Congenital Muscular Dystrophy

Background

Congenital muscular dystrophies (CMD) are extremely rare and greatly heterogeneous neuromuscular disorders with onset at birth or early infancy, characterized by hypotonia, delayed motor development, and progressive weakness. The clinical presentation is variable and can affect other organs, including the eyes, brain, lungs, and heart. Serum creatine kinase (CK) is elevated in several cases but not all. Appropriate muscle biopsy studies are crucial for accurate diagnosis.

In 1903, Batten described 3 children who had proximal muscle weakness from birth. Biopsy of their muscles showed evidence of chronic myopathy without distinguishing characteristics. In 1908, Howard coined the term congenital muscular dystrophy (CMD) when he described another infant with similar features. Ullrich first described the combination of joint hyperlaxity and proximal contractures in 1930 in the German literature; this was the first case of what is now known as Ullrich congenital muscular dystrophy.

In 1960, Fukuyama et al described a common congenital muscular dystrophy in Japan that always had features of muscular dystrophy and brain pathology.^[1] Other diseases involving the muscle, eye, and brain were subsequently described: a Finnish variant (originally called muscle-eye-brain disease and Walker-Warburg syndrome. As has become clear with molecular genetics, all of these CMDs are likely caused by a similar molecular pathologic event, abnormal glycosylation of α-dystroglycan.

In a study of 116 patients in the United Kingdom, the most common congenital muscular dystrophies were collagen VI-related disorders (19%), with α-dystroglycanopathy congenital muscular dystrophy (12%) and merosin-deficient congenital muscular dystrophy (MDC1A) (10%) being next in frequency. An Australian study in 2008 showed dystroglycanopathy as the most common congenital muscular dystrophy (25%) on that continent, followed by collagen VI-related disorders (12%). Fukuyama congenital muscular dystrophy is the most prevalent form (49.2%) in Japan, followed by collagen VI deficiency at 7.2%.^[1]

In general, CMDs are autosomal recessive diseases resulting in severe proximal weakness at birth (or within the first 12 mo of life) that is either slowly progressive or nonprogressive. Contractures are common, and CNS abnormalities can occur. Muscle biopsy shows signs of dystrophy, including a marked increase in endomysial and perimysial connective tissue; variability in fiber size with small, round fibers; immature muscle fibers; and (uncommonly) necrotic muscle fibers. No distinguishing features are present in muscle biopsy specimens, differentiating these disorders from the congenital myopathies.

Classifications of congenital muscular dystrophy

Several authors of review articles have proposed classifications for the congenital muscular dystrophies. Recent classification schemes follow the following pattern:^{[2, 3]}

Defects of structural proteins

• Merosin deficient CMD (MDC1A); Lamininα2, Gene LAMA 2 (6q22-q23)
• UCMD1; Collagen 6A1
• UCMD2; Collagen 6A2
• UCMD3; Collagen 6A3
• Integrin α7-deficient CMD; Integrin α7
• CMD with epidermolysis bullosa; Plectin

Defects of glycosylation

• Walker-Walburg syndrome; multiple genes
• Muscle-eye brain disease, multiple genes
• Fukuyama CMD; Fukutin
• Other phenotypes associated with mutations in glycosyltransferase genes

Proteins of the endoplasmic reticulum and nucleus

• Rigid spine syndrome; Selenoprotein N, 1
• Rigid spine syndrome; Selenocysteine insertion sequence-binding protein 2
• LMNA-deficient CMD; Laminin A/C

Mitochondrial membrane protein

• CMD with mitochondrial structural abnormalities; Choline kinase beta

The OMIM classification of defects of glycosylation is as follows:

• Muscular dystrophy-dystroglycanopathy A1 (MDDGA1 ) – POMT1 mutation
• MDDGA2 – POMT2 mutation
• MDDGA3 – POMGNT1 mutation
• MDDGA4 – Fukutin mutation
• MDDGA5 – FKRP mutation
• MDDGA6 – LARGE mutation
• MDDGA7 – ISPD mutation
• MDDGA8 – GTDC2 mutation
• MDDGA10 – TMEM5 mutation
• MDDGA11 – G3GALNT2 mutation
• MDDGA12 – SGK196 mutation
• MDDGA – B3GNT1 mutation

Genetic features

Only the muscular dystrophies with known genetic mutations are discussed in more detail later in this article. Several rare forms of congenital muscular dystrophy are not discussed in this article because of the lack of precise molecular and/or genetic information. The diagnosis of congenital muscular dystrophy is now based on clinical findings, muscle biopsy results, and genetic information.

• References

Pathophysiology

The pathophysiology of the congenital muscular dystrophies depends on the specific genetic defect for each of the dystrophies and is discussed with each of the congenital muscular dystrophies below.

• References

Epidemiology

Frequency

An Italian study identified mutations in 220 of 336 patients (65.5%). The most common forms of CMD were those with α-dystroglycan glycosylation deficiency (40.18%) followed by those with laminin α2 deficiency (24.11%) and collagen VI deficiency (20.24%). The forms of CMD dystrophy related to mutations in SEPN1 and LMNA were less frequent (6.25% and 5.95%, respectively).^[4]

In Japan, Fukuyama congenital muscular dystrophy is fairly common. It is approximately 50% as common as Duchenne muscular dystrophy. The estimated prevalence is approximately 7–12 cases per 100,000 children.^[1] In Italy, the prevalence of all congenital muscular dystrophies has been estimated to be 4.7 cases per 100,000 children, while in Sweden the incidence is estimated at 6.3 cases per 100,000 births. Only about 25–50% of patients with CMD have an identifiable genetic mutation.^[2]

The prevalence and incidence of the congenital muscular dystrophies varies in different regions of the world. For example, in a study of 116 patients in the United Kingdom, the most common congenital muscular dystrophies were collagen VI–related disorders (19%), with α-dystroglycanopathy congenital muscular dystrophy (12%) and merosin-deficient congenital muscular dystrophy (MDC1A) (10%) being next in frequency.^[5] The Australian study by Peat and colleagues in 2008^[6] showed dystroglycanopathy as the most common congenital muscular dystrophy (25%) on that continent, followed by collagen VI–related disorders (12%). Fukuyama congenital muscular dystrophy is the most prevalent form (49.2%) in Japan, followed by collagen VI deficiency at 7.2%.^[7]

Mortality/Morbidity

Morbidity and mortality rates depend on the type of congenital muscular dystrophy.

The major causes of morbidity and mortality are related to respiratory insufficiency, bulbar and limb weakness, contractures, seizures, ocular pathology, and mental retardation and associated brain pathology.

Some children die in infancy, whereas others can live into adulthood with only minimal disability.

Demographics

These autosomal recessive diseases affect both sexes equally.

Patients with congenital muscular dystrophy present at birth or within the first year of life.

• References

History

Congenital muscular dystrophy with laminin-alpha2 deficiency (MDC1A, classic CMD, merosin-deficient CMD)

This is the most common congenital muscular dystrophy in some countries and may account for approximately 40% of all cases.

MDC1A is caused by mutations in the laminin α2 gene (LAMA2) linked to chromosome 6q22-q23 and inherited as autosomal recessive. Laminins are extracellular glycoproteins that bind with other extracellular and transmembrane proteins to form the frame of the basal lamina that surrounds individual myofibers. Each laminin is a heterodimer composed of a heavy chain (α) and two light chains (β and γ). The major laminin of adult skeletal muscle is laminin-2 (also known as merosin), and only mutations of LAMA2 gene encoding laminin α2 cause muscular dystrophy.

Reduced fetal movements may be noted in utero.

At birth or in the first few months of life, patients may have severe hypotonia, weakness, feeding difficulty, and respiratory insufficiency.

Contractures are common.

External ophthalmoplegia may occur late but is rare.

Most infants eventually sit unsupported, but standing and walking with support is achieved in only about 25%.

Weakness is static or minimally progressive, but death often occurs after 10–30 years due to respiratory failure.

Complications are related to respiratory compromise, feeding difficulty, scoliosis, and (in approximately one third) cardiac abnormalities,

A sensory motor demyelinating neuropathy is present in many patients, but it may not be clinically relevant.

CNS manifestations may be present.

