Adult neuronal ceroid lipofuscinosis (ANCL) is a general term for several rare genetic disorders that belong to a group of progressive, degenerative neurometabolic disorders known as the neuronal ceroid lipofuscinoses (NCLs). These disorders share certain similar symptoms and are distinguished in part by the age at which such symptoms appear. The onset of ANCL is usually around the age of 30, but these disorders can occur during the teen-aged years or in people more than 50 years old. The NCLs as a group are characterized by abnormal accumulation of certain fatty, granular substances (i.e., pigmented lