Muscular dystrophy- congenital- megaconial type


Congenital muscular dystrophy (CMD) is the term used to describe muscular dystrophy that is present at birth. CMD describes a number of autosomal recessive diseases of muscle weakness and possible joint deformities, present at birth and slowly progressing. Life expectancies for affected individuals vary, although some forms of CMD do not affect life span at all. All such known dystrophies are genetically recessive and result from mutations in a variety of different genes, including those encoding the laminin-α2 chain, fukutin-related protein, LARGE and fukutin, amongst others. Currently there is no cure. Physical and occupational therapy, surgery, wheelchairs and other assistive technology may be helpful Several authors of review articles have proposed classifications for the CMDs. In 2004, Muntoni and Voit suggested the following scheme: * Extracellular matrix protein defects o Laminin-alpha2–deficient CMD (MDC1A) o Ullrich CMD (UCMDs 1,2, and 3) * Integrin-alpha7 deficiency (ITGA7) * Glycosyltransferases (abnormal O-glycosylation [O-linked mannose pathway] of alpha-dystroglycan) o Walker-Warburg syndrome o MEB disease o Fukuyama CMD (FCMD) o CMD plus secondary laminin deficiency 1 (MDC1B) o CMD plus secondary laminin deficiency 2 (mutation in fukitin-related protein, MDC1C) o CMD with mental retardation and pachygyria (mutation in LARGE, MDC1D) * Proteins of the endoplasmic reticulum - Rigid-spine syndrome (RSMD1)


* CMD with laminin-alpha2 deficiency o This is an autosomal recessive disease caused by a mutation on chromosome 6 in the LAMA2 gene that codes for laminin-alpha2. o More than 90 different missense, nonsense, splice-site, and deletion mutations have been described. o Expression of laminin-alpha2 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. o Laminin-alpha2 is expressed in the basement membrane of striated muscle, cerebral blood vessels, Schwann cells, and skin. o 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 (alpha2-beta1-gamma1) and laminin 4 (alpha2-beta2-gamma1) are expressed in muscle. + Laminins bind to a number of molecules, most importantly to the 2 main transmembrane receptors: alpha-dystroglycan and various integrins. + 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-alpha2 results in a secondary loss of alpha-dystroglycan and integrin-alpha7 (not dystrophin or sarcoglycans), with resultant impairment of myogenesis, synaptogenesis, force generation, and mechanical stability. * Ullrich CMD o 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). o Collagen type VI is expressed in the extracellular matrix of nearly all cell types and is composed of alpha1, alpha2, and alpha3 chains, which intracellularly form a triple helix monomer. o Six-chain dimers and then 12-chain tetramers are formed with stabilization by disulfide bonds. The tetramers are excreted into the extracellular space. o Tetramers aggregate into beaded collagen microfibrils, which require the presence of all 3 alpha chains. o Mutations in all 3 alpha chains have been associated with UCMD (and Bethlem myopathy). o Collagen type VI has cell adhesion properties and binds to numerous extracellular matrix proteins, including decorin, biglycan, perlecan, fibronectin, proteoglycans, and other collagens. o 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. o How mutations cause disease and why some mutations cause UCMD and others cause Bethlem myopathy is unclear. However, it is becoming clear that UCMD 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" UCMD patients with a great deal of clinically similarity. Furthermore, some mutations in collagen type VI can cause both diseases. Lastly, cases of UCMD have now been described with an autosomal dominant inheritance similar to that associated with Bethlem myopathy. + Hypotheses include site-specific mutation effects relating to different domains in each alpha chain or different, tissue-specific transcriptional regulation events. + These effects may lead to improper assembly of tetramers, reduced secretion of normal tetramers, or reduced secretion of abnormal monomers and/or tetramers that subsequently form abnormal tetramers and/or collagen microfibrils. * Integrin-alpha7 deficiency * This is an autosomal recessive disorder caused by a mutation on chromosome 12 in the gene for integrin-alpha7. * Integrin-alpha7 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-alpha7-beta1 is the primary integrin in skeletal and cardiac muscle and skeletal myotubes. * It functions as a transmembrane link between laminin-alpha2 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. * 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 Mallory body–like inclusions, and other early-onset myopathies including presentation with the dropped head syndrome. o The term SEPN -related myopathy has been proposed to classify all of these diseases, in part because they predominantly affect axial musculature and lead to scoliosis and respiratory insufficiency, and because several mutations may cause more than one phenotype. o The axial muscles share the property of being tonically contracted in order to maintain posture and suggest a possible specific mechanical constraint related to selenoprotein N cellular function. * Glycotransferases (abnormal O-glycosylation of alpha-dystroglycan). * All of these CMDs are thought to be due to mutations in glycotransferase genes, which result in abnormal glycosylation and therefore abnormal function of alpha-dystroglycan. * Alpha-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 CMDs, alpha-dystroglycan is often correctly localized to the muscle cell membrane, but its function is impaired. * Alpha-dystroglycan (and beta-dystroglycan) are transcribed from