• Mild mental retardation or perceptual-motor difficulties are observed in a few cases.
• Seizures occur in up to 30% of patients.
• White-matter hypomyelination and hypodensity, most often in periventricular areas, as noted on MRI, are invariably present after age 6 months, even in patients with normal intelligence.
• White-matter changes are not correlated with the amount of laminin-α2, the patient's intelligence, or the presence of seizures. However, patients with severe abnormalities may have low intelligence quotient (IQ) scores.
• Structural brain changes have been reported in a few patients and include enlargement of the lateral ventricles, focal cortical dysplasia, occipital polymicrogyria and/or agyria, and hypoplasia of the pons and/or cerebellum.

Clinical variants of MDC1A occur with some mutations when only partial laminin-α2 deficiency is present.

• Patients may present with hypotonia during infancy, but they become ambulatory and maintain ambulation for many years.
• Others may present in childhood with a limb-girdle phenotype or with a phenotype resembling rigid spine muscular dystrophy (RSMD) (see below) or Emery-Dreifuss muscular dystrophy.
• Clues to the presence of laminin-α2 deficiency include MRI abnormalities, seizures, and demyelinating neuropathy. (Leukodystrophies may result in a similar phenotype.)

A large series of patients with LAMA2 mutations was described, highlighting the differences between the severe homogenous presentation typical of patients with absent merosinimmunostaining with the more heterogeneous presentation of those with residual merosin expression.^[8] Patients with complete lack of merosin were more severely affected, often presenting within the first week of life; however, 46% of patients with residual merosin also had a severe course indistinguishable from patients with complete lack of merosin. These patients were rarely able to achieve independent ambulation (6% did walk), were more likely to need ventilator support (39% vs 8%) and enteral feeding (48% vs 6%) as compared to patients with residual merosin, and were more likely to have nonsense mutations.

Ullrich congenital muscular dystrophy (collagen VI–deficient congenital muscular dystrophy)

Collagen VI–deficient congenital muscular dystrophy is the second most common variant of congenital muscular dystrophy worldwide and was originally described by Ullrich in 1930. Mutations in collagen VI genes (COL6) cause different phenotypes, including Ullrich congenital muscular dystrophy, Bethlem myopathy, and autosomal recessive myosclerosis myopathy. Ullrich congenital muscular dystrophy is usually an autosomal recessive disorder, but the disease has occasionally been reported to be caused by heterozygous mutations in the COL6A1 and COL6A2 genes.

Typical features include presentation in the neonatal period with hypotonia, kyphosis of the spine, proximal joint contractures, torticollis, and hip dislocation.^[9]

Combined with the above is distal joint hyperlaxity with a protruding calcaneus. Patients with severe disease may lack hyperlaxity.

Kyphosis and proximal contractures may improve with therapy, but contractures recur and eventually involve previously lax distal joints.

Weakness involves distal more than proximal muscles. Many patients never walk, but some walk for a short time. Progressive disability, usually due to contractures, leads to loss of ambulation after 3-10 years.

Respiratory insufficiency invariably develops in the first or second decade.

Facial dysmorphism is common and includes micrognathia, a round face with drooping of the lower lids, and prominent ears.

Skin changes can include follicular hyperkeratosis, keratosis pilaris, and keloids.

Intelligence and brain MRIs are normal.

Cardiac function is normal.

Bethlem myopathy: Ullrich congenital muscular dystrophy is allelic and shares several features with a more mild myopathy termed Bethlem myopathy. Ullrich congenital muscular dystrophy is typically due to an autosomal recessive mutation in the gene for collagen type VI, whereas Bethlem myopathy is due to autosomal dominant mutations in the same gene. Typical features of Bethlem myopathy include the following:

Onset usually occurs in the first or second decade, but may be as late as the sixth decade.

Flexion contractures of the fingers, wrists, elbows, and ankles are noted. Proximal contractures include at the knees, hips and shoulders. Contractures may improve in childhood.

Joint laxity occurs and may precede the contractures. Lax joints may become contracted.

Patients have hypotonia and proximal muscle weakness and wasting, including respiratory muscles. In rare cases, patients have no weakness.

Weakness is slowly progressive. Patients usually having a normal life expectancy. Mild improvement may occur around puberty. However, adult progression may result in need for a wheelchair after 40-50 years.

Skin changes are similar to Ullrich congenital muscular dystrophy.

In intermediate cases, features of both diseases are noted with childhood-onset weakness, Ullrichlike distal laxity, and Bethlemlike contractures of finger flexors.

In severe cases, congenital contractures, torticollis, hip dislocation, delayed motor milestones, and late loss of ambulation are similar to findings in Ullrich congenital muscular dystrophy.

An LGMD phenotype with proximal weakness and no significant contractures has been described.^[10]

Cases described as myosclerosis (contractures without weakness and a woody feeling upon palpation of muscles) have also been described.^[11]

Integrin-alpha7 deficiency

This rare disorder has been described in only a few children, who presented with hypotonia in infancy and delayed motor milestones (eg, walked at age 2-3 y).

One patient had mental retardation, and another had contractures and respiratory failure.

One patient has been followed longitudinally and required noninvasive ventilation at age 8 years and became wheelchair bound at age 12 years.^[12]

Congenital muscular dystrophy with familial junctional epidermolysis bullosa

Since first being described in the 1970s, several more reports have described patients with epidermolysisbullosa and muscular dystrophy.^[2]

Epidermolysisbullosa can be severe, even resulting in death and presents with severe blistering often secondary to trauma or heat.

Other skin findings can include nail dystrophy and scalp alopecia.

Muscle weakness is proximal, progressive often leading to wheelchair use by the second decade and may correlate with residual plectin function.

Myasthenic syndrome has also been described with ptosis, ophthamoplegia and facial weakness and may respond to pyridostigmine.^[13]

Other systemic features include growth retardation, anemia, laryngeal webs, tooth decay, pyloric atresia, infantile respiratory insufficiency, and cardiomyopathy.

In some cases, skin manifestations are mild and may not cause significant disability. Presentation may then be as a late onset (20-40 y) muscular dystrophy.^[14]

An LGMD syndrome without epidermolysisbullosa has been described as presenting in early childhood with delayed walking. Proximal weakness eventually progresses and results in loss of ambulation.^[15]

Congenital muscular dystrophy with rigid spine (RSMD1)

Presentation is at birth or within the first year of life, with variable degrees of proximal weakness and hypotonia.

Most patients eventually walk, but in rare and severe cases, patients never gain independent ambulation. Scapular winging and facial and bulbar weakness are common. Low food intake may be responsible in part for very reduced BMI values (mean 14 kg/m²) in a study of 11 patients with SEPN mutations.^[16]

In contrast to Ullrich congenital muscular dystrophy, contractures are not present at birth, but they usually develop at age 3-10 years.

• The most characteristic pattern is spinal rigidity and scoliosis.
• Contractures of the face, proximal limbs, and finger extensors may also be present.

Respiratory insufficiency is common and progressive and may be more severe than limb weakness. Forced vital capacity ranged from 18–65% of predicted in 11 patients aged 6–16 years, with 4 aged 2–11 years requiring nighttime noninvasive ventilation.^[16] Ventilatory assistance may be needed as early as the first decade of life to treat nocturnal hypoventilation.

Muscle weakness is slowly progressive, and ambulation may be maintained for many years.

The cardiac system is usually normal, but conduction blocks have been reported.

Intelligence and brain MRIs are normal.

In patients with a mutation in selenocysteine insertion sequence-binding protein 2 (SECISBP2, SBP2), there is a multisystem disorder that includes an axial muscular dystrophy similar to SEPN-1 related myopathies.^[17]

• Hypotonia, axial muscle weakness, and spinal rigidity, as well as mild facial, proximal, and respiratory weakness are noted.
• Other features include azoospermia, cutaneous photosensitivity, impaired T-cell proliferation, increased fat mass with enhanced insulin sensitivity, and hearing loss.

LMNA-deficient CMD

This is caused by a mutation in the gene that encodes for proteins Laminin A/C

Mutations in LMNA cause a wide variety of disorders discussed in detail in the Medscape Reference article Emery-Dreifuss Muscular Dystrophy, including a CMD with rigid spine.

Congenital muscular dystrophy with mitochondrial structural abnormalities

This syndrome is caused by a mutation in the choline beta kinase gene.^[18]

Clinical features present in most patients include hypotonia starting in early infancy, generalized muscle weakness, marked mental retardation with most not acquiring meaningful language, and microcephaly.

