Congenital muscular dystrophy (CMD) is a general term referring to a group of hereditary diseases characterized by early-onset hypotonia and muscle weakness, progressive muscle wasting, and possibly ocular and central nervous system malformations. Disease severity, quality of life and life expectancy varies from patient to patient. Causal treatment is not available and only supportive therapy can be provided. The latter typically comprises physical therapy, orthopedic devices, surgical interventions, and respiratory support, if needed.
Congenital hypotonia and poor spontaneous movement often constitute the first findings in CMD patients . Those neonates are also called "floppy infants". They may face enormous difficulties with respiration and the ingestion of food. Such severe disease usually entails a very short life expectancy. Individuals suffering from milder CMD show mild to moderate delays of motor development; they may or may not reach independent ambulation. Parents of children suffering from milder CMD are often unable to clearly define a time of symptom onset. They may present their child due to delayed attainment of gross motor milestones in infancy or childhood. In any case, muscle weakness augments over time. Initially unremarkable facial features tend to change and CMD patients eventually acquire myopathic facial characteristics. Macrocephaly may be noted. Additionally, joint mobility continually decreases and patients are prone to develop spinal deformities such as scoliosis, kyphosis and lordosis. If independent ambulation has been reached, it may be lost.
Muscular dystrophy may affect the eye muscles and CMD patients may develop ophthalmoplegia. Furthermore, malformations of ocular structures may be seen in those affected by CMD. In detail, microphthalmia, microcornea, iris hypoplasia, narrow anterior chamber angle with subsequent glaucoma, cataracts, retinal colobomas and detachment, hypoplastic or absent optic nerves have been described in CMD patients, particularly in those with abnormal glycosylation of α-dystroglycan .
Besides muscular dystrophy and ocular malformation, central nervous system disorders are a hallmark of many types of CMD. Indeed, central nervous system involvement is one of the most important parameters when establishing the diagnosis: It is to be expected in most α-dystroglycanopathies, except in CMD type 1C . In CMD type 1A, mental retardation is rarely observed and seizures affect up to 30% of affected individuals only, but brain imaging may reveal white matter anomalies . Disturbances of mental development is not typical of CMD type Ullrich and Bethlem myopathy.
Due to the heterogeneity of CMD and ongoing doubts regarding the genetic causes of certain types of the disease, anamnestic and clinical data remain essential for diagnosis. In detail, it is important to assess :
Analyses of blood samples typically reveal slightly to markedly elevated levels of creatine kinase, but don't yield specific results that would allow for a reliable diagnosis. Highest concentrations of creatine kinase are measured in those suffering from CMD type 1A (primary merosin deficiency) or α-dystroglycanopathies (secondary merosin deficiency).
In order to provide a reliable diagnosis, histological examinations of muscle biopsy samples and genetic tests have to be realized. Magnetic resonance imaging of skeletal muscles is generally done before the decision on a certain biopsy site is taken. After performing the biopsy, immunohistochemical staining of muscle samples for glycosylated α-dystroglycan, laminin subunit α2, and collagen VI should be realized in order to distinguish the respective groups of CMD . Microscopic examination of the native specimen usually reveals non-specific dystrophic changes of muscle fibers, e.g., fiber size variability, degeneration of muscle fibers, fibrosis, and lipomatosis . Finally, molecular biological techniques are applied to identify the causal gene mutation. Because ultimately, genetic tests for CMD rely on multi-gene panels that include several genes associated with CMD, some authors state that muscle biopsies are no longer indispensable in cases where anamnestic and clinical data justify the tentative diagnosis of CMD .
Causal treatment is not available and according to current knowledge, disease progression cannot be delayed pharmacologically. Thus, supportive therapy remains the only alternative. A multidisciplinary approach is required to improve a patient's quality of life. In this regard, tailor-made therapies are to be provided. They should be adapted to the individual patient's necessities and disease progression. In detail, affected individuals may need respiratory aids, non-invasive respiratory support, or mechanical ventilation. Orthopedic devices and physical therapy are often helpful to improve or maintain mobility, but surgical interventions may become necessary, too. Additionally, psychological support should be provided to CMD patients and their families.
The patient's prognosis largely depends on the type of CMD they are suffering from: Severe CMD is often early fatal, while individuals affected by mild CMD usually survive into adulthood and maintain a relatively good quality of life. In general, CMD follow a progressive course. Even though stagnation or even improvement may be noted in the short term, progressive weakness, limb-girdle muscle wasting, joint contractures and spinal deformities increasingly affect the patient's ability to cope with everyday life .
CMD are genetic disorders that are mainly inherited in an autosomal recessive manner. Nevertheless, autosomal dominant inheritance may be observed, particularly in those suffering from collagen VI-related CMD. Thus, the recognition of a certain pattern of inheritance upon the analysis of a patient's pedigree may considerably shorten the list of differential diagnoses.
