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Congenital Muscular Dystrophy Clinical Presentation

  • Author: Glenn Lopate, MD; Chief Editor: Amy Kao, MD  more...
Updated: Dec 24, 2015


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.

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.[5] 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

Typical features include presentation in the neonatal period with hypotonia, kyphosis of the spine, proximal joint contractures, torticollis, and hip dislocation.[6]

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.[7]

Cases described as myosclerosis (contractures without weakness and a woody feeling upon palpation of muscles) have also been described.[8]

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.[9]

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.[10]

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.[11]

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.[12]

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.[13]

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.[13] 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.[14]

  • 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.[15]

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. [16]

One report found 3 children from 2 families with a limb girdle phenotype (LGMD2M) and a mutation in fukutin.[17] 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.[18] 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.[19] 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.[20, 21]

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)[22] and LGMD2N (POMT2).[23]

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.[19]

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).[19] 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.[21]

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.[24]

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.[25]



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.[26]

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.[27] 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.[28] 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.[29]

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.[30, 31]

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.[32]

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. [13]
  • 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.[14]

Congenital muscular dystrophy with mitochondrial structural abnormalities

Mutation in choline kinase beta on chromosome 22 cause this autosomal recessive disorder.[15]

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.[33]

More severe phenotypes appear to be associated with mutations predicted to result in a severe disruption of the respective genes.[21]

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.[21]

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,[19] as well as in LGMD 2N.[23]

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.[19] 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.[34]

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.[35]

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 (LARGEmyd). 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 LARGEmyd 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.[36, 37]

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.[38]

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.[39]

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.[40]

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,[38] as well as in families with patients having Walker-Warburg syndrome or muscle-eye-brain phenotypes.[41]

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.[42]

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.[43]

  • 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.[44]

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.[45]

  • 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.[46]

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. [46] A separate report highlighted a primary cardiac presentation with dilated cardiomyopathy and life-threatening dysrhythmias. [47]
  • 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. [48]
  • DPM3 -Dolichol-phosphate mannosyltransferase 3mutation described in 1 patient resulted in mild intellectual impairment. [49] 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.
Contributor Information and Disclosures

Glenn Lopate, MD Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Consulting Staff, Department of Neurology, Barnes-Jewish Hospital

Glenn Lopate, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, Phi Beta Kappa

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Kenneth J Mack, MD, PhD Senior Associate Consultant, Department of Child and Adolescent Neurology, Mayo Clinic

Kenneth J Mack, MD, PhD is a member of the following medical societies: American Academy of Neurology, Child Neurology Society, Phi Beta Kappa, Society for Neuroscience

Disclosure: Nothing to disclose.

Chief Editor

Amy Kao, MD Attending Neurologist, Children's National Medical Center

Amy Kao, MD is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, Child Neurology Society

Disclosure: Have stock from Cellectar Biosciences; have stock from Varian medical systems; have stock from Express Scripts.

Additional Contributors

Robert Stanley Rust, Jr, MD, MA Thomas E Worrell Jr Professor of Epileptology and Neurology, Co-Director of FE Dreifuss Child Neurology and Epilepsy Clinics, Director, Child Neurology, University of Virginia School of Medicine; Chair-Elect, Child Neurology Section, American Academy of Neurology

Robert Stanley Rust, Jr, MD, MA is a member of the following medical societies: Child Neurology Society, Society for Pediatric Research, American Headache Society, International Child Neurology Association, American Academy of Neurology, American Epilepsy Society, American Neurological Association

Disclosure: Nothing to disclose.

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Dystrophin-glycoprotein complex. 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 congenital muscular dystrophy (CMD). Furthermore, mutations in collagen (not shown), which binds alpha-dystroglycan through perlecan and other proteoglycans, can cause CMD. Mutations in dystrophin, the sarcoglycans, dysferlin, and caveolin-3 can also cause muscular dystrophies. Reprinted with permission from Cohn RD. Dystroglycan: important player in skeletal muscle and beyond. In: Neuromuscular Disorders. Vol. 15. Cohn RD. Elsevier; 2005: 207-17. 7, 20
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