Introduction. Overview

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1 Congenital muscular dystrophies Emma Clement MD ( Dr. Clement of Great Ormond Street Children's Hospital has no relevant financial relationships to disclose. ) Heinz Jungbluth MD PhD ( Dr. Jungbluth of King's College London has no relevant financial relationships to disclose. ) Salvatore DiMauro MD, editor. ( Dr. DiMauro, Director Emeritus of H Houston Merritt Clinical Center for the Study of Muscular Dystrophy and Related Diseases at Columbia University, has no relevant financial relationships to disclose.) Originally released August 7, 2004; last updated June 9, 2016; expires June 9, 2019 Introduction This article includes discussion of congenital muscular dystrophies, laminin alpha 2-deficient congenital muscular dystrophy (MDC1A, merosin-deficient congenital muscular dystrophy type 1A), collagen VI-related MCD (Ullrich congenital muscular dystrophy, Bethlem myopathy), integrin-related congenital muscular dystrophy, dystroglycanopathy (Walker-Warburg, muscle-eye-brain disease, Fukuyama congenital muscular dystrophy, congenital muscular dystrophy with intellectual disability, congenital muscular dystrophy without intellectual disability, MDC1C, MDC1D, MDDGA1-14), CDG 1e (DPM1-related), CDG 1u (DPM2-related), CDG 1o (DPM3-related), CDG 1m (DOLKrelated), rigid spine muscular dystrophy (RSMD1, SEPN1-related congenital muscular dystrophy), ACTA1-related congenital muscular dystrophy, Emery-Dreifuss muscular dystrophy type 2 (EDMD2, lamin A/C-related congenital muscular dystrophy), congenital muscular dystrophy with adducted thumbs (nesprin-related congenital muscular dystrophy), megaconial congenital muscular dystrophy (CHKB-related congenital muscular dystrophy), TRAPPC11- related congenital muscular dystrophy, congenital muscular dystrophy 1C, congenital muscular dystrophy type 1C, dystrophia muscularis congenita, Fukuyama congenital muscular dystrophy, integrin alpha7 deficiency, laminin alpha2 deficient congenital muscular dystrophy, merosin-deficient congenital muscular dystrophy, muscle-eye-brain disease, muscle-eye-brain syndrome, muscular dystrophy congenital type 1A, muscular dystrophy congenital type 1C, muscular dystrophy congenital type 1D, rigid spine muscular dystrophy 1, rigid spine syndrome, and type II lissencephaly: cobblestone lissencephaly. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations. Overview The congenital muscular dystrophies are a heterogeneous group of inherited, mostly autosomal recessive disorders. The clinical features range from severe and often early fatal disorders, often associated with brain involvement, to milder conditions with survival into adult life. The advances in the genetic basis of congenital muscular dystrophies have significantly improved our understanding of their pathogenesis and clinical diversity. A classification of congenital muscular dystrophies according to combined clinical features and biochemical defects is now widely used. More than 25 genes are known to cause congenital muscular dystrophies phenotypes and this number is likely to continue to rise with increasing availability of next generation sequencing technology. Allelic mutations at most of the known loci can give rise to a very wide spectrum of phenotypic severity. Key points Congenital muscular dystrophy encompasses a group of conditions that presents at birth or within the first months of life with weakness, hypotonia, and delayed motor milestones. Contractures are a common feature, and mental retardation is seen in some. Skeletal muscle biopsy shows dystrophic change and additional immunohistochemical abnormalities of variable specificity. Some forms of congenital muscular dystrophy are associated with characteristic features on brain or muscle MRI. Congenital muscular dystrophy results from abnormalities in proteins of the muscle cell, usually components of the extracellular matrix, basal lamina, or external membrane. A further subgroup results from abnormalities in the posttranslational modification of the key external receptor alpha dystroglycan. Historical note and terminology Congenital muscular dystrophy was first described over a century ago by Frederick Eustace Batten. Progress in this field was relatively slow until the 1990s. Since this time, huge advances have been made with pathological and

2 molecular characterization of many different subtypes of congenital muscular dystrophy. This has been facilitated to a large degree by the activity of the European Neuromuscular Centre (ENMC) Congenital Muscular Dystrophy Consortium, which convenes dedicated workshops on the subject (Dubowitz 1994; Dubowitz 1996; Dubowitz 1997; Dubowitz 1999; Muntoni and Guicheney 2002; Muntoni et al 2002a; Muntoni et al 2003; Muntoni et al 2005; Muntoni et al 2009; Bonnemann et al 2010; Bonnemann et al 2011; Saunter et al 2016). Workshop reports can be accessed at A comprehensive historical review can be found in Voit and Tome 2004 (Voit and Tome 2004). The classification of congenital muscular dystrophy has historically always been problematic due to the inherent heterogeneity of this group. The first attempt to formally classify congenital muscular dystrophies divided them into classical congenital muscular dystrophy without intellectual impairment or overt CNS changes and cases with clear CNS involvement (Dubowitz 1994). As our understanding of the biochemical and molecular basis of these conditions has progressed, a classification has evolved based on the primary biochemical defect (Muntoni and Voit 2004; Bonnemann et al 2014). This is summarized below and more comprehensively in Table 1. (1) Defects in the extracellular matrix, peripheral membrane, or basal lamina (a) Laminin alpha 2-deficient congenital muscular dystrophy (MDC1A ) (b) Collagen VI-related congenital muscular dystrophy (Ullrich congenital muscular dystrophy and Bethlem myopathy) (c) Collagen XII-related congenital muscular dystrophy (d) Integrin-related congenital muscular dystrophy (2) Congenital muscular dystrophies resulting from abnormal glycosylation of alpha dystroglycan: a very heterogeneous group. Phenotypes are categorized by OMIM as MDDGA 1-14 and include Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama congenital muscular dystrophy. Known genes include POMT1, fukutin, and FKRP. Refer to Table 1 for a full list. (3) Congenital disorders of glycosylation with abnormal glycosylation of alpha dystroglycan (a) CDG 1e (DPM1-related) (b) CDG 1u (DPM2-related) (c) CDG 1o (DPM3-related) (d) CDG 1m (DOLK-related) (4) Intracellular and nuclear forms (a) Rigid spine