age.

The movement of the needle produces a burst of electrical discharges that then subside over several seconds. Calibration: 200 µV, 1 second. See also Chapter 30 and Figs. 30.8A–B .

(From Swift TR, Ignacio OJ, Dyken PR. Neonatal dystrophia myotonica. Am J Dis Child . 1975;129:734–737.)

Ventricular dilation has been observed in approximately 80% of newborns studied by ultrasonography, computed tomography (CT), or magnetic resonance imaging (MRI). In one study, macrocephaly was present in approximately 70% of the infants in the presence or absence of ventricular dilation. However, head circumference within the upper half of the normal range is more common than is overt macrocephaly. The ventricular dilation is nonprogressive and is not accompanied by rapid head growth or signs of increased intracranial pressure. The occasional occurrence of periventricular echodensities on ultrasound scans or hyperintensity on subsequent T2-weighted MRI scans may reflect periventricular leukomalacia occurring in association with neonatal respiratory disturbance. However, this white matter change could also reflect an abnormality of myelination. A small corpus callosum was documented by MRI in four of seven infants in another study. The possibility of an abnormality in neuronal development was raised by the demonstration by magnetic resonance (MR) spectroscopy of decreased levels of N -acetylaspartic acid, a neuronal marker (see Chapter 4 ), in 5 infants and children with congenital myotonic dystrophy.

Pathology.

Muscle pathology in congenital myotonic dystrophy is different from that observed in the adult with the disease and consists particularly of features of immaturity. In a detailed postmortem analysis of three infants, Sarnat and Silbert and others demonstrated particular involvement of limb muscles around arthrogrypotic joints, pharyngeal muscles, and the diaphragm. The features indicative of a disturbance of maturation included small round muscle fibers with large internal nuclei and sparse myofibrils, reminiscent of fetal myotubes ( Fig. 33.8 ). Moreover, differentiation of fibers into distinct histochemical types was incomplete. Similarly, electron microscopy showed dilated transverse tubules that were aligned longitudinally, like fetal myotubes, as well as poorly formed Z-bands, simple mitochondria, peripheral halo of absent mitochondria, and many satellite cells, which are also features of immature muscle. Investigators have suggested that these changes principally represent an arrest in fetal muscle maturation. Others have viewed these changes as signs of abnormal development. Pathological findings in pancreas (nesidioblastosis), kidney (persistent renal blastema), and other organs (cryptorchidism and patent ductus arteriosus) support the concept of a disturbance of maturation.

Congenital myotonic dystrophy: muscle pathology.

These specimens were obtained at autopsy from an affected infant who never established spontaneous respiration and died at 14 days of age. Many of the histological features are those of immature muscle. (A) Cross section of rectus abdominis. The muscle fibers are small, round, and loosely arranged, and most contain a single large internal nucleus or a central pale space (hematoxylin and eosin [H&E] stain, ×400). (B) Longitudinal section of diaphragm. The large vesicular internal nuclei are aligned in rows within the muscle fibers with clear vacuolated spaces between them. The sarcomeric striations are poorly distinguished (H&E stain, ×400).

(From Sarnat HB, Silbert SW. Maturational arrest of fetal muscle in neonatal myotonic dystrophy . Arch Neurol . 1976;33:466–474.)

The neuropathological substrate for the intellectual failure is unclear. A study of three adult patients with subnormal IQ scores by Rosman and Rebeiz revealed pachygyria in two and disordered cortical architectonics with neuronal heterotopias in all three. These findings were not observed in a later study of four infants from the same institution. However, another report from a different institution also described cerebral cortical neuronal heterotopias in four infants and neuronal heterotopias in two studied postmortem. Thus the neuropathological basis for the consistent impairment of intellect is not currently established conclusively. It seems reasonable to postulate that an aberration of maturation, as in muscle and other organs, is present. A study of the organizational aspects of brain development (see Chapter 7 ) would be of interest.

Pathogenesis and Etiology.

The disorder is inherited as an autosomal dominant trait through the mother in virtually every case . In addition, the risk of congenital myotonic dystrophy bears a distinct relationship with the disease in the mother. The earlier the onset and the more severe the maternal disease, the greater is the risk for the severe congenital form of myotonic dystrophy in the child. This phenomenon is consistent with anticipation (i.e., the occurrence of progressively earlier onset and more severe disease in successive generations).

Molecular genetic studies have provided major insight into the reasons for anticipation and related aspects of congenital myotonic dystrophy ( Box 33.2 ). Thus myotonic dystrophy has been shown to be associated with an increase in the number of specific (CTG [cytosine-thymine-guanine]) trinucleotide repeats in an unstable DNA region of the 3′ untranslated region of the myotonic dystrophy gene, which is located at chromosome 19q13.3. Moreover, the number of repeats increases with maternal transmission of the gene and a correlation of the number of repeats (i.e., the extent of the so-called expansion of the triplet repeat region on chromosome 19) exists with severity and early onset of the disease in the infant. This molecular genetic phenomenon underlies anticipation. Current data suggest that paternal transmission of the unstable trinucleotide repeat is associated with reduced amplification or even contraction of the region of repeats, in contrast to the situation with maternal transmission. This feature of paternal transmission may be related to negative selection of sperm with large repeat numbers and may explain the exclusively maternal transmission of congenital myotonic dystrophy. At any rate, determination of the number of repeats from a DNA sample of a woman can be used to estimate the likelihood of transmitting severe congenital myotonic dystrophy, and, in an affected infant, such a determination can be used to estimate the likely severity of the disorder. However, correlations are not perfect, in part because of somatic mosaicism (i.e., the extent of repeat expansion varies from tissue to tissue, even in postmitotic tissue). Somatic mosaicism has been documented in congenital myotonic dystrophy, although it is less pronounced than in the adult form of the disease.

The gene affected in myotonic dystrophy (MDPK) encodes a serine-threonine protein kinase; myogenin, the beta-subunit of the L-type calcium channels, and phospholemman are the substrates for this enzyme, which appears to function normally in patients with DM1. Normal leukocyte DNA contains 5 to 37 copies of the CTG trinucleotide. In permutation carriers , the size of the unstable CTG array is 30 to 50 repeats; however, it varies between 50 and 4000 repeats in symptomatic individuals. Infants with congenital myotonic dystrophy are likely to have more than 1000 repeats in their leukocyte DNA, although a number of these patients may have CTG expansions of less than 1000 repeats. The features of congenital myotonic dystrophy appear to be related to a toxic RNA gain-of-function effect. Thus the trinucleotide repeats appear to bind and sequester multiple RNA- and DNA-binding proteins, such as the muscleblind-like (MBNL) protein family, thereby leading to multiple deleterious effects (see Box 33.2 ), including dysregulation of alternative splicing of pre-mRNAs. Sequestration of MBNL1 leads to increased synthesis of the less responsive neonatal isoform of the insulin receptor and overproduction of the neonatal isoform of the skeletal muscle chloride channel; this imbalance results in insulin resistance and a significant reduction in chloride conductance, causing myotonia.

The diagnosis is suspected if the mother has clinical or EMG features of DM1 or if she has a confirmed genetic diagnosis; the diagnosis is made in the neonate by identifying the abnormally expanded CTG repeat in the DMPK gene.

Management.

