Osteogenesis imperfecta (OI), commonly known as brittle bone disease, is a group of genetic disorders that primarily affect the bones, causing them to break easily. Meaning “imperfect bone formation,” individuals with OI experience fractures from mild trauma or sometimes without any apparent cause. The severity varies greatly, ranging from mild cases with few fractures to severe forms where breaks can occur even before birth.
The Role of Collagen Genes
The underlying cause of most OI cases lies in genetic mutations that disrupt the body’s ability to produce or properly process type I collagen. Collagen is the most abundant protein in the human body, serving as a foundational component in bones, skin, tendons, and other connective tissues. In bones, type I collagen acts like a flexible framework, providing both strength and elasticity to the mineralized structure.
Approximately 90% of OI cases are linked to mutations in two specific genes: COL1A1 and COL1A2. These genes contain the instructions for building the alpha chains that assemble into type I collagen molecules. Mutations can lead to two main problems: either a reduced quantity of normal collagen is produced, or the body produces collagen that is structurally abnormal. Both scenarios result in bones that are weaker and more fragile, making them susceptible to fractures.
How Osteogenesis Imperfecta is Inherited
Osteogenesis imperfecta is passed down through families in two main genetic patterns. Autosomal dominant inheritance is the most common, responsible for about 80-85% of OI cases. In this pattern, only one copy of the altered gene in each cell is enough to cause the condition.
If a parent has autosomal dominant OI, there is a 50% chance with each pregnancy that their child will inherit the mutated gene and develop the disorder. Autosomal recessive inheritance is less common. This occurs when a child inherits a mutated gene from both parents, who are carriers.
When There Is No Family History
Sometimes, a child is diagnosed with osteogenesis imperfecta even when there is no known family history. This situation arises due to a spontaneous or “de novo” mutation. A de novo mutation is a new genetic change that occurs either in the egg or sperm cell of a parent, or very early during fetal development.
In these instances, the affected child is the first in their family to have the condition. The child now carries the mutation and could potentially pass it on to their own children in the future. This mechanism explains why severe forms of OI, like type II, often appear in families without a prior history.
Classifying Types and Genetic Diagnosis
The specific genetic mutation plays a significant role in determining the type and severity of osteogenesis imperfecta. OI has been classified into different types based on clinical features, with Type I being the mildest and Type II the most severe. Type I OI is characterized by a reduced amount of normal collagen, leading to fragile bones and often blue-tinted sclerae. More severe types, such as Type II and Type III, involve structurally abnormal collagen, resulting in frequent fractures that can occur at birth and lead to significant bone deformities.
Healthcare providers use genetic testing to confirm an OI diagnosis and identify the specific gene mutation involved. Techniques like DNA sequencing can analyze an individual’s DNA sample to pinpoint mutations in genes such as COL1A1, COL1A2, and other less common OI-associated genes. This genetic information is valuable for accurate diagnosis, guiding treatment strategies, and offering clarity for family planning.