muscular dystrophy (RSMD1, SEPN1-related congenital muscular dystrophy) (b) ACTA1- related congenital muscular dystrophy (c) EDMD2 (Lamin A/C-related congenital muscular dystrophy) (d) Congenital muscular dystrophy with adducted thumbs (nesprin-related congenital muscular dystrophy) (e) Megaconial type congenital muscular dystrophy (choline kinase beta-related congenital muscular dystrophy) (f) TRAPPC11- related CMD Clinical manifestations Presentation and course The musculoskeletal system is always affected in congenital muscular dystrophy, although the severity of symptoms and maximal motor achievement is very variable. The main musculoskeletal features are weakness, hypotonia, and muscle wasting (or, rarely, hypertrophy), but may also include torticollis, spinal rigidity, scoliosis, contractions, and congenital dislocation of the hips. In most forms, the weakness is apparent in the first few months of life and is usually relatively static, with increasing disability more often the result of contractures and scoliosis (Muntoni and Voit 2004). Respiratory involvement may be a significant cause of morbidity if not managed proactively. Cardiac involvement in congenital muscular dystrophy is not usually a major feature, with a few exceptions. Patients with congenital-onset autosomal dominant Emery-Dreifuss muscular dystrophy are at risk of conduction defects, and dystroglycanopathy patients with FKTN and FKRP mutations may develop dilated cardiomyopathy or left ventricular systolic dysfunction (Murakami et al 2006; D'Amico et al 2008; Quijano-Roy et al 2008; Finsterer et al 2010). Dilated cardiomyopathy has also been reported in patients with CHKB mutations (Mitsuhashi et al 2011). Subclinical cardiac involvement is also

3 thought to affect up to one third of patients with merosin-deficient congenital muscular dystrophy type 1A (Jones et al 2001; Geranmayeh et al 2010). Structural and functional brain involvement is common in the congenital muscular dystrophies. This may range from characteristic white matter changes, often seen in merosin-deficient congenital muscular dystrophy type 1A, to dramatic structural changes, including agyria inevitably associated with profound mental retardation as seen in Walker-Warburg syndrome. Seizures and learning difficulties are seen in a number of congenital muscular dystrophy subtypes, for example, merosin-deficient congenital muscular dystrophy type 1A. In others, such as Ullrich congenital muscular dystrophy and Bethlem myopathy, intelligence and MRI brain imaging is expected to be normal. Eye involvement may be prominent in the more severe dystroglycanopathy phenotypes in which structural abnormalities such as anterior chamber defects, retinal abnormalities, cataracts, and severe myopia are commonly observed. External ophthalmoplegia, pronounced on upward gaze, is a recognized feature in merosin-deficient congenital muscular dystrophy type 1A, and visual evoked responses are usually abnormal (Mercuri et al 1995). Cataracts have also been reported in TRAPPC11- related congenital muscular dystrophy (Liang et al 2015). Specific congenital muscular dystrophies are outlined in more detail below and in Table 2. Defects in proteins of the extracellular matrix, peripheral membrane, or basal lamina. Collagen VI related disorders: Ullrich congenital muscular dystrophy and Bethlem myopathy. Both autosomal recessive and dominant mutations in collagen VI genes cause Ullrich congenital muscular dystrophy with approximately equal frequency (Baker et al 2005; Lampe and Bushby 2005). This is 1 of the most common forms of congenital muscular dystrophy across all populations. It is characterized by neonatal onset, hypotonia, proximal muscle weakness, and contractures with distal joint laxity and extended talipes. Presenting features may also include congenital dislocation of the hip, torticollis, protruding calcanei, and kyphosis. Motor achievement is variable; some patients achieve independent ambulation, but this is typically lost by the early teenage years. Functional motor ability is further compromised by the development of contractures, which eventually affect the previously lax ankles, wrists, and fingers, whereas the interphalangeal joints tend to remain lax. Scoliosis and spinal rigidity are frequently problematic. Respiratory insufficiency requiring ventilatory support is almost invariable by the mid-teenage years, and most affected individuals never have forced vital capacity above 60% of predicted values. Cardiac abnormalities are not a feature. Intelligence is normal. The development of characteristic skin changes, including hyperkeratosis and abnormal scarring, may facilitate the diagnosis (Ullrich 1930; Voit 1998; Mercuri et al 2002a; Muntoni et al 2002b; Lampe and Bushby 2005; Nadeau and Muntoni 2008). The natural history of a relatively large population of children affected by Ullrich congenital muscular dystrophy has been published by Nadeau and colleagues and Brinas and colleagues (Nadeau et al 2009; Brinas et al 2010). Bethlem myopathy, usually an autosomal dominant entity, is a much milder disorder. It is a slowly progressive proximal myopathy with development of contractures of the wrists, elbows, ankles, and long finger flexors. Although the phenotype is milder than that of Ullrich congenital muscular dystrophy, patients may present in the first years of life, usually with hypotonia, torticollis, or congenital dislocation of the hip. Patients may rarely develop respiratory insufficiency in later life (Haq et al 1999; Pepe et al 2002). Skin changes may be similar to those seen in Ullrich congenital muscular dystrophy. Patients may also display an intermediate phenotype, suggesting that Bethlem myopathy and Ullrich congenital muscular dystrophy represent either end of a spectrum of collagen VI related disorders. More recently, a group of patients with features reminiscent of Collagen-VI related disorders have been found to have mutations in COL12A1, a fibril-associated collagen. Both recessive and dominant mutations have been reported. Joint hyperlaxity is a prominent feature in these patients (Hicks et al 2014; Zou et al 2014). For excellent reviews on collagen VI-related congenital muscular dystrophy, see Muntoni and Voit, Lampe and Bushby, Nadeau and colleagues, Brinas and associates (Muntoni and Voit 2004; Lampe and Bushby 2005; Nadeau et al 2009; Brinas et al 2010). Laminin alpha 2-deficient congenital muscular dystrophy type 1A. MDC1A, also known as merosin-deficient congenital muscular dystrophy type 1A, results from mutations in LAMA2 encoding the laminin alpha2 chain of merosin.