Other features seen in some patients include dilated cardiomyopathy and ichthyosiform skin changes.

Glycosyltransferase deficiency (abnormal O-glycosylation of alpha-dystroglycan)

Mutations in 12 genes involved in glycosylation of α-dystroglycan are known to cause congenital muscular dystrophy.

Initially, mutations in different genes were thought to cause separate disorders. However, it has now been clearly demonstrated that mutations in these genes can result in overlapping phenotypes with a wide range of phenotypic variability. Similarly, many of the originally described phenotypes can be caused by more than one gene mutation.

In these congenital muscular dystrophies, the severity of changes in affected tissue has a rank order. This order is possibly related to the degree of preserved α-dystroglycan function.

In the mildest disease, only the skeletal muscle is affected. This is classified by OMIM as type C; limb-girdle phenotype. Type B represents congenital onset with or without mental retardation.

As severity progresses, the cerebellum and then the pons, eyes, and cerebrum are affected. This most severe form is classified by OMIM as type A; congenital with brain and eye abnormalities.

An order of worsening severity in each affected tissue is also observed.

• In mild disease, patients may have normal muscle and only mild eye and cerebellar abnormalities.
• In intermediate disease, patients may have mild dystrophic changes, myopia, pontocerebellar hypoplasia, and focal pachygyria.
• In severe disease, patients may have active muscle fiber degeneration and necrosis, nonfunctioning eyes, severe pontocerebellar hypoplasia, and agyria.

Fukuyama congenital muscular dystrophy (mutation in fukutin)

Patients often present in utero with poor fetal movements.

Weak sucking, lack of head control, and a weak mouth are noted in the neonatal period.

At age 2-8 years, most patients can stand or walk a few steps, but patients with severe disease may be able to sit only with support.

Progressive weakness and respiratory failure ensue, with death usually occurring in the mid teens. However, death can occur as late as the mid-20s or as early as age 2 years.

In most patients, cardiac disease develops after age 10 years, resulting in dilated cardiomyopathy and congestive heart failure.

Mild cases have abnormal eye movements, poor pursuits, and strabismus.

Severe cases may cause retinal detachment, microphthalmos, cataracts, hyperopia, or severe myopia.

Cerebral changes are always present.

• Type II lissencephaly(cobblestone lissencephaly) is the characteristic finding in this disease, as in all other glycosyltransferase deficiencies.
• Abnormalities range from cobblestone polymicrogyria and/or pachygyria to complete agyria due to neuronal migration abnormalities.
• Dysplasia of the pyramidal tracts is common.
• Ventricular dilation, if present, is mild.
• Delayed myelination is noted on MRI.
• Cerebellar cysts are common.
• Seizures occur in about 50% of patients.
• Mental retardation is present, and, in severe cases, patients may only have rudimentary language. In a few cases, very mild mental retardation is present.^[19]

One report found 3 children from 2 families with a limb girdle phenotype (LGMD2M) and a mutation in fukutin.^[20] Onset was before 1 year with hypotonia. Deterioration occurred with febrile illness and there was improvement with corticosteroids. Intelligence and brain MRI were normal.

Another report found 6 patients in 4 families with dilated cardiomyopathy with no or minimal limb girdle muscle involvement and normal intelligence.^[21] Cardiac symptoms began in the second to fifth decade, followed by mild proximal weakness.

Muscle-eye-brain (MEB) disease

Mutations in POMT1, POMT2, POMGnT1, FKRP, and LARGE can cause this syndrome. In a series of 92 patients with congenital muscular dystrophy, 14 were found to have muscle-eye-brain disease/Fukuyama congenital muscular dystrophy phenotype.^[22] Muscle-eye-brain disease and Fukuyama congenital muscular dystrophy were combined because of the similar phenotypes. In another large series of 81 patients from Italy, the MEB/FKRP phenotype was the most common, present in 54% of patients with CMD and reduced α-dystroglycan staining. One third of patients had a mutation in POMGnT1.^{[23, 24]}

Severely affected patients cannot sit or turn, they lack visual contact, and they often die in the first 1-2 years.

Moderately affected patients can often sit and speak a few words. They may have severe myopia, but they can make visual contact.

Mildly affected patients may be able to walk for a short time, they can speak in sentences, and they have preserved vision.

Seizures are common.

Eye abnormalities are similar but more severe than those of Fukuyama congenital muscular dystrophy. Severe myopia, retinal dysplasia, optic colobomas, hyperplastic primary vitreous, glaucoma, cataracts, and retinal detachment are common.

CNS abnormalities are always present, including moderate-to-severe mental retardation.

Cerebral changes are similar to those of Fukuyama congenital muscular dystrophy but are more variable.

• Mild changes include only cerebellar cysts, vermal hypoplasia, and flattening of the pons.
• Severe changes can include type II lissencephaly, pachygyria and/or polymicrogyria/agyria, and a cobblestone appearance on gross inspection. Absent septum pellucidum, absent corpus callosum, and hypoplasia of the pyramidal tract have been reported.
• Ventricular dilation may be severe and may result in obstructive hydrocephalus and the need for shunt placement.
• MRI may show evidence of dysmyelination.

Walker-Warburg syndrome

Mutations in all glycotransferases can cause this most severe form of congenital muscular dystrophy. Presentation is in utero or at birth, with hypotonia, poor suck and swallow, and contractures.

Progressive disease results in no developmental progress. The average time to death is 9 months.

Eye abnormalities include microphthalmos, hypoplastic optic nerve, ocular colobomas, retinal detachment, cataracts, glaucoma, iris malformation, and corneal opacities, all of which lead to blindness.

Brain abnormalities include complete type II lissencephaly with agyria.

• Other cerebral defects include a thin cortical mantle, an absent corpus callosum, fusion of the cerebral hemispheres, and hypoplasia of the pyramidal tracts.
• Posterior fossa abnormalities include severe cerebellar atrophy of the vermis and hemispheres, arachnoid cysts, and a hypoplastic brainstem.
• Meningocele or encephalocele, usually of the posterior fossa, is present in 25% of patients.
• Microcephaly, ventricular dilation, and obstructive hydrocephalus are common.

FKRP congenital muscular dystrophy

A wide spectrum of disease phenotypes have been described, from in utero or lethal Walker-Warburg syndrome or muscle-eye-brain disease to intermediate forms; CMD with cerebellar involvement and CMD with mental retardation and microcephaly to a mild limb-girdle muscular dystrophy phenotype.

The severe end of the spectrum includes muscular dystrophy and structural brain abnormalities similar to Walker-Warburg syndrome or muscle-eye-brain disease. Severe cases can manifest with congenital muscular dystrophy, pontocerebellar hypoplasia, cerebellar cysts, agyria, thickening of the frontal cortex, myopia, and retinal detachment causing blindness. Congenital muscular dystrophy with mild mental retardation and cerebellar cysts has been described.

An intermediate form is similar to congenital muscular dystrophy due to laminin-α2 mutations.

• Presentation is at birth with hypotonia and weakness with delayed motor milestones
• Some patients can sit or take a few steps in the first decade, but progressive weakness leads to respiratory insufficiency and death or ventilatory dependence in the first or second decade.
• Hypertrophy of the legs and tongue is noted.
• Atrophy of proximal muscles and, late in the disease, distal muscles, is common.
• Facial weakness is usually present.
• Mild dilated cardiomyopathy can occur.
• Intelligence and brain MRIs are normal.

The mild form manifests with a limb-girdle phenotype and is allelic with limb-girdle muscular dystrophy type 2I. Presentation varies from the first year to the teens to mid adulthood.

• With early-onset disease, loss of ambulation occurs in the teens, with subsequent scoliosis and ankle contractures similar to those of Duchenne muscular dystrophy. Muscle and tongue hypertrophy is common. Facial weakness is often present. Respiratory failure in the second decade often leads to death or the need for ventilatory assistance.
• With onset in the teens or adulthood, ambulation can be preserved until the sixth or seventh decade, but respiratory failure may develop before the sixth or seventh decade.
• Dilated cardiomyopathy develops in 50% of patients with early- or late-onset weakness.

POMT1 and POMT2 congenital muscular dystrophy

A wide spectrum of disease manifestation has been described, ranging from severe cases presenting as Walker-Warburg syndrome and mild cases presenting as a limb-girdle muscular dystrophy classified as LGMD2K (POMT1)^[25] and LGMD2N (POMT2).^[26]

Severe cases have structural brain defects similar to those in Walker-Warburg syndrome or muscle-eye-brain disease.

