SNP Shot: Genomic Insights

Collagen VI-related dystrophy encompasses a range of conditions affecting both skeletal muscles (responsible for movement) and connective tissue (providing support and flexibility to skin, joints, and other body structures). Individuals with these disorders typically experience muscle weakness and joint contractures, which are deformities that limit joint movement and progressively worsen. These dystrophies vary in severity, with Bethlem muscular dystrophy being the mildest, an intermediate form of moderate severity, and Ullrich congenital muscular dystrophy being the most severe.

Bethlem muscular dystrophy usually presents with low muscle tone (hypotonia) in infancy. Muscle weakness can emerge at any point in life, but commonly appears during childhood or early adulthood. This weakness progresses slowly, with about two-thirds of individuals older than 50 requiring walking aids, particularly outdoors. Joint contractures usually develop by adulthood, most commonly affecting the fingers, elbows, shoulders, and ankles. In older age, respiratory muscle weakness may develop, leading to breathing difficulties. Some individuals with this milder form also exhibit skin abnormalities, such as small bumps (follicular hyperkeratosis) on the arms and legs, soft, velvety skin on the palms and soles, and impaired wound healing resulting in shallow scars.

The intermediate form of collagen VI-related dystrophy is characterized by the onset of muscle weakness during infancy. Affected children are typically able to walk, though walking becomes increasingly challenging as they enter early adulthood. Contractures develop in childhood, affecting the fingers, elbows, shoulders, and ankles. Some individuals with this form experience respiratory muscle weakness, requiring the use of mechanical ventilation, particularly during sleep, to assist with breathing.

Ullrich congenital muscular dystrophy is marked by severe muscle weakness that begins shortly after birth. Some affected individuals are never able to walk, while others can only walk with assistance. Those who can walk often lose this ability, typically by early adolescence. Contractures develop in the shoulders, elbows, hips, and knees, further restricting movement. Many individuals also exhibit loose joints (joint laxity) in the fingers, wrists, toes, ankles, and other joints. Continuous mechanical ventilation is often necessary to support breathing during sleep, and some individuals may require it during the day as well. Similar to Bethlem muscular dystrophy, some individuals may have follicular hyperkeratosis, soft, velvety skin on the palms and soles, and abnormal wound healing.

Because individuals with collagen VI-related dystrophy often present with overlapping symptoms across the various forms, assigning a precise diagnosis can be challenging. This overlap, coupled with their shared underlying cause, has led to the recognition of these previously distinct conditions as part of a single disease spectrum.

Inheritance:

Collagen VI-related dystrophy is often inherited in an autosomal dominant pattern. This means that only one copy of the mutated gene in each cell is needed to cause the condition. Bethlem muscular dystrophy is typically inherited in this manner, with the affected individual inheriting the variant from one affected parent. The intermediate and Ullrich congenital muscular dystrophies can also follow this pattern, often arising from new mutations in the gene in individuals with no family history of the disorder. Less commonly, collagen VI-related dystrophy can be inherited in an autosomal recessive manner, requiring both copies of the gene in each cell to have mutations. Some cases of Ullrich congenital muscular dystrophy, the intermediate form, and rare instances of Bethlem muscular dystrophy are inherited this way. In autosomal recessive inheritance, each parent carries one copy of the mutated gene, but they usually don't exhibit any signs or symptoms of the condition.