Pediatric Annals

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Congenital Muscular Dystrophy

Eugenio Mercuri, MD; Cheryl Longman, PhD

Abstract

Congenital muscular dystrophy (CMD) is a clinically and genetically heterogenous group of disorders that present at birth, or within the first few months of life, with hypotonia, muscle weakness, contractures, and motor developmental delay.1 The classification of CMD recently has been updated according to advances in our understanding of the genetic basis of CMD and its underlying mechanisms. During the past few years, several new genes responsible for individual forms of CMD have been identified. Currently, ten CMD forms have been mapped, and the genes responsible for nine of these are known.

While previous classifications relied on clinical, imaging and biopsy findings,1 the new classification also takes into account the protein defects underlying the various CMD forms.2 This classification enables the identification of three main groups:

* Forms of CMD caused by mutations in genes encoding structural proteins of the basement membrane or extracellular matrix of skeletal muscle fibers. These include forms due to mutations in the genes encoding collagen VI, laminin a2 (merosin), and integrin α7.

* Forms of CMD caused by mutations in genes encoding putative or proven glycosyltransferase enzymes that are involved in the glycosylation of ct-dystroglycan. These include Fukuyama CMD, muscle-eye-brain disease, Walker-Warburg syndrome, MDClC, and MDClD, caused by mutations in the FCMD, POMGnTl, POMTl, FKRP, and LARGE genes, respectively.

* The form of CMD with rigid-spine syndrome secondary to mutations in the SEPNl gene, which encodes selenoprotein N, an endoplasmic reticulum protein of unknown function.

Table 1 (see page 562) provides a list of the genetically recognized forms of CMD according to this new classification. This classification only includes forms of CMD in which the primary genetic defect has been identified, but there are several other forms with distinctive phenotypes in which the protein or genetic defect has not yet been found. This article describes in detail the forms of CMD most frequently found in clinical practice, identifying specific clinical, imaging, and histopathological features that are helpful in differential diagnosis.

FORMS OF CMD

The most common forms of CMD observed in clinical practice are merosin-deficient CMD, which has typical clinical, imaging and biopsy features; forms of CMD with rigid spine (eg, UIlrich CMD, due to mutations in the collagen VI genes; RSMDl, due to mutations in the SEPNl gene); and forms of CMD due to abnormal glycosylation of a-dystroglycan, collectively termed dystroglycanopathies.

Merosin-deficient CMD

Merosin-deficient CMD is the most common form of CMD and is caused by mutations in the LAMA2 gene, located on chromosome 6q22-23, which encodes a protein called merosin.3'4 Merosin is a subunit of laminin, a large, extracellular matrix protein that links with dystrophin on the inner side of the muscle membrane through a group of dystrophinassociated glycoproteins (sarcoglycans and dystroglycan).

The typical clinical features of Ullrich CMD are marked distal laxity associated with contractures of the proximal joints, a rigid spine, and normal intelligence. Contractures and hypotonia, often associated with torticollis and hip dysplasia, frequently are present at birth, but a proportion of children present with delayed motor milestones.

Maximum functional ability is variable. Some patients with Ullrich CMD achieve only assisted ambulation, while others have mild motor delay but acquire the ability to walk independently. Failure to thrive and early and marked respiratory involvement are invariable features that become obvious by the end of the first decade. Other characteristic findings include protrusion of the calcanei, follicular hyperkeratosis, and a predisposition to hypertrophie (keloid) scars.19,20

Serum creatine kinase (CK) is normal or only mildly elevated in Ullrich CMD. Muscle biopsy often shows myopathie changes rather than clearly dystrophic changes. Collagen VI is generally deficient in muscle and skin on immunofluorescence.21 However,…

Congenital muscular dystrophy (CMD) is a clinically and genetically heterogenous group of disorders that present at birth, or within the first few months of life, with hypotonia, muscle weakness, contractures, and motor developmental delay.1 The classification of CMD recently has been updated according to advances in our understanding of the genetic basis of CMD and its underlying mechanisms. During the past few years, several new genes responsible for individual forms of CMD have been identified. Currently, ten CMD forms have been mapped, and the genes responsible for nine of these are known.