Intermediate patients have congenital muscular dystrophy and mental retardation but no or mild structural brain abnormalities.

In the mildest cases, presentation is with a limb girdle phenotype (LGMD2K or LGMD 2N). Presentation is within the first decade with proximal weakness. The course is slowly progressive. Mild-to-moderate mental retardation is present, while only mild or no structural brain abnormalities have been described.

It appears that most if not all patients with POMT1 mutations have either structural or functional brain disease. This is not true for the mildest cases with mutations in fukutin, FKRP, and POMGnT1 in which mild cases may have no structural or functional brain defects.^[22]

In a large cohort of patients from Australia, Turkey, and the United Kingdom with decreased α-dystroglycan staining, mutations in POMT2 (25%) were the most common (cases with mutation in FKRP were excluded).^[22] In a large cohort of patients from Italy with CMD and abnormal α-dystroglycan staining, mutations in POMT1 were the most frequent (40%) of the 6 genes involved in glycosylation.^[24]

LARGE congenital muscular dystrophy

Mutations in the LARGE gene are the rarest cause of CMD with defect of α-dystroglycan glycosylation. One case has been described in a 17-year-old female adolescent who presented with weakness and hypotonia at age 5 months. She had profound mental retardation and an MRI that showed mild white-matter abnormalities and structural malformations suggestive of aberrant neuronal migration. An abnormal electroretinogram suggested eye abnormalities.

Two sisters of first cousin parents had a similar course. Presentation was in the first year of life with hypotonia and delayed motor and cognitive milestones. They walked at 2 years, but with difficulty and muscle hypertrophy was noted. Mental retardation was present. Only mild eye abnormalities were noted, but severe abnormalities on brain MRI were seen including ventricular dilatation, cerebellar hypoplasia, high signal periventricular and deep white matter abnormalities, and in the more affected sibling pachygyria of the frontal lobes.^[27]

Two siblings with consanguineous parents had a phenotype similar to Walker-Warburg syndrome with presentation at birth with severe hypotonia and respiratory difficulty. CKs were markedly elevated. Both patients died within 6 months. Both had eye abnormalities and brain imaging showing severe hydrocephalus and structural brain disease.^[28]

• References

Causes

Congenital muscular dystrophy with laminin-alpha2 deficiency (MDC1A)

This is an autosomal recessive disease caused by a mutation on chromosome 6 in the LAMA2 gene that codes for laminin-α2.

More than 90 different missense, nonsense, splice-site, and deletion mutations have been described.

Expression of laminin-α2 is related to disease severity. Complete lack of expression is always associated with a severe phenotype. Partial loss of expression is often associated with a mild phenotype, but severe phenotypes have also been described.

Laminin-α2 is expressed in the basement membrane of striated muscle, cerebral blood vessels, Schwann cells, and skin.

Laminins are glycoproteins that form the backbone of the basement membrane in almost every cell type.

• Twelve laminin genes (5 alpha, 4 beta, 3 gamma) are known.
• Each laminin is a heterotrimer (alpha-beta-gamma). Laminin 2 (α2-beta1-gamma1) and laminin 4 (α2-β2-γ1) are expressed in muscle.
• Laminins bind to a number of molecules, most importantly to the extracellular matrix proteins neurexin, agrin and collagen VI and to the transmembrane proteins α-dystroglycan, integrins and syndecans.
• They are thought to play a role in cell-to-cell recognition, cell shape, differentiation, movement, transmission of force, and tissue survival.
• Loss of laminin-α2 results in a secondary loss of α-dystroglycan and integrin-α7 (not dystrophin or sarcoglycans), with resultant impairment of myogenesis, synaptogenesis, force generation, and mechanical stability.

Ullrich congenital muscular dystrophy

This is an autosomal recessive (or more rarely dominant) disorder caused by a mutation in 1 of the 3 collagen type VI genes (COL6A1, COL6A2, COL6A3).

Collagen VI is manufactured primarily in interstitial fibroblasts and not in myogenic cells, but it is deposited in the extracellular matrix around nearly all cell types.^[29]

Collagen VI is composed of equal amounts of α1, α2, and α3 chains, which intracellularly form a triple helix heterotrimeric monomer. Two of the triple helix monomers associate in an antiparallel arrangement to form six-chain dimers, and then 2 dimers associate in parallel to form a 12-chain tetramers all stabilized by disulfide bonds. The tetramers are excreted into the extracellular space.

Tetramers aggregate into beaded collagen microfibrils, which require the presence of all 3 α chains.

Mutations in all 3 α chains have been associated with Ullrich congenital muscular dystrophy (and Bethlem myopathy).

Collagen type VI has cell adhesion properties and binds to numerous extracellular matrix proteins, including decorin, biglycan, perlecan, fibronectin, proteoglycans, and other collagens.

The major role of collagen type VI is likely to assist in anchoring the basement membrane to the underlying connective tissue and to act as a scaffold for the formation of the collagen fibrillar network. It also plays a role in cell-cycle signaling during cellular proliferation and differentiation. Lastly, it likely has a role in tissue homeostasis by assisting in interactions between cells and the extracellular matrix and by its role in the development of the extracellular matrix supramolecular structure.

How mutations cause disease and why some mutations cause Ullrich congenital muscular dystrophy and others causeBethlem myopathy is not entirely clear. However, Ullrich congenital muscular dystrophy and Bethlem myopathy are likely 2 ends of a spectrum of collagen type VI diseases. This is based on the finding of severe Bethlem myopathy patients and mild Ullrich congenital muscular dystrophy patients with a great deal of clinical similarity. Furthermore, some mutations in collagen type VI can cause both diseases.

About 50% of patients with Ullrich CMD have been shown to have de novo dominant negative mutations, and not the previously thought autosomal recessive mutations

Bethlem myopathy is most often an autosomal dominant disease although rare autosomal recessive cases have been described.

Genotype-phenotype correlations were found in a study of early onset collagen VI myopathies.^[30] Early-severe patients (never walked) had complete absence or strongly reduced secretion of collagen VI and most had homozygous premature termination codon mutations in the triple helical region. Moderate-progressive patients (initially able to walk, but loss of ambulation at 4-25 years) most often (83%) had complete absence or strongly reduced secretion of collagen VI and had mutations that where either dominant de novo exon skipping or missense mutations affecting the triple helical domain. Mild patients (remained ambulatory into third decade) in only 50% of cases had absent or reduced secretion of collagen VI.

In contrast to the above study where the most severe cases had absent collagen VI secretion, other reports suggest that the severity of dominantly acting mutations appears to depend on the ability of the mutant protein to be incorporated into the secreted tetramer. The farther the process can proceed, the more severe the dominant negative effect will be.^[31] Patients with Bethlem myopathy secrete very little mutant protein, while patients with Ullrich congenital muscular dystrophy have more mutant protein secreted and incorporated into collagen tetramers and subsequent microfibrils.

Integrin-alpha7 deficiency

This is an autosomal recessive disorder caused by a mutation on chromosome 12 in the gene for integrin-α7.

Integrin-α7 is a member of the integrin family, which comprises transmembrane adhesion molecules that exist as heterodimers composed of one alpha and one beta chain.

Integrin-α7-β1 is the primary integrin in skeletal and cardiac muscle and skeletal myotubes.

It functions as a transmembrane link between laminin-α2 and the muscle membrane that is independent of the dystrophin-glycoprotein complex (see below). The complex bridges the inner cytoskeleton (F-actin) and the basal lamina. Mutations in laminin-α2, integrin α7, and O-glycosyltransferases that glycosylate alpha-dystroglycan all can cause CMD. Mutations in collagen, which binds α -dystroglycan through perlecan and other proteoglycans, can cause CMD. Mutations in dystrophin, the sarcoglycans, dysferlin, and caveolin-3 can also cause muscular dystrophies.^[32]

It may play a role in myoblast migration and in the formation of myotendinous and neuromuscular junctions.

Congenital muscular dystrophy with familial junctional epidermolysis bullosa

This is an autosomal recessive disorder caused by a mutation on chromosome 8 in the plectin gene.^{[33, 34]}

Plectin contains intermediate filament and actin binding domains and is in the plakin family of proteins.

