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 variable. The main musculoskeletal features are weakness, hypotonia, muscle wasting, and, rarely, hypertrophy. Torticollis, spinal rigidity, scoliosis, contractures, and congenital dislocation of the hip may also occur. 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 (127). 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 cardiac conduction abnormalities, and dystroglycanopathy patients with FKTN and FKRP mutations may develop dilated cardiomyopathy or left ventricular systolic dysfunction (128; 41; 155; 63). Dilated cardiomyopathy has also been reported in patients with CHKB mutations (121). Up to 15% of patents with SEPN-1 related myopathy may develop right ventricular dysfunction, which is typically secondary to comorbid pulmonary failure (22). Subclinical cardiac involvement is also thought to affect up to one third of patients with merosin-deficient congenital muscular dystrophy type 1A (93; 70). Disproportionate respiratory failure in ambulatory patients may occur in SEPN-1 related myopathy/rigid spine muscular dystrophy, and collagen VI-related myopathies (164; 153). Hepatic steatosis and cholestatic liver disease have also been noted in those with TRAPPC11-related congenital muscular dystrophy (100).

Structural and functional brain involvement is common in the congenital muscular dystrophies. This ranges from the characteristic white matter abnormality seen in merosin-deficient congenital muscular dystrophy type 1A (MDC1A), to striking structural changes, such as agyria seen in Walker-Warburg syndrome. Seizures and learning difficulties are variably 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, 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 (116). Cataracts have been reported in TRAPPC11- related congenital muscular dystrophy (103) and MDCCA1D (198).

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 (11; 99). Approximately 50% to 75% of incident cases in families are the result of de novo variants (14).

Ullrich congenital muscular dystrophy is one of the most common forms of congenital muscular dystrophy across all populations. It is characterized by neonatal onset, hypotonia, proximal muscle weakness, proximal joint contractures, and distal joint laxity. Other reported findings include extended talipes, 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 pilaris and abnormal scarring, may facilitate the diagnosis (184; 193; 117; 125; 99; 131). Scalp involvement including hair loss, scalp itching, and scalp psoriasis has also been described (171). The natural history of a relatively large population of children affected by Ullrich congenital muscular dystrophy has been published by Brinas and colleagues (23).

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 later in life (78; 143). 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 continuous spectrum of collagen VI-related neuromuscular disorders. A retrospective, multicenter study of 119 patients with collagen VI–related disease found that early maximal motor milestones of rising from the floor unassisted and climbing four steps without a railing helped to distinguish between the three phenotypes of Ullrich congenital muscular dystrophy, intermediate disease, and Bethlem myopathy (134). Additionally, long-term motor outcomes and pulmonary function were strongly correlated with early maximal motor ability achieved.

For excellent reviews on collagen VI-related congenital muscular dystrophy, more information can be found in studies completed by Muntoni and Voit, Lampe and Bushby, Brinas and associates, Bonnemann, and Di Martino and associates (127; 99; 23; 19; 46).

Collagen XII-related congenital muscular dystrophy. A group of patients with an overlapping phenotype reminiscent of collagen VI-related disorders and Ehlers-Danlos syndrome have been found to harbor mutations in COL12A1, a fibril-associated collagen leading to both muscle and connective tissue defects, currently coined as myopathic Ehlers-Danlos syndrome. Both recessive and dominant mutations have been reported. Patients with dominant mutations tend to demonstrate a mild Bethlem phenotype with hypotonia at birth and with late development of contractures and delayed motor milestones, whereas those with recessive loss-of-function mutations have been described with a severe congenital myopathy phenotype. In contrast to Bethlem patients, those with COL12A1 mutations tend to be limited by muscular endurance rather than contractures during childhood. Joint hyperlaxity is a prominent feature in these patients, and they tend to have normal muscle bulk as opposed to decreased bulk seen in other congenital myopathies and collagen VI-related dystrophies. MRI tends to demonstrate severe and selective wasting of the rectus femoris as opposed to the “outside-in” phenomenon observed in other collagen VI-related myopathies (86; 212; 201). The phenotypic spectrum of Collagen XII related muscular dystrophy is continuing to expand with the discovery of newer variants (151; 44; 37).

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. This is a common cause of congenital muscular dystrophy (173).

Merosin-deficient congenital muscular dystrophy type 1A with complete absence of merosin on skeletal muscle biopsy (90% of cases) 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. The need for assisted ventilation at birth is not common. Affected individuals rarely acquire independent ambulation, but most are able to sit unsupported. Mobility is additionally 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. A cohort of 42 patients with complete absence of merosin demonstrated a linear annual decline in forced vital capacity of 2.9%, with most requiring ventilatory support by the early teenage years (208). Other features include partial external ophthalmoplegia and cardiac abnormalities in the form of cardiomyopathy, hypokinesis, or subclinical cardiac involvement (93; 70; 161). A review found that in 41% of LAMA-2 related muscular dystrophies, a cardiac abnormality was present, with left ventricular systolic dysfunction and arrhythmias being the most commonly described abnormalities (22).