the gene DAG1 and cleaved into 2 components. * The C-terminal region of alpha-dystroglycan binds beta-dystroglycan independent of glycosylation. * Binding of alpha-dystroglycan to extracellular matrix proteins laminin, neurexin, agrin, and perlecan is glycosylation dependent. * Alpha-dystroglycan is heavily glycosylated. o The predicted molecular weight of alpha-dystroglycan is 75 kd, but its molecular weight on Western blot testing is 120-156 kd, suggesting it is heavily glycosylated. o Alpha-dystroglycan has a mucinlike domain with several serine or threonine residues as potential O-glycosylation sites. o A unique carbohydrate structure containing O-linked mannose has only been found on alpha-dystroglycan in mammals. This linkage is likely disrupted in the CMDs caused by defects in O-glycosylation. * Alpha-dystroglycan is crucial in the formation and maintenance of the basement membrane. Complete disruption of alpha-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 CMD * This is an autosomal recessive disease caused by a mutation in the fukitin 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 FCMD. 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. * Recent cases of a homozygous null mutation in the fukitin gene resulted in a severe WWS phenotype. * Fukitin protein is a putative glycosyltransferase and has sequence homologies to a bacterial glycosyltransferase, but its exact role and enzymatic substrate have not been determined. o The highest levels of expression are in skeletal muscle, the heart, and the brain. Cellular localization is thought to be within the Golgi apparatus. o Patients with FCMD have complete loss of glycosylated alpha-dystroglycan in the brain and muscle. o Alpha-dystroglycan binding to laminin-alpha2, neurexin, and agrin is greatly diminished. o Laminin-alpha2 expression is decreased in muscle. o Electron microscopy reveals a disruption in muscle basal lamina. * MEB disease * This autosomal recessive disease was first described in association with a mutation in the POMGnT1 gene 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 alpha-dystroglycan. * Since the initial description, mutations in FKRP and POMT1 (see below) have been described in patients with an MEB phenotype. * Furthermore, mutations in the POMGnT1 gene have been described in patients with a WWS phenotype in a patient with severe autistic features as the main presentation. * POMGnT1, like fukitin is thought to be localized to the Golgi apparatus. * Muscle tissue shows a loss of glycosylated alpha-dystroglycan; a preserved core alpha-dystroglycan; and loss of laminin-alpha2-, 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 alpha-dystroglycan was reduced, and POMGnT1 -mutant mice had multiple developmental defects in muscle, eyes, and the brain, similar to the phenotypes observed in human MEB disease. * Walker-Warburg syndrome * This autosomal recessive disease was first described in association with a mutation in the POMT1 gene O-mannosyltransferase 1 that catalyzes the first step of Ser/Thr O-mannosylation. Since then, POMT1 and POMT2 (a closely related isoform) have been shown to be necessary to achieve O-mannosyltransferase activity. * After the initial description, patients with a WWS phenotype have also been described with mutations in POMT2, POMGnT1, fukitin, and FKRP. Together, mutations in these 5 genes account for only approximately on third of all cases of WWS, and further genetic heterogeneity is likely. * POMT1 gene mutations have also been described in patients with a MEB 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 alpha-dystroglycan and loss of laminin-alpha2 binding. * CMD plus secondary laminin deficiency 2 (fukitin-related protein deficiency) * 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 WWS, MEB disease, and limb-girdle muscular dystrophy type 2I. A recent study suggested that mutations in FKRP that cause CMD1C 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 not be because of loss of function but, instead, may occur because of improper cellular targeting. * 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. * Alpha-dystroglycan is abnormal in all patients with an FKRP mutation. o The most severely affected patients have a profound loss of alpha-dystroglycan. o Patients with a Duchennelike phenotype have a moderate reduction. o Patients with a limb-girdle phenotype have only subtle alterations in alpha-dystroglycan immunostaining. * CMD with mental retardation and pachygyria (mutation in LARGE) * 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 fukitin 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 the one patient with a mutation in LARGE showed reduced immunostaining for alpha-dystroglycan, reduced molecular weight of alpha-dystroglycan, and impaired laminin-alpha2 binding. * Modulation of LARGE expression or activity may be a feasible therapeutic strategy for persons with glycosyltransferase-deficient CMDs. o Interaction of LARGE with the N -terminal domain of alpha-dystroglycan is an essential step for substrate recognition necessary to initiate functional glycosylation. o Overexpression of LARGE ameliorates the dystrophic phenotype of LARGEmyd mice and induces the synthesis of glycan-enriched alpha-dystroglycan with high affinity for extracellular ligands. o Gene transfer of LARGE into the cells of individuals with several different CMDs restores alpha-dystroglycan receptor function and allows glycan-enriched alpha-dystroglycan to coordinate laminin organization on the cell surface. * CMD plus secondary laminin deficiency 1 * Linkage of this disorder has been mapped to 1q42, but the genetic defect is not known. * Immunostaining of muscle showed markedly reduced binding to alpha-dystroglycan and laminin-alpha2.