4 Merosin-deficient congenital muscular dystrophy type 1A with complete absence of merosin on skeletal muscle biopsy causes a severe predictable phenotype. It presents in the neonatal period or first few months of life with profound proximal and axial weakness, hypotonia, and delayed motor milestones. However, the need for assisted ventilation at birth is not common. Affected individuals rarely acquire independent ambulation, but most are able to sit unsupported, although mobility is further compromised by the development of contractures and scoliosis. Most patients with complete absence of merosin will need ventilatory support and enteral tube feeding at some stage. Respiratory insufficiency, if left untreated, often leads to death in the first decade of life. Other features include partial external ophthalmoplegia and cardiac abnormalities in the form of cardiomyopathy, hypokinesis, or subclinical cardiac involvement (Jones et al 2001; Geranmayeh et al 2010). Intelligence is usually normal in merosin-deficient congenital muscular dystrophy type 1A. MRI brain imaging invariably reveals diffuse white matter changes after 6 months of life, thought to be due to dysmyelination and occasionally confused with hypoxic brain damage or primary white matter disease if the diagnosis of congenital muscular dystrophy has not been already established (Tome et al 1994; Philpot et al 1995; Vainzof et al 1995). Structural brain abnormalities may include hypoplasia of the cerebellum (up to one third) and occasionally neuronal migration abnormalities, usually of the occipital lobes, often associated with mental retardation (Dubowitz et al 2000). Seizures are common and affect 20% to 30% of children. Merosin-deficient congenital muscular dystrophy type 1A is also associated with a motor demyelinating neuropathy and reduced nerve conduction velocities. In addition, visual and somatosensory evoked responses are usually abnormal (Matsumura et al 1997). Patients with partial merosin deficiency usually have a less severe phenotype, but there are notable exceptions to this rule (Nissinen et al 1996; Guicheney et al 1998; Pegoraro et al 1998; Talts and Timpl 1999; Hayashi et al 2001). Useful review papers include Jones and colleagues and Geranmayeh and associates (Jones et al 2001; Geranmayeh et al 2010). Integrin alpha7 and integrin alpha9 deficiency. Congenital muscular dystrophy due to integrin alpha7 deficiency is a rare form of congenital muscular dystrophy associated with mental retardation and mildly raised CK. It is due to mutations in the gene encoding integrin alpha7 (ITGA7). Immunostaining of the skeletal muscle biopsy showed myopathic features with absent integrin alpha7 subunit and normal expression of laminin alpha2 (Vachon et al 1997; Hayashi et al 1998). Mutations in integrin alpha9 have been reported in a French-Canadian cohort with congenital muscular dystrophy and features overlapping those of the collagen VI related disorders. Those patients had distal joint laxity, contractures, hypotonia, and a slowly progressive myopathy with mild to moderate respiratory impairment. Intelligence was usually normal and CK was normal or only mildly elevated (Tetreault et al 2006; Tetreault et al 2009). Congenital muscular dystrophies resulting from abnormal glycosylation of alpha dystroglycan. The dystroglycanopathies are a heterogeneous group of autosomal recessive disorders characterized by hypoglycosylation of alpha dystroglycan on skeletal muscle biopsy. They include congenital muscular dystrophy variants with structural changes affecting the brain and eyes. The phenotype can be very variable, with muscle involvement ranging from profound weakness of congenital onset to later-onset limb-girdle muscular dystrophy phenotypes. Structural brain and eye abnormalities are also a common feature. Table 1 summarizes the known genes (Muntoni et al 2004; Muntoni and Voit 2004; Balci et al 2005; Godfrey et al 2006; Lefeber et al 2009). Several well recognized conditions are present in this group, including Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama congenital muscular dystrophy. However, as an increasing number of dystroglycanopathy genes have been identified, so the classification boundaries have been blurred. In an attempt to rationalize the nomenclature in this group, a new OMIM classification has emerged, containing 3 broadly defined dystroglycanopathy groups. At the severe end of the spectrum lies muscular dystrophy-dystroglycanopathy A (MDDGA), which is defined as congenital muscular dystrophy with brain and eye abnormality; progressing to MDDGB, which is defined as congenital muscular dystrophy with/without mental retardation; to the milder end of the spectrum, MDDGC, which is defined as limb-girdle muscular dystrophy. These are further subdivided according to the gene involved; currently 14 are described (MDDGA1-MDDGA14). Whether or not this system will supersede the historical names remains to be seen, but it does provide a useful framework when considering this complex group of disorders (Godfrey et al 2011).