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 (182; 148; 187). 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 (49). Seizures, predominantly focal with onset after the age of 6, are common and affect 20% to 30% of children and generally have a good response to antiepileptic medication (07; 135). 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 (112).

Patients with partial merosin deficiency usually have a less severe phenotype, but there are notable exceptions to this rule (137; 77; 142; 175; 83).

Useful review papers include Jones and colleagues, Geranmayeh and associates, and Sarkozy and colleagues (93; 70; 161).

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). This condition is associated with myopathic features on skeletal muscle biopsy with absent integrin alpha7 subunit and normal expression of laminin alpha2 (186; 82; 205).

Mutations in integrin alpha9 (ITGA9) have been reported in a French-Canadian cohort with congenital muscular dystrophy and features overlapping those of the collagen VI–related disorders. Reported findings included 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 (178; 179).

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 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 a common feature. Table 1 summarizes the known genes (126; 127; 12; 72; 102).

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, the classification boundaries have been blurred. In an attempt to rationalize the nomenclature in this group, a new OMIM classification has emerged, containing three 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, defined as congenital muscular dystrophy with/without intellectual disability; 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 (73).

The key dystroglycanopathy phenotypes have been well described and are summarized below.

Walker-Warburg syndrome cerebro-ocular dysplasia. This is a severe form of congenital muscular dystrophy associated with ocular dysplasia and major brain developmental anomalies. The CNS features typically dominate the clinical presentation. Patients have structural brain abnormalities, including complete agyria or severe “cobblestone” or Type II lissencephaly, marked hydrocephalus, severe cerebellar involvement, and complete or partial absence of the corpus callosum. Eye abnormalities include congenital cataracts, microphthalmia, and buphthalmos. Additionally, these patients have a characteristic cochlear hypoplasia type 4, which can be identified on MRI or CT scans (174). Motor development is minimal or absent, and death before 1 year of age is usual (38). A family has been described with multiple individuals affected with Walker-Warburg syndrome in addition to cystic kidneys (130). Numerous genes are associated with this clinical phenotype.

Muscle-eye-brain disease. Muscle-eye-brain disease is also a multisystem congenital muscular dystrophy. This disorder was originally reported in Finland and remains especially prominent in Finland even today. The cerebral and ocular abnormalities are less pronounced in muscle-eye-brain disease than those in Walker-Warburg syndrome. 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-eye-brain disease. Structural eye involvement is a feature and may include congenital glaucoma, progressive myopia, retinal atrophy, and juvenile cataracts. Individuals 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 (38).

Fukuyama congenital muscular dystrophy. Fukuyama congenital muscular dystrophy is one of the most common autosomal recessive disorders in Japan, with an incidence of 2.9 per 100,000 births, and is due to the presence of an FKTN founder mutation that is more prevalent within this population (89). Reports of the disease outside of Japan are rare (66). The classical picture is a combination of generalized muscle weakness, severe brain involvement with intellectual disability, frequent occurrence of seizures, and abnormal eye function (66). Pseudohypertrophy of the tongue, calves, and quadriceps muscles may also be seen. Cerebral developmental anomalies include 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 (180; 181).

About 50% of classical Fukuyama congenital muscular dystrophy cases have ocular involvement that may consist of abnormal eye movements, poor visual pursuits, strabismus, pronounced myopia, hyperopia, or cataracts (181).

Congenital muscular dystrophy type 1C. Mutations in the FKRP gene are also found in patients with congenital muscular dystrophy type 1C, a congenital muscular dystrophy that is allelic to Fukuyama congenital muscular dystrophy. This disorder is characterized by pronounced muscle involvement without functional brain abnormalities in most, but not all, cases (24). 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 may also occur in some patients with this condition (118; 24; 183). Hypertrophy of the leg muscles and striking tongue hypertrophy may be seen. A subgroup of patients with congenital muscular dystrophy type 1C have brain involvement, with variable severity, ranging from mild intellectual disability and structural changes of the cerebellum with cerebellar cysts to patients with more severe features resembling Walker-Warburg syndrome (15; 16; 183).

Limb-girdle muscular dystrophy type 2I (LGMD2I, MIM #607155) also occurs due to mutations in the FKRP gene. The clinical presentation consists of limb-girdle pattern of weakness in childhood and progression in the teen years that can resemble a dystrophinopathy phenotype (26; 113; 163).

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, MIM #608840), associated 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 (25; 47; 104; 12).

A small number of patients are known to have mutations in DAG1 (80; 158; 40). The reported phenotypes associated with DAG1 mutations include a severe congenital muscular dystrophy with eye and brain involvement, a more mild limb-girdle presentation, and a case with isolated hyperCKemia associated with compound heterozygous missense mutations. Congenital muscular dystrophy associated with DAG1 mutations are primary dystroglycanopathies, whereas congenital muscular dystrophies caused by mutations in the other genes in this group 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 with 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) (71; 73). The identification of mutations in several more genes (B3GALNT2, SGK196, B3GNT1, GMPPB, ISPD, and GTDC2) has further added to the heterogeneity within this group (29; 32; 34; 172; 177; 204).

