CLN11 disease is a disorder that primarily affects the nervous system. Individuals with this condition typically show signs and symptoms in adolescence or early adulthood. This condition is characterized by recurrent seizures (epilepsy), vision loss, problems with balance and coordination (cerebellar ataxia), and a decline in intellectual function.

Seizures in CLN11 disease often involve a loss of consciousness, muscle stiffness (rigidity), and generalized convulsions (tonic-clonic seizures).

Vision loss is gradual over time and is due to a condition called retinitis pigmentosa, which is caused by the breakdown of the light-sensitive layer at the back of the eye (retina). People with CLN11 disease can also develop clouding of the lenses of the eyes (cataracts) and rapid, involuntary eye movements (nystagmus).

Affected individuals can also develop muscle twitches (myoclonus), walking problems and falling (gait disturbance), and impaired speech (dysarthria). Over time, people with CLN11 disease develop short-term memory loss and loss of executive function, which is the ability to plan and implement problem-solving strategies and actions. They may also become irritable and impulsive. Some affected individuals experience visual hallucinations involving people or animals.

CLN11 disease is one of a group of disorders known as neuronal ceroid lipofuscinoses (NCLs). All of these disorders affect the nervous system and typically cause progressive 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.

CLN11 disease results from mutations in the GRN gene. This gene provides instructions for making a protein called progranulin. Progranulin is active in many different tissues in the body, where it helps control the growth, division, and survival of cells. Progranulin's function in the brain is not well understood, although it appears to play an important role in the survival of nerve cells (neurons).

GRN gene mutations that cause CLN11 disease result in a complete loss of functional progranulin protein. This lack of progranulin causes the death of nerve cells in the brain, although the exact mechanism is unknown. Widespread loss of neurons in CLN11 disease leads to the development of signs and symptoms in adolescence or early adulthood.

Normal Function

The GRN gene provides instructions for making a protein called progranulin. This protein is primarily found in the membrane of cellular structures called lysosomes, which are specialized compartments that digest and recycle materials. Within lysosomes, progranulin can be cut (cleaved) into smaller proteins, known as granulins, which are thought to function similar to progranulin.

Progranulin is found in tissues throughout the body, but it is most active in cells that are dividing rapidly, such as skin cells (fibroblasts), immune system cells, and certain brain cells. This protein helps regulate the growth, division, and survival of these cells. It also plays important roles in early embryonic development, wound healing, and the body's immune response to injury (inflammation). Progranulin is active in several types of brain cells. However, little is known about this protein's role in the brain. It appears to be critical for the survival of nerve cells (neurons).

Health Conditions Related to Genetic Changes

CLN11 disease

At least eight mutations in the GRN gene have been found to cause CLN11 disease. This condition is characterized by recurrent seizures (epilepsy), vision loss, problems with balance and coordination (cerebellar ataxia), and a decline in intellectual function that typically begin in adolescence or early adulthood.

Most of the GRN gene mutations that cause CLN11 disease disrupt how the gene's information is spliced together to make the blueprint for producing the progranulin protein. As a result, there is a complete loss of functional progranulin protein. This lack of progranulin leads to the death of nerve cells in the brain. Although the exact mechanism is unknown, it is thought to involve impaired function of lysosomes. Unlike in GRN-related frontotemporal lobar degeneration (described below), people with CLN11 disease do not appear to have build up of the TDP-43 protein in their brain cells. In CLN11 disease, loss of neurons from many regions of the brain leads to the development of epilepsy, cerebellar ataxia, and other signs and symptoms in adolescence or early adulthood.

GRN-related frontotemporal lobar degeneration

More than 65 mutations in the GRN gene have been identified in people with GRN-related frontotemporal lobar degeneration. This condition is a progressive brain disorder that can affect behavior, language, and movement. The symptoms of this disorder usually become noticeable in a person's fifties or sixties.

The most common GRN gene mutation, which is written as Arg493Ter or R493*, creates a premature stop signal in the instructions for making progranulin. Most of the mutations that cause GRN-related frontotemporal lobar degeneration prevent any protein from being produced from one copy of the GRN gene in each cell. As a result of these genetic changes, cells make only half the usual amount of progranulin. In rare cases, affected individuals have mutations in both copies of their GRN gene. Each of these mutations allow for some functional protein to be produced and when measured, the total amount of progranulin produced amounts to about half of the usual amount.

It is unclear how a shortage of progranulin leads to the features of GRN-related frontotemporal lobar degeneration. However, studies have shown that the disorder is characterized by the buildup of a protein called TAR DNA-binding protein 43 (TDP-43) in certain brain cells. The TDP-43 protein forms clumps (aggregates) that may interfere with cell functions and ultimately lead to cell death. Researchers are working to determine how mutations in the GRN gene, and the resulting loss of progranulin, are related to a buildup of TDP-43 in the brain.

The features of GRN-related frontotemporal lobar degeneration result from the gradual loss of neurons in regions near the front of the brain called the frontal and temporal lobes. The frontal lobes are involved in reasoning, planning, judgment, and problem-solving, while the temporal lobes help process hearing, speech, memory, and emotion. The death of neurons in these areas causes problems with many critical brain functions. However, it is unclear why the loss of neurons occurs in the frontal and temporal lobes more often than other brain regions in people with GRN-related frontotemporal lobar degeneration.

Other Names for This Gene

• acrogranin
• CLN11
• GEP
• GP88
• granulin
• granulin-epithelin
• granulins
• granulins precursor
• GRN_HUMAN
• PC cell-derived growth factor
• PCDGF
• PEPI
• PGRN
• proepithelin
• progranulin

Genomic Location

CLN11 disease is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Having a mutation in both copies of the GRN gene eliminates production of any functional progranulin protein.

The parents of individuals with CLN11 disease each carry one copy of the mutated GRN gene in every cell and generally produce about half the normal amount of progranulin protein. Individuals with one GRN gene mutation typically do not show signs and symptoms of CLN11 disease, but they may develop another condition called GRN-related frontotemporal lobar degeneration in which cognitive decline begins between a person's forties and sixties. Some people with two GRN gene mutations that allow the production of some functional progranulin protein develop GRN-related frontotemporal lobar degeneration.

The prevalence of CLN11 disease is unknown; at least 11 cases have been described in the scientific literature.