Knobloch syndrome is a rare condition characterized by severe vision problems and a skull defect.

A characteristic feature of Knobloch syndrome is extreme nearsightedness (high myopia). In addition, several other eye abnormalities are common in people with this condition. Most affected individuals have vitreoretinal degeneration, which is breakdown (degeneration) of two structures in the eye called the vitreous and the retina. The vitreous is the gelatin-like substance that fills the eye, and the retina is the light-sensitive tissue at the back of the eye. Vitreoretinal degeneration often leads to separation of the retina from the back of the eye (retinal detachment). Affected individuals may also have abnormalities in the central area of the retina, called the macula. The macula is responsible for sharp central vision, which is needed for detailed tasks such as reading, driving, and recognizing faces. Due to abnormalities in the vitreous, retina, and macula, people with Knobloch syndrome often develop blindness in one or both eyes.

Another characteristic feature of Knobloch syndrome is a skull defect called an occipital encephalocele, which is a sac-like protrusion of the brain (encephalocele) through a defect in the bone at the base of the skull (occipital bone). Some affected individuals have been diagnosed with a different skull defect in the occipital region, and it is unclear whether the defect is always a true encephalocele. In other conditions, encephaloceles may be associated with intellectual disability; however, most people with Knobloch syndrome have normal intelligence.

Mutations in the COL18A1 gene can cause Knobloch syndrome. The COL18A1 gene provides instructions for making a protein that forms collagen XVIII, which is found in the basement membranes of tissues throughout the body. Basement membranes are thin, sheet-like structures that separate and support cells in these tissues. Collagen XVIII is found in the basement membranes of several parts of the eye, including the vitreous and retina, among other tissues. Little is known about the function of this protein, but it appears to be involved in normal development of the eye.

Several mutations in the COL18A1 gene have been identified in people with Knobloch syndrome. Most COL18A1 gene mutations lead to an abnormally short version of the genetic blueprint used to make the collagen XVIII protein. Although the process is unclear, the COL18A1 gene mutations result in the loss of collagen XVIII protein, which likely causes the signs and symptoms of Knobloch syndrome.

When the condition is caused by COL18A1 gene mutations, it is sometimes referred to as Knobloch syndrome type I. Research indicates that mutations in at least two other genes that have not been identified may cause Knobloch syndrome types II and III. Although they are caused by alterations in different genes, the three types of the condition have similar signs and symptoms.

Normal Function

The COL18A1 gene provides instructions for making a protein that forms collagen XVIII. Three COL18A1 proteins, called alpha 1 subunits, attach to each other to form collagen XVIII. Collagen XVIII is found in the basement membranes of tissues throughout the body. Basement membranes are thin, sheet-like structures that separate and support cells in these tissues.

There are three versions (isoforms) of the alpha 1 subunit of collagen XVIII, which form three different lengths of the collagen XVIII protein. The short version of collagen XVIII is found in basement membranes throughout the body, including several parts of the eye. The two longer versions are found primarily in the liver. In addition, a piece of collagen XVIII can be cut off to form the protein endostatin. Endostatin is able to block the formation of blood vessels (angiogenesis) and is known as an anti-angiogenic factor.

Little is known about the function of collagen XVIII, but it appears that all of the isoforms are involved in normal development of the eye.

Health Conditions Related to Genetic Changes

Knobloch syndrome

At least a dozen mutations in the COL18A1 gene have been identified in people with Knobloch syndrome, a condition characterized by severe vision problems and a skull defect called an occipital encephalocele. Most COL18A1 gene mutations lead to an abnormally short version of the genetic blueprint used to make the alpha 1 subunit of collagen XVIII. There are a few other mutations that replace single protein building blocks (amino acids) in the protein sequence. Although the process is unclear, the COL18A1 gene mutations result in the loss of collagen XVIII. Most COL18A1 gene mutations affect all isoforms of collagen XVIII, but at least one mutation affects only the short isoform. The loss of one or all isoforms of the collagen XVIII protein likely causes the signs and symptoms of Knobloch syndrome. It is unclear whether endostatin is involved in this condition.

Other Names for This Gene

• antiangiogenic agent
• collagen alpha-1(XVIII) chain
• collagen type XVIII alpha 1
• collagen, type XVIII, alpha 1
• endostatin
• FLJ27325
• FLJ34914
• KNO
• KNO1
• KS
• MGC74745
• multi-functional protein MFP

Genomic Location

• 25% chance to be affected
• 50% chance to be an unaffected carrier like each parent
• 25% chance to be unaffected and not a carrier

Knobloch syndrome is a rare condition. However, the exact prevalence of the condition is unknown.