Congenital disorders of glycosylation with abnormal glycosylation of alpha dystroglycan

Congenital disorders of glycosylation and primary muscle dystroglycanopathies were initially thought to be distinct disease entities. It is now recognized that a group of conditions demonstrate features that show clinical overlap between the two conditions.

Congenital disorders of glycosylation type 1e. Yang and colleagues reported an infant presenting as congenital muscular dystrophy with borderline microcephaly, hypotonia, camptodactyly, and severe motor delay with elevated CK (202). The transferrin profile was consistent with a type 1 congenital disorder of glycosylation, and alpha dystroglycan immunostaining on skeletal muscle biopsy was reduced. Mutations were found in dolichyl-phosphate mannosyltransferase polypeptide 1 (DPM1).

Congenital disorders of glycosylation type 1u. Mutations in dolichyl-phosphate mannosyltransferase polypeptide 2 (DPM2) were identified in two 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 (120). Less severe presentations including truncal hypotonia, congenital heart defects, intellectual disability, generalized muscle wasting, and mildly elevated CK have been described, expanding the clinical phenotype (157; 211).

Congenital disorders of glycosylation type 1o. Mutations in dolichyl-phosphate mannosyltransferase polypeptide 3 (DPM3) were identified in a patient with muscular dystrophy, dilated cardiomyopathy, and stroke-like episodes with no associated eye or other brain involvement (102). Abnormal glycosylation of serum transferrin with a pattern suggestive of a disorder in N-glycosylation was reported in this individual. Five additional patients have since been described from four unrelated families with phenotypes including global developmental delay, seizures, white matter abnormalities, weakness, and variable degrees of cardiomyopathy (132). This report further supports DPM3 as an etiology for a muscle-brain phenotype.

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 (101). Mutations in DOLK were found, a gene known to be mutated in patients with congenital disorders of glycosylation type 1m.

GMPPB-associated congenital muscular dystrophy (MDDGA14). Mutations in GMPPB are associated with a form of congenital muscular dystrophy that overlaps with congenital myasthenia. This is believed to be secondary to the role of GDP-mannose pyrophosphorylase B (GMPPB) not only in glycosylation of alpha-dystroglycan but also glycosylation of acetylcholine receptors and other neuromuscular junction proteins. Other phenotypes also include early- and adult-onset limb-girdle muscular dystrophy, often with evidence of neuromuscular junction defects. Individuals characteristically have a limb-girdle pattern of weakness with sparing of the ocular, facial, and bulbar muscles. The most severely affected patients present in infancy with a congenital muscular dystrophy, intellectual disability, and cataracts. Fatiguability may not be easily demonstrable but is detectable with repetitive nerve stimulation electrodiagnostic testing in affected muscles. CK levels range from 2 to greater than 50 times over the upper limit of normal, and muscle biopsy shows dystrophic change with reduction of staining of alpha dystroglycan. Patients may show clinical improvement with pyridostigmine treatment, and there have been isolated responses reported with 3,4-DAP, salbutamol, or steroids (159; 136; 149). A multicenter cross-sectional study in an Italian cohort further expanded the genotypic-phenotypic correlations of GMPPB mutations to include asymptomatic hyperCKemia, pseudo-metabolic myopathy, and arthrogryposis (08).

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 (103). Five cases of early-onset TRAPPC11-related muscular dystrophy have been described, with presentation in infancy of motor delay, elevated CK, cataracts, liver disease, intellectual disability, cardiomyopathy, and structural brain abnormalities, including cerebellar atrophy (123).

GOSR2-related congenital muscular dystrophy. Mutations in GOSR2 were first reported in 2011, with additional cases described in 2013 and 2014. Initial reports demonstrated progressive myoclonic epilepsy, ataxia, scoliosis, and a mildly elevated CK (maximum 2467 U/L). Although patients were nonambulatory by adolescence or early adulthood, EMG and muscle histology were reported as normal. A new c.2T>G mutation was identified in 2018 in two individuals, which resulted in a more severe phenotype in GOSR2-related disease with CK levels up to 5000 U/L, cerebral atrophy on brain MRI, and medically refractory epilepsy as well as a muscle biopsy demonstrating dystrophic features with alpha-dystroglycan hypoglycosylation. It is felt that the novel mutation more likely results in increased disruption of Golgi function than the more common c.430G>T mutation and that GOSR-2 disease likely falls on a spectrum of progressive myoclonic epilepsy on the milder end and congenital muscular dystrophy on the more severe end (100).

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 (51). 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. Two large natural history studies have been published (170; 192).

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 (139).

Autosomal dominant Emery-Dreifuss muscular dystrophy (LMNA-related congenital muscular dystrophy). This is one of several 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 (18). 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. Congenital onset disease is associated with more severe cardiac complications than observed in Emery-Dreifuss muscular dystrophy (155). LMNA mutations have also been found in infants with a predominantly inflammatory myopathic appearance on muscle biopsy who later develop contractures and cardiac involvement (97).

