Batten disease, also called neuronal ceroid lipofuscinoses or NCLs, refers to a group of severe neurological conditions caused by defects in the processes involved in breaking down a substance called lipofuscin.
Lipofuscin accumulates inside cells in structures called lysosomes — the parts of the cell responsible for breaking down waste — becoming toxic. It also accumulates in cells and tissues elsewhere in the body, such as the eyes, skin, and muscles.
Brain cells are particularly sensitive to the toxic effects of excess lipofuscin accumulation. For this reason, individuals with Batten disease display symptoms of brain damage, such as seizures and vision loss, as well as progressive cognitive and motor difficulties.
Genetics of Batten disease
A genetic defect, typically inherited from both parents, causes Batten disease. More than 400 mutations have been identified in 14 different genes, referred to as CLN1 through CLN14. Mutations in each of these genes cause a distinct disease type, also named CLN1 through CLN14 disease. They are collectively known as Batten disease.
Batten disease also may be classified according to the age at which symptoms begin, namely as congenital, infantile, late infantile, juvenile, or adult types. More than one gene can be associated with any one of the different types of Batten disease.
What exactly causes Batten?
Scientists do not yet fully understand how Batten-causing mutations lead to lipofuscin accumulation. While some forms of Batten disease are linked to mutations that cause certain enzymes to be absent or deficient, other forms are thought to be caused by defective proteins needed for neurons (nerve cells) and other cells to work correctly. The lack of working proteins causes the buildup of “junk” substances and lipofuscin in the lysosomes.
However, the exact functions of some of these proteins have yet to be discovered. It also is unknown if the lipofuscin itself is toxic or whether the accumulation is a marker of damaged lysosomal function.
Different mutations underlie the varying forms of Batten disease. Mutations in the PPT1 gene decrease or eliminate the production or function of an enzyme called palmitoyl-protein thioesterase 1, which normally breaks down fatty acids in cells. These mutations are known to cause CLN1 disease.
CLN2 disease is caused by mutations in the TPP1 gene. Such mutations reduce or eliminate the production or the activity of an enzyme called tripeptidyl peptidase 1.
Mutations in the CLN3 gene lead to the production of defective forms, or reduced amounts, of the protein battenin, which is located in lysosomes and whose exact function is unknown. CLN3 disease is caused by these mutations.
Data show that mutations in the DNAJC5 gene lead to the production of an altered protein called cysteine string protein alpha. This protein is involved in recycling other proteins that are crucial in allowing nerve cells to relay information. These mutations are known to cause CLN4 disease.
Mutations in the CLN5 gene are thought to cause CLN5 disease, and lead to a lack of a functional form of the ceroid-lipofuscinosis neuronal protein 5 (CLN5). Scientists believe this protein breaks down fats and maintains the protective layer that surrounds neurons — called myelination — and protein transport.
Defects in CLN6 protein — whose function has not been identified — are the result of mutations in the CLN6 gene. CLN6 disease is known to be caused by these mutations.
CLN7 disease is caused by mutations in the MFSD8 gene, which lead to the production of a protein called major facilitator superfamily domain-containing protein 8, with an altered structure or function. The exact role of this protein is not known, but it is thought that it may be involved in transporting molecules into lysosomes for recycling and disposal.
Mutations in the CLN8 gene are thought to cause defects in the CLN8 protein. While its function is not well understood, it is believed to be involved in transporting molecules to a part of a cell known as the endoplasmic reticulum, or ER. The ER is important in protein production, processing, and transport. These mutations cause CLN8 disease.
Other mutations, these in the CTSD gene, are known to cause CLN10 disease by creating a lack of cathepsin D, an enzyme which normally works to modify proteins. Cathepsin D is present in many types of cells and is active in lysosomes.
The function of a protein known as progranulin is impaired by mutations in the GRN gene. While the exact function of progranulin is unknown, it is thought to assist lysosome function. Mutations in this gene cause CLN11 disease.
The ATP13A2 gene gives rise to ATP13A2, a lysosomal transport protein. CLN12 disease results from mutations in that gene.
Mutations in the CTSF gene lead to defects in a protein known as cathepsin F, the exact functions of which are unknown, although it is thought to facilitate lysosomal function. Such mutations cause CLN13 disease.
Finally, mutations in the KCTD7 gene cause defects in a protein called potassium channel tetramerization domain containing 7, which transports potassium in and out of cells. CLN14 disease is known to be caused by mutations in this gene.
Inheritance of Batten disease
Batten disease is most commonly inherited in an autosomal recessive manner, meaning a child has to inherit two defective copies of a gene — one from each biological parent — for symptoms to develop.
In rare cases, the disease can also be passed down in an autosomal dominant manner. This means that a child with only one mutated copy of a gene still develops the disease. More commonly, though, individuals who inherit only one defective gene are disease carriers and could pass Batten on to their own children.
Last updated: May 21, 2021
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