CLN3 disease is an inherited disorder that primarily affects the nervous system. After 4 to 6 years of normal development, children with this condition develop vision impairment, intellectual disability, movement problems, speech difficulties, and seizures, which worsen over time.

In children with CLN3 disease, problems with vision often begin between the ages of 4 and 8 years. Vision impairment is caused by a breakdown of the light-sensitive tissue at the back of the eye (retinal degeneration), which worsens with age. People with CLN3 disease are often blind by late childhood or adolescence. Also around age 4 to 8, children with CLN3 disease start to fall behind in school. They have difficulty learning new information and lose previously acquired skills (developmental regression), usually beginning with loss of the ability to speak in complete sentences.

Seizures and movement abnormalities often develop in adolescence in people with CLN3 disease. These abnormalities include muscle rigidity or stiffness, clumsiness, slow or diminished movements (hypokinesia), and a stooped posture. Over time, affected individuals lose the ability to walk or sit independently and require wheelchair assistance. Rarely, people with CLN3 disease develop a distorted view of reality (psychosis) or false perceptions (hallucinations). Some affected individuals have an abnormal heart rhythm (arrhythmia) later in life. Most people with CLN3 disease live into early adulthood.

CLN3 disease is one of a group of disorders known as neuronal ceroid lipofuscinoses (NCLs), which may also be collectively referred to as Batten disease. All these disorders affect the nervous system and typically cause worsening problems with vision, movement, and thinking ability. The different NCLs are distinguished by their genetic cause. Each disease type is given the designation "CLN," meaning ceroid lipofuscinosis, neuronal, and then a number to indicate its subtype.

CLN3 disease is caused by mutations in the CLN3 gene, which provides instructions for making a protein that is found in tissues throughout the body. The CLN3 protein is part of many compartments within cells, including lysosomes, which are cellular compartments that digest and recycle different types of molecules. However, the exact function of the CLN3 protein is unclear. Research has shown that this protein is involved in many cellular processes, but it is uncertain which of them is the primary role of the protein, or if these processes instead represent downstream effects.

It is unclear how mutations in the CLN3 gene lead to the characteristic features of CLN3 disease. One CLN3 gene mutation, found in the vast majority of cases, leads to the production of an abnormally short protein. As a result, the abnormal CLN3 protein is broken down or may interfere with normal cellular processes. Other mutations reduce the amount of normal protein or impair its function. It is not known how loss of this protein causes the signs and symptoms of CLN3 disease.

CLN3 disease, like other NCLs, is characterized by the accumulation of proteins and other substances in lysosomes. These accumulations occur in cells throughout the body; however, nerve cells seem to be particularly vulnerable to their effects. The accumulations can cause cell damage leading to cell death. The progressive death of nerve cells in the brain and other tissues leads to the neurological signs and symptoms of CLN3 disease. However, it is unclear how mutations in the CLN3 gene are involved in the buildup of substances in lysosomes.

Normal Function

The CLN3 gene provides instructions for making a protein that is found in tissues throughout the body, yet its function is unclear. The CLN3 protein is found in many compartments within cells, but its role in lysosomes is most well-studied. Lysosomes are cellular compartments that digest and recycle different types of molecules. The CLN3 protein spans the membrane surrounding lysosomes, helping to facilitate communication between it and the rest of the cell.

Studies have associated the CLN3 protein with many cellular processes, including recycling of worn-out cell parts and unneeded proteins (autophagy), maintenance of the relative acidity (pH) of lysosomes, the movement of molecules from the cell surface into the cell (endocytosis), transportation (trafficking) of proteins to where they are needed in the cell, self-destruction of cells (apoptosis), cell growth and division (proliferation), and maintenance of the body's water balance (osmoregulation). It is uncertain which of these varied functions is the primary role of the CLN3 protein, or if these processes instead represent downstream effects.

Health Conditions Related to Genetic Changes

CLN3 disease

More than 65 mutations in the CLN3 gene have been found to cause CLN3 disease. CLN3 disease is an inherited disorder that begins in childhood and primarily affects the nervous system. People with this condition develop worsening vision impairment, intellectual disability, movement problems, speech difficulties, and seizures.

One CLN3 gene mutation, found in the vast majority of cases, deletes about 1,000 DNA building blocks (base pairs) in the gene. This mutation, which is usually called the 1 kilobase (kb) deletion, often occurs in both copies of the CLN3 gene. The 1 kb deletion removes a piece of the CLN3 gene and leads to the production of an abnormally short protein. As a result, the abnormal CLN3 protein is broken down or may interfere with normal cellular processes. Other mutations reduce the amount of normal protein or impair its function. It is not known how loss of this protein causes the signs and symptoms of CLN3 disease.

CLN3 disease is characterized by the accumulation of proteins and other substances in lysosomes. These accumulations occur in cells throughout the body; however, nerve cells seem to be particularly vulnerable to their effects. The accumulations can cause cell damage leading to cell death. The progressive death of nerve cells in the brain and other tissues leads to the neurological signs and symptoms of CLN3 disease. However, it is unclear how mutations in the CLN3 gene are involved in the buildup of substances in lysosomes.

Other disorders

Mutations in the CLN3 gene can cause vision impairment without the other signs and symptoms of CLN3 disease (described above), which is known as CLN3-associated isolated retinal degeneration. In affected individuals, vision impairment is caused by a breakdown of the light-sensitive tissue at the back of the eye (retinal degeneration). People with CLN3-associated isolated retinal degeneration typically have decreased sharpness of vision (visual acuity) and increased sensitivity to light (photophobia). There are two types of this condition, which are distinguished by the age at which vision problems begin. The early-onset form begins in late childhood or adolescence, and the late-onset form begins in early to mid-adulthood.

Research suggests that the CLN3 gene mutations that cause CLN3-associated isolated retinal degeneration are less severe than those that cause CLN3 disease. As a result, a partially functional CLN3 protein is produced, which leads to the development of visual problems in affected individuals without the neurological features characteristic of CLN3 disease.

Other Names for This Gene

• BATTENIN
• BTN1
• BTS
• ceroid-lipofuscinosis, neuronal 3
• CLN3_HUMAN
• JNCL
• MGC102840

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

CLN3 disease is the most common type of NCL, but its exact prevalence is unknown; more than 400 cases have been described in the scientific literature. Collectively, all forms of NCL affect an estimated 1 in 100,000 individuals worldwide.