Congenital muscular dystrophy
Congenital muscular dystrophy (CMD) is an inherited group of muscular disorders characterized by muscle weakness evident at birth or within the first year of life. These conditions are genetically and clinically diverse, with two main categories: syndromic CMD, which includes additional multisystem involvement and developmental delays, and nonsyndromic CMD, where muscle disease is the primary concern. CMD arises from genetic defects affecting critical proteins needed for muscle function and proper development of the eyes and brain. The most common inheritance patterns are autosomal recessive, although some forms may be autosomal dominant.
Symptoms of CMD vary widely but generally include hypotonia, muscle weakness, contractures, and developmental challenges. Diagnosis typically involves muscle biopsies showing dystrophic changes and may include genetic testing and imaging studies for syndromic forms. While there is no specific cure for CMD, treatment focuses on managing symptoms through physical therapy, medications, and surgical interventions. Genetic counseling is recommended for families with a history of the disorder, as understanding inheritance patterns can aid in family planning. Overall, the severity and outcomes of CMD can range significantly, with some individuals living into adulthood while others may experience severe complications early in life.
Congenital muscular dystrophy
ALSO KNOWN AS: Hereditary progressive muscular dystrophy; Fukuyama congenital muscular dystrophy; Ullrich congenital muscular dystrophy; rigid spine syndrome; Walker-Warburg syndrome; muscle-eye-brain disease
DEFINITION The term congenital muscular dystrophy (CMD) refers to a group of inherited, genetically and clinically heterogeneous disorders. Their common denominator is muscular weakness, evident at birth or in the first year of life, with dystrophic changes on skeletal muscle biopsy. Two main clinical categories can be defined. Syndromic CMD comprises disease forms with multisystem involvement and developmental delay. Nonsyndromic CMD includes subtypes characterized by muscular disease only. After a century of clinical characterization efforts, molecular and genetic advances have improved diagnostic precision and suggested potential therapeutic strategies. This complex spectrum of disorders results from defects in genes needed for normal muscle function, as well as eye and brain development.
Risk Factors
Family history is the only known risk factor. No ethnic group is selectively affected, except the Japanese population in the Fukuyama form.
Etiology and Genetics
The most common CMDs have autosomal recessive inheritance, with the exception of Ullrich CMD (UCMD), for which cases of autosomal dominant transmission have been reported. In autosomal recessive forms, both copies of the gene in each cell display the mutation. Each sibling of a proband (subject) has a 25 percent chance of having the disease and a 50 percent chance of being an asymptomatic carrier (heterozygote). Each unaffected sibling of a patient has a 66 percent chance of carrying the mutated gene.
The many CMD phenotypes are caused by overlapping genetic defects affecting essential muscle proteins required early in life for proper motor development. In the mid-1990s, a deficiency in merosin (skeletal muscle laminin) was discovered in a number of patients. This protein is the backbone of muscle cell basal membrane and is essential for cell adhesion, migration, and survival. Subsequent studies localized the genetic defect to the region coding for the laminin alpha 2 chain of merosin. Soon thereafter, a defect was found in a subunit of the protein integrin, which bridges laminin and intracellular proteins. Merosin also binds the “sugar” branches of dystroglycan, an important glycoprotein that stabilizes the muscle cell and is also expressed in the developing nervous system. Perturbations in the glycosylation (“sugarcoating”) of dystroglycan lead to its inability to function and bind merosin. Therefore, deficiencies in glycosyltransferases (enzymes catalyzing the transfer of sugar groups) result in severe, syndromic disease forms, with eye and brain involvement: Fukuyama CMD (FCMD), muscle-eye-brain disease (MEBD), and Walker-Warburg syndrome (WWS). Inadequate neuronal migration results in lissencephaly (“cobblestone” cortex, broad or absent folds), enlarged ventricles, and brain stem and cerebellar developmental defects.
Disturbances in cell adhesion and signaling also contribute to UCMD pathogenesis, which is caused by the deficit in collagen VI, a ropelike extracellular matrix molecule.
All these findings, together with the need for accurate clinical diagnosis and genetic counseling, prompted a CMD classification emphasizing a combination of clinical, biochemical and genetic criteria. Based on the categories proposed by Thomas Voit and Fernando Tomé in 2004, four disease groups are distinguished: defects of laminin alpha 2, primarily affecting the basement membrane (congenital muscular dystrophy type 1A: MDC1A); defects due to abnormal glycosylation of dystroglycan (FCMD, MEB, WWS, and other rare CMD types: MDC1B, MDC1C, MDC1D); disorders with marked contractures (UCMD and rigid spine syndrome, or RSS); and alpha-7 integrin deficiency.
In the first group, classic CMD (MDC1A) is caused by mutations in the laminin alpha 2 gene, on chromosome 6q22-q23, spanning all protein domains. Many missense, nonsense, splice-site, and deletion mutations have been described. Complete lack of expression accounts for approximately half of all CMD cases and usually leads to a more severe phenotype. Molecular diagnosis is not a priority in most patients, given the relatively homogeneous clinical presentation, neuroimaging findings, and immunohistochemical analysis. However, it serves to ascertain the status of a second fetus for the parents of an affected child.