Management of the affected infant is, in considerable part, an ethical decision. For optimal development, adequate nutrition and ventilation must be ensured, and respiratory support and tube feedings may be needed for days to weeks. Survivors are usually able to suck and swallow adequately for oral nutrition by 8 to 12 weeks of age. When ventilatory support is required for more than 3 to 4 weeks, the mortality rate exceeds 25%. However, the use of nasal continuous positive airway pressure has facilitated weaning in affected infants after such prolonged mechanical ventilation. In infants with particularly poor gastric motility, metoclopramide, which decreases the smooth muscle threshold for the action of acetylcholine, may be especially useful.

Subsequent problems relate to both the muscle and central nervous system (CNS). Supportive measures for the myopathy are required. Most of the joint deformities can often be managed with a nonsurgical approach, although more aggressive management of the foot and ankle deformities may prevent gait disturbances.

Congenital Muscular Dystrophy Without Overt Structural or Functional Brain Abnormalities.

CMD caused by a primary deficiency of merosin (i.e., laminin alpha-2 chain; see later), MDC1A, accounts for approximately 20% to 30% of cases of CMD (see Table 33.2 ). In 1979, an initial series of five infants with CMD was reported with no clinical sign of CNS disease (except for one with seizures) but with marked hypodensity of cerebral white matter on CT. Over the next decade, subsequent reports of a similar relationship between CMD and abnormal cerebral white matter, primarily on CT scans, were published. With the discovery that this disorder is associated with a deficiency of a critical basal lamina component (i.e., the laminin alpha-2 chain), recognition of the relative frequency of this disorder increased dramatically. The clinical presentation with weakness and hypotonia in merosin-deficient CMD is more severe than that in other merosin-positive CMDs. Indeed, motor function usually does not evolve past sitting or standing with orthotic support; ambulation is hardly ever achieved ( Table 33.3 ). Contractures are common and involve the hips, knees, elbows, and ankles, although severe neonatal arthrogryposis is rare. Nevertheless, in our experience, merosin-deficient CMD and congenital myotonic dystrophy are the two most common muscle disorders leading to multiple congenital contractures. Weakness tends to affect the upper limbs more severely than the lower limbs. Facial weakness is often prominent. A typical clinical sign is limitation of eye movements, particularly of the upgaze, but this is often noted in the second decade of life. Disturbance of chewing and swallowing, with a tendency for aspiration, is very common; a feeding tube may be needed. As many as 20% to 30% die of cardiopulmonary complications in the first year or so of life. A less severe phenotype, associated with partial deficiency of merosin , has been reported. ^a

a References .

Despite the uniform occurrence of diffusely abnormal cerebral white matter by brain imaging in merosin-deficient CMD (see later discussion), clinical neurological abnormalities are unusual. Approximately 20% to 30% of patients develop seizure disorders, usually later in childhood, and approximately 5% to 10% of patients exhibit cognitive deficits.

Muscle biopsy shows dystrophic changes, and immunofluorescence with antimerosin antibodies demonstrates decreased or absent staining; in severe infantile cases, there is total absence or only traces of the laminin alpha-2 chain protein. Sometimes an extensive inflammatory infiltrate may be seen.

The diagnosis of merosin-deficient CMD is confirmed by detecting a recessive mutation(s) (homozygous or compound heterozygous state) in the laminin alpha-2 chain ( LAMA2 ) gene.

Partial merosin deficiency may occur in the setting of other CMDs, such as dystroglycanopathies. CMD with secondary deficiency of merosin is rare in the neonatal period and likely represents a heterogeneous disorder. Formerly, the best characterized of this group was CMD related to FKRP mutations (see later). However, the more recent recognition that this disorder may be associated with overt CNS abnormalities makes it more appropriate to discuss later.

Merosin-positive CMD encompasses multiple clinical phenotypes, but the three most likely to be encountered in the neonatal period are Ullrich syndrome, congenital laminopathy, and rigid spine syndrome (see Table 33.2 ). The term classic merosin-positive CMD has become obsolete as molecular genetic studies characterize distinct disorders.

Ullrich CMD is a type of merosin-positive CMD with a characteristic clinical phenotype. Neonatal presentation with hypotonia, weakness, proximal joint contractures, torticollis, hip dislocation, spine kyphosis, and marked distal hyperlaxity is characteristic. In older infants and children, other typical features include prominent calcanei, keratosis pilaris, and hypertrophic scars (keloids). Subsequent motor development is severely delayed, and walking independently occurs only in the minority. The defect involves the gene (COL6A) for collagen VI, an extracellular matrix protein. Most cases of neonatal onset are autosomal recessive. Collagen VI is composed of three alpha chains encoded by three genes: COLA1, COLA2 , and COLA3 .

Congenital laminopathy is another CMD (L-CMD) related to recessive or dominant de novo mutations in the lamin A/C gene ( LMNA ) ( Table 33.4 ). LMNA mutations cause the dominant form of Emery-Dreifuss muscular dystrophy. Early onset in infancy has been described with severe axial weakness, wasting of cervicoaxial muscles, limited spontaneous movement, and dropped head syndrome as well as cardiac arrhythmias and feeding and respiratory difficulties. Muscle biopsy usually shows a dystrophic pattern and sometimes inflammatory infiltrates.

Rigid spine syndrome is a third merosin-positive CMD that usually presents clinically after the neonatal period with hypotonia and axial weakness. Neonatal onset has been reported. Subsequently, the characteristic spinal extensor contractures become apparent, with resulting spinal rigidity, scoliosis, and restrictive respiratory disease. The defect involves the gene (SEPN1) for an endoplasmic reticulum protein, selenoprotein N, the function of which is unknown.

Congenital Muscular Dystrophy With Overt Structural or Functional Brain Abnormalities.

CMD may be accompanied by prominent involvement of the CNS, manifested by severe neurological deficits (e.g., intellectual disability; see Table 33.2 ). Although primary merosin deficiency is associated with a morphological disturbance of cerebral white matter (see later), no clinical neurological abnormalities occur in most cases. Because these disorders are related to abnormalities of glycosylation of alpha-dystroglycan, they are often grouped as dystroglycanopathies . The term dystroglycanopathies includes a group of muscle diseases, with hypoglycosylation of alpha-dystroglycan on muscle biopsy, often associated with central nervous system structural abnormalities and less frequently with eye pathology. Some of the entities in this category are associated with disorders of neuronal migration, cerebral white matter abnormalities, hindbrain anomalies, and marked clinical neurological abnormalities; they are termed FCMD, WWS, and MEB. There are also mild dystroglycanopathies with late onset and no structural or functional brain or eye involvement; these are not discussed here. The Online Mendelian Inheritance in Man (OMIM) database subdivides the group of muscular dystrophies with deficit of dystroglycan glycosylation or muscular dystrophy-dystroglycanopathy (MDDG) into three broad phenotypical groups: A, B, and C. Primarily the type A severe phenotypes are discussed here.

FCMD (see Tables 33.2 and 33.4 ) has been described in several hundred Japanese children and in a much smaller number of children in North America, Europe, and Australia. The disorder exhibits the same basic clinical features referable to muscle involvement as the CMDs without CNS involvement: (1) onset in the neonatal period, (2) marked diffuse weakness and hypotonia, (3) facial weakness, and (4) joint contractures that develop particularly in infancy after the neonatal period. The clinical course of the motor function is generally characterized by slow acquisition of skills, usually the ability to crawl or to stand with support, until approximately the age of 8 years, when motor functions begin to deteriorate, ultimately to a lower level. The progression relates both to worsening of contractures and to apparent increasing weakness. Most patients become bedridden by the age of 10 years, and life expectancy is usually approximately 20 years.

The hallmark of FCMD is the evidence of major CNS disease. Intellectual disability is essentially constant, and the usual IQ level is between 30 and 50. ^a

a References .