5 The key dystroglycanopathy phenotypes have been well described and are summarized below. Walker-Warburg syndrome. This is a severe form of congenital muscular dystrophy with onset prenatally or at birth. The CNS features typically dominate the clinical presentation. Patients have structural brain abnormalities, including complete agyria or severe cobblestone (type 2) lissencephaly, marked hydrocephalus, severe cerebellar involvement, and complete or partial absence of the corpus callosum. Eye abnormalities include congenital cataracts, microphthalmia, and buphthalmos. Motor development is minimal or absent, and death before 1 year of age is usual (Cormand et al 2001). Muscle-eye-brain disease. Muscle-eye-brain disease is a congenital muscular dystrophy with brain abnormality less pronounced than that seen with Walker-Warburg syndrome, originally reported in the Finnish population. Typically, muscle-eye-brain disease patients present in the neonatal period with hypotonia and poor visual alertness. MRI brain findings feature cortical abnormalities, including pachygyria and polymicrogyria; cerebellar abnormalities, including hypoplasia, dysplasia, and cysts; and brain stem abnormalities. Epilepsy is a common complication of muscle-ey- -brain disease. Structural eye involvement is a feature and may include congenital glaucoma, progressive myopia, retinal atrophy, and juvenile cataracts. Individuals may, rarely, acquire the ability to walk, although this is delayed. Significant learning difficulties are expected, although patients occasionally manage to learn a few spoken words (Cormand et al 2001). Fukuyama congenital muscular dystrophy. Fukuyama congenital muscular dystrophy is the second most frequent form of muscular dystrophy in Japan after Duchenne muscular dystrophy, due to the presence of a FKTN founder mutation within this population. Reports of the disease outside of Japan are rare (Fukuyama 1960). The classical picture is a combination of generalized muscle weakness, severe brain involvement with mental retardation, frequent occurrence of seizures, and abnormal eye function (Fukuyama et al 1960). Pseudohypertrophy of the tongue, calves, and quadriceps muscles is common. Structural brain involvement includes cobblestone lissencephaly, white matter abnormalities, midbrain hypoplasia, and cerebellar abnormalities, including polymicrogyria and cysts. Respiratory failure in the mid-to-late teens is an invariable complication (Kobayashi et al 1998; Toda et al 2000). About 50% of classical Fukuyama congenital muscular dystrophy cases show signs of ocular involvement ranging from abnormal eye movements, poor visual pursuit, and strabismus to severe myopia, hyperopia, or cataracts. Congenital muscular dystrophy type 1C. Mutations in FKRP are found in patients with congenital muscular dystrophy type 1C, a congenital muscular dystrophy characterized by pronounced muscle involvement without functional brain abnormalities in most, but not all, cases (Brockington et al 2001a). Patients typically present in the first few months of life with hypotonia and weakness and do not acquire independent ambulation. Weakness is not particularly progressive, but disability is compounded by the development of scoliosis and respiratory decline, usually necessitating non-invasive ventilation, in the second decade. Dilated cardiomyopathy is also a finding in some (Mercuri et al 2000; Brockington et al 2001a; Topaloglu et al 2003). Another characteristic is enlargement of the leg muscles, sometimes followed by striking tongue hypertrophy. A subgroup of patients with congenital muscular dystrophy type 1C have brain involvement, with variable severity, ranging from mild mental retardation and structural changes of the cerebellum with cerebellar cysts to patients with more severe features resembling Walker-Warburg syndrome (Beltran-Valero de Bernabe et al 2002; Beltran-Valero de Bernabe et al 2004; Topaloglu et al 2003). Limb-girdle muscular dystrophy type 2I (LGMD2I, MIM #607155) is a milder condition allelic to congenital muscular dystrophy type 1C (Brockington et al 2001b; Mercuri et al 2003). GMPPB-associated congenital muscular dystrophy (MDDGA14). The phenotype in these patients overlaps congenital muscular dystrophy and congenital myasthenia. These individuals characteristically have a limb-girdle pattern of weakness with sparing of the ocular, facial, and bulbar muscles. Fatiguability may not be easily clinically demonstrable on clinical examination but is detectable on EMG. CK levels are approximately 10 times the upper limit of normal, and muscle biopsy shows dystrophic change with reduction of staining of alpha dystroglycan staining. Patients may show clinical improvement with pyridostigmine treatment (Rodriguez Cruz et al 2016). Other dystroglycanopathy phenotypes. Other less common dystroglycanopathy phenotypes include congenital muscular dystrophy type 1B (MDC1B, MIM #604801) linked to 1q42; congenital muscular dystrophy type 1D (MDC1D,

6 MIM #608840), reported in a patient with mutations in the LARGE gene; and limb-girdle muscular dystrophy type 2K (LGMD2K, MIM #609308), a condition found in the Turkish population and resulting from a founder mutation in POMT1 (Brockington et al 2000; Dincer et al 2003; Longman et al 2003; Balci et al 2005). A small number of patients are known to have mutations in DAG1 (Hara et al 2011; Riemersma et al 2015). The reported phenotype appears to typically be a severe congenital muscular dystrophy with eye and brain involvement although a limb-girdle presentation has also been noted. This form represents a primary dystroglycanopathy, whereas the remaining variants are more correctly referred to as secondary dystroglycanopathies. It is now evident that the clinical features of patients with secondary dystroglycanopathies depend more on the severity of the primary gene defect than on the gene involved. Indeed, the spectrum of all of these conditions has expanded considerably from the original description of a specific phenotype associated to a specific gene defect. This is exemplified by mutations in the fukutin-related protein (FKRP) gene, in which the severity ranges from severe congenital onset with structural brain involvement resembling Walker-Warburg syndrome to mild limb-girdle presentation in adult life (LGMD21), but is also found with other dystroglycanopathy genes (Godfrey et al 2007; Godfrey et al 2011). The identification of mutations in several more genes (B3GALNT2, SGK196, B3GNT1, GMPPB, ISPD, and GTDC2) has further added to the sense of heterogeneity within this group (Buysse et al 2013; Carss et al 2013; Cirak et al 2013; Stevens et al 2013; Tasca et al 2013; Yoshida-Moriguchi et al 2013). Overlap between primary muscle dystroglycanopathies and systemic congenital disorders of glycosylation. Congenital disorders of glycosylation and primary muscle dystroglycanopathies were initially thought to be distinct disease entities. Several cases have been reported that show clinical overlap between the 2 conditions. Congenital disorders of glycosylation type 1o. Abnormal glycosylation of serum transferrin with a pattern suggestive of a disorder in N-glycosylation was identified in a patient with muscular dystrophy, dilated