Collagen 6 (Ullrich-Bethlem)
Collagen 6 Related Dystrophies are characterized by proximal weakness, distal hyperlaxity, joint contractures, skin changes, and respiratory insufficiency. COL6-RD comprises a continuum of overlapping phenotypes that range from Ullrich CMD (early onset/severe), Intermediate, and Bethlem MD (late onset/mild). This disorder is caused by genetic mutations in one of three genes: COL6A1, COL6A2 or COL6A3. Inheritance may be autosomal dominant or recessive.
Proximal muscle weakness
Rigid spine, scoliosis and kyphosis
Skin changes, including hyperkeratosis pilaris, keloid scarring, velvety skin on palms and soles
Normal to mildly elevated CK
Absence of a cardiac phenotype with proactive respiratory management
Upon suspecting a diagnosis of COL6-RD based on clinical findings, muscle imaging, and/or muscle or skin immunohistochemical staining, diagnosis may be confirmed by genetic testing that results in pathogenic mutations in COL6A1, COL6A2, or COL6A3.
If genetic testing reveals one or more variant of unknown significance (VOUS), segregation testing, muscle imaging, and Collagen 6 immunoreactivity of muscle or dermal fibroblasts can provide further information. Our colleagues at the Bönnemann Laboratory at the National Institutes of Health may be able to provide additional analysis.
Collagen 6 is a protein found in the extracellular matrix (ECM) of muscle, blood vessels, nerves, skin, tendons, cartilage, intervertebral discs, lenses, and internal organs. The ECM's function is to provide structural and biochemical support to surrounding cells. The ECM of skeletal muscle is known as the "myomatrix" [Bönnemann 2011], and contains three genetically distinct subunits of Collagen 6 -- a1, a2, and a3, that form a triple helical monomer that eventually align to form tetramers. These tetramers are then secreted extracellularly, aligned end-to-end, forming beaded microfilaments as the final product of the Collagen 6 assembly.
Genetic mutations that cause COL6-RD can be associated with autosomal dominant or recessive inheritance. Affected individuals with Bethlem MD are most often found to have dominant mutations, and those with Intermediate COL6-RD or Ullrich CMD are frequently found to have de novo (spontaneous) dominant mutations. Less commonly, recessive mutations are found to be the cause of disease.
Management and Surveillance
Surveillance of respiratory-related symptom progression should be monitored through regular pulmonary function testing in both the sitting and supine positions, and via polysomnography with capnography to assess for nocturnal hypoventilation. Introduction of night time non-invasive ventilation may be indicated, with daytime ventilatory support potentially indicated in subsequent years. Proactive pulmonary surveillance is key to maintaining overall health and quality of life as respiratory insufficiency is the leading cause of illness, hospitalization, and failure to thrive.
Affected individuals often do not meet growth chart expectations, and should not be compared to those of similar age who are unaffected. Close monitoring of nutrition and growth to ensure an upward trajectory is vital, even if that trajectory is at a slower rate.
Regular orthopedic and physical therapy examinations to assess changes in muscle weakness, joint contractures and scoliosis is recommended so that appropriate interventions and the introduction of mobility devices are timely.
Annual cardiac assessments with echocardiogram and EKG to ensure there is no right-side heart strain as a result of untreated respiratory failure is recommended.
For a deeper dive into Collagen 6-RD, please visit the recently updated comprehensive Gene Reviews page, hosted by the National Institute for Bioinformatics (NCBI).