WWS is the more severe of the two CMDs, with prominent ocular as well as CNS abnormalities (see Tables 33.2 and 33.4 ; see Chapter 6 ). Indeed, the life expectancy in this disorder is less than 3 years. In the newborn, the muscle disorder is often overshadowed by the severe CNS (cobblestone lissencephaly, pontocerebellar hypoplasia, severe white matter abnormality) and ocular (microphthalmia, hypoplastic optic nerves, colobomata, retinal detachment) abnormalities. Severe disturbances of feeding and tube or gastrostomy feeding are nearly invariable.

MEB is a similar CMD, with ocular and CNS abnormalities, although it is milder than WWS (see Tables 33.2 and 33.4 ). Thus an initial report from Finland describes 18 affected patients with the clinical features referable to CMD, intellectual disability of variable severity in 15 of the 18 reported patients, occasional seizures, and, distinctively, a wide variety of ocular abnormalities. These ocular defects include high myopia, congenital or infantile glaucoma, hypoplasia of the retina and optic nerve, coloboma of the optic nerve, and cataracts. Many subsequent reports further delineate this type of CMD. ^b

b References .

Although patients with MEB that is overt at birth may exhibit severe abnormalities, in general the features of this disorder are milder than those observed with WWS, and both of these cerebro-ocular types of CMD exhibit differences from FCMD (see Table 33.4 ).

There is also a fourth group of CMD patients (OMIM classification type B) with posterior fossa/cerebellar abnormalities on imaging or a normal MRI; these patients may be intellectually normal or have an associated intellectual disability. In this group, cerebellar abnormalities may be the only structural brain defects; they include cerebellar cysts and hypoplasia or dysplasia. Albeit supratentorial defects may also occur, cerebellar cysts in the absence of supratentorial white matter or cortical involvement have been described mostly in patients with mutations in the fukutin-related protein (FKRP) gene. Although FKRP-related CMD usually manifests beyond the neonatal period and is not considered in detail, neonatal onset is well documented. Weakness and hypotonia are apparent in the first weeks or months of life, although a phenotype as severe as primary deficiency of merosin has been observed. Subsequent motor development is markedly impaired, and respiratory muscle weakness leading to ventilatory failure occurs in the first or second decade of life. In neonatal-onset cases, severe cognitive deficits are common. Muscle biopsy shows a partial deficiency of laminin alpha-2 protein; thus this disorder was previously classified as CMD with secondary deficiency of merosin. However, the principal defect involves FKRP, presumed to be a glycosyl transferase, with alpha-dystroglycan the likely substrate. More than half of 25 reported cases with FKRP mutations have had prominent CNS abnormalities and thus should be included with the CMD group with overt CNS abnormalities. The neurological abnormalities have included intellectual disability, and the CNS structural deficits have included subependymal heterotopias, focal pachygyria, white matter abnormalities, cerebellar cysts, marked cerebellar dysplasia, and pontine hypoplasia. These CNS deficits are consistent, at least in part, with neuronal migrational disturbance and overlap with those observed in FCMD, WWS, and MEB. This similarity is noteworthy because, as discussed earlier, the last three types of CMD with overt CNS abnormalities all also involve disturbances of glycosylation of alpha-dystroglycan.

Laboratory Studies.

When all types of CMD (see Table 33.2 ) are considered, the serum CK level is elevated in most cases, particularly early in the course of the disease. However, the presence and degree of elevation vary with the type of disorder. In the largest series of cases ( n = 50) of the now obsolete entity known as merosin-positive classic (pure) CMD , 54% of infants had elevated CK levels, and the average elevation was approximately three times the upper limit of normal. In another series of 24 cases, CK elevation was 2.5-fold above the normal upper limit. The important clinical point is that a normal CK level does not exclude the diagnosis. By contrast, in merosin-negative CMD , the CK levels are consistently and markedly elevated to approximately 10-fold to 20-fold higher than the upper limit of normal. In FCMD, CK levels generally range from 10-fold to 50-fold higher than the normal upper limit. Levels are similarly very high in MEB and in WWS. In all cases, CK levels tend to decline with the patient’s age. The EMG reveals the changes of myopathy (see Table 30.4 ), including small-amplitude, brief-duration, and polyphasic motor unit potentials.

CT and, preferably, MRI scans of the head are useful in identifying the cerebral white matter abnormality characteristic of primary merosin-deficient CMD ( Fig. 33.9 ). The appearance on CT is decreased attenuation of cerebral white matter and, on MRI, increased signal on T2-weighted images. The cerebral white matter is affected diffusely, whereas the cerebellar white matter is unaffected. The cerebral white matter abnormality is generally not apparent in the first weeks of life and becomes apparent by approximately 6 months of age (see Fig. 33.9 ). However, utilization of T2-weighted images with a fast spin-echo sequence has demonstrated the white matter abnormality at 5 days of age. The abnormal white matter signal is most prominent in structures myelinated after birth (e.g., cerebral white matter) rather than in those structures that are myelinated before birth (e.g., brain stem and cerebellar white matter). Thus the abnormality may reflect a delay or arrest in myelination, and the finding in the affected white matter of abnormally increased apparent diffusion coefficients, characteristic of immature white matter, is perhaps consistent with this notion. Although the cerebral white matter abnormality is the unifying feature of the primary merosin-negative cases, several reports document the occurrence of cortical gyral dysplasia, especially in the occipital region, in isolated cases (~ <10%). Hypoplasia of the cerebellum was observed by MRI to varying degrees in 6 of 14 well-studied cases, and associated cerebellar cysts have also been described.

Evolution of cerebral white matter abnormality in merosin-deficient congenital muscular dystrophy, as demonstrated by magnetic resonance imaging (T2-weighted images).

(A) At 3 weeks of age, the appearance of cerebral white matter was within normal limits. (B) At 6 months of age, abnormal signal intensity in cerebral white matter was clearly apparent. (C) At 12 months of age, the white matter was extremely abnormal.

(From Mercuri E, Pennock J, Goodwin F, Sewry C, et al. Sequential study of central and peripheral nervous system involvement in an infant with merosin-deficient congenital muscular dystrophy. Neuromuscul Disord . 1996;6:425–429.)

In FCMD , the most striking abnormality is the gyral disturbance ( Fig. 33.10 ). The two major findings detectable by MRI are as follows: (1) a thick cortex with shallow sulci in the frontal regions, consistent with polymicrogyria, and (2) a thick cortex with a smooth surface in the temporo-occipital regions, consistent with lissencephaly-pachygyria. These findings correlate well with the neuropathology (see later discussion). Additional consistent features are white matter changes similar to those described earlier for merosin-deficient CMD. However, distinction of these two entities by MRI is straightforward because of the marked gyral abnormalities in FCMD. Moreover, the white matter abnormality in the latter diminishes with age. The corpus callosum is slightly hypoplastic in most of the Fukuyama cases.

Congenital muscular dystrophy and cerebellar abnormalities with POMT2 mutations.

(A) Enlarged cisterna magna and mild cerebellar vermis hypoplasia in a 16-month-old child with POMT2 mutations (sagittal T1-weighted brain MR image). (B) Cerebellar cysts in a 7-year-old with POMT2 mutations (coronal T1-weighted MR image). MR , Magnetic resonance.

(Adapted with permission from Messina S, et al. POMT1 and POMT mutations in CMD patients: a multicentric Italian study. Neuromusc Disord . 2008;18:565–571.)