In any case, the tentative diagnosis of CMD should be confirmed by means of genetic analyses. To date, about 30 genes have been associated with CMD . When interpreting sequencing results, it should be taken into account that certain types of CMD may be caused by mutations of different genes. On the other hand, mutations of one and the same gene may result in distinct types of CMD - a fact that further highlights the importance of a comprehensive workup and the consideration of anamnestic, clinical, and laboratory findings. Certain types of CMD, such as CMD type 1B, could not yet be related to specific mutations  and even if modern molecular biological techniques are applied, some patients still remain undiagnosed   .
For a detailed listing of CMD and causative mutations, the interested reader is referred elsewhere .
In Italy, the overall prevalence of CMD has been estimated to <1 in 100,000 inhabitants . A total of 336 patients have been considered in the respective study and causative mutations have been identified in 220 cases. About 40% of all patients were found to suffer from CMD with abnormal glycosylation of α-dystroglycan, about 24% had CMD with merosin deficiency, and 20% were tested positive for Collagen VI-related CMD . It should be noted, though, that incidence and prevalence of certain types of CMD vary considerably between distinct geographical regions. For instance, Fukuyama muscular dystrophy, a type of CMD with insufficient glycosylation of α-dystroglycan, is one of the most common autosomal recessive disorders in Japan, but is rarely diagnosed outside this country. Its incidence in Japan may be as high as 4 in 100,000 births .
Dystrophin is a protein required for physiological muscle function. It is located within the sarcolemma, i.e., the membrane of striated muscle cells. It is part of the cytoskeleton and one of its main functions is to connect the muscle fiber's actin filaments with the plasma membrane. Dystrophin forms part of a multi-subunit-complex, the so-called dystrophin-associated glycoprotein complex. This complex constitutes a physical link between actin filaments and dystrophin on the inner side of the cell, and the basal lamina surrounding each muscle fiber. The majority of CMD-related genes encodes for proteins that are either part of the dystrophin-associated glycoprotein complex or affect its function. For instance, CMD type 1A is caused by mutations of the LAMA2 gene, which encodes for laminin subunit α2, which is expressed in the basement membrane, while the glycosylation of α-dystroglycan, a component of the dystrophin-associated glycoprotein complex and receptor for extracellular matrix protein, is disturbed in patients suffering from Fukuyama muscular dystrophy, muscle-eye-brain disease, or CMD types 1B, 1C, and 1D   .
Affected families may benefit from genetic counseling. Genetic analyses should be conducted to identify DNA sequence anomalies in any CMD patient and to clarify whom they were inherited from. On the other hand, such tests are very useful to check whether prospective parents related to an affected individual carry any of the mutations associated with CMD and whether their future child is at risk to develop such the disease. Ideally, these studies are realized before pregnancy. However, prenatal testing is also possible .
No recommendations can be given to prevent CMD provoked by de novo mutations.
CMD is a general term that refers to a heterogeneous group of diseases. Those disease have a few things in common, though: They are hereditary diseases that result from DNA sequence anomalies, symptoms are apparent at birth or manifest early in life, and affected individuals are at high risks of restrictive lung disease and orthopedic deformities .
Before genetic analyses became widely available, the diagnosis of CMD largely relied on the results of histological examinations of biopsy samples. Consequently, distinct types of CMD were classified according to pathohistological findings  . Meanwhile, most CMD have been associated with certain genetic defects, and the classification system of CMD has repeatedly been revised . Further updates are to be expected in the future. Currently, the term CMD does at least comprise the following disorders :
Congenital muscular dystrophy (CMD) is a general term. It refers to distinct hereditary diseases characterized by early-onset hypotonia and muscle weakness as well as high risks of restrictive lung disease and orthopedic deformities. These disease are caused by mutations of genes that encode for proteins required for normal muscle function. First symptoms are usually apparent at birth, but may also manifest in infancy or childhood. In general, CMD follow a progressive course and cause increasing delays in motor development. Disease severity varies from patient to patient, though: Severe CMD may lead to early death, while those affected by milder forms of the disease may survive into adulthood and maintain a relatively good quality of life.
Besides progressive muscle wasting, the following may be noted in CMD patients:
The time of onset and distribution of orthopedic deformities, the involvement of the central nervous system, the eyes and the heart may provide valuable clues as to the type of CMD. Besides clinical data, the results of histological examinations of muscle biopsy samples and genetic tests are of major importance when establishing a diagnosis.
Unfortunately, causal treatment is not available and only supportive therapy can be provided. CMD patients benefit from a multidisciplinary approach to treatment that may involve physical therapy, orthopedic devices, surgical interventions, and respiratory support, among others.