While previous classifications relied on clinical, imaging and biopsy findings,1 the new classification also takes into account the protein defects underlying the various CMD forms.2 This classification enables the identification of three main groups:

* Forms of CMD caused by mutations in genes encoding structural proteins of the basement membrane or extracellular matrix of skeletal muscle fibers. These include forms due to mutations in the genes encoding collagen VI, laminin a2 (merosin), and integrin α7.

* Forms of CMD caused by mutations in genes encoding putative or proven glycosyltransferase enzymes that are involved in the glycosylation of ct-dystroglycan. These include Fukuyama CMD, muscle-eye-brain disease, Walker-Warburg syndrome, MDClC, and MDClD, caused by mutations in the FCMD, POMGnTl, POMTl, FKRP, and LARGE genes, respectively.

* The form of CMD with rigid-spine syndrome secondary to mutations in the SEPNl gene, which encodes selenoprotein N, an endoplasmic reticulum protein of unknown function.

Table 1 (see page 562) provides a list of the genetically recognized forms of CMD according to this new classification. This classification only includes forms of CMD in which the primary genetic defect has been identified, but there are several other forms with distinctive phenotypes in which the protein or genetic defect has not yet been found. This article describes in detail the forms of CMD most frequently found in clinical practice, identifying specific clinical, imaging, and histopathological features that are helpful in differential diagnosis.

FORMS OF CMD

The most common forms of CMD observed in clinical practice are merosin-deficient CMD, which has typical clinical, imaging and biopsy features; forms of CMD with rigid spine (eg, UIlrich CMD, due to mutations in the collagen VI genes; RSMDl, due to mutations in the SEPNl gene); and forms of CMD due to abnormal glycosylation of a-dystroglycan, collectively termed dystroglycanopathies.

Merosin-deficient CMD

Merosin-deficient CMD is the most common form of CMD and is caused by mutations in the LAMA2 gene, located on chromosome 6q22-23, which encodes a protein called merosin.3'4 Merosin is a subunit of laminin, a large, extracellular matrix protein that links with dystrophin on the inner side of the muscle membrane through a group of dystrophinassociated glycoproteins (sarcoglycans and dystroglycan).

Table

TABLE 1.Genetically Recognized Forms of Congenital Muscular Dystrophy (CMD)

TABLE 1.

Genetically Recognized Forms of Congenital Muscular Dystrophy (CMD)

Patients with merosin-deficient CMD have a homogeneous phenotype, with several typical clinical and imaging findings.3'5'6 Hypotonia is the most common presenting feature at birth or in the first months of Ufe. Joint contractures and congenital dislocation of the hip also are common presentations. Some patients present with respiratory and feeding problems.

Children with merosin-deficient CMD generally achieve the ability to sit unsupported, and sometimes to stand and walk with support, but do not achieve independent ambulation. Respiratory problems are frequent, and patients often develop nocturnal hypoventilation, requiring supportive ventilation. Feeding problems and failure to thrive also are frequent.7

Brain magnetic resonance imaging (MRI) shows the typical white matter changes that are a consistent feature in these patients. These changes affect both hemispheres diffusely but spare the internal capsule, corpus callosum, basal ganglia, thalami, and cerebellum.8 In some children with merosin-deficient CMD, the white matter changes are associated with structural brain changes, such as cortical dysplasia or cerebellar hypoplasia.8'9 Cognitive function generally is normal in children with isolated white matter changes but can be impaired in patients with additional structural brain changes.10 Epilepsy is not uncommon, occurring in approximately 20% of cases.2 Because merosin is expressed in Schwann cells, a demyelinating neuropathy, demonstrated by reduced peripheral motor nerve conduction velocity, is also a frequent feature of merosin-deficient CMD.11

In contrast to the classical patients with complete merosin deficiency, a proportion of patients with mutations in the LAMA2 gene have only partial deficiency of merosin in muscle. These cases have the same changes on brain MRI but have a less severe clinical phenotype, with some patients with milder cases achieving independent ambulation.12

The muscle biopsy in merosin-deficient CMD shows a dystrophic pattern with reduction or absence of laminin ct2 immunolabelling.13 A partial reduction of the laminin a2 chain sometimes can only be demonstrated by the use of two different antibodies, directed against 80 kDa and 300 kDa fragments of the merosin protein.14 Laminin ct2 also can be demonstrated in the skin, and a skin biopsy can provide useful information when muscle is unavailable.15

ULLRICH CMD

This form of CMD with rigid spine, originally described by Ullrich in 1930, is reported to be the second most common form of CMD.2 Ullrich CMD can be caused by autosomal recessive mutations in the COL6A1 or COL6A2 genes on chromosome 21q22 or the COL6A3 gene on chromosome 2q37.16'17 Recently, a small number of Ullrich CMD patients with de-novo autosomal dominant mutations in each of these genes have been described,18 thus complicating genetic counseling in this form of CMD.