cardiomyopathy, and strokelike episodes with no associated brain or eye involvement (Lefeber et al 2009). Mutations in dolichyl-phosphate mannosyltransferase polypeptide 3 (DPM3) were identified. Although this patient had a form of limb-girdle muscular dystrophy, it is conceivable that more severe DPM3 mutations might cause a congenital muscular dystrophy variant. Congenital disorders of glycosylation type 1u. Mutations in dolichyl-phosphate mannosyltransferase polypeptide 2 (DPM2) were identified in 2 siblings who had previously been reported because of a distinctive phenotype characterized by muscular dystrophy, severe mental retardation, microcephaly, myoclonic epilepsy, and cerebellar hypoplasia on brain MRI (Messina et al 2009). Congenital disorders of glycosylation type 1e. Yang and colleagues reported an infant with the phenotype of a congenital muscular dystrophy with borderline microcephaly, hypotonia, camptodactyly, and severe motor delay with elevated CK (Yang et al 2013). The transferrin profile was consistent with a type 1 congenital disorder of glycosylation, and reduced alpha dystroglycan immunostaining on skeletal muscle biopsy was observed. Mutations were found in dolichyl-phosphate mannosyltransferase polypeptide 1 (DPM1). Congenital disorders of glycosylation type 1m. In 2011, Lefeber and colleagues reported cases of congenital muscular dystrophy with prominent cardiomyopathy, raised CK, and hypoglycosylation of alpha dystroglycan (Lefeber et al 2011). Mutations in DOLK were found, a gene known to be mutated in patients with CDG1m. Intracellular and nuclear forms of congenital muscular dystrophy. Rigid spine muscular dystrophy type 1. Mutations in selenoprotein N,1 (SEPN1) give rise to rigid spine muscular dystrophy type 1. SEPN1 is a protein that appears to have an important role in protecting the cells from reactive oxidative species. The most common presentation of rigid spine syndrome muscular dystrophy 1 is that of axial hypotonia and weakness in the first year of life, usually in a child with otherwise normal motor milestones. Motor difficulties secondary to mild-to-moderate proximal muscle weakness, mild Achilles tendon tightness, and rigidity of the spine are also common (Dubowitz 1973). Ambulation is usually maintained into adulthood. The overall muscle bulk is reduced, especially in the medial aspects of the thighs, and serum CK is typically normal. The most prominent clinical features are spinal rigidity and scoliosis, which may develop between 3 and 12 years of age. Contractures are usually mild and mainly affect the ankles. Nasal speech secondary to palatal weakness is common. Vital capacity due to stiffness of the rib cage is low and decreases over time, and this is almost invariably aggravated by diaphragmatic weakness leading to respiratory insufficiency. A retrospective study on a large population of patients with a SEPN1-

7 related myopathy has been published (Scoto et al 2011). ACTA1-related congenital muscular dystrophy. Congenital muscular dystrophy with a rigid spine is also seen in patients with LMNA and collagen VI mutations. Two siblings were reported with congenital muscular dystrophy and rigid spine and found to have homozygous missense mutations in ACTA1, the gene usually associated with nemaline myopathy. Interestingly, in these patients, alpha-actin expression in skeletal muscle was conserved in contrast to the alpha-actin expression observed in previous reports of recessive ACTA1 disease (O'Grady et al 2015). Autosomal dominant Emery-Dreifuss muscular dystrophy (LMNA-related congenital muscular dystrophy). This is 1 of a number of disorders caused by mutations in lamin A/C (LMNA), and although not usually viewed as a congenital muscular dystrophy, severe congenital cases have been reported (Bonne et al 1999). Severity ranges from congenital hypotonia without acquisition of head or trunk control to isolated infantile dropped head syndrome. Muscle weakness and amyotrophy characteristically involve the neck and proximal upper extremities, but spare the facial muscles. Distal joint contractures and a rigid spine with thoracic lordosis develop early. Most children do not acquire the ability to stand unsupported, and a few are never able to sit unsupported. These patients have more severe cardiac complications than observed in Emery-Dreifuss muscular dystrophy (Quijano-Roy et al 2008). LMNA mutations have also been found in infants with a predominantly inflammatory myopathic appearance on muscle biopsy who later develop contractures and cardiac involvement (Komaki et al 2011). Congenital muscular dystrophy with adducted thumbs. Mutations in SYNE1 that encodes nesprin-1 give rise to a rare congenital muscular dystrophy variant with adducted thumbs, cerebellar hypoplasia, and cataracts (Voit et al 2007). Congenital muscular dystrophy with structural mitochondrial abnormalities (megaconial CMD) due to defects in choline kinase (CHKB). This novel form of congenital muscular dystrophy has been associated with mutations in CHKB, an enzyme involved in phosphatidylcholine biosynthesis (Mitsuhashi et al 2011). Most patients have early-onset muscle wasting, intellectual disability, microcephaly, cardiomyopathy, ichthyosiform skin changes, and neurosensory hearing loss. Brain MRI is normal, and serum CK markedly elevated (Mitsuhashi et al 2011; Quinlivan et al 2013; Haliloglu et al 2015). TRAPPC11-related congenital muscular dystrophy. Transport protein particle (TRAPP) is a multimeric complex involved in endoplasmic reticulum to Golgi trafficking. Mutations in TRAPPC11 were initially described in LGMD2S. These patients had limb-girdle muscular dystrophy or myopathy with intellectual impairment and a movement disorder. Liang and colleagues described a single patient with compound heterozygous TRAPPC11 mutations and congenital onset weakness, steatosis of the liver (associated with hepatomegaly), and cataracts. MRI brain scan showed slightly reduced periventricular white matter volume. Muscle CT showed involvement of the posterior compartment of the lower extremities (Liang et al 2015). Prognosis and complications The prognosis of the congenital muscular dystrophies is mainly determined by the overall severity of the condition and the degree of associated cardiorespiratory involvement. Commonly associated structural CNS abnormalities may cause substantial learning difficulties and epilepsy. Ocular abnormalities are another relatively common cause of associated morbidity. Specific considerations for individual entities are detailed below. Defects in proteins of the extracellular matrix, peripheral membrane, or basal lamina. Collagen VI related disorders. Ullrich congenital muscular dystrophy. The most significant complication is respiratory failure with nocturnal hypoventilation that can manifest itself in the first decade of life. Scoliosis necessitating surgical correction is also common. Merosin-deficient congenital muscular dystrophy type 1A. The most significant complication is respiratory failure with nocturnal hypoventilation that can manifest itself in the first few years of life. Scoliosis necessitating surgical correction and failure to thrive is also frequently found. Integrin alpha7 deficiency. No information is available.