It is ubiquitously expressed but with highest concentrations in squamous epithelial cells, muscle and at the blood-brain barrier and is concentrated at sites of stress such as hemidesmosomes, desmosomes, Z-lines, and intercalated disks.

Plectin interacts with various cytoskeletal proteins, including several types of intermediate filaments (eg, vimentin, desmin, lamin B, cytokeratins), actin, integrin β4, dystrophin, α-spectrin, desmoplakin, and microtubule associated proteins, as well as being able to link intermediate filaments with microtubules.

Plectin, like all plakins, acts as a cytolinker of various elements of the cytoskeleton, maintaining cell integrity. It also serves as a scaffolding platform for proteins involved in cell signaling.^[35]

Rigid-spine syndrome with muscular dystrophy type 1 (deficiency of selenoprotein N)

This is an autosomal recessive disease due to a mutation in the selenoprotein N gene (SEPN1).

Selenoprotein N is a ubiquitously expressed glycoprotein that localizes to the endoplasmic reticulum and has an unknown function, but it is involved in oxidation/reduction reactions.

Increased levels are present in myoblasts, with lower levels in myotubes or mature muscle fibers. This finding suggests a role in early muscle development or in muscle cell proliferation or regeneration.

Mutations in selenoprotein N also cause multiminicore disease, congenital myopathy with desmin inclusions, and a congenital fiber type size disproportion related syndrome.

• The term SEPN -related myopathy has been proposed to classify all of these diseases, in part because different mutations in the same gene may cause more than 1 muscle biopsy phenotype. However, there is considerable clinical phenotypic overlap with congenital or early-onset hypotonia, predominantly affected axial musculature leading to poor head control and scoliosis, and prominent respiratory insufficiency.^[16]
• The axial muscles share the property of being tonically contracted to maintain posture and suggest a possible specific mechanical constraint related to selenoprotein N cellular function.

A mutation in selenocysteine insertion sequence-binding protein 2 leads to multisystem selenoprotein deficiency (including selenoprotein N) that causes an axial muscular dystrophy similar to that caused by mutation in SEPN1, as well as resulting in azoospermia, impaired T-lymphocyte proliferation, abnormal mononuclear cell cytokine secretion, telomere shortening, and photosensitivity.^[17]

Congenital muscular dystrophy with mitochondrial structural abnormalities

Mutation in choline kinase beta on chromosome 22 cause this autosomal recessive disorder.^[18]

Choline kinase beta catalyzes phosphorylation of choline by ATP committing choline to the pathway for biosynthesis of phosphatidylcholine, which accounts for about 50% of phospholipids in biological membranes.

Muscle tissue from 3 individuals had undetectable levels of choline beta kinase and decreased levels of phosphatidylcholine.

Mitochondria were displaced to the periphery of muscle fibers and were abnormally large.

Glycotransferases (abnormal O-glycosylation of α-dystroglycan)

All of these congenital muscular dystrophies are thought to be due to mutations in glycotransferase genes or accessory proteins of glycotransferases, which result in abnormal glycosylation and therefore abnormal function of α-dystroglycan. Immunolabeling of α-dystroglycan correlates with clinical severity (cases with absent labeling had the most severe phenotype) in patients with mutations of POMT1, POMT2, and POMGnT1, but not in patients with mutations in fukutin, FKRP, or LARGE.^[36]

More severe phenotypes appear to be associated with mutations predicted to result in a severe disruption of the respective genes.^[24]

α-dystroglycan is thought to act as a link between the basal lamina and the cytoskeleton. It is present in muscle, nerve, and brain. In these congenital muscular dystrophies, α-dystroglycan is often correctly localized to the muscle cell membrane, but its function is impaired.

α-dystroglycan (and β-dystroglycan) are transcribed from the gene DAG1 and cleaved into 2 components.

The C-terminal region of α-dystroglycan binds β-dystroglycan independent of glycosylation.

Binding of α-dystroglycan to extracellular matrix proteins laminin, neurexin, agrin, and perlecan is glycosylation dependent.

α-dystroglycan is heavily glycosylated.

• The predicted molecular weight of α-dystroglycan is 75 kd, but its molecular weight on Western blot testing is 120-156 kd, suggesting it is heavily glycosylated.
• α-dystroglycan has a mucinlike domain with several serine or threonine residues as potential O-glycosylation sites.
• A unique carbohydrate structure containing O-linked mannose has only been found on α-dystroglycan in mammals. This linkage is likely disrupted in the congenital muscular dystrophies caused by defects in O-glycosylation.

α-dystroglycan is crucial in the formation and maintenance of the basement membrane. Complete disruption of α-dystroglycan in mice is embryonically lethal because of improper formation of the Reichert membrane, which is the basement membrane that separates the embryo from the maternal circulation. Similarly, disruption of the POMT1 gene (see below) in a mouse model also results in embryonic lethality due to inability to form the Reichert membrane.

POMT1-associated congenital muscular dystrophy (MDDGA1, muscular dystrophy-dystroglycanopathy, type A [with brain and eye abnormalities])

POMT1 mutations were first described in the autosomal recessive Walker-Warburg syndrome. The gene codes for the glycotransferase O-mannosyltransferase 1 that along with POMT2 catalyzes the first step of Ser/Thr O-mannosylation.

POMT1 gene mutations have also been described in patients with a muscle-eye-brain phenotype and in patients with limb-girdle muscular dystrophy type 2K who have onset of limb-girdle weakness in the first decade associated with mild-to-moderate mental retardation.

In a large Italian cohort of patients with CMD and reduced α-dystroglycan on muscle immunohistochemistry, cases with normal brain MRI, microcephaly and mental retardation were more frequently associated with mutations in POMT1 and POMT2.^[24]

The POMT1 protein is ubiquitously expressed with highest concentrations in testis, skeletal and cardiac muscle, and fetal brain tissue.

Muscle tissue shows severe loss of α-dystroglycan and loss of laminin-α2 binding.

POMT2-associated congenital muscular dystrophy (MDDGA2)

POMT2 mutations were first described in the Walker-Warburg syndrome. The gene codes for the glycotransferase O-Mannosyltransferase 2 that along with POMT1 catalyzes the first step of Ser/Thr O-mannosylation of α-dystroglycan.

POMT2 gene mutations have also been described in cases of muscle-eye-brain disease and in cases with a limb-girdle muscular dystrophy and mental retar dation,^[22] as well as in LGMD 2N.^[26]

The POMT2 glycotransferase is widely expressed and localizes to the endoplasmic reticulum.

Muscle tissue shows reduced α-dystroglycan staining.

POMGnT1-associated congenital muscular dystrophy (MDDGA3)

POMGnT1 mutations were first described as the autosomal recessive muscle-eye-brain disease. The gene codes for the glycotransferase O-mannose beta-1,2-N-acetylglucosaminyltransferase that catalyzes the second step of Ser/Thr O-mannosylation (the transfer of N-acetylglucosamine to O-mannose) of α-dystroglycan.

Since the initial description, POMGnT1 mutations have also been described in Walker-Warburg syndrome as well as in a patient presenting with severe autistic features.

One patient with a limb-girdle muscular dystrophy phenotype with no mental retardation was described in an analysis of 92 people with congenital muscular dystrophy.^[22] Another patient developed proximal weakness at age 12 years and became wheelchair-bound at age 19 years. She had normal cognitive development and intelligence and has been classified as LGMD 2O.^[37]

POMGnT1, like fukutin, is thought to be localized to the Golgi apparatus.

Muscle tissue shows a loss of glycosylated α-dystroglycan; a preserved core α-dystroglycan; and loss of laminin-α2-, agrin-, and neurexin-binding activity.

A genetic model has been generated by gene trapping with a retroviral vector inserted into the second exon of the mouse POMGnT1 locus, abolishing expression of POMGnT1 mRNA. Glycosylation of α-dystroglycan was reduced, and POMGnT1 -mutant mice had multiple developmental defects in muscle, eyes, and the brain, similar to the phenotypes observed in human muscle-eye-brain disease.

Fukuyama congenital muscular dystrophy (fukitin, MDDGA4)

This is an autosomal recessive disease caused by a mutation in the fukutin gene on 9q that is most common in Japan and is rare elsewhere in the world.

A homozygous ancestral 3-kb retrotransposal insertion into the 3' untranslated region of the gene accounts for 87% of all cases of Fukuyama congenital muscular dystrophy. This results in a relatively mild phenotype.

