ceroid-lipofuscinosis, neuronal 8
The CLN8 gene provides instructions for making a protein whose precise function is not known but is thought to play a transport role within cells. Specifically, the CLN8 protein likely helps to transport materials in and out of a cell structure called the endoplasmic reticulum, which is involved in protein production, processing, and transport. Based on the structure of the CLN8 protein, it may also be involved in regulating the levels of fats (lipids) in cells.
At least 20 mutations in the CLN8 gene have been found to cause late-infantile neuronal ceroid lipofuscinosis (NCL). This condition impairs motor and mental development beginning in early childhood, causing movement disorders and a decline in intellectual function. In addition, affected children often develop recurrent seizures (epilepsy) and vision impairment. Most of the CLN8 gene mutations that cause late-infantile NCL change single protein building blocks (amino acids) in the CLN8 protein, likely decreasing protein activity.
Fatty substances called lipopigments accumulate in cell structures called lysosomes of people with late-infantile NCL. Lysosomes digest and recycle different types of molecules. These accumulations can result in cell dysfunction and eventually cause cell death, especially in brain cells, which are particularly vulnerable to damage caused by lipopigments. However, it is unclear how mutations in the CLN8 gene are involved in the buildup of lipopigments and the signs and symptoms of late-infantile NCL.
Late-infantile NCL caused by CLN8 gene mutations was once thought to be specific to people of Turkish descent. While CLN8 gene mutations are a frequent cause of the disorder in this population, mutations in this gene have since been found in populations worldwide.
Nearly all individuals with Northern epilepsy have the same mutation in both copies of the CLN8 gene in each cell. Northern epilepsy is a type of NCL characterized by recurrent seizures beginning in childhood followed by intellectual decline and movement problems. The mutation that causes this condition replaces the amino acid arginine with the amino acid glycine at position 26 in the CLN8 protein (written as Arg26Gly or R26G). The effects of this mutation on protein function are unclear.
Unlike other forms of NCL that result in the accumulation of large amounts of lipopigments in cells, Northern epilepsy is associated with very little lipopigment buildup. People with Northern epilepsy do develop mild brain abnormalities resulting from cell death, but the cause of this brain cell death is unknown. It is also unclear how changes in the CLN8 protein and a loss of brain cells cause the neurological problems associated with Northern epilepsy.
- ceroid-lipofuscinosis, neuronal 8 (epilepsy, progressive with mental retardation)