Table

TABLE 2.Differential Diagnosis of CMD

TABLE 2.

Differential Diagnosis of CMD

The typical clinical features of Ullrich CMD are marked distal laxity associated with contractures of the proximal joints, a rigid spine, and normal intelligence. Contractures and hypotonia, often associated with torticollis and hip dysplasia, frequently are present at birth, but a proportion of children present with delayed motor milestones.

Maximum functional ability is variable. Some patients with Ullrich CMD achieve only assisted ambulation, while others have mild motor delay but acquire the ability to walk independently. Failure to thrive and early and marked respiratory involvement are invariable features that become obvious by the end of the first decade. Other characteristic findings include protrusion of the calcanei, follicular hyperkeratosis, and a predisposition to hypertrophie (keloid) scars.19,20

Serum creatine kinase (CK) is normal or only mildly elevated in Ullrich CMD. Muscle biopsy often shows myopathie changes rather than clearly dystrophic changes. Collagen VI is generally deficient in muscle and skin on immunofluorescence.21 However, while deficiency of collagen VI is a clear marker of Ullrich CMD, normal collagen VI expression in muscle or skin does not exclude the diagnosis.20

Rigid Spine MD (RSMDI)

This form of CMD with rigid spine is characterized by spinal rigidity, early respiratory failure, and slowly progressing weakness. It results from autosomal recessive mutations in the SEPNl gene on chromosome Ip36, which encodes an endoplasmic reticulum protein, selenoprotein N.22

Developmental milestones in this type of CMD often are normal. However, patients with RSMDl develop Achilles tendon contractures and spinal rigidity in the first few years of life. One of the striking clinical features in this form is weakness of the axial muscles associated with milder proximal muscle weakness, hi some cases, patients exhibit midface hypoplasia, a long, tubular nose, and a thin, marfanoid habitus.23,24

Patients affected by RSMDl generally achieve independent ambulation and rarely lose this, although they may experience some difficulties with ambulation because of contractures. The rigid spine is associated with progressive scoliosis, which may require surgery. Progressive respiratory involvement typically is observed in the first decade, and respiratory failure requiring nocturnal ventilatory support is invariable in the second decade, when patients are still ambulant.

Serum CK is either normal or minimally elevated. Muscle biopsy changes are variable, ranging from minimally myopathie to dystrophic. Immunohistochemistry does not provide additional diagnostic help, as there are no specific antibodies to detect possible deficits of selenoprotein N.

Differential Diagnosis

Patients with Ullrich CMD and RSMDl have significant clinical overlap, and differential diagnosis in individual cases can be difficult Ulhich CMD generally has early onset with neonatal signs such as hypotonia or torticollis or delayed developmental milestones, while these signs are generally milder in patients with RSMD 1 . Patients with Ullrich CMD have marked skin changes and distal laxity, which are generally less obvious in RSMDl. Patients with RSMDl, in contrast, have more marked axial hypotonia. Collagen VI expression in muscle and fibroblasts helps to target the appropriate genetic investigations.

DYSTROGLYCANOPATHIES

The dystroglycanopathies are a group of disorders resulting from mutations in genes encoding known or putative glycosyltransferase enzymes.25·26 This group includes the forms of CMD with structural brain changes and eye abnormalities - Fukuyama CMD, muscle-eye-brain disease (MEB), and Walker-Warburg syndrome (WWS) - as well as more recently described forms that have variable brain involvement The clinical phenotype in the dystroglycanopathies is usually severe, and structural brain changes and mental retardation often are present.