Patients who are compound heterozygous for the ancestral mutation and another loss-of-function mutation have more severe disease.

Cases of a homozygous null mutation in the fukutin gene resulted in a severe Walker-Warburg syndrome or muscle-eye-brain disease phenotype. There are also cases with a mild limb girdle phenotype now designated as LGMD2M.

Fukutin is a putative glycosyltransferase and has sequence homologies to a bacterial glycosyltransferase, but its exact role and enzymatic substrate have not been determined.

The highest levels of expression are in skeletal muscle, the heart, and the brain. Cellular localization is thought to be within the Golgi apparatus.

Patients with Fukuyama congenital muscular dystrophies have complete loss (or nearly complete loss) of glycosylated α-dystroglycan in the brain and muscle.

α-dystroglycan binding to laminin-α2, neurexin, and agrin is greatly diminished.

Laminin-α2 expression is decreased in muscle.

Electron microscopy reveals a disruption in muscle basal lamina.

FKRP deficiency-associated congenital muscular dystrophy (MDDGA5)

This autosomal recessive disease was initially described in a patient with a mutation in the FKRP gene, which encodes a 55-kd ubiquitously expressed protein with high est c oncentrations in skeletal muscle, the heart, and the placenta. Since then, mutations in FKRP have been described in patients with Walker-Warburg syndrome, muscle-eye-brain disease, and limb-girdle muscular dystrophy type 2I.

Studies suggest that mutations in FKRP that cause severe phenotypes alter FKRP expression from the Golgi apparatus to the endoplasmic reticulum, whereas mutations that cause the milder limb-girdle muscular dystrophy type 2I phenotype do not. The authors hypothesized that glycosylation defects caused by mutations in FKRP may be due to the combined effects of loss of function and improper cellular targeting. Since the effects from individual mutations are likely complex and variable, this may explain the wide spectrum of phenotypes seen with FKRP mutations.^[38]

FKRP is predicted to be a member of the O-glycosyltransferase or phosphosugartransferase family, but its exact role and enzymatic substrate have not been determined.

α-dystroglycan is abnormal in all patients with an FKRP mutation.

• The most severely affected patients have a profound loss of α-dystroglycan.
• Patients with a Duchenne-like phenotype have a moderate reduction.
• Patients with a limb-girdle phenotype have only subtle alterations in α-dystroglycan immunostaining.

LARGE congenital muscular dystrophy (MDDGA6)

This autosomal recessive disease is due to a mutation in a putative glycosyltransferase that is homologous to the mutation in the myodystrophy mouse (LARGE^myd). Like fukutin and POMGnT1, LARGE is also localized to the Golgi apparatus. However, when mutated, it localizes to the endoplasmic reticulum and, like FKRP, is likely then targeted for degradation.

The LARGE^myd mice have a severe progressive muscular dystrophy, mild cardiomyopathy, retinal involvement, and CNS involvement.

Muscle biopsy samples from 1 patient with a mutation in LARGE showed reduced immunostaining for α-dystroglycan, reduced molecular weight of α-dystroglycan, and impaired laminin-α2 binding.

Modulation of LARGE expression or activity may be a feasible therapeutic strategy for persons with glycosyltransferase-deficient congenital muscular dystrophies.

• Interaction of LARGE with the N-terminal domain of α-dystroglycan is an essential step for substrate recognition necessary to initiate functional glycosylation.
• Overexpression of LARGE ameliorates the dystrophic phenotype of LARGE^myd mice and induces the synthesis of glycan-enriched α-dystroglycan with high affinity for extracellular ligands.
• Gene transfer of LARGE into the cells of individuals with several different congenital muscular dystrophies restores α-dystroglycan receptor function and allows glycan-enriched α-dystroglycan to coordinate laminin organization on the cell surface.

ISPD-associated congenital muscular dystrophy (MDDGA7)

Recessive mutations in the isoprenoidsynthetase domain (ISPD) may be a relatively common cause of Walker-Warburg syndrome, representing about 10% of cases.^{[39, 40]}

While not a glycotransferase, mutations impair the ability of POMT1/2 to transfer O-mannose. This leads to a reduction in functional glycosylation of α-dystroglycan and loss of its laminin-binding epitope.

It was initially described in severe cases of Walker-Warburg syndrome and in families with patients having cobblestone lissencephaly.^[41]

It can also result in limb-girdle muscular dystrophy with or without mental retardation, limb-girdle muscular dystrophy with cerebellar involvement, and congenital muscular dystrophy without mental retardation.^[42]

Other features include progressive loss of ambulation usually in the mid teens, muscle pseudohypertrophy, and respiratory and cardiac involvement.

Muscle biopsy shows reduced or absent α-dystroglycan immunohistochemical labeling.

GTDC2-associated congenital muscular dystrophy (MDDGA8)

Recessive mutations in glycotransferase-like domain-containing protein 2 (GTDC2) are a rare cause of Walker-Warburg syndrome.^[43]

The original description was based on whole exome sequencing of consanguineous Walker-Warburg affected families.

GTDC2 is predicted to be a glycotransferase and knockdown of this gene in zebrafish replicates many features of Walker-Warburg syndrome.

TMEM5-associated congenital muscular dystrophy (MDDGA10)

Recessive mutations in transmembrane protein 5 (TMEM5) have been found in cases of cobblestone lissencephaly,^[41] as well as in families with patients having Walker-Warburg syndrome or muscle-eye-brain phenotypes.^[44]

The function of TMEM5 is unknown. However, it contains an exostosin domain, present in EXT1, which encodes a known glycotransferase .

B3GALNT2-associated congenital muscular dystrophy (MDDGA11)

Recessive mutations in b-1,3-N-acetylgalactosaminyltransferase 2 (B3GALNT2) cause a Walker-Warburg or muscle-eye-brain disease phenotype.^[45]

Presentation is with motor and cognitive delay, hypotonia, and hydrocephalus. Milder cases can take a few steps, with severe cases gaining no milestones. Epilepsy is common. Eye abnormalities include optic nerve hypoplasia, microphthalmia, and lens opacities. Severe brain involvement is present in all cases.

Immunostaining muscle for α-dystroglycan shows a reduction in functional glycosylation.

Knockdown of B3GALNT2 in zebrafish recapitulate the human phenotype.

SGK196-associated congenital muscular dystrophy (MDDGA12)

Heterozygous missense mutations in protein kinase-like protein SGK196 in one family caused a Walker-Warburg phenotype.^[46]

• Hypotonia, weakness, CK of 7000 U/L, and a muscle biopsy showing dystrophy are noted.
• Eye abnormalities include hyperplastic primary vitreous, myopia, and microphthalmia.
• Brain abnormalities include hydrocephalus, agyria, and hypoplasia of the cerebellum and brainstem.

SGK196 was identified as likely required for glycosylation of a-dystroglycan.

• A haploid screen for the Lassa virus, which hijacks glycosylated a-dystroglycan to enter cells, was used to identify cells with the absence of a-dystroglycan carbohydrate chains or biochemically related chains.
• Knockout mice have hydrocephalus and cerebellar dysplasia.

B3GNT1-associated congenital muscular dystrophy

Two homozygous mutations in b-1,3-N-acetylglucoaminyltransferase (B3GNT1) in one family caused a Walker-Warburg syndrome.^[47]

Features included hydrocephalus, Dandy-Walker malformation, cobblestone lissencephaly, cerebellar dysplasia, retinal dysplasia, seizures, and hypotonia.

Serum CK was elevated and muscle biopsy showed reduced glycosylation of a-dystroglycan.

Overexpression of B3GNT1 results in increased a-dystroglycan glycosylation.

Morpholino knockdown of zebrafish B3GNT1 results in a phenotype similar to Walker-Warburg syndrome.

GMPPB-associated congenital muscular dystrophy

Using exome and Sanger sequencing, homozygous or heterozygous mutations in Mannose-1-phophate guanyltransferase beta (GMPPB) were found in patients with a severe congenital muscular dystrophy or a milder limb-girdle muscular dystrophy phenotype.^[48]

• Presentation is from birth to 4 years, usually with hypotonia, spasticity, microcephaly, poor head control, feeding difficulties, and weakness.
• All patients but one (presented at 4 years) had intellectual delay, often severe.
• Epilepsy and motor delay were common.
• CK was elevated to 630-8450 U/L.
• Ophthalmologic findings include retinal dysfunction, cataracts, strabismus, nystagmus, and ptosis.
• MRI findings include pontine and cerebellar hypoplasia, although 4 patients had no abnormalities.
• Muscle biopsy showed reduced a-dystroglycan glycosylation.