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 (194). Additional manifestations may include restrictive lung disease, clubfeet, and dilated cardiomyopathy (96).

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 (121). 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 (121; 156; 79; 106).

INPP5K-related muscular dystrophy. This form of autosomal recessive congenital muscular dystrophy is associated with mutations in INPP5K. Affected individuals present with progressive weakness from early childhood. Additional features found in some affected individuals include early onset cataracts, short stature, variable intellectual disability, microcephaly, and seizures. The clinical overlap with Marinesco Sjogren syndrome has been highlighted, although the cerebellum is normal on MRI. Muscle biopsy is dystrophic with a variably reported reduction in dystroglycan glycosylation and vacuoles, and, in one case, dense membranous structures associated with myonuclei were observed (165). CK and alkaline phosphatase are raised, and EMG is myopathic (198).

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

Laminin alpha 2-deficient congenital muscular dystrophy. 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.

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. Patients typically never start walking, or if they do, lose ambulation by 10 years of life.

Bethlem congenital muscular dystrophy. This is a milder form of collagen VI-related dystrophies with early mild proximal weakness and distal joint laxity. Contractures typically occur by the end of the first decade of life, and walking is maintained into adulthood. Approximately two thirds of patients may require a walking aid by 60 years of age. Decline in respiratory function is variable with onset in adulthood (31).

Collagen XII-related congenital muscular dystrophy. This is a milder phenotype than Bethlem with later onset of contractures and more prominent kyphosis rather than scoliosis. Delayed motor milestones are expected, but patients are able to live overall normal lives with limitations more related to endurance rather than contractures.

Integrin alpha7 deficiency. Psychomotor milestones are delayed, and early-onset torticollis may require surgery. Patients may acquire independent ambulation but are typically unable to run or climb stairs without assistance (28).

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 reached 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 mid-twenties 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 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 more severe disease with earlier onset of the described complications.

Congenital disorders of glycosylation with abnormal glycosylation of alpha dystroglycan

Congenital disorders of glycosylation type 1e. Patients are hypotonic at birth with severe developmental delay, microcephaly, and dysmorphic features. Course is often complicated by epilepsy (95; 68; 42; 202).

Congenital disorders of glycosylation type 1u. Severe hypotonia is seen at birth along with dysmorphic features, congenital contractures of joints, and scoliosis. There is often associated onset of focal, generalized, or myoclonic seizures and profound psychomotor developmental delays. Patients typically pass away within the first 3 years of life (13).

Congenital disorders of glycosylation type 1o. Motor development is delayed, and complications of epilepsy and mild intellectual impairment or learning difficulties are present. MRI may demonstrate white matter abnormalities around the lateral ventricles (65).

Congenital disorders of glycosylation type 1m. Motor milestones are delayed, and there is potential complication of dilated cardiomyopathy with secondary development of heart failure or cardiac arrhythmias (101.)

TRAPPC11-related congenital muscular dystrophy. Mutations have been associated with various multisystemic complications in addition to muscular dystrophy to include intellectual disability, seizures, microcephaly, cerebral atrophy, hepatic steatosis and cholestatic liver disease, reduced tear production, and achalasia (100).

Intracellular and nuclear forms of congenital muscular dystrophy

Rigid spine muscular dystrophy type 1 (SEPN1-related congenital muscular dystrophy). 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.

ACTA1 related congenital muscular dystrophy. Developmental motor milestones are achieved early but with inability to run by age 2 years and frequent falling. There is slow progression of weakness and development of kyphoscoliosis through adolescence. Mild restrictive lung disease is notable by the 3rd decade with rigid spine phenotype but without need for nocturnal ventilation prior to the second decade of life (139).

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, conduction abnormalities, 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 bilateral clubbed feet, 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 merosin-deficient congenital muscular dystrophy type 1A.

Clinical vignette: 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. 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.

Clinical vignette: 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 (20).

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 to mutations in one of three COL6 genes: COL6A1 and COL6A2 on chromosome 21q22.3 and COL6A3 on chromosome 2q37 (30; 141; 99). It is believed that approximately 50% of cases are the result of de novo dominant mutations (99). Large deletions removing an entire COL6 gene have also been reported (64). Although the more severe Ullrich congenital muscular dystrophy is thought to be more commonly autosomal recessive, there have been reports of heterozygous mutations causing a dominant inheritance pattern (11). Allelic variants give rise to the autosomal dominant or autosomal recessive and milder 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 (LAMA2), mapped to chromosome 6q22-23 (182; 84). Most mutations are nucleotide substitutions, small deletions, or insertions, resulting in nonsense or splice site changes leading to premature chain truncation (77; 173; 206).

Integrin alpha7 and integrin alpha9 deficiency.

Integrin alpha7 deficiency. Recessive mutations in the integrin alpha7 gene have been reported in four patients (82; 205).

Integrin alpha9 deficiency. Recessive mutations in the integrin alpha9 gene have been identified in a Canadian family originally linked to chromosome 3 (178).