8 Congenital muscular dystrophies resulting from abnormal glycosylation of alpha dystroglycan. Walker-Warburg syndrome. Most affected infants do not survive beyond the age of 3 years. Muscle-eye-brain disease. Long-term survival is possible, and 85% of the Finnish patients reach adulthood. Ocular complications include retinal dysplasia, persistent hyperplastic primary vitreous, glaucoma, and cataracts. Later, progressive high myopia may lead to retinal detachment. Epilepsy is common and cardiac involvement is rare. Fukuyama congenital muscular dystrophy. The life expectancy averages about 15 years, but survival into the midtwenties is becoming increasingly possible. Epilepsy is common, and cardiac involvement (dilated cardiomyopathy) is almost invariable and typically develops in the second decade of life. In patients with severe progressive myopia, retinal detachment may occur. Congenital muscular dystrophy type 1C. In muscular dystrophy congenital type 1C patients without brain involvement, the life expectancy is reduced because of the severe respiratory involvement leading to respiratory insufficiency in the first or second decade of life. Cardiomyopathy is common but usually not severe. Patients with central nervous system involvement usually have a more severe disease with earlier onset of the described complications. Congenital muscular dystrophy type 1D. The only patient reported to date was alive and well, from a general health point of view, at the age of 17 years. Intracellular and nuclear forms of congenital muscular dystrophy. Rigid spine muscular dystrophy type 1. Respiratory failure occurs in ambulant patients because the combination of diaphragmatic weakness and stiffness of the thoracic cage are typical complications of rigid spine muscular dystrophy 1. Most patients require nocturnal ventilation in the second or even first decade of life. Autosomal dominant Emery-Dreifuss muscular dystrophy. In the severe congenital form of autosomal dominant Emery- Dreifuss muscular dystrophy, early feeding and respiratory complications characterize the course, followed by severe cardiac complications that can be observed in the first decade of life, such as dilated cardiomyopathy or conduction system disease, or both. Clinical vignette Defects in proteins of the extracellular matrix, peripheral membrane, or basal lamina. Collagen VI related disorders. Ullrich congenital muscular dystrophy. A 16-month-old child was referred because of difficulties in walking as a result of muscle weakness and ankle instability. He was born with extended talipes, torticollis, and subluxed hips. On examination, the child had normal facial expression, striking distal joint laxity, proximal contractures, and kyphosis. Serum CK was only slightly elevated. The skin examination showed a malar rash and follicular hyperkeratosis. Laminin alpha 2-deficient congenital muscular dystrophy type 1A. This child presented in the first few weeks of life, when trunk and head control difficulties were noted. Mild talipes were also present. On examination, there was mild facial weakness, severe head lag, and more severe weakness in the arms than in the legs. Calf muscles were slightly prominent. Serum CK was elevated more than 15 times normal levels. Brain scan at 2 months was normal. The repeated brain MRI at 9 showed a strikingly abnormal signal of the supratentorial white matter typical of merosindeficient congenital muscular dystrophy type 1A. Congenital muscular dystrophies resulting from abnormal glycosylation of alpha dystroglycan. Walker-Warburg syndrome. A 2-week-old infant was referred following a pregnancy complicated by polyhydramnios. Severe generalized muscle weakness, proximal contractures, and hydrocephalus were noticed at birth, together with buphthalmos and cataracts. A brain scan showed a marked dilatation of the ventricular structures, lissencephaly, absent corpus callosum, and hypoplastic cerebellum. The child had absent psychomotor development. A serum CK was elevated at 12,000 IU/l. Muscle-eye-brain disease. A 7-month-old girl was assessed because of global developmental delay and severe myopia.

