Batten disease, also called neuronal ceroid lipofuscinoses (NCLs), refers to a group of severe neurological conditions marked by seizures and vision loss, as well as progressive cognitive and motor difficulties.

Genetics of Batten disease

Batten disease is caused by a genetic defect, typically inherited from both parents. More than 400 mutations in 14 different genes, referred to as CLN1 to CLN14, have been identified. Mutations in each of these genes cause a distinct disease type, also named CLN1 to CLN14 disease. They are collectively known as Batten disease.

Batten disease may also be classified according to the age at which symptoms begin (congenital, infantile, late infantile, juvenile, or adult). More than one gene can be associated with any one of the five types of Batten disease.

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 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.

Biology of Batten disease

Patients with Batten disease have defects in the processes involved in breaking down a substance called lipofuscin (also known as a lipopigment, because it is typically seen as green-yellow deposits of fats and proteins under a UV light microscope). Lipofuscin accumulates inside cells in components called lysosomes (parts of the cell responsible for breaking down waste), becoming toxic.

Brain cells are particularly sensitive to the toxic effects of excess lipofuscin accumulation. For this reason, Batten patients regardless of disease type display symptoms of brain damage, although the adult form is generally the least severe form. Lipofuscin also accumulates in cells and tissues elsewhere in the body, such as the eye, skin, and muscles.

Disease-causing mutations

Scientists do not yet fully understand how Batten-causing mutations lead to lipofuscin accumulation. While some forms of Batten disease are linked mutations that cause certain enzymes to be absent or deficient, other forms are thought to be caused by defective proteins involved in other biological processes. The exact functions of some of these proteins have yet to be discovered.

The following is a summary of known Batten mutations and their impact:

  • CLN1 disease is caused by mutations in the PPT1 gene. This leads to a lack of the PPT1 enzyme, which normally breaks down fatty acids in cells.
  • CLN2 disease is caused by mutations in the TPP1 gene. This leads a lack of the TPP1 enzyme, which normally breaks down protein in cells.
  • CLN3 disease is caused by mutations leading to the production of defective forms of battenin, a protein located in lysosomes. The exact function of battenin is unknown.
  • CLN4 disease is caused by mutations in the DNAJC5 gene. This leads to the production of altered CSPα, a protein involved in recycling other proteins that are crucial in allowing nerve cells to relay information.
  • CLN5 disease is thought to be caused by mutations in genes encoding for proteins that normally play a role in breaking down cell waste; nerve cells appear particularly vulnerable. It is not exactly known which proteins are involved.
  • CLN6 disease is thought to be caused by defects in protein processing and transport.
  • CLN7 disease is caused by mutations in the MFSD8 gene. The exact role of the protein that this gene encodes is not known, but it is thought that it may be involved in transporting molecules into lysosomes for recycling and disposal.
  • CLN8 disease is thought to be caused by defects in proteins that are involved in transporting molecules to a part of a cell known as the endoplasmic reticulum. The endoplasmic reticulum is important in protein production, processing, and transport.
  • CLN9 disease was initially thought to be a separate Batten subtype, but recently it has become clear that this is a variant of CLN5 disease.
  • CLN10 disease is caused by mutations in the CTSD gene. This leads to a lack of the cathepsin D enzyme, which normally works to modify proteins.
  • CLN11 disease is caused by mutations in the GRN gene. This impairs the function of a protein known as progranulin. While the exact function of progranulin is unknown, it is thought to assist lysosome function.
  • CLN12 disease is caused by mutations in the ATP13A2 gene. This gene encodes for an enzyme in the ATPase family, which normally transports inorganic compounds and other molecules.
  • CLN13 disease is caused by mutations in the CTSF gene. This leads to defects in a protein known as cathepsin F, the exact functions of which are unknown, although it is thought to facilitate lysosomal function.
  • CLN14 disease is caused by mutations in the KCTD7 gene. This causes defects in a protein that transports potassium in and out of cells.

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