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 one gene can cause many different phenotypes (173). This heterogeneity can make targeted individual gene testing difficult, and panel testing is advantageous. For a list of the known genes refer to Table 1.

Walker-Warburg syndrome. Recessive mutations in POMT1, POMT2, POMGNT1, and ISPD represent a large proportion of cases (15; 189; 200). Walker-Warburg syndrome-causing mutations have been found in most of the dystroglycanopathy genes including LARGE, FKRP, FKTN, GTDC2, TMEM5, and SGK196, and B3GALNT2 (21; 20; 03).

Muscle-eye-brain disease. The gene originally reported in association with this phenotype is POMGNT1 (203). Mutations in POMGNT1 have now been reported in many patients from different ethnic backgrounds (176). Milder allelic mutations have been associated with limb-girdle muscular dystrophy (35). Other glycosyltransferases including FKRP, ISPD, GMPPB, 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 (89). 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 (43; 169), whereas milder allelic variants have been described in ambulant patients without intellectual disability (72; 128).

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 (20). 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 one family (104). The mouse homologue is mutated in the myodystrophy mouse (75).

Muscular dystrophy, congenital with cataracts and intellectual disability. This condition is due to biallelic mutations in INPP5K. The condition shows phenotypic overlap with Marinesco Sjogren syndrome due to mutations in SIL1 (198).

Overlap between primary muscle dystroglycanopathies and systemic congenital disorders of glycosylation. Mutations in four 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 (122). Interestingly, mutations in the same gene have also been implicated in multiminicore disease (60) and in Mallory-body myopathy (59).

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, alpha-actin expression in skeletal muscle was conserved in these patients (139).

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. There have been case reports of mutations in the TRAPPC11 gene causing congenital muscular dystrophy. Described individuals have compound heterozygous mutations (103; 100; 160).

CELL BIOLOGY AND PATHOPHYSIOLOGY

Defects in proteins of the extracellular matrix, peripheral membrane, or basal lamina

Collagen VI-related disorders. Collagen VI is an extracellular matrix protein composed of three chains: alpha1 and alpha2 encoded by COL6A1 (MIM #120220) and COL6A2 (MIM #120240) and alpha3 encoded by the larger COL6A3 (MIM #120250) (27; 85; 196). The collagen chains undergo a complex assembly process, ultimately forming a microfibrillar network in the reticular layer of basement membranes (55; 209). Studies suggest that one of the main functions of collagen VI is a structural role, anchoring the basement membrane to the underlying connective tissue (98). 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 (88). These findings, therefore, link a defect of the extracellular matrix to a mitochondrial dysfunction followed by apoptosis (04). For an in-depth review of the role of collagen VI in the musculoskeletal system, please see the review by Di Martino and colleagues (46).

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 self-association 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 two 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 (185). 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 (57). 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 (146). 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 (33; 91).

Mutations in DAG1 encoding the dystroglycan precursor protein have been reported in few cases (80; 158). The remaining genes implicated in this group are putative or proven enzymes involved in the O-mannosylation of alpha dystroglycan (127): POMT1 forms a complex with POMT2 that catalyzes the first step in the assembly of the O-mannosyl glycan (189), whereas POMGNT1 is the second enzyme in the O-mannosylation process. Mutations in these three 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 (203; 199; 108; 189; 109; 197; 29; 34; 45; 54).

Muscular dystrophy, congenital with cataracts and intellectual disability. INPP5K is localized to the endoplasmic reticulum and encodes inositol polyphosphate-5-phosphatase K (SKIP). It is thought to be involved in protein processing and myoblast differentiation. Abnormalities of phosphoinositide metabolism have not previously been associated with a congenital muscular dystrophy phenotype (198).

Congenital disorders of glycosylation type 1e, 1u, and 1o. The defective enzymes in these conditions are DPM1, DPM2 and DPM3, which are subunits involved in Dol-P-Man synthase activity. Mutations of this enzymatic complex eventually affect the availability of mannose substrate, which, in turn, affects the glycosylation of dystroglycan (102; 120; 13).

Congenital disorder of glycosylation type1m. DOLK encodes the dolichol kinase responsible for formation of dolichol-phosphate. Dolichol-P is converted to dolichol-P-mannose, the monosaccharide donor for N-glycosylation inside the ER lumen and for O-mannosylation of alpha-dystroglycan. DOLK mutations lead to reduced dystroglycan O-mannosylation, likely via reduced availability of dolichol-P-mannose.

Intracellular and nuclear forms of congenital muscular dystrophy

Rigid spine muscular dystrophy type 1. Subcellular studies revealed that selenoprotein N,1 is an endoplasmic reticulum glycoprotein with a main isoform corresponding to a 70 kDa protein containing a single selenocysteine residue (144). Although the specific function is unknown, it is thought to have a role in early development and in protecting cells from oxidative stress damage (144; 05; 06; 191; 61).