9 Pregnancy was uncomplicated, but a neonatal ultrasound had shown mild ventricular dilatation. On examination, the child had generalized hypotonia and weakness, but also a subtle sign of upper motor neuron involvement. Muscles were prominent and a serum CK was elevated at 8000 IU/l. A brain scan showed brainstem hypoplasia, thinning of the corpus callosum, cerebellar cysts, and frontoparietal polymicrogyria. Intracellular and nuclear forms of congenital muscular dystrophy. Rigid spine muscular dystrophy type 1. A 3-year-old girl was referred because of difficulties walking long distances and in keeping her head upright. She had mild facial weakness, nasal speech, thoracic scoliosis, and diaphragmatic muscle weakness. Her motor milestones had been normal, and there were only mild contractures of the Achilles tendons. Serum CK levels were normal. Autosomal dominant Emery-Dreifuss muscular dystrophy. Congenital presentation represents the severe end of the autosomal dominant Emery-Dreifuss muscular dystrophy spectrum. An 18-month-old Caucasian girl was born at 37 weeks after a pregnancy complicated by poor fetal movements. Bilateral talipes was noted at birth. Motor milestones were severely delayed; at the age of 9 months, she had not yet acquired head control, and she never achieved independent sitting. She had profound axial hypotonia and distal wasting; serum CK was elevated between 5 and 10 times normal values. Congenital muscular dystrophy with structural mitochondrial abnormalities (megaconial CMD) due to defects in the choline kinase protein. A 6-year-old boy was floppy from birth. He gained head control at 8 months of age, sat alone at 13 months of age, and walked unsupported at 2 years and 8 months of age. He never spoke any meaningful words. On examination at the age of 5 years, he showed generalized muscle weakness and hypotonia. Facial muscles were mildly affected. He always used the Gowers maneuver to stand up. He had ichthyotic skin changes in proximal areas. At the age of 5 years, his development was equivalent to that of a 12-month-old boy. He developed generalized seizures at the age of 6 years. His IQ testing was 44. CK was mildly elevated to 413 U/L. Lactate was normal. Biological basis Etiology and pathogenesis Congenital muscular dystrophies are predominantly autosomal recessive conditions. The known genes are summarized in Table 1 and briefly described below. Also see Bonnemann and colleagues for a review (Bonnemann et al 2014). GENETICS. Defects in proteins of the extracellular matrix, peripheral membrane, or basal lamina. Collagen VI related disorders. Ullrich congenital muscular dystrophy. This condition is due mutations in 1 of the 3 collagen VI chain genes (Camacho Vanegas et al 2001; Lampe and Bushby 2005). Severe de novo dominant mutations were described in patients with typical features of Ullrich congenital muscular dystrophy (Pan et al 2003). It is believed that approximately 50% of cases are the result of de novo dominant mutations (Lampe and Bushby 2005). Large deletions removing an entire COL6 gene have also been reported (Foley et al 2011). The genes responsible for this form are COL6A1 and COL6A2 on chromosome 21q22.3 and COL6A3 on chromosome 2q37. Milder allelic variants give rise to the autosomal dominant or autosomal recessive Bethlem myopathy. Laminin alpha 2-deficient congenital muscular dystrophy type 1A. Merosin-deficient congenital muscular dystrophy type 1A is due to recessive mutations in the laminin alpha2 chain gene, mapped to chromosome 6q22-23 (the LAMA2 gene) (Tome et al 1994; Helbling-Leclerc et al 1995). Several mutations have been found, most of which are nucleotide substitutions, small deletions, or insertions, resulting in nonsense or splice site changes (Guicheney et al 1998). Integrin alpha7 and integrin alpha9 deficiency. Integrin alpha7 deficiency. Recessive mutations in the integrin alpha7 gene have been reported in 3 patients (Hayashi et al 1998). Integrin alpha9 deficiency. Recessive mutations in the integrin alpha9 gene have been identified in a Canadian family

10 originally linked to chromosome 3 (Tetreault et al 2006). Congenital muscular dystrophies resulting from abnormal glycosylation of alpha dystroglycan. It is important to note that many different dystroglycanopathy genes can give rise to seemingly identical or similar phenotypes. Additionally, mutations in 1 gene can cause many different phenotypes. This is exemplified by mutations in the fukutin-related protein (FKRP) gene, in which severity ranges from Walker-Warburg syndrome to mild limb-girdle presentation in adult life. This heterogeneity can make targeted individual gene testing difficult, and this is a group of conditions where panel testing is beneficial. For a list of the known genes refer to Table 1. Walker-Warburg syndrome. Recessive mutations in POMT1, POMT2, and ISPD represent a large proportion of cases (Beltran-Valero de Bernabe et al 2002; van Reeuwijk et al 2005; Willer et al 2012). Walker-Warburg syndrome-causing mutations have been found in most of the dystroglycanopathy genes including LARGE, FKRP, FKTN, GTDC2, TMEM5, and SGK196 (Bouchet et al 2007; Bonnemann et al 2014). Muscle-eye-brain disease. The gene originally found to be responsible for muscle-eye-brain disease is the glycosyltransferase POMGNT1 (Yoshida et al 2001). Mutations in POMGNT1 have now been reported in at least 30 patients from different ethnic backgrounds (Taniguchi et al 2003). Milder allelic mutations have been associated with limb-girdle muscular dystrophy (Clement et al 2008). Other glycosyltransferases including FKRP, ISPD, and TMEM5 are also known to cause a muscle-eye-brain disease phenotype. Fukuyama congenital muscular dystrophy. The gene responsible for Fukuyama congenital muscular dystrophy is the FKTN gene. A recessive retrotransposal insertion into the 3' UTR of FKTN mrna accounts for 87% of Fukuyama congenital muscular dystrophy chromosomes in Japan, hence, explaining its prevalence in this country (Kobayashi et al 1998). This is considered to be a relatively mild mutation, as it only partially reduces the stability of the full-length mrna. Severe FKTN mutations have been reported in a few patients with Walker-Warburg-like features (de Bernabe et al 2003; Silan et al 2003), whereas milder allelic variants have been described in ambulant patients without mental retardation (Godfrey et al 2006; Murakami et al 2006). Congenital muscular dystrophy type 1C. The gene responsible for congenital muscular dystrophy type 1C is the fukutin-related protein (FKRP) gene. A similar phenotype can be caused by mutations in FKTN, ISPD, and GMPPB. Recessive mutations can be identified in patients ranging from the mildest limb-girdle muscular dystrophy type 2I to the severe Walker-Warburg-like spectrum of