Morpholino knockdown of zebrafish GMPPB caused hydrocephalus and muscular dystrophy.

GMPPB catalyzes the synthesis of GDP-mannose from GTP and mannose-1-phosphate. GDP-mannose is required for O-mannosylation of proteins, including a-dystroglycan.

Congenital disorders of glycosylation

These are rare, autosomal recessive disorders in the metabolism of dolichols.^[49]

Dolichol (a-saturated polyprenol) is present in all tissues and most organelle membranes. It functions as a carbohydrate donor to growing oligosaccharide chains of glycoproteins and glycolipids. This includes N-linked protein glycosylation of a-dystroglycan.

Mutations in 3 genes have been reported to cause a congenital muscular dystrophy phenotype:

• DOLK (DK1) -Dolichol kinase mutation results in microcephaly, ichthyosis, seizures, hypotonia, elevated CK, liver dysfunction, and progressive dilated cardiomyopathy.^[49] A separate report highlighted a primary cardiac presentation with dilated cardiomyopathy and life-threatening dysrhythmias.^[50]
• DPM2 – Dolichol-phosphate mannosyltransferase 2 mutation described in 3 patients results in microcephaly, hypotonia, elevated CK, elevated transaminases, difficulty swallowing, seizures, cerebellar hypoplasia, cortical visual impairment without structural eye abnormality, and muscle biopsy showing marked reduction in O-mannosylglycans on a-dystroglycan.^[51]
• DPM3 -Dolichol-phosphate mannosyltransferase 3mutation described in 1 patient resulted in mild intellectual impairment.^[52] Mild weakness was noted at age 11 years. At age 20 years, there was dilated cardiomyopathy, elevated CK, muscle biopsy with markedly reduced glycosylation of a-dystroglycan, and normal brain MRI.

• References

Clinical Aspects

Congenital muscular dystrophy manifests at birth or within the first 2 years of life. The typical presentation is congenital hypotonia, delayed motor skills, and slowly progressive muscle weakness. Phenotypic expression varies greatly among patients, such as with the distribution of hypotonia and weakness. Some patients have predominant axial hypotonia with head lag and later spine rigidity, as in selenoprotein 1; SEPN1-related and lamin A/C (LMNA)-related congenital muscular dystrophies, while patients with generalized hypotonia/weakness and contractures, with or without joint laxity, are likely to have collagen-related congenital muscular dystrophies.

CNS involvement and MRI findings are key in the differential diagnosis of congenital muscular dystrophy. Patients can present with mild to severe cognitive impairment and learning disabilities. Seizures occur in patients with MDC1A at a frequency of 8% to 20%.^[53]  Brain MRI findings include white matter changes (T2 hyperintensity) and cortical dysplasia in α-dystroglycanopathy congenital muscular dystrophy. Ophthalmic abnormalities, including visual impairment and retinal abnormalities, are often present in α-dystroglycanopathy congenital muscular dystrophy. Cardiomyopathy can be seen in late stages but is usually limited to a few types of congenital muscular dystrophy including fukutin, fukutin-related protein (FKRP), protein-O-mannosyltransferase 1 (POMT1)-related congenital muscular dystrophies or limb-girdle muscular dystrophy, and LMNA-related congenital muscular dystrophy. In a study of 115 patients with α-dystroglycanopathy congenital muscular dystrophy in Italy, only seven were found to have abnormal cardiac function:^[54] five with dilated cardiomyopathy, one with a cardiac conduction defect, and one with mitral regurgitation. Sudden cardiac death was reported almost exclusively in LMNA-related congenital muscular dystrophy.    

Respiratory failure can be an early symptom after birth, requiring ventilation. Otherwise, restrictive lung disease, nocturnal hypoventilation, and respiratory failure may not be evident until more advanced stages of disease. In the same Italian study, 14 patients out of 115 with α-dystroglycanopathy congenital muscular dystrophy had abnormal respiratory function. Ten of the 14 required nocturnal noninvasive ventilatory support (NIV), while the others required invasive ventilation. In a case series of patients with SEPN1-related congenital muscular dystrophy, respiratory function data were collected from 41 patients between 1 and 60 years old. The need for nocturnal NIV increased with age. At the age of 15 years, 50% of the patients required a ventilator, with an increase to 75% at the age of 20 years. Sleep studies were found to be abnormal at a mean age of 13.2 years, anticipating the need for nocturnal NIV, which became necessary in 66% of patients during the second decade of life.^[55]

• References

Approach Considerations

The most important diagnostic tools are CK level, nerve conduction study, and EMG with or without repetitive nerve stimulation, brain MRI, muscle biopsy, and specific genetic or metabolic testing.

• References

Laboratory Studies

Persons with Ullrich congenital muscular dystrophy, rigid spine with muscular dystrophy (deficiency of selenoprotein N), and integrin-α7 deficiency have creatine kinase (CK) levels that are normal to mildly elevated (≤5 times normal).

CK levels are usually more than 1000 in patients with congenital muscular dystrophy with familial junctional epidermolysis bullosa.

CK levels are mildly to markedly elevated (2-150 times normal) in most patients with congenital muscular dystrophy due to abnormal glycosylation or with laminin-α2 mutations.

• References

Imaging Studies

Persons with congenital muscular dystrophies due to mutations in genes for selenoprotein N and in genes for the extracellular matrix proteins integrin-α7 and collagen type VI have normal brain MRI findings.

Patients CMD with familial junctional epidermolysis bullosa often have brain atrophy and enlarged ventricles on MRI.

In those with congenital muscular dystrophies due to mutations in laminin-α2 or with any other congenital muscular dystrophy due to abnormal O-glycosylation, brain MRI findings are abnormal.

• The mildest changes are seen in deficiency of laminin-α2, with periventricular white matter changes being the most common abnormality (increased T2 signal).
• In the congenital muscular dystrophies due to abnormalities in O-glycosylation, the abnormalities vary, even in patients with mutations in the same gene. Brain MRIs can be normal, or they can show severe changes, such as agyria and severe pontocerebellar hypoplasia.
• All patients with muscle-eye-brain disease and Fukuyama congenital muscular dystrophy have abnormal MRIs, which show a range from mild changes of only cerebellar hypoplasia or cysts to severe disease, as described above.
• The most severe changes are seen in Walker-Warburg syndrome, with most patients having severe agyria, pontocerebellar hypoplasia, and, in many patients, encephalocele or myelomeningocele.

Muscle MRI can help differentiate muscular dystrophies with rigidity of the spine^[56]

• SEPN1 – Selective involvement of the sartorius, gastrocnemius spared
• COL6A – Bethlem myopathy (BM) patients had concentric atrophy and peripheral involvement, most obvious in vasti and gastrocnemius
• COL6A - Ullrich CMD patients had diffuse involvement of thigh muscles with selective sparing of anteromedial thigh muscles; more diffuse than BM, but similar peripheral involvement of gastrocnemius
• LMNA – Involvement of vasti at thigh level, medial > lateral gastrocnemius, soleus involved
• LGMD2A (CAPN3) – Selective involvement of adductor magnus and posterior thigh muscles, medial > lateral gastrocnemius, soleus involved

• References

Other Tests

Electromyography (EMG) and nerve conduction study (NCS)

EMG and NCS should be performed in all patients with suspected congenital muscular dystrophy to confirm myopathy and to exclude other diseases.

NCS results are normal except in some cases with mutations in laminin-α2, in which mild neuropathic changes may be seen (some with demyelinating features).

EMG usually shows typical small-amplitude, narrow-duration motor-unit potentials with early recruitment.

Prenatal diagnosis

Prenatal diagnosis had been performed most commonly in families with mutations in laminin-α2, in part, because this is the most common congenital muscular dystrophy.

Laminin-α2 is expressed in 9-week trophoblasts, allowing immunohistochemical detection of protein in chorionic villus. However, in families with partial laminin-α2 deficiency, protein detection may not be reliable. Linkage analysis can also be performed but is also at times unreliable, especially in families with partial laminin-α2 deficiency or no brain MRI abnormalities. However, the combination of these 2 techniques along with rigorous controls has been highly accurate and reliable in the prenatal diagnosis of laminin-α2 mutations. The most reliable technique is direct mutation analysis, although this is more time consuming because the entire gene sequence must be analyzed.