Congenital muscular dystrophies due to mutations in nuclear envelope proteins

Autosomal dominant Emery-Dreifuss muscular dystrophy. Lamins are structural protein components of the nuclear lamina, a protein network underlying the inner nuclear membrane that determines nuclear shape and size. The lamins constitute a class of intermediate filaments. Defects in lamin A/C give rise to a wide variety of conditions, often but not invariably affecting skeletal and cardiac muscles.

Congenital muscular dystrophy with structural mitochondrial abnormalities (CMDmt) due to defects in the choline kinase protein. Choline kinase beta is the first enzymatic step in a biosynthetic pathway for phosphatidylcholine, the most abundant phospholipid in eukaryotes. In the muscle of three affected individuals with CHKB nonsense mutations, choline kinase activities were undetectable, and phosphatidylcholine levels were decreased (121).

Epidemiology

Information about congenital muscular dystrophy prevalence and incidence is limited. Epidemiological data suggest a prevalence of between 0.56/100,000 (74) and 0.99/100,000 (107). Of note, there is a high incidence of Fukuyama congenital muscular dystrophy in Japan estimated at 2.9 per 100,000 births due to a founder effect in the FKTN gene (89). Fukuyama congenital muscular dystrophy is consequently the second most frequent form of muscular dystrophy in Japan after Duchenne muscular dystrophy (66). Over twenty separate variants of congenital muscular dystrophy are now recognized, although clinical and genetic data suggest that further heterogeneity is to be expected (127; 71; 73; 17).

Dystroglycanopathies are the most common subgroup found in an Italian cohort of congenital muscular dystrophy, representing approximately 40% of patients (74). Among patients in the United Kingdom, the most common form of congenital muscular dystrophy is laminin alpha 2-deficient congenital muscular dystrophy (37%), followed by dystroglycanopathies (26.5%) and Ullrich congenital muscular dystrophy (15.7%), SEPN1-related muscular dystrophy (11.65%), and LMNA-related muscular dystrophy (8.8%). Other forms of congenital muscular dystrophy are likely to be less common, allowing for the fact that a proportion remain without a molecular diagnosis (36; 173). A study from China found a similar distribution, with LAMA2-related congenital muscular dystrophy being the most common (36.4%) followed by COL6-related congenital muscular dystrophy (23.2%), and dystroglycanopathies (21%) (69).

Prevention

Prenatal diagnosis is possible and has been performed for many subtypes where the genetic mutation is known.

Differential diagnosis

Confusing conditions

The differential diagnosis of the congenital muscular dystrophies includes other forms of congenital muscular dystrophy and conditions with overlapping clinico-pathological features, in particular the congenital myopathies, congenital myasthenic syndromes, and congenital disorders of glycosylation (20; 140).

Diagnostic workup

For an excellent comprehensive review see Bonnemann and colleagues (20).

Patient history, examination, and baseline investigations. The baseline assessment for patients with congenital muscular dystrophy includes a detailed history and clinical examination. Features particularly relevant for congenital muscular dystrophy include age of onset, pattern of weakness and contractures, muscle wasting or hypertrophy, cardiorespiratory impairment, feeding difficulties, eye and brain involvement, and presence of skin changes. A history of consanguinity should also be sought.

Serum CK determination is one of the most useful investigations, and the extent to which it is elevated may provide a clue to the specific diagnosis. In the dystroglycanopathies, CK is typically high, sometimes up to 50 times the upper limit of normal; in collagen VI myopathies and rigid spine muscular dystrophy type 1, the CK level is usually only mildly elevated or normal.

Skeletal muscle and skin biopsy. Skeletal muscle biopsy continues to place a role in the diagnostic assessment of patients with congenital muscular dystrophy, despite replacement by genetic testing as the first-line diagnostic test. Overtly dystrophic features, ie, the presence of necrotic and regenerating fibers, are supportive of the diagnosis but may be absent in some patients. There is no correlation between the extent of muscle biopsy changes and clinical disease severity. In addition, muscle involvement may be selective and change with disease progression; hence, biopsy findings are dependent on the individual muscle sampled as well as the age of the patient at the time of biopsy. In the era of genetic testing, muscle biopsy continues to play a role in those cases for whom genetic testing is negative or there are inconclusive results, such as variants of undetermined significance. In these cases, underlying pathology and potentially immunochemical labeling can be of use to further identify the underlying etiology for the patient’s presentation (133). Immunochemical labeling, for laminin alpha2 in merosin-deficient congenital muscular dystrophy type 1A for instance, may provide a definitive diagnosis in some cases (52).

In patients for whom a muscle sample is not available, pathological analysis of skin biopsy may be helpful. In merosin-deficient congenital muscular dystrophy type 1A, for example, laminin alpha2 may be reduced or absent in the epidermal-dermal junction (52). Fibroblasts cultured from skin biopsy are of particular value in the investigation of collagen VI-related myopathies where fibroblasts may be used to extract RNA for protein expression studies or for analysis of collagen VI expression (119; 92).