In WWS and MEB , the dominant finding is the gyral abnormality. In its full form, as in WWS, the appearance of type II lissencephaly ( cobblestone lissencephaly) and pachygyria is striking and is associated with diffuse white matter abnormality of the type observed in merosin-deficient CMD. Again, the distinction by MRI from the latter disorder is straightforward because of the presence of the gyral disturbance as well as marked dysgenesis of cerebellum and hypoplasia of the pons, especially in WWS.

Additional laboratory studies of interest include measurements of cerebral visual and somatosensory evoked responses and of peripheral nerve conduction velocities in merosin-deficient CMD (see Table 33.3 ). Thus, for somatosensory evoked responses, latencies have been delayed in all patients studied, and for visual evoked responses, latencies have been delayed in approximately 90% of patients. Nerve conduction velocity studies have shown moderately slow values in more than 80% of merosin-deficient cases studied thus far. One infant studied in the newborn period had normal values but exhibited slowed conduction when studied again at 6 months of age. No abnormalities in cerebral evoked responses or motor nerve conduction velocities have been observed in merosin-positive CMD.

The demonstration of laminin alpha-2 deficiency in skin biopsy and in cultured fibroblasts in primary merosin-deficient cases indicates the potential value of this approach for the diagnosis of merosin-deficient CMD. In addition, the prenatal demonstration of merosin deficiency in trophoblastic tissue obtained from chorionic villus samples indicates the value of this approach (with simultaneous linkage analysis) in prenatal diagnosis.

Pathology.

Muscle biopsy in all types of CMDs shows striking changes, consistent with a dystrophic process. Notable are marked variations in fiber size in a nongrouped distribution, internal nuclei, and marked replacement of muscle by fat and connective tissue ( Fig. 33.11 ). ^a

a References .

a References .

Congenital muscular dystrophy: muscle pathology.

Note nongrouped changes with marked variation in fiber size and extensive replacement of muscle by connective tissue (light brown areas) and fat (clear areas) . Hematoxylin and eosin stain, ×400.

Immunofluorescence analysis for merosin.

(A) Normal muscle. (B and C) Muscle from two infants with congenital muscular dystrophy. (A) Normal muscle shows strong, continuous staining around the periphery of the myofibers. (B) Similar staining is evident in one of the infants with congenital muscular dystrophy, despite the marked variation in fiber size and increased connective tissue. Thus, this infant has classic merosin-positive congenital muscular dystrophy. In C, however, minimal staining for merosin is apparent. This infant has merosin-deficient congenital muscular dystrophy.

(From North KN, Specht LA, Sethi RK, Shapiro F, et al. Congenital muscular dystrophy associated with merosin deficiency. J Child Neurol . 1996;11:291–295.)

The neuropathology in infants with the merosin-deficient CMD with cerebral white matter abnormalities is not clearly known. The little neuropathological information available is inconclusive. The findings that the white matter abnormality becomes most apparent later in infancy and is associated with disturbances of visual and somatosensory evoked potentials and the MRI findings suggesting a defect in postnatal myelin development (see earlier discussions) suggest that myelination is altered in some way. Laminin alpha-2 chain is expressed in the basement membrane of blood vessels that form the blood-brain barrier and also along developing axonal tracts, where interaction with oligodendrocytes may occur. Disturbances at either or both loci could lead to disturbed myelin development and the abnormal signal with increased water diffusion on MRI or the edema by MR spectroscopy.

The neuropathology in infants with FCMD is striking. ^a

a References .

Fukuyama congenital muscular dystrophy with associated encephalopathy (migrational disturbance).

This cerebrum and cerebellum are from a child with severe hypotonia and weakness from birth and severe intellectual disability. The child died at 6 years, 5 months of age; the muscle pathology was consistent with congenital muscular dystrophy. (A) Coronal section of cerebrum. Note the polymicrogyric cortex involving the superomedial and lateral convexity, the pachygyric cortex involving the lateral convexity, and the agyric cortex involving the temporal lobes. (B) Horizontal section of cerebellum and brain stem. Note the marked and diffuse polymicrogyria involving the cerebellar cortex.

(From Kamoshita S, Konishi Y, Segawa M, Fukuyama Y. Congenital muscular dystrophy as a disease of the central nervous system. Arch Neurol . 1976;33:513–516.)

The neuropathology in the two CMDs with prominent ocular and brain abnormalities has been described. ^b

b References .

Pathogenesis and Etiology.

The pathogenesis and etiology of this group of disorders focus on the sarcolemmal membrane and the related proteins that link the extracellular matrix to the actin filaments of the myocytic cytoskeleton. ^c

c References .

The dystrophin-associated protein complex. This schematic shows the location of key proteins involved in the extracellular matrix–dystroglycan–dystrophin axis; a number of these proteins are described in this chapter, in particular α-dystroglycan (α-DG), the laminin α2 chain of the merosin trimer, the integrin complex and collagen VI.

(Adapted with permission from Muntoni F, Voit T. The congenital muscular dystrophies in 2004: a century of exciting progress. Neuromusc Disord . 2004;14:635–649.)

The molecular basis of primary merosin-deficient CMD is well established. Laminin-2 or merosin is the critical alpha-dystroglycan – binding basement membrane protein of the muscle extracellular matrix. The critical laminin alpha-2 chain of laminin 2 is encoded by the LAMA2 gene on chromosome 6q2; this is the gene that is defective in merosin-deficient CMD. Laminin alpha-2 chain is also present in basement membrane of Schwann cells, and thus its lack may underlie the defect of peripheral nerve described earlier. Moreover, as noted earlier, laminin alpha-2 is present in blood vessels and along developing axons in human brain (see earlier). How these observations relate to the cerebral white matter abnormality remains to be clearly elucidated. Demonstration of the deficient protein in muscle and skin facilitates diagnosis in the infant, and demonstration of the defect in chorionic villus samples facilitates prenatal diagnosis.

The molecular basis of classic (pure) merosin-positive CMD is heterogeneous and reflects the nature of the underlying genetic defects.

As discussed earlier, the molecular basis of Ullrich CMD involves the three genes (COL6A1, COL6A2, COL6A3) for collagen VI (see earlier). This defect results in a prominent loss of the basal lamina of muscle fibers and interrupts the vital link between the extracellular space and the intracellular cytoskeleton, as described earlier.

The molecular basis of rigid spine syndrome involves a deficiency of the gene (SEPN1) selenoprotein N, an endoplasmic reticulum protein (see earlier). The function of this protein remains elusive; however, it may be involved in protecting cells against oxidative stress.

The molecular bases for the CMDs with overt CNS abnormalities (i.e., FCMD, WWS, MEB and others), the dystroglycanopathies, all involve defects in dystroglycan and multiple glycosyl transferase genes catalyzing the O -linked glycosylation of alpha-dystroglycan (see Table 33.2 ). ^a

a References .

Mutations in the FKTN , FKRP , and ISPD genes can result in severe WWS or MEB phenotypes, in intermediate phenotypes such as those associated with cerebellar cysts or normal brain MRI, or even in milder limb-girdle muscular dystrophies. Although the mutated gene cannot be predicted from the clinical phenotype, there are certain features that may suggest a particular gene or number of genes.

• •
  

  In WWS, although POMT1 was the first genetic defect to be described, mutations in all known dystroglycanopathy genes have been described.

  
  
• •
  

  In MEB, mutations have been identified in POMGnT1 (the first linked to MEB), POMT1, POMT2, ISPD, and FKRP.

  
  
• •
  

  Cerebellar cysts have been described in association with mutations in FKRP, POMGnT1, and ISPD genes but may rarely also be seen with POMT1 and POMT2 mutations.