* Defects of extracellular matrix proteins * CMD with laminin-alpha2 deficiency (MDC1A, classic CMD, merosin-deficient CMD) o This is the most common CMD and accounts for approximately 40% of all cases. o Reduced fetal movements may be noted in utero. o At birth or in the first few months of life, patients may have severe hypotonia, weakness, feeding difficulty, and respiratory insufficiency. o Contractures are common. o External ophthalmoplegia may occur late. o Most infants eventually sit unsupported, but standing is rare. o Weakness is static or minimally progressive. o Complications are related to respiratory compromise, feeding difficulty, scoliosis, and (in approximately one third) cardiopulmonary disease. o A sensory motor demyelinating neuropathy is present in many patients, but it may not be clinically relevant. o 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-alpha2, 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. o Clinical variants of MDC1A occur with some mutations when only partial laminin-alpha2 deficiency is present. + Patients may present with hypotonia during infancy, but they become ambulatory and maintain ambulation for many years. + The phenotype of limb-girdle dystrophy may also be present; this includes RSMD (see below) or Emery-Dreifuss muscular dystrophy–type syndrome. + Clues to the presence of laminin-alpha2 deficiency include MRI abnormalities, seizures, and demyelinating neuropathy. (Leukodystrophies may result in a similar phenotype.) * Ullrich CMD o Typical features include presentation in the neonatal period with hypotonia, kyphosis of the spine, proximal joint contractures, torticollis, and hip dislocation. o Combined with the above is distal joint hyperlaxity with a protruding calcaneus. Patients with severe disease may lack hyperlaxity. o Kyphosis and proximal contractures may improve with therapy, but contractures recur and eventually involve previously lax distal joints. o Most patients never walk, but some walk for a short time. However, progressive disability, usually due to contractures, leads to loss of ambulation after 2-10 years. o Respiratory insufficiency invariably develops in the first or second decade. o Facial dysmorphism is common and includes micrognathia, a round face with drooping of the lower lids, and prominent ears. o Skin changes typically include follicular hyperkeratosis. o Intelligence and brain MRIs are normal. o Cardiac function is normal. o UCMD is allelic and shares several features with a more mild myopathy termed Bethlem myopathy. UCMD 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 occurs in the first or second decade. + Flexion contractures of the fingers, wrists, elbows, and ankles are noted. + Joint laxity occurs and may precede the contractures. + Patients have proximal muscle weakness and wasting, including respiratory muscles. In rare cases, patients have no weakness. + Weakness is slowly progressive, with patients usually having a normal life expectancy. However, some may need aid for ambulation after 40 years. + In severe cases, congenital contractures, torticollis, hip dislocation, delayed motor milestones, and late loss of ambulation are similar to findings in UCMD * Integrin-alpha7 deficiency o 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). o One patient had mental retardation, and another had contractures and respiratory failure. * Presentation is at birth or within the first year of life, with variable degrees of proximal weakness and hypotonia. o Presentation is at birth or within the first year of life with variable degrees of proximal weakness and hypotonia. o Most patients eventually walk, but in rare and severe cases, patients never gain independent ambulation. o In contrast to UCMD, 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. o Respiratory insufficiency is common and progressive and may be more severe than limb weakness. Ventilatory assistance may be needed as early as the first decade of life in order to treat nocturnal hypoventilation. o Muscle weakness is slowly progressive, and ambulation may be maintained for many years. o The cardiac system is usually normal. o Intelligence and brain MRIs are normal. * Glycosyltransferases (abnormal O-glycosylation of alpha-dystroglycan) o Mutations in 6 genes involved in O-glycosylation of alpha-dystroglycan are known to cause CMD. o Initially, mutations in different genes were thought to cause separate disorders. However, it has now been clearly demonstrated that mutations in each