Fukuyama CMD

Fukuyama CMD is virtually restricted to Japan, where it is the second most common form of childhood MD, after Duchenne MD.27'28 It is an autosomal recessive disorder that results from mutations in the FCMD gene, located on chromosome 9ql3, which encodes a putative glycosyltransferase, fukutin.29,30

Fukuyama CMD has early neonatal onset with hypotonia, weakness, and poor suck reflex. Motor milestones are delayed markedly, and only a few patients achieve independent ambulation. With time, motor function gradually deteriorates because of increasing weakness and contractures, and by the end of the first decade of life, most of these children are immobile.

The range of cognitive impairment is very wide but often profound; more than half of the patients are unable to speak.27,28 Seizures also are frequent1 Brain MRI shows cobblestone lissencephaly with areas of polymicrogyria, macrogyria, and agyria, often associated with ventricular dilatation and white matter changes that sometimes, however, improve with age.

Eye abnormalities occur in approximately 60% to 70% of patients withFukuyama MD but are rarely severe, myopia being the most frequent abnormality. Serum CK usually is elevated markedly, and muscle immunohistochemistry reveals markedly reduced glycosylated a-dystroglycan and a secondary reduction in merosin.

Muscle-Eye-Brain Disease

This form of congenital MD is common in Finland but has also recently been reported worldwide. Mutations in the 22 exon POMGnTl gene, located on chromosome lq32-34, have been identified in the classical Finnish cases and in a proportion of patients from other geographical regions.31,32 The POMGnTl gene encodes a glycosyltransferase, protein O-linked mannose β1,2-N-acetylglucosaminyltransf erase I.33

Patients with muscle-eye-brain disease phenotypes, resulting from mutations in the FKRP gene, also have been described34 and reviewed anecdotally. These cases were found to be clinically indistinguishable from patients with POMGnTl mutations.

Clinical manifestations include severe mental retardation, muscle weakness, and poor vision. Most patients have symptoms by age 2 months that include severe hypotonia, sucking difficulties, and failure to thrive. They have a typical facial appearance, with a large head, prominent forehead, and wide fontanelle. Motor development is extremely delayed, but a small minority eventually achieve ambulation with or without support.

Clinical signs of central nervous system involvement, such as spasticity and increased reflexes, become more obvious with time, and motor ability deteriorates further.35 Severe mental retardation and epilepsy are extremely frequent. Survival is variable, and some patients survive into their 40s and 50s.

Brain MRI shows signs of cobblestone lissencephaly with pachygyria over the frontal, temporal, and parietal regions and polymicrogyria over the occipital region. Enlarged ventricles, brainstem hypoplasia and cerebellar hypoplasia are also very frequent.36,38

Ocular involvement is an invariable feature, ranging from severe myopia and retinal hypoplasia to congenital and infantile glaucoma, nystagmus, and cataract. The combination of low electroretinogram and high visual evoked potentials is an exceptional and striking feature of this disorder. CK is often but not always grossly elevated.

The muscle biopsy shows a dystrophic picture, with variation in fiber size and an increase in connective tissue and adipose tissue. Muscle immunohistochemistry reveals markedly reduced labelling of glycosylated a-dystroglycan and a secondary reduction in merosin labelling.

Walker-Warburg Syndrome

Walker-Warburg syndrome is a rare autosomal recessive disorder presenting with eye and brain malformations and muscular dystrophy.39 It has been reported in patients of many different nationalities and races and is a highly genetically heterogeneous disorder. Mutations in several different genes are already known to cause Walker-Warburg syndrome, but these explain only a minority of cases.40

The first gene found to cause WalkerWarburg syndrome was POMTl. This gene, which encodes the glycosyltransferase, protein O-mannosyltransf erase 1, is mutated in up to 20% of Walker-Warburg syndrome CaSeS.4143 Walker-Warburg phenotypes have also recently been described in patients with mutations in the FCMD or FKRP genes.34'44'45 In addition, mutations in the POMTl gene have been described in patients with a milder limb girdle muscular dystrophy, associated with mental retardation but a normal brain MRI.46 This highlights the overlapping phenotypes that can result from mutations in different glycosyltransferase genes.

Walker-Warburg syndrome is the most severe phenotype of the muscleeye-brain syndromes.39 There often are antenatal signs, with decreased fetal movements and polyhydramnios. Many infants require resuscitation at birth, and the majority are stillborn or die in the perinatal period. Median survival for the live-born infants is 18 weeks, and only 5% to 10% survive more than 5 years,39 showing profound cognitive and motor problems and epilepsy.