Disturbances in the glycosylation of alpha-dystroglycan impair its interaction with laminin and sarcolemmal proteins, especially beta-dystroglycan. Muscle degeneration is the result. Because alpha-dystroglycan is also present in the basement membrane of the glia limitans in the developing cerebral cortex, defective glycosylation results in the disturbances in neuronal migration that underlie the occurrence of cobblestone lissencephaly (see Chapter 6 ). As noted earlier, more than half of the cases of CMD related to FKRP mutations and FKRP deficiency, which exhibit CNS abnormalities milder but mechanistically similar to those of the three main disorders discussed here (WWS, MEB, FCMD), are relevant in this context, because the FKRP also appears to be a glycosyltransferase for alpha-dystroglycan.

Management.

Because the course in most patients with any of the types of CMD is nonprogressive for months to years, it is important to attempt to correct existing contractures by physical therapy (i.e., passive stretching or serial splints) and to prevent the development of contractures by active and passive exercises. The development of fixed deformities is often more deleterious to future motor abilities than is muscle weakness. Although no specific therapies are available, more details concerning supportive management are available in specialized sources.

Clinical Features.

The infantile clinical syndrome , first described by Carroll and Brooke in 1979, is characterized by the onset of facial weakness in early infancy. The weakness is distinctive in that most patients are unable to move the upper lip and later have a peculiar horizontal smile. Difficulty in closing the eyes is prominent, and the infant may sleep with the eyes open. The whole face tends to be smooth and expressionless. Difficulty in sucking is common. However, motor milestones are usually not significantly delayed, and 8 of 11 patients in the largest series walked alone by 15 months of age. Later, in infancy and early childhood, progressive weakness and wasting of axial and limb muscles supervene, particularly in the proximal upper extremities but then also in the lower ones. Of five patients who had reached 15 years of age or more, four were no longer walking, and the remaining patient was walking with difficulty. A similarly progressive disease course has been documented by other investigators. In a report of seven infantile-onset cases, the age at onset was between infancy and 4.5 years and the mean duration between onset of first symptoms and wheelchair dependency was 9.9 years. In a recently reported series of patients enrolled in the Italian FSHD registry, 54.5% showed clinical signs during the first 10 years; however, no patients had perinatal onset. The other clinical accompaniment, observed in the series of Carroll and Brooke, was sensorineural hearing loss in 6 of 11 children; this loss was severe in 2 children. Approximately 50% of subsequently reported cases have exhibited sensorineural hearing loss. Later in childhood, some patients have developed retinal telangiectasia, exudation, and detachment (Coats syndrome) in addition to sensorineural hearing loss. Intellectual disability was observed in 30% of cases in one series ; it was also documented with epilepsy in other cases.

Pathology.

Muscle pathology was striking in six of the nine patients studied in detail by Carroll and Brooke, and it exhibited an inflammatory response suggestive of polymyositis ( Fig. 33.15 ). Inflammatory changes in FSHD have been noted by others. ^a

a References .

Congenital facioscapulohumeral dystrophy.

(A) Hematoxylin and eosin stain. (B) Gomori trichrome stain. Note striking inflammatory response in muscle and significant variation in fiber size and many small basophilic fibers. In A, note mononuclear inflammatory cells around perimysial blood vessels.

(Courtesy Alan Pestronk, MD. http://neuromuscular.wustl.edu/pathol/fsh.htm .)

Pathogenesis and Etiology.

The genetic abnormality in this dominantly inherited disease is located at chromosome 4q35. The frequency of de novo mutations is high. However, on careful examination, as many as half of the apparently sporadic cases were found to have an affected parent. Frequently parents are carriers with somatic mosaicism of the mutation and thus may appear unaffected. The defect is particularly interesting and involves a reduction in the number of repeats of a 3.3-kb repeat sequence, D4Z4, at the 4q35 locus. Normal individuals carry 11 or more D4Z4 repeats; patients with FSHD have 1 to 10 copies. There is an inverse and coarse relationship between the onset and severity of the disease and the size of the D4Z4 repeat array. Most patients with 1 to 3 D4Z4 units are usually severely affected with seizures, cognitive delay, and hearing loss and are typically sporadic cases. However, only about half of the contractions are pathogenic, because the array needs to be on an FSHD-permissive chromosome 4 that contains a polyadenylation signal for DUX4 . This gene is embedded within each D4Z4 repeat and encodes a germline transcription factor. In somatic cells, the D4Z4 repeat is epigenetically repressed, which results in silencing of the DUX4 gene. When the repeat contracts in FSHD1 patients, the epigenetic silencing is released, causing the expression of the DUX4 gene and protein, which is toxic to mature skeletal muscle. Normal-sized D4Z4 repeat arrays can also be depressed by heterozygous mutations in the structural maintenance of chromosomes flexible hinge domain containing protein 1 (SMCHD1) gene on chromosome 18, which encodes for a chromatin modifier; this explains the pathogenesis of FSHD2, in which the D4Z4 repeat is of normal size. SMCHD1 mutations in patients with FSHD1-sized D4Z4 repeat arrays of 9 to 10 units cause a more severe phenotype ( Fig. 33.16 ).

Facioscapulohumeral dystrophy (FSHD) is characterized by a greater likelihood of expression of the germline transcription factor DUX4 in skeletal muscle. Normally, the D4Z4 repeat array contains 11 to 100 units of D4Z4, each encoding a copy of the DUX4 gene. These long D4Z4 arrays have a repressive chromatin structure; rarely, traces of DUX4 expression can be observed only on FSHD-permissive chromosomes that contain a DUX4 polyadenylation signal ( DUX4 -PAS). In the common FSHD1 form, a contraction of the D4Z4 repeat array to a size of 1 to 10 units results in a less repressive chromatin structure and a greater likelihood of DUX4 expression in skeletal muscle. SMCHD1 is a chromatin modifier involved in the establishment and maintenance of a repressed D4Z4 chromatin structure in somatic cells. Mutations in SMCHD1 in FSHD2 also lead to a less repressive D4Z4 chromatin structure and an increase in DUX4 expression. In some families, FSHD1 and FSHD2 can cosegregate and the combination of both genetic defects leads to greater levels of DUX4 expression and a more severe phenotype. (Reprinted with permission from Liew WKM, van der Maarel SM, Tawil R. Facioscapulohumeral dystrophy.

In: Darras BT, Jones HR Jr, Ryan MM, De Vivo DC, eds. Neuromuscular Disorders of Infancy, Childhood and Adolescence: A Clinician’s Approach . 2nd ed. San Diego: Academic Press; 2015:chap 32, 620–630.)

Laboratory Studies.

The serum CK level is moderately elevated in nearly all patients. The EMG reveals low-amplitude and short-duration motor unit potentials, indicative of myopathy. Nerve conduction studies are normal. However, these tests have become obsolete because, in suspected cases, the diagnosis can be confirmed by examining the leukocyte DNA for the D4Z4 repeat contraction and SMCHD1 mutations.

Management.

Management is similar to that for progressive myopathy in late childhood and adolescence. Of importance for the physician evaluating the newborn with facial weakness is the recognition that FSHD may be present; family members must be examined and perhaps have their leukocyte DNA evaluated. The parents should be counseled that, although the disorder in the affected parent is mild, a distinct possibility exists of a more severe form in the child (i.e., the phenomenon of anticipation). ^a

a References .

Central Core Disease.

Central core disease , originally described by Shy and Magee in 1956, was the first of the specific congenital myopathies to be defined. Subsequent reports further delineated a fairly discrete clinical syndrome.