severity. Double nonsense or frame-shifting mutations have not been described and are probably not compatible with life. Congenital muscular dystrophy type 1D. Recessive mutations in the LARGE gene have been reported in 1 family (Longman et al 2003). The mouse homologue is mutated in the myodystrophy mouse (Grewal et al 2001). Overlap between primary muscle dystroglycanopathies and systemic congenital disorders of glycosylation. Mutations in 4 genes have been identified in this group; DPM1, DPM2, DPM3, and DOLK. See Table 1. Intracellular and nuclear forms of congenital muscular dystrophy. Rigid spine muscular dystrophy type 1. Recessive mutations in the selenoprotein N,1 (SEPN1) cause rigid spine muscular dystrophy type 1 (Moghadaszadeh et al 2001). Interestingly, mutations in the same gene have also been implicated in multiminicore disease (Ferreiro et al 2002) and in Mallory-body myopathy (Ferreiro et al 2004). ACTA1-related congenital muscular dystrophy. Two siblings were reported with homozygous missense mutations in ACTA1, the gene usually associated with nemaline myopathy. In contrast to other recessive ACTA1 disorders, alphaactin expression in skeletal muscle was conserved in these patients (O'Grady et al 2015). Autosomal dominant Emery-Dreifuss muscular dystrophy. Regarding the severe autosomal dominant Emery-Dreifuss muscular dystrophy cases, de novo dominant mutations in the gene encoding for lamin A/C (LMNA) are invariably found in these patients. Congenital muscular dystrophy with structural mitochondrial abnormalities (CMDmt) due to defects in the choline kinase protein. Recessive mutations in the gene encoding choline kinase beta (CHKB) characterize this variant. TRAPPC11-related congenital muscular dystrophy. A single patient has been reported with congenital onset muscular

11 dystrophy. This individual had compound heterozygous mutations in TRAPPC11. CELL BIOLOGY AND PATHOPHYSIOLOGY. Defects in proteins of the extracellular matrix, peripheral membrane, or basal lamina. Collagen VI related disorders. Ullrich congenital muscular dystrophy. Collagen VI is an extracellular matrix protein composed of 3 chains: alpha1 and alpha2 encoded by COL6A1 (MIM #120220) and COL6A2 (MIM #120240) and alpha3 encoded by the larger COL6A3 (MIM #120250) (Bruns 1984; Hessle and Engvall 1984; von der Mark et al 1984). The collagen chains undergo a complex assembly process, ultimately forming a microfibrillar network in the reticular layer of basement membranes (Engvall et al 1986; Zhang et al 2002). Studies suggest that 1 of the main functions of collagen VI is a structural role, anchoring the basement membrane to the underlying connective tissue (Kuo et al 1997). The reduced or absent collagen VI leads to reduced contractile force and disturbed intracellular calcium homeostasis. In addition, loss of contractile strength associated with ultrastructural alterations of sarcoplasmic reticulum and mitochondria have been demonstrated (Irwin et al 2003). These findings, therefore, link a defect of the extracellular matrix to a mitochondrial dysfunction followed by apoptosis (Angelin et al 2007). Experimental evidence suggests a possible beneficial effect of cyclosporine, a drug that, amongst other effects, reduces the mitochondrial damage (Merlini et al 2008). Laminin alpha 2-deficient congenital muscular dystrophy type 1A. Laminins are situated in the cell basement membrane and act as barriers to cell penetration and infiltration. Merosin-deficient congenital muscular dystrophy type 1A results from mutations in laminin alpha2 (LAMA2, MIM #156225), which encodes the laminin alpha2 chain that forms part of merosin (laminin 2). Laminins are secreted into the extracellular matrix. They are capable of selfassociation and, thereby, form a mesh of polymers that binds to a number of other macromolecules such as nidogen, agrin, and collagen IV in the extracellular matrix and to the 2 main transmembrane laminin receptors, dystroglycan, and various integrins. Through their interactions, laminins contribute to cell-cell recognition, differentiation, cell shape, movement, transmission of force, and tissue survival (Vachon et al 1996). Most mutations in LAMA2 result in complete absence of laminin alpha2 protein, with a minority causing a partial deficiency. Integrin alpha7 deficiency. Integrins are heterodimeric transmembrane glycoproteins consisting of an alpha and a beta chain. Integrin alpha7b1 is a major laminin alpha2 receptor in skeletal myotubes and mature myofibers. Integrin alpha7b1 expression and localization is laminin alpha2-dependent. Integrins are molecules involved in cell adhesion, migration, and survival. Congenital muscular dystrophies resulting from abnormal glycosylation of alpha dystroglycan. The dystrophin-associated glycoprotein complex is present along the sarcolemma of skeletal muscle fibers and contains a number of cytoplasmic, transmembrane, and extracellular matrix proteins (Ervasti and Campbell 1991). Central to the dystrophin-associated glycoprotein complex are alpha and beta dystroglycan, formed by post-translational cleavage of the dystroglycan peptide. The main function of the dystrophin-associated glycoprotein complex in skeletal muscle is to confer structural stability to the sarcolemma during contraction and relaxation, acting as a shock absorber and protecting skeletal muscle from damage (Petrof et al 1993). In the dystroglycanopathies, the common pathological feature is the finding of hypoglycosylation of alpha dystroglycan on skeletal muscle biopsy. The formation of the major O-linked mannose glycan on alpha dystroglycan involves the action of specific enzymes (glycosyltransferases) that add monosaccharides in a stepwise manner, a process that affects protein conformation and function (Chiba et al 1997; Jimenez-Mallebrera et al 2005). Mutations in DAG1 encoding the dystroglycan precursor protein have been reported in few cases (Hara et al 2011; Riemersma et al 2015). The remaining genes implicated in this group are putative or proven enzymes involved in the O-mannosylation of alpha dystroglycan (Muntoni and Voit 2004): POMT1 forms a complex with POMT2 that catalyzes the first step in the assembly of the O-mannosyl glycan (van Reeuwijk et al 2005), whereas POMGNT1 is the second enzyme in the O-mannosylation process. Mutations in these 3 genes interrupt the O-mannosylation pathway resulting in hypoglycosylation of alpha dystroglycan. The precise function of FKTN, FKRP, LARGE, B3GNT1, GTDC2, TMEM5, B3GALNT2, SGK196, GMPPB, and ISPD in facilitating the glycosylation of alpha dystroglycan has yet to be elucidated (Yoshida et al 2001; Willer et al 2002; Manya et al 2004; van Reeuwijk et al 2005; Manzini et al 2012; Vuillaumier- Barrot et al 2012; Buysse et al 2013; Cirak et al 2013; Di Costanzo et al 2014; Endo 2015).