Molecular genetic testing. The gold standard diagnostic testing in the investigation of congenital muscular dystrophy is the identification of a pathogenic DNA sequence variant. Gene panel testing for congenital muscular dystrophy has become increasingly accessible. The interpretation of variants remains a challenge for some genes, notably COL6. In such cases, alternative supportive evidence of pathogenicity is required and may include family segregation studies in conjunction with pathological and clinical investigations. In addition to the above, one technology that shows promise is RNA-sequencing analysis, which can help identify or confirm splice aberrations in variants of undetermined significance in candidate genes identified on DNA analysis. Additionally, RNA sequencing, when compared to databases such as the Genotype-Tissue Expression Consortium project (GTEx), may aid in discovering abnormal splicing events not identified by whole genome or exome sequencing. In a prior cohort, this technology led to a diagnosis in 66% of patients where clinical phenotype and DNA sequencing had identified a possible candidate gene as well as allowed for diagnosis in 21% of patients, with no strong candidate gene previously identified with DNA analysis (39).

Muscle and brain imaging. Muscle ultrasound used in the clinic setting may demonstrate increased echogenicity in muscles, indicative of muscle pathology. Muscle magnetic resonance imaging (MRI), increasingly important in the investigation of muscle disorders, often shows a specific pattern of muscle involvement in the different subtypes of congenital muscular dystrophy and the congenital myopathies that may help direct molecular testing (09; 114).

Several of the congenital muscular dystrophies have associated brain abnormalities. These can have dramatic appearances on MRI brain scans and can be pathognomonic for a particular condition (147; 105; 154; 35; 07; 87; 90; 161; 174; 168).

Electrophysiology. Electrophysiology does not play a major role in the assessment of the congenital muscular dystrophies. However, in some variants, particularly merosin-deficient congenital muscular dystrophy type 1A, abnormalities in keeping with peripheral nerve involvement may be observed on electrophysiological testing (116; 166). Electrophysiology may be required to investigate the possibility of a congenital myasthenic syndrome in cases with overlapping clinical features. GMPPB-associated congenital muscular dystrophy is of note as it has features (including abnormal neurophysiology) that overlap congenital myasthenia and congenital muscular dystrophy (159).

Diagnostic considerations for defects in proteins of the extracellular matrix, peripheral membrane, or basal lamina

Collagen VI–related disorders.

Ullrich congenital muscular dystrophy. Serum CK levels are typically normal or slightly elevated. The necessary test to reach a final diagnosis is a muscle biopsy for collagen VI immunostaining. This is usually abnormal in Ullrich congenital muscular dystrophy (30); however, the changes in some patients with COL6A gene mutations can be subtle and limited to the basal lamina (92). Patients with completely absent protein tend to be more severely affected.

The identification of the causative mutation in one of the three COL6 genes will eventually confirm the diagnosis at the molecular level.

Laminin alpha 2-deficient congenital muscular dystrophy type 1A. Supportive clinical features are the presence of the classical white matter brain changes and a mild demyelinating peripheral motor neuropathy. Serum CK levels are typically elevated (more than 10 times normal values). A muscle biopsy is necessary to look at laminin alpha2 chain expression; this protein is also expressed in skin. The identification of the causative mutation in LAMA2 will be necessary to confirm the diagnosis.

Integrin alpha7 deficiency. Serum CK levels are normal or minimally elevated. The direct diagnosis of integrin alpha7 deficiency from immunostaining is hampered by the developmental regulation seen in the first 2 years of life, when integrin alpha7 expression is low.

Diagnostic considerations for congenital muscular dystrophies resulting from abnormal glycosylation of alpha dystroglycan

Brain MRI and ophthalmological examination will help to recognize the typical associated features. Serum CK levels are typically elevated (more than 10 times normal values). The immunostaining of skeletal muscle with alpha dystroglycan will typically show virtually absent staining using antibodies that recognize a glycosylated epitope (15; 210). Genetic analysis may confirm diagnosis, although a large proportion of this group remains without a molecular diagnosis after analysis of the known genes.

Overlap between primary muscle dystroglycanopathies and systemic congenital disorders of glycosylation. This subgroup of conditions will show reduced alpha-dystroglycan staining on skeletal muscle biopsy, elevated CK, and an abnormal transferrin profile. Dilated cardiomyopathy may be a feature in the DOLK group and myoclonic epilepsy in the DPM2 group.

Diagnostic considerations for intracellular and nuclear forms of congenital muscular dystrophy

Rigid spine muscular dystrophy type 1. Serum CK levels are usually normal or mildly elevated. The muscle biopsy typically shows significant intramyofibrillar disruption, at times featuring minicores. Mutations of SEPN1 have been reported in patients with typical minicore disease (60), but also Mallory body myopathy (59). Mutation analysis of SEPN1 is necessary to confirm the diagnosis.

Autosomal dominant Emery-Dreifuss muscular dystrophy. The muscle pathology in these cases is relatively nonspecific, and the only reliable diagnosis is the identification of a mutation in LMNA.