Clinical Features.

The clinical syndrome consists of hypotonia and weakness, apparent usually in the neonatal period. However, many infants are not recognized as exhibiting muscle disease until months later. Muscle weakness is usually more prominent in the lower limbs and the proximal muscles ( Fig. 33.19A ), and tendon reflexes are usually preserved, although diminished or absent in proportion to the weakness. Congenital hip dislocation is also common. Mild facial weakness is not unusual. Ptosis, extraocular muscle weakness, dysphagia, and respiratory difficulties have not been features. However, severe neonatal weakness, arthrogryposis, and respiratory failure have been described in a subset of infants with CCD.

Central core disease.

(A) Photograph of twins, one of whom has the disease. Note the weakness of the proximal upper extremities. (B) Transverse section stained for NADH (nicotinamide adenine dinucleotide) shows absence of enzyme activity in large central cores.

([A] Reprinted with permission from Cohen ME, Duffner PK, Heffner R. Central core disease in one of identical twins. J Neurol Neurosurg Psychiatry . 1978;41:659–663. [B] Reprinted with permission from Dowling JJ, North KN, Goebel HH, Beggs AH. Congenital and other structural myopathies. In: Darras BT, Jones HR Jr, Ryan MM, De Vivo DC, eds. Neuromuscular Disorders of Infancy, Childhood and Adolescence: A Clinician’s Approach . 2nd ed. San Diego: Academic Press; 2015:chap 28, 502–537.)

With the exception of the last subgroup of infants with severe neonatal presentation who do not walk independently and continue to require respiratory support, the course of the disease is usually nonprogressive, and infants attain motor milestones albeit at a slow rate. Slow progression of weakness may occur, but even without this progression, contractures, pes cavus or planus, and kyphoscoliosis may result. In a series of 11 patients followed to the age of 4 to 20 years, 2 were unable to walk alone and 2 had difficulty climbing stairs. An increased risk of malignant hyperthermia (e.g., during anesthesia) must be recognized to avoid unexpected death.

Multiminicore Disease.

Multiminicore disease (MmD) should be discussed briefly in this context of core myopathies. The classic form of MmD typically has its clinical onset in the neonatal period or early infancy. Neonatal hypotonia and weakness, although generalized, tend to predominate in the axial muscles. Mild facial weakness is common. Respiratory difficulties generally appear later, as do spinal abnormalities, especially scoliosis. Some patients with MmD become ventilator-dependent while still ambulant. Motor development is prominently delayed. The clinical course is static in most patients, although approximately 20% of patients exhibit mild progression. The pathology is distinctive and consists of the occurrence of multifocal core-like areas, best seen as areas of reduced activity on oxidative enzyme stains ( Fig. 33.20 ).

Multiminicore myopathy.

(A) Transverse section stained with NADH (nicotinamide adenine dinucleotide) demonstrates foci of decreased oxidative enzyme activity throughout the muscle fiber. (B) Low-power electron microscopic view of longitudinal muscle sections demonstrates focal loss of cross striations, corresponding to areas of decreased mitochondrial enzyme activity.

(Reprinted with permission from Dowling JJ, North KN, Goebel HH, Beggs AH. Congenital and other structural myopathies. In: Darras BT, Jones HR Jr, Ryan MM, De Vivo DC, eds. Neuromuscular Disorders of Infancy, Childhood and Adolescence: A Clinician’s Approach . 2nd ed. San Diego: Academic Press; 2015:chap 28, 502–537.)

Pathogenesis is likely heterogeneous, with primarily sporadic and autosomal recessive cases reported. In separate cohorts, defects in the SEPN1 gene, the gene mutated in rigid spine syndrome (see discussion of CMD earlier) and in some later-onset forms of congenital fiber-type disproportion, and in the RYR1 gene, the gene mutated in CCD, have been identified. In addition, mutations in the beta-myosin heavy chain gene ( MYH7 ) and the giant sarcomeric protein titin (TTN) have been described in patients with MmD (see Table 33.5 ). The clinical overlap with CMD with rigid spine syndrome and the histological overlap with CCD are consistent with these initial genetic findings.

Clinical Features.

The clinical presentation in infants with manifestations from the neonatal period can be divided into three syndromes. First, as in typical CCD, hypotonia and weakness are relatively mild and are sometimes even overlooked in the newborn period. This variety is termed the typical congenital or classical form of nemaline myopathy . Second, marked neonatal hypotonia and weakness occur with no spontaneous movements or respiration at birth. Severe contractures or arthrogryposis and sometimes fractures complete this syndrome of severe congenital nemaline myopathy. Cardiac involvement in the form of dilated or hypertrophic cardiomyopathy may occur rarely, but in general cardiac contractility is normal. The pregnancy may be complicated by decreased fetal movements and polyhydramnios, and death in utero associated with fetal akinesia may occur. Third, marked neonatal hypotonia and weakness occur, but with some movement and respiratory effort and no severe contractures. This serious disorder, although not so marked as the severe cases, is termed intermediate congenital nemaline myopathy . In one large series of nemaline myopathy ( n = 143), approximately 50% of patients presented in the neonatal period; of these, 35% had the severe congenital form, 45% had the intermediate congenital form, and 20% had the typical congenital form. Accompanying the severe and intermediate forms were marked facial diplegia and feeding disturbances. The milder, typical form is associated with varying degrees of facial diparesis and feeding difficulties as well as distal involvement in addition to the proximal muscle weakness. Various skeletal anomalies—including high-arched palate, long dysmorphic face, prognathism malocclusion, pectus excavatum, and pigeon chest —may be seen. In surviving infants, pes cavus, kyphoscoliosis, and lumbar lordosis evolve.

The course of the typical, milder nemaline myopathy is generally considered to be nonprogressive or slowly progressive. However, in a study with a 5- to 25-year follow-up, 10 of 12 patients exhibited clinical deterioration, and only 8 of 12 were walking unsupported. Ten of 12 patients had developed scoliosis. Similar findings with 3- to 24-year follow-up were reported in a later study.

The course in those infants with the two more severe forms of the disease (i.e., the severe and intermediate forms) is generally unfavorable. Thus, in one series, 74% of patients with severe congenital disease died, generally before 1 year of age, and 28% of patients with intermediate congenital disease died. Among the infants with the severe form, a requirement for ventilation at birth or in the first month was followed by death in more than 90% of cases. Such infants fail to establish adequate ventilation after birth because of their weak respiratory muscles. This weakness results in failure of full expansion of the lungs, and aspiration is often added secondary to difficulty with secretions. Infants usually die in the neonatal period or in the first months of life. However, long-term survival in these patients, who are usually bedridden and receiving mechanical ventilation, has been observed. Moreover, rare affected infants with the need for mechanical ventilation at birth, severe weakness, and markedly impaired feeding have improved over the ensuing 2 to 3 years to become independent of mechanical ventilation and to achieve the ability to stand or even walk.

Laboratory Studies.

Laboratory investigations have included either normal or slightly elevated values for the serum CK level. The EMG may be normal but often exhibits short-duration and small-amplitude potentials of myopathy; signs of denervation have also been observed, particularly late in the disease, ^a

a References .

Pathology.

Muscle pathology is distinctive and diagnostic in the presence of the clinical features. Although the rod bodies are readily overlooked on routine hematoxylin and eosin staining, Gomori trichrome, toluidine blue, and other selected stains demonstrate them well ( Fig. 33.21 ). Predominance of type I fibers, which are also small, is consistent. ^b

b References .