Genetic testing

Genetic testing is available for all congenital muscular dystrophies (see http://www.ncbi.nlm.nih.gov/sites/GeneTests/?db=GeneTests)

• References

Procedures

Muscle biopsy is indicated in all cases of suspected congenital muscular dystrophy to help confirm the diagnosis and exclude other causes of weakness. 

In congenital muscular dystrophy, the muscle biopsy shows dystrophic changes with abnormal variation in fiber size (associated with whorled or split fibers) and rare hypercontracted fibers. An increase in internal nuclei is evident, with a variable increase in endomysial connective and adipose tissue. Prominent muscle necrosisis infrequent and may be absent in congenital muscular dystrophy.

The immunohistochemical examination is extremely important in the differential diagnosis; specific antibodies for merosin, collagen VI, and glycosylated α-dystroglycan may identify specific protein deficiencies. Depending on the clinical findings, a muscle biopsy may be done early or late in the diagnostic process.

Neurogenic changes may be prominent in MDC1A (merosin deficiency) while immunohistology shows complete or partial deficiency of laminin α2. In complete merosin deficiency, both the C-terminal and N-terminal antibodies to laminin α2 fail to stain muscle fibers. On the other hand, the light chains of laminin α2 (β1 and γ1) are preserved, and other laminin α chains (α4 and α5) are upregulated. Muscle biopsy in MDC1A may be neurogenic but is usually dystrophic. In collagen VI–deficient congenital muscular dystrophies, collagen IV shows normal expression, while collagen VI may or may not label normally. The muscle biopsy commonly shows a range from moderate myopathic changes to severe dystrophic features depending on the severity and duration of the disease. Collagen VI immunostaining is helpful if it shows anabsence or reduction in basement membrane (basal lamina) labeling, but normal labeling does not exclude Ullrich congenital muscular dystrophy or Bethlem myopathy. Immunohistochemistry in α-dystroglycanopathy congenital muscular dystrophy shows normal expression of β-dystroglycan in the sarcolemma, accompanied by absent or reduced α-dystroglycan.

Congenital muscular dystrophy with laminin-α2 deficiency

• Complete laminin-α2 deficiency

  • Patients may have severe dystrophic pathology with muscle-fiber degeneration and regeneration, fiber necrosis, and endomysial and perimysial fibrosis.
  • Mononuclear cell infiltrates may be present in biopsy samples obtained from infants.
  • Immunohistochemical studies show complete loss of staining for laminin-α2.
  • Antibodies must be used against both the 300- and 80-kd subunits.
  • α-dystroglycan staining is also absent.
  • Approximately 95% of biopsy samples with absent laminin-α2 staining have a mutation in the LAMA2 gene.

   

  

   
• Partial laminin-α2 deficiency

  • Mild myopathic features often occur with little or no necrosis.
  • Partial staining for laminin-α2 may be seen in patients with laminin-α2-deficient congenital muscular dystrophy and in those with any congenital muscular dystrophy associated with a glycosyltransferase enzyme deficiency.

   

  

   

Ullrich congenital muscular dystrophy

• Variation ranges from mildly myopathic to dystrophic in terms of muscle fiber size, muscle fiber necrosis, and fibrosis.
• Collagen type VI staining around surface of muscle fiber is usually reduced or absent, but staining may occur in connective tissue.
• In Bethlem myopathy, routine muscle biopsy and collagen type VI immunohistochemistry usually are normal.

Integrin-α7 deficiency

• Mild variations in muscle-fiber size are noted.
• Staining for integrin-α7 is decreased. This may also be seen in congenital muscular dystrophy with laminin-α2 deficiency.

Congenital muscular dystrophy with familial junctional epdermolysis bullosa

• Variation in muscle fiber size, internal nuclei, increased connective tissue, muscle fiber necrosis and regeneration
• Plectin immunostaining is reduced in muscle Z-lines and skin

Rigid spine with muscular dystrophy (deficiency of selenoprotein N)

• Myopathic features include small, round muscle fibers, endomysial fibrosis and type 1 fiber predominance or atrophy.
• Regenerating and degenerating muscle fibers and fiber necrosis are rare. Severe cases may have significant fibrosis but still little or no necrosis.
• Minicores may be present.

Glycotransferases (abnormal O-glycosylation of α-dystroglycan)

• All of the α-dystroglycanopathies have similar muscle pathologies that differ in the degree of severity, which is likely correlated with the degree of preserved α-dystroglycan function.
• Patients have muscle fiber degeneration and/or necrosis and regeneration, variability in muscle fiber size, and endomysial and/or perimysial fibrosis
• Muscle tissue may look fairly normal in persons with muscle-eye-brain disease and with mutations in FKRP shortly after birth.
• Immunohistochemical studies show decreased staining for α-dystroglycan, which is localized correctly to the muscle cell surface. Western blot studies show a decreased molecular weight of α-dystroglycan in affected patients. A secondary decrease in staining for laminin-α2 may be noted in some biopsy samples.

• References

Medical Care

No specific treatment is available for any of the congenital muscular dystrophies.

Aggressive supportive care is essential to preserve muscle activity, to allow for maximal functional ability, and to prolong the patient's life expectancy.

• The primary neuromuscular concerns include prevention and correction of skeletal abnormalities, such as scoliosis, foot deformities, and contractures, to maintain ambulation.
• Aggressive use of passive stretching, bracing, and orthopedic procedures, such as spinal fusion, allows the patient to remain independent for as long as possible.

Pulmonary complications are the other main concern.

• Early monitoring and intervention to treat respiratory insufficiency is important because effective therapies can help to improve function and prolong life expectancy.
• Such therapies include noninvasive bilevel positive airway pressure and/or continuous positive airway pressure or permanent ventilation via a tracheostomy.

Cardiac complications are especially common in patients with a mutation in FKRP and occasionally in patients with laminin-α2 deficiency. Treatment of dilated cardiomyopathy with ACE inhibitors and beta-blockers may be necessary.

Children with congenital muscular dystrophy may have other neurologic treatment issues, including seizure management, need for supplementary gastric tube feedings, ophthalmologic care, and general medical concerns that occur in profoundly retarded children.

As with other hereditary myopathies, a team approach, including a neurologist, pulmonologist, ophthalmologist, cardiologist, orthopedic surgeon, physical medicine specialist, orthotist, and counselors, is required to ensure the best possible care.

In patients with CMD with familial junctional epidermolysis bullosa besides the above standard measures, management must include supportive care to protect the skin from blistering, appropriate dressings, and prevention of secondary infections. Activities should minimize skin trauma.

• References

Surgical Care

Orthopedic surgery is often necessary in patients who live several years with their disease to prevent contractures and scoliosis.

• References

Consultations

According to evidence-based guidelines from the American Academy of Neurology, multidisciplinary care by experienced teams is important for diagnosing and promoting the health of children with CMD.^[57]

Consultation with the following may prove helpful:

• Ophthalmologist
• Pulmonologist
• Cardiologist
• Orthopedic surgeon
• Epileptologist
• Physical medicine specialist
• Dermatologist (patients with CMD with familial junctional epidermolyis bullosa)

• References

Further Outpatient Care

Muscle function, contractures, visual function, seizures, the ability to perform activities of daily living, and cardiopulmonary functions should be assessed at each follow-up visit.

• References

Further Inpatient Care

Patients with alpha-dystroglycanopathies may require prolonged hospitalization. For example, neonates or infants may have progressive disease and have feeding difficulties, cardiopulmonary complications, seizures, or profound mental retardation.

Older children may need admission for orthopedic care or cardiopulmonary complications.

• References

Complications

Complications include the following:

• Feeding difficulties
• Respiratory failure
• Seizures
• Contractures and/or scoliosis
• Blindness

• References

Prognosis

The prognosis depends on the type of congenital muscular dystrophy.

With severe disease, such as Walker-Warburg syndrome, patients usually die within the first few years of life.

In congenital muscular dystrophy with laminin-α2 deficiency and in some cases of mutations in FKRP, patients occasionally have a relatively normal life span.

• References

Patient Education

Genetic counseling is often helpful to patients and their families to assist in family planning.

• References