eMedicine Specialties > Neurology > Pediatric Neurology

Congenital Muscular Dystrophy

Author: Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Chief of Neurology, St Louis ConnectCare, Consulting Staff, Barnes Jewish Hospital
Contributor Information and Disclosures

Updated: Feb 12, 2009

Introduction

Background

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. All of these are caused by a similar molecular pathologic event.

In general, congenital muscular dystrophies are autosomal recessive diseases resulting in severe proximal weakness at birth (or within the first 12 months 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.

Several authors of review articles have proposed classifications for the congenital muscular dystrophies. In 2004, Muntoni and Voit suggested the following scheme:²

• Extracellular matrix protein defects
  • Laminin-α2–deficient CMD (MDC1A)
  • Collagen 6A1, Collagen 6A2, Collagen 6A3 - Ullrich CMD (UCMDs 1,2, and 3)
• Integrin-α7 deficiency (ITGA7)
• Glycosyltransferases (abnormal O-glycosylation [O-linked mannose pathway] of α-dystroglycan)
  • POMT1 (O-Mannosyltransferase 1)
  • POMT2 (O-Mannosyltransferase 2)
  • POMGnT1 (O-linked mannose β1,2-N-acetylglucosaminyltransferase)
  • Fukutin
  • FKRP (Fukutin-related protein)  
  • LARGE (Lacetylglucosaminyltransferase-like protein) 
• Proteins of the endoplasmic reticulum
  • Selenoprotein N - rigid spine syndrome (RSMD1)

Genetic features

All of these muscular dystrophies have known genetic mutations and 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.

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.

Frequency

International

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. 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. Approximately 50% of all congenital muscular dystrophies are caused by mutations in genes causing defects in O-glycosylation of α -dystroglycan.

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.

Sex

These autosomal recessive diseases affect both sexes equally.

Age

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

Clinical

History

Congenital muscular dystrophy with laminin-α2 deficiency (MDC1A, classic CMD, merosin-deficient CMD)

• This is likely the most common congenital muscular dystrophy and accounts 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.
• Most infants eventually sit unsupported, but standing is rare.
• Weakness is static or minimally progressive, but in severe cases death may occur after 10-30 years due to respiratory failure.
• Complications are related to respiratory compromise, feeding difficulty, scoliosis, and (in approximately one third) cardiopulmonary disease.
• 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 changes, 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.
  • 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.)

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.
• 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. Most patients never walk, but some walk for a short time. Progressive disability, usually due to contractures, leads to loss of ambulation after 2-10 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. 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 joints may include 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.
  • 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.
  • Skin changes are similar to Ullrich congenital muscular dystrophy.

Integrin-α7 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.

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.³
• 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.³ 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.
• Intelligence and brain MRIs are normal.

Glycosyltransferases (abnormal O-glycosylation of α-dystroglycan)

• Mutations in 6 genes involved in O-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.
• As severity progresses, the cerebellum and then the pons, eyes, and cerebrum are affected.
• 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 is the characteristic finding in this disease, as in all other glycosyltransferases.
  • 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.⁴
• One report found 3 children from 2 families with a limb girdle phenotype (LGMD2M) and a mutation in fukutin.⁵  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.⁶  Cardiac symptoms began in the second to fifth decade, followed by mild proximal weakness.

Muscle-eye-brain (MEB) disease

• Mutations in POMT1, POMT2, POMGnT1, fukutin, and FKRP 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.⁷ (muscle-eye-brain disease and Fukuyama congenital muscular dystrophy were combined because of the similar phenotypes). 
• 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.
• CNS abnormalities are always present, including moderate-to-severe mental retardation.
• 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.
• 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 6 glycotransferases have resulted in 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 a mild limb-girdle muscular dystrophy.
• 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 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.⁸
• 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). 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.⁷

LARGE congenital muscular dystrophy

• 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 other 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.⁹

Physical

See History.

Causes

Congenital muscular dystrophy with laminin-α2 deficiency

• 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.
  • Seven laminin genes (4 alpha, 2 beta, 1 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 transmembrane receptors: α-dystroglycan and integrin α7/β1.
  • 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.¹⁰
• Collagen VI is composed of α1, α2, and α3 chains, which intracellularly form a triple helix heteromonomer. Six-chain dimers and then 12-chain tetramers are formed with stabilization 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 cause Bethlem 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.
  • Bethlem myopathy is an autosomal dominant disease. Heterozygous single amino acid substitutions, splice site mutations resulting in exon skipping, and in-frame deletions are common mutation types.
  • The genetics of Ullrich congenital muscular dystrophy is more complex with up to 50% of patients having de novo dominant negative mutations, and not the previously thought autosomal recessive mutation.
  • The severity of dominantly acting mutations appear to be dependent 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.¹¹  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-α7 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.
• It may play a role in myoblast migration and in the formation of myotendinous and neuromuscular junctions.

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 some forms of multiminicore disease, a rare 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.³
  • 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.

Glycotransferases (abnormal O-glycosylation of α-dystroglycan)

• All of these congenital muscular dystrophies are thought to be due to mutations in glycotransferase genes in the O-Mannose pathway, which result in abnormal glycosylation and therefore abnormal function of α-dystroglycan. In some of the mutations described the degree of glycosylation correlates to the severity of disease with more severe disease associated with less α-dystroglycan glycosylation.    
• 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.

Fukuyama congenital muscular dystrophy

• 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.

POMGnT1- associated congenital muscular dystrophy

• 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.⁷
• 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.

POMT1 -associated congenital muscular dystrophy

• 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.
• 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.

FKRP deficiency–associated congenital muscular dystrophy

• 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 highest concentrations 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.¹²
• FKRP is predicted to be a member of the O-glycosyltransferase or phosphosugar transferase 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

• 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 the 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.

POMT2- associated congenital muscular dystrophy

• 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 one case with a limb-girdle muscular dystrophy and mental retardation.⁷
• The POMT2 glycotransferase is widely expressed and localizes to the endoplasmic reticulum. 
• Muscle tissue shows reduced α-dystroglycan staining.

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