Case example of nemaline myopathy.

(A) Photograph of patient at age 3. The classical facial appearance, particularly of lower facial weakness, of nemaline myopathy is depicted. (B) Photomicrograph of the muscle biopsy from the patient MLL. Abundant nemaline rods ( arrowhead ), principally subsarcolemmal in location, are present, confirming the histopathologic diagnosis of nemaline myopathy. Stain, modified Gomori trichrome.

(Reprinted with permission from Dowling JJ, North KN, Goebel HH, Beggs AH. Congenital and other structural myopathies. In: Darras BT, Jones HR Jr, Ryan MM, De Vivo DC, eds. Neuromuscular Disorders of Infancy, Childhood and Adolescence: A Clinician’s Approach . 2nd ed. San Diego: Academic Press; 2015:chap 28, 502–537.)

The rod body is derived from lateral expansion of the Z-disk, the band found normally at either end of the sarcomere. ^c

c References .

Nemaline myopathy. Electron microscopy of nemaline bodies.

The rods have the same electron density as the Z-lines of adjacent sarcomeres (×28,350).

(Reprinted with permission from Dowling JJ, North KN, Goebel HH, Beggs AH. Congenital and other structural myopathies. In: Darras BT, Jones HR Jr, Ryan MM, De Vivo DC, eds. Neuromuscular Disorders of Infancy, Childhood and Adolescence: A Clinician’s Approach . 2nd ed. San Diego: Academic Press; 2015:chap 28, 502–537.)

Nemaline myopathy. Electron micrograph showing intranuclear rod in a single nucleus.

Rods are also present in the adjacent muscle fiber, where there is loss of the regular sarcomeric structure (×36,000).

(Reprinted with permission from Dowling JJ, North KN, Goebel HH, Beggs AH. Congenital and other structural myopathies. In: Darras BT, Jones HR Jr, Ryan MM, De Vivo DC, eds. Neuromuscular Disorders of Infancy, Childhood and Adolescence: A Clinician’s Approach . 2nd ed. San Diego: Academic Press; 2015:chap 28, 502–537.)

Pathogenesis and Etiology.

The pathogenesis of nemaline myopathy relates to defects in one of 11 genes, 7 of which encode proteins of skeletal muscle thin filaments (see Table 33.5 ). Approximately 60% to 75% of cases of severe congenital nemaline myopathy are related to defects of ACTA1 , the gene for alpha-actin. Most of the remaining cases are related to nebulin, KLHL40, KLHL41, and leiomodin-3 defects and are principally autosomal recessive. Mutations in the genes for alpha-tropomyosin, beta-tropomyosin, and troponin are rare causes of severe disease. KLHL40 and KLHL41, which belong to the kelch protein family, are thought to be involved in ubiquitination and protein degradation, while leiomodin-3 is considered essential for the organization of sarcomeric thin filaments ( Fig. 33.24 ).

Clinical and histological features in nemaline myopathy due to LMOD3 mutations.

(A and B) Photographs of patients with LMOD3 nemaline myopathy. (A) Most affected individuals had severe generalized muscle weakness and hypotonia at birth and died in infancy (female patient with severe congenital nemaline myopathy, deceased at 4 months). (B) Female patient has less severe weakness and has survived into childhood (alive at 10 years). Note the severe facial and jaw weakness. (C) Control Gomori trichrome image (5-month-old child). (D and E) Skeletal muscle biopsy findings in D female patient alive at 1 year 7 months and (E) male patient alive at 4 months. (D) Some biopsies had only a few scattered atrophic myofibers within abundant connective tissue. Nemaline bodies appear as purple or blue inclusions ( arrow ). (F) Control electron microscopy (EM) image (6-week-old child, rectus abdominis muscle). (G and H) EM images from some patient biopsies show myofibers with ordered sarcomeres adjacent to myofibers with disordered sarcomeres and thickened Z-discs. (I and J) Many nemaline bodies appear as thickened Z-discs, (I) sometimes in pairs interconnected by thin filaments. Some nemaline bodies resemble thickened Z-discs surrounded by a short thin filament fringe . Scale bar: 50 µm (C–E); 2 µm (F–H); 500 nm (I and J).

(Reprinted with permission from Yuen M, Sandaradura SA, Dowling JJ,, et al. Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy. J Clin Invest . 2014;124:4693–4708. Erratum in J Clin Invest . 2015;125:456–457.)

Management.

Management of the typical nonprogressive or slowly progressive form of nemaline myopathy depends principally on physical therapy and related techniques. However, respiratory failure may occur during infancy, rapidly and unexpectedly, with a fatal outcome, even in apparently stable or improving patients. ^a

a References .

Clinical Features.

The clinical features of myotubular myopathy can be divided roughly into two syndromes. Less commonly, hypotonia and weakness are relatively mild and are sometimes overlooked in the newborn period. These autosomal varieties, also known as centronuclear myopathies, generally do not manifest frequently in the neonatal period. The more common disorder affects male infants and is characterized by marked hypotonia and weakness with respiratory failure. Many examples of this severe, malignant, X-linked neonatal form of myotubular myopathy (XLMTM) have been described. ^b

b References .

Polyhydramnios and decreased movement are noted in 50% to 60% of these fetuses during pregnancy. Failure to breathe effectively at birth often leads to asphyxia (and the mistaken diagnosis of hypoxic-ischemic encephalopathy for the subsequent motor deficits), and striking impairments of neonatal axial, appendicular, and facial movements well as sucking and breathing are apparent. Family history may reveal miscarriages and neonatal deaths in the maternal line. Ptosis is common, and extraocular muscle weakness is also often present. Indeed, the constellation of marked facial weakness, ptosis, and ophthalmoplegia with generalized hypotonia and weakness is highly suggestive of myotubular myopathy rather than other congenital myopathies ( Table 33.6 ) of either the mild or severe varieties. Cardiomyopathy does not occur, and cognition is normal in survivors.

The course in the severely affected male infants with the X-linked syndrome has been considered to be nearly uniform evolution to a fatal outcome. However, a more recent series of 55 affected male infants shows that 64% survived beyond 1 year of age, although 60% of these long-term survivors were entirely ventilator-dependent. Only 13% of the long-term survivors did not require at least intermittent mechanical ventilation. Similar data have been reported in other series. In the severely affected infant, because of the failure of lung expansion and the superimposed aspiration secondary to swallowing difficulties, atelectasis and pneumonia are the usual causes of death in the first days or weeks of life. Motor outcome in long-term survivors is very unfavorable in most, who are often bedridden or in wheelchairs. However, in a series of 36 patients, 3 were said to exhibit “no significant disability at 6 months, 5 years, and 7 years, respectively,” and in another group of 55 cases, 7 had only slightly delayed motor milestones. Several patients have developed other medical conditions—such as gallstones, nephrocalcinosis, vitamin K-responsive bleeding diathesis, spherocytosis, and hepatic peliosis—with associated fatal abdominal hemorrhages.

Pathology.

The muscle pathology is distinctive and diagnostic in the presence of the clinical findings. ^a

a References .

b References .

Myotubular myopathy.

(A) Muscle biopsy from a patient with X-linked myotubular myopathy. Note the histologic resemblance of muscle to fetal myotubes. (B) Central nuclei (longitudinal section): quadriceps biopsy from an 8-month-old patient with X-linked myotubular myopathy showing large central nuclei. Note the widely spaced nuclei, which affects the number seen in transverse section. Most fibers are less than 10 mm in diameter.