Brain MRI shows cobblestone lissencephaly with agyria and additional areas of macrogyria and polymicrogyria. The cortex is abnormally thick and, frequently, the corpus callosum and septum pellucidum are absent or hypoplastic. Cerebellar hypoplasia and other cerebellar abnormalities also are constant features, often associated with ventricular dilatioa38

Eye abnormalities are present in all patients and include abnormal differentiation of the retina, microphthalmia, anterior chamber malformations, glaucoma, and cataract. Serum CK usually is elevated. Muscle immunohistochemistry reveals a severe depletion of a-dystroglycan and a secondary reduction in merosin labeling.

Congenital MD Type 1C

This recently described form of congenital MD originally was reported by Brockington et al.,47 who identified mutations in the Fukutin-related protein (FKRP) gene on chromosome 19q13. As in Fukuyama CMD, the FKRP gene encodes a putative glycosyltransferase whose mode of action is not yet known.

Mutations in Fukutin-related protein subsequently were found to underlie a common form of limb-girdle MD, type 21 (LGMD2I).48 The spectrum of phenotypes resulting from mutations in FKRP is the broadest of all the glycosyltransferase genes so far, and ranges from severe muscular dystrophy with cobblestone complex lissencephaly, eye involvement and an early fatal outcome, to mild LGMD2I patients who have minimal physical disability in late adulthood.34,49

Patients affected by the congenital MD form (MDClC) generally have an early onset of symptoms, with hypotonia and feeding difficulties at birth and markedly delayed motor milestones. Most achieve the ability to sit, but they rarely achieve independent ambulation.

One of the striking clinical features in MDClC is generalized hypertrophy of the lower limb muscles, with wasting and more severe weakness in the upper limbs. There also are contractures of the fingers, Achilles tendons, and hip flexors that become marked with time. In the second decade of life, children with MDClC commonly develop respiratory failure and echocardiographic evidence of left ventricular dilatation.47,49

Brain involvement is variable in patients with FKRP mutations. While the original MDClC patients had normal intelligence and normal brain MRI, there have been several subsequent reports of cases with mild mental retardation and cerebellar cysts, with or without cerebellar atrophy and white matter abnormalities.50'51 More recently, FKRP mutations have also been found in two patients with a typical muscle-eye-brain disease phenotype and in one classical patient with Walker-Warburg syndrome.34

Serum CK is markedly elevated. Muscle immunohistochemistry reveals a severe depletion of ot-dystroglycan and a secondary reduction in merosin.

Other Dystroglycanopathies

MDClB. This form is characterized by proximal girdle weakness, generalized muscle hypertrophy, rigidity of the spine, and contractures of the Achilles tendons. It was originally described in a consanguineous family from the United Arab Emirates. Recently, this form has been assigned to chromosome Iq42.52

MDClD. Mutations in the 16 exon LARGE gene, located on chromosome 22ql2.3-13.1, and encoding a putative glycosyltransferase, have been identified in one UK patient with CMD, severe mental retardation, and cobblestone lissencephaly.53

FURTHER READING

This article provides general information on the most common forms of CMD. From a practical point of view, the pediatrician should be aware of the variability of clinical features associated with different phenotypes and keep in mind the need for assessing respiratory and cardiac function and feeding in each. Table 2 (see page 564) gives examples of specific features that may help the clinician in the differential diagnosis of CMD. For a more systematic review on the genetics and pathogenesis of the various forms of CMD, including less common forms, a recent review by Muntoni and Voit is recommended.2

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47. Brockington M, Blake DJ, Prandini P, et al. Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha2 deficiency and abnormal glycosylation of alpha-dystroglycan. Am J Hum Genet. 2001;69(6):1198-1209.

48. Brockington M, Yuva Y, Prandini P, et al. Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 21 as a milder allelic variant of congenital muscular dystrophy MDC1C. Hum Mol Genet. 2001;10(25):2851-2859.

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53. Longman C, Brockington M, Torelli S, et al. Mutations in the human LARGE gene cause MDClD, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of alpha-dystroglycan. Hum Mol Genet. 2003;12(21):2853-2861.

TABLE 1.

Genetically Recognized Forms of Congenital Muscular Dystrophy (CMD)

TABLE 2.

Differential Diagnosis of CMD

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