The second group includes overlapping, heterogeneous phenotypes caused by mutations affecting glycosyltransferases and related proteins involved in posttranslational modification of dystroglycan. Fukuyama CMD is characterized by mutations (mainly insertion) in the fukutin gene on chromosome 9q31-q33, resulting in a complete loss of glycosylated dystroglycan. The main gene affected in MEBD is POMGNT1 (O-linked mannose beta 1,2- N-acetylglucosaminyltransferase, on locus 1p34.1), but additional glycosyltransferases have been implicated. A Walker-Warburg is most severe and can be caused by mutations in all six transferases: fukutin(9q31-q33), protein-O-mannosyltransferase 1 (POMT1, on 9q34.1), protein-O-mannosyltransferase 2 (POMT2, 14q24.3), fukutin-related protein (FKRP, 19q13.33), POMGNT1 (1p34.1) and “L-acetylglucosaminyltransferase-like” (LARGE, 22q12.3-q13.1). Congenital muscular dystrophy type 1B (MDC1B) is associated with mutations at the locus 1q42, MDC1C with mutations in FKRP, and MDC1D with LARGE alterations.
In the third group, Ullrich CMD is caused by deficiencies in collagen VI, related to mutations in one of three genes: COL6A1 (21q22.3), COL6A2 (21q22.3), and COL6A3 (2q37). RSS is due to a mutation in the selenoprotein N1 gene (locus 1p36.13). This glycoprotein has uncertain functions but seems to be implicated in reduction-oxidation reactions.
In the fourth group, a mutation on chromosome 12, at the 12q13 locus, leads to CMD with integrin alpha 7 deficiency.
According to a 2023 study by the online journal StatPearls, the most common form of congenital muscular dystrophy is known as Duchenne muscular dystrophy, which primarily affected boys. The prevalence rate of Duchenne muscular dystrophy was about 1 in 3,600 boys, while the overall rate for all types of the condition was 0.82 in 100,000 children.
Symptoms
Symptoms vary according to the type of disease. The classical clinical description is centered on congenital hypotonia (diminished muscle tone, “floppy” appearance), muscle weakness, contractures, and joint deformities. All are evident before age two. The clinical course is variable. Depending on disease type, infants may display weak sucking, failure to meet motor milestones, or seizures. Spinal rigidity and scoliosis are RSS characteristics. Eye abnormalities include strabismus, myopia, retinal detachment, microphthalmos (small eyes), and cataracts. Learning disabilities or mental retardation can be present (such as in FCMD and MEBD), although in many forms the IQ is normal.
Screening and Diagnosis
Carrier testing is clinically available for some forms. Prenatal testing is available for classic CMD, FCMD, MEBD, WWS, MDC1C, MDC1D, and RSS. Laboratories may offer custom for other types of CMD.
Muscle biopsies show dystrophic changes in all CMDs. The dystrophic pattern is characterized by variation in fiber size, fibrosis, and sometimes fatty infiltration. Inflammation, necrosis (death), and regeneration of muscle fibers are less prominent. Immunostaining of muscle tissue reveals merosin deficiency in 50 percent of CMDs. Serum levels of creatine (an released by damaged muscle) are often high. In syndromic CMD, brain magnetic resonance imaging (MRI) reveals developmental anomalies, such as lissencephaly and pontocerebellar underdevelopment. Abnormal white matter signal and dysmyelination are also noted. Classic CMD shows white matter changes, mostly around ventricles, after age six months.
Molecular confirms the diagnosis in some forms, such as MDC1A, syndromic CMD, UCMD, and RSS.
Treatment and Therapy
No specific treatment exists for any CMD. The management is tailored to specific disease subtypes and patients. Symptomatic antiepileptic and antispastic medication may be necessary. Physical therapy helps preserve muscle function and prevent contractures. Surgical intervention for orthopedic complications and ventilatory assistance may be needed. Occupational and speech therapy are often undertaken.
Prevention and Outcomes
Genetic counseling and carrier testing should be considered by individuals with affected family members. Morbidity and mortality are mainly connected to respiratory insufficiency, muscle weakness and contractures, seizures, feeding difficulty, and ocular and cardiac complications. Some patients die in infancy, while others can live into adulthood. Weakness is static or minimally progressive in classic CMD, with survival up to thirty years after diagnosis. With severe disease, such as WWS, patients die within the first years of life.
Bibliography
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Goebel, Hans H., Caroline A. Sewry, and Roy O. Weller, eds. Muscle Disease: Pathology and Genetics. 2nd ed. Hoboken: Wiley, 2013. Print.
Muntoni, Francesco, and Thomas Voit. “The Congenital Muscular Dystrophies in 2004: A Century of Exciting Progress.” Neuromuscular Disorders 14 (2004): 635–49. Print.
Nussbaum, Robert L., Roderick R. McInnes, and Huntington F. Willard. Thompson and Thompson Genetics in Medicine. 7th ed. New York: Saunders, 2007. Print.
Pasrija, Divij, and Prasanna Tadi. "Congenital Muscular Dystrophy." StatPearls, 3 July 2023, www.ncbi.nlm.nih.gov/books/NBK558956/. Accessed 6 Sept. 2024.
Voit, Thomas, and Fernando M. S. Tomé. “The Congenital Muscular Dystrophies.” Myology: Basic and Clinical. Ed. Andrew G. Engel and Clara Franzini-Armstrong. 3rd ed. New York: McGraw-Hill Medical, 2004. Print.
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