([B] Reprinted with permission North KN, Wang CH, Clarke N, et al.; International Standard of Care Committee for Congenital Myopathies. Approach to the diagnosis of congenital myopathies. Neuromuscul Disord . 2014;24:97–116.)

Myotubular myopathy.

This electron micrograph is from a muscle biopsy of a term infant with myotubular myopathy. A central nucleus surrounded by mitochondria is shown. Z-bands are in register ( arrowheads ) , unlike fetal myotubes.

(From Sarnat HB. Myotubular myopathy: arrest of morphogenesis of myofibers associated with persistence of fetal vimentin and desmin. Four cases compared with fetal and neonatal muscle. Can J Neurol Sci . 1990;17:109–123.)

Pathogenesis and Etiology.

The pathogenesis of myotubular myopathy is not entirely understood; a maturational arrest has been suggested because of the resemblance of the abnormal fibers to fetal myotubes and the persistence of other features of fetal myotubes, as noted in the previous section. Insight into the potential mechanism of this maturational defect has been gained by identification of the gene at Xq28 (MTM1). MTM1 encodes a protein, myotubularin, that is a phosphatidylinositol phosphatase. Mutations in MTM1 are the most common cause of XLMTM. Myotubularin is involved in diverse and numerous cellular processes, including excitation-contraction coupling, neuromuscular junction structure, satellite cell proliferation and survival, endosomal trafficking, autophagy, and cytoskeletal organization. Which of these functions is altered and how the disturbance leads to the disease remain unclear. Mutations in other genes can also cause myotubular or centronuclear myopathy, with mutations in dynamin-2 ( DNM2 ) recognized as an autosomal dominant cause of the disease (see Table 33.5 ). Autosomal recessive mutations have been identified in BIN1, RYR1 , and TTN genes. In an Italian cohort of 30 patients with centronuclear myopathy of congenital onset, mutations were identified in 25 (83%): 15 in MTM1 , 6 in DNM2 , 3 in RYR1 , and 1 in TTN . The DNM2 mutations causing a presentation in the first years of life are de novo. The clinical picture of infants and children with autosomal recessive centronuclear myopathy may be indistinguishable from the X-linked form, hence the need for genetic diagnosis, especially in the case of male infants.

Laboratory Studies.

Laboratory investigations have included only an occasionally elevated serum CK level. The EMG is usually myopathic, although not impressively so; as with nemaline myopathy, fibrillation potentials are occasionally observed. Chest radiographs often show very thin ribs. A histological diagnosis is usually made by muscle biopsy, and genetic testing is then undertaken to detect a mutation in one of the genes associated with centronuclear myopathy. However, if the phenotype is obvious, the clinician may not order a muscle biopsy and instead proceed directly with genetic testing.

Management.

Management of the severe X-linked form of myotubular myopathy is as discussed for the severe congenital forms of nemaline myopathy (see previous section). The ethical issues concerning ventilatory support of the severely affected infants are obvious.

Clinical Features.

The clinical syndrome of the more than 70 reported cases has included particularly hypotonia and weakness of limb, neck, respiratory, trunk, facial, bulbar, and extraocular muscles. The last feature, ophthalmoparesis, is present in more than half of the patients who are overtly symptomatic in the neonatal period but in fewer than 10% of those who present later. In most cases the deficits in the cases of early neonatal onset are severe. Other musculoskeletal abnormalities are common, such as a long thin face, a high-arched palate, a tented upper lip, limb contractures, short stature, congenital hip dislocations, foot deformities, torticollis, and, later, scoliosis. These abnormalities represent primarily postural deformities, generated either prenatally or postnatally.

The course is variable, but in general it varies according to the time of onset. Thus, among the infants with overt disease of neonatal onset, fully 40% have died because of the combination of bulbar and respiratory muscle weakness. Most surviving infants have had a static course, with generally severe weakness. Infants with slightly later onset are more likely to have the static and then improving course, often considered characteristic of the disorder or, more precisely, group of disorders.

Laboratory Studies.

The serum CK level is usually normal. The EMG can be normal, but it usually exhibits myopathic changes, albeit often not severe.

Pathology.

Muscle pathology establishes the diagnosis. The essential features are the predominance of type I fibers (i.e., type I fibers account for more than 55% of the total [normally, type I fibers account for 30%–55% of the total]) and the small size of type I fibers (i.e., a disparity of 12% or more in the mean diameters of type I and II fibers [normally, the diameters are approximately equal]; Fig. 33.27 ). Subsequently, hypertrophy of type II fibers appears to occur, and the discrepancy between the size of the fibers may become marked. (In several cases, type II fibers were hypotrophic. )

Congenital fiber-type disproportion.

Two muscle biopsies from an affected child. (A) First biopsy. Note the striking disparity in size of fibers (hematoxylin and eosin stain, ×150). (B) Second biopsy. Histochemical preparation shows many small fibers that stain dark with adenosine triphosphatase reaction at pH 4.3 (i.e., type I fibers) (ATPase stain, pH 4.3, ×250).

(Courtesy Peter Kang, MD, University of Florida, Gainesville, Florida.)

Fiber-type disproportion of the variety observed with CFTD may be observed with other congenital myopathies , particular nemaline myopathy, myotubular myopathy, and congenital myotonic dystrophy. However, in these disorders, additional changes in muscle coexist and serve to emphasize the nosological status of the disorders as well as to lead to the correct diagnosis. Moreover, fiber-type disproportion has been observed in spondyloepimetaphyseal dysplasia and in CNS disorders, such as Krabbe leukodystrophy, adrenoleukodystrophy, and perinatal asphyxia ; in one series, cerebellar hypoplasia was the most common CNS abnormality. Once the known causes of CFTD have been excluded on clinical and pathological grounds, there appears to remain a group of patients in which CFTD is the primary pathological condition.

Pathogenesis and Etiology.

The pathogenesis of CFTD is likely heterogeneous. A functional abnormality in maturation of the motor unit has been suggested for several reasons: (1) similar myopathology can be produced by denervation or cross innervation; (2) type IIc fibers, the fetal precursor of types IIa and IIb fibers, are often present in increased numbers; and (3) fiber-type disproportions of various types may occur with developmental disturbances of brain. The nature of the postulated disturbance in motor unit development is unclear. Numerous documentations of normal anterior horn cells and peripheral nerves in congenital fiber-type disproportion are available.

Approximately 45% of cases have a positive family history; approximately two thirds of these suggest autosomal dominant inheritance, and one third suggest autosomal recessive. In a series of neonatal-onset cases ( n = 3), mutations in the ACTA1 gene (different from those for nemaline myopathy) were detected (see Table 33.5 ). The clinical features were similar to those in the severely affected cases noted earlier except for the absence of ophthalmoparesis. A report of eight cases with onset in the first year or later in infancy and childhood noted defects in the SEPN1 gene (see the description of MmD, next). Mutations of the TPM3 gene, which encodes slow alpha-tropomyosin, are the most common cause of CFTD. This may explain the selective involvement of type 1 fibers in CFTD, since TPM3 is a type 1 fiber–specific protein. Although the mechanism remains unknown, recessive mutations in RYR1 have also been detected in a relatively large subset of CFTD patients with extreme fiber-size disproportion and may be responsible for the observed ophthalmoparesis in certain cases. In several Japanese patients with CFTD, mutations of the LMNA gene were recently identified ; such patients may be at risk for developing cardiomyopathy.

Management.

The most essential aspect of management is recognition that this disorder may be associated with improvement. Thus even severely affected infants should receive vigorous supportive care, and every effort should be made to prevent contractures.