Diagnostic considerations for congenital muscular dystrophy with structural mitochondrial abnormalities (CMDmt) due to defects in the choline kinase protein

Megaconial type congenital muscular dystrophy. Many of these children have a severe autistic phenotype, which limits the possibility of a detailed examination. The elevated serum CK and the ichthyosiform skin changes may aid in suggesting the diagnosis, which can be further suspected by the pathological finding of giant mitochondria on electron microscopy. The condition needs to be further confirmed by the appropriate genetic studies.

Management

Evidence-based guidelines for the congenital muscular dystrophies have been published (94).

At present, management of the congenital muscular dystrophies remains predominantly supportive and based on multidisciplinary care, including regular physiotherapy to preserve mobility and limit development of contractures, monitoring for cardiorespiratory complications to allow timely institution of treatment, and management of other complications, such as epilepsy. Steroid therapy has been used, with some benefit, particularly in the dystroglycanopathy group and in Fukuyama congenital muscular dystrophy (72; 58; 129).

There are many areas of research looking to develop targeted therapies. Preclinical trials are in progress using a range of strategies, including exon skipping (81; 01), adeno-associated viral (AAV) vectors (152), antisense oligonucleotides (ASOs) (02), and targeting cell matrix adhesion and fibrotic pathways (162). For excellent reviews, see (48; 207; 62).

Specific management considerations for individual entities are outlined below.

Defects in proteins of the extracellular matrix, peripheral membrane, or basal lamina

Collagen VI–related disorders.

Ullrich congenital muscular dystrophy. Regular overnight sleep studies are indicated to monitor the onset of nocturnal hypoventilation.

Laminin alpha 2-deficient congenital muscular dystrophy type 1A. Regular overnight sleep studies are indicated because nocturnal hypoventilation invariably develops. Gastrostomy feeding might be required in case of failure to thrive.

Congenital muscular dystrophies resulting from abnormal glycosylation of alpha dystroglycan

Walker-Warburg syndrome. Ventriculoperitoneal shunt can be indicated in cases of obstructive hydrocephalus.

Muscle-eye-brain disease and Fukuyama congenital muscular dystrophy. Symptomatic treatment of the various medical complications and prevention of respiratory failure secondary to nocturnal hypoventilation is recommended.

Intracellular and nuclear forms of congenital muscular dystrophy

Rigid spine muscular dystrophy type 1. Regular overnight sleep studies are indicated to monitor the development of the respiratory failure secondary to nocturnal hypoventilation.

Congenital muscular dystrophies due to mutations in nuclear envelope proteins.

Autosomal dominant Emery-Dreifuss muscular dystrophy. Regular overnight sleep studies, echocardiograms, and Holter ECGs are used to detect early cardiac involvement. Implantation of defibrillators is advised in cases with associated cardiac conduction disease.

Special considerations

Pregnancy

There is limited information specifically addressing congenital muscular dystrophies and pregnancy. However, mothers with congenital neuromuscular disorders and muscular dystrophies are known to have an increased risk of preeclampsia, premature rupture of membranes, preterm labor, cardiac dysrhythmia, requirements for blood transfusions, and given birth by cesarean section. Additionally, there is a higher risk of infants being born preterm and small for gestational age (145; 67). A single case report of a mother with Bethlem myopathy noted an uneventful vaginal delivery; however, the patient experienced progression of her mobility impairment during the second trimester, which returned to baseline following delivery (138). In general, cesarean delivery is recommended for women with advanced or generalized weakness as an elective procedure, but vaginal delivery could be considered. Mothers affected by neuromuscular disorders such as congenital muscular dystrophy are best managed by a multidisciplinary team including an obstetrician, neurologist, geneticist, anesthetist, and respiratory and general medicine specialists. Knowing a mother’s genetic mutation can help with counseling regarding both risk of inheritance and the association of the mutation with malignant hyperthermia (10).

Anesthesia

The usual precautions should be taken for all patients with a congenital muscular dystrophy and elevated serum CK. The European Neuromuscular Centre recently released a consensus statement on anesthesia in patient with neuromuscular disorders and included a subsection on congenital muscular dystrophies and myopathies (188). Specific anesthesia-related complications have been reported in only a small number of patients with specific congenital muscular dystrophies:

Ullrich congenital muscular dystrophy. Although only a few case reports are available, there has been a reported risk of difficult intubation, with most reporting use of total intravenous anesthesia in order to maintain spontaneous ventilation and to avoid the theoretical risk of anesthesia-induced rhabdomyolysis with halogenated anesthetics (150; 190; 76; 110; 56; 53).

Laminin alpha 2-deficient congenital muscular dystrophy type 1A. A malignant hyperthermia-like reaction has been reported in a patient affected by laminin alpha 2-deficient congenital muscular dystrophy type 1A (167).

Congenital muscular dystrophy type 1C and 1B. Myoglobinuria following general anesthetic has been reported in at least one patient with mutations in FKRP, and spontaneous myoglobinuria in a patient with congenital muscular dystrophy 1B. This corresponds to the high incidence of exercise-induced myalgia and myoglobinuria in patients with FKRP-related limb-girdle muscular dystrophy type 2I (111).