of the different 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. o In these CMDs, the severity of changes in affected tissue has a rank order. This order is possibly related to the degree of preserved alpha-dystroglycan function. o In the mildest disease, only the skeletal muscle is affected. o 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. o In mild disease, patients may have normal muscle and only mild eye and cerebellar abnormalities. o In intermediate disease, patients may have myopia, pontocerebellar hypoplasia, and focal pachygyria. o In severe disease, patients may have active muscle fiber degeneration and necrosis, nonfunctioning eyes, severe pontocerebellar hypoplasia, and agyria. * Fukuyama CMD * 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. * Eye abnormalities are present in approximately 50% of patients. o Mild cases have abnormal eye movements, poor pursuits, and strabismus. o Severe cases may cause retinal detachment, microphthalmos, cataracts, hyperopia, or severe myopia. * Cerebral changes are always present. o Type II lissencephaly is the characteristic finding in this disease, as in all other glycosyltransferases. o Abnormalities range from cobblestone polymicrogyria and/or pachygyria to complete agyria due to neuronal migration abnormalities. o Dysplasia of the pyramidal tracts is common. o Ventricular dilation, if present, is mild. o Delayed myelination is noted on MRI. o Cerebellar cysts are common. o Seizures occur in 50% of patients. o Severe mental retardation is present, although many patients learn to talk. * MEB disease * 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. o Eye abnormalities are similar but more severe than those of FCMD. Severe myopia, retinal dysplasia, optic colobomas, hyperplastic primary vitreous, glaucoma, cataracts, and retinal detachment are common. o Cerebral changes are similar to those of FCMD but are more variable. o Mild changes include only cerebellar cysts, vermal hypoplasia, and flattening of the pons. o 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. o Ventricular dilation may be severe and may result in obstructive hydrocephalus and the need for shunt placement. o MRI may show evidence of dysmyelination. * Walker-Warburg syndrome * 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. o Other cerebral defects include a thin cortical mantle, an absent corpus callosum, fusion of the cerebral hemispheres, and hypoplasia of the pyramidal tracts. o Posterior fossa abnormalities include severe cerebellar atrophy of the vermis and hemispheres, arachnoid cysts, and a hypoplastic brainstem. o Meningocele or encephalocele, usually of the posterior fossa, is present in 25% of patients. o Microcephaly, ventricular dilation, and obstructive hydrocephalus are common. * CMD plus secondary laminin deficiency 2 (mutation in fukitin-related protein, FKRP) * A wide spectrum of disease phenotypes have been described, from in utero or lethal WWS or MEB disease to a mild limb-girdle muscular dystrophy. * The severe end of the spectrum includes muscular dystrophy and structural brain abnormalities. CMD with mild mental retardation and cerebellar cysts has been described. Severe cases can manifest with CMD, pontocerebellar hypoplasia, cerebellar cysts, agyria, thickening of the frontal cortex, myopia, and retinal detachment causing blindness. * The typical form is similar to MDC1A. o Presentation is at birth with hypotonia and weakness with delayed motor milestones o 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. o Hypertrophy of the legs and tongue is noted. o Atrophy of proximal muscles and, late in the disease, distal muscles, is common. o Facial weakness is usually present. o Mild dilated cardiomyopathy can occur. o 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. * CMD with mental retardation and pachygyria (mutation in LARGE) * 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 MRIs showed white-matter abnormalities and structural malformations suggestive of aberrant neuronal migration. An abnormal electroretinogram suggested eye abnormalities. * CMD plus secondary laminin deficiency 1 (linked to band 1q42) * Patients present in the first year of life with hypotonia and weakness. * Motor milestones are delayed, but ambulation is achieved by age 3 years. * Limb-girdle and facial weakness are prominent. * Muscle hypertrophy is common. * Respiratory failure leads to death or the need for ventilatory assistance. * Intelligence and brain MRIs are normal.