CLN1 disease is an inherited disorder that primarily affects the nervous system. Individuals with this condition have normal development in infancy, but typically by 18 months they become increasingly irritable and begin to lose previously acquired skills (developmental regression). In affected children, nerve cells in the brain die over time, leading to an overall loss of brain tissue (brain atrophy) and an unusually small head (microcephaly). Children with CLN1 disease have decreased muscle tone (hypotonia), intellectual and motor disability, and rarely are able to speak or walk. Some affected children develop repetitive hand movements. By age 2, individuals with this condition often have muscle twitches (myoclonus), recurrent seizures (epilepsy), and vision loss. Some affected children develop frequent respiratory infections. As the condition worsens, children have severe feeding difficulties that often require a feeding tube. Children with CLN1 disease usually do not survive past childhood.

Some people with CLN1 disease do not develop symptoms until later in childhood or in adulthood. As with younger affected children, older individuals develop a decline in intellectual function, myoclonus, epilepsy, and vision loss. In these individuals, life expectancy depends on when signs and symptoms of CLN1 disease develop and their severity; affected individuals may survive only into adolescence or through adulthood. Adults with CLN1 disease may also have movement disorders, including impaired muscle coordination (ataxia) or a pattern of movement abnormalities known as parkinsonism.

CLN1 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.

Mutations in the PPT1 gene cause CLN1 disease. The PPT1 gene provides instructions for making an enzyme called palmitoyl-protein thioesterase 1. This enzyme is active in cell compartments called lysosomes, which digest and recycle different types of molecules. Palmitoyl-protein thioesterase 1 removes fats called long-chain fatty acids from certain proteins, which helps to break down the proteins. Palmitoyl-protein thioesterase 1 is also thought to be involved in a variety of other cell functions.

PPT1 gene mutations that cause CLN1 disease decrease or eliminate the production or function of palmitoyl-protein thioesterase 1. A reduction of functional enzyme impairs the removal of fatty acids from certain proteins. These partially broken down fats and proteins accumulate in lysosomes. While accumulation of these substances occurs in cells throughout the body, nerve cells appear to be particularly vulnerable to damage caused by the abnormal cell materials. Early and widespread loss of nerve cells in CLN1 disease leads to severe signs and symptoms and death in childhood.

In the later-onset cases of CLN1 disease, PPT1 gene mutations result in the production of a palmitoyl-protein thioesterase 1 enzyme that has a reduced level of normal function; however, protein function in these individuals is higher than in those who have the condition beginning in early childhood. As a result, long-chain fatty acids are removed from some proteins, allowing for a small amount of proteins to be broken down. Since it takes longer for these substances to accumulate in lysosomes and cause nerve cell death, the signs and symptoms of CLN1 disease in these individuals occur later in life.

Normal Function

The PPT1 gene provides instructions for making an enzyme called palmitoyl-protein thioesterase 1. This enzyme is found in structures called lysosomes, which are compartments within cells that break down and recycle different types of molecules. Palmitoyl-protein thioesterase 1 removes certain fats called long-chain fatty acids from specific proteins, typically a fatty acid called palmitate. Removing these fatty acids helps break the proteins down when they are no longer needed. Palmitoyl-protein thioesterase 1 is also thought to be involved in a variety of other cell functions, such as the development of synapses, which are the connections between nerve cells where cell-to-cell communication occurs.

Health Conditions Related to Genetic Changes

CLN1 disease

More than 65 mutations in the PPT1 gene have been found to cause CLN1 disease. This condition impairs mental and motor development causing difficulty with walking, speaking, and intellectual function. In addition, affected children often develop recurrent seizures (epilepsy) and vision loss. Signs and symptoms of CLN1 disease typically appear by age 18 months but can begin later, sometimes in adulthood, in some individuals.

The PPT1 gene mutations that cause CLN1 disease decrease or eliminate the production or function of palmitoyl-protein thioesterase 1. The most common mutation causing CLN1 disease worldwide, written as Arg151Ter or R151X, replaces the protein building block (amino acid) arginine with a premature stop signal in the instructions used to make the enzyme. This mutation results in an abnormally short, nonfunctional version of the enzyme. Another mutation causes most cases of the disorder in people of Finnish descent; this genetic change replaces arginine with the amino acid tryptophan at position 122 in the palmitoyl-protein thioesterase 1 enzyme (written as Arg122Trp or R122W).

PPT1 gene mutations that cause CLN1 disease lead to a shortage of functional enzyme, which impairs the removal of long-chain fatty acids from certain proteins. These partially broken down fats and proteins accumulate in lysosomes. While accumulations of these substances occurs in cells throughout the body, nerve cells appear to be particularly vulnerable to damage caused by the abnormal cell materials. Early and widespread loss of nerve cells in CLN1 disease leads to severe signs and symptoms and death in childhood.

In the later-onset cases of CLN1 disease, PPT1 gene mutations result in the production of a palmitoyl-protein thioesterase 1 enzyme that has a reduced level of normal function; however, protein function in these individuals is higher than in those who have the condition beginning in early childhood. As a result, long-chain fatty acids are removed from some proteins, allowing for a small amount of proteins to be broken down. Because it takes longer for these substances to accumulate in lysosomes and cause nerve cell death, the signs and symptoms of CLN1 disease in these individuals occur later in life.

Other Names for This Gene

• ceriod-lipofuscinosis, neuronal 1
• CLN1
• INCL
• palmitoyl-protein hydrolase 1
• PPT
• PPT-1
• PPT1_HUMAN

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.

The incidence of CLN1 disease is unknown; more than 200 cases have been described in the scientific literature. Collectively, all forms of NCL affect an estimated 1 in 100,000 individuals worldwide. NCLs are more common in Finland, where approximately 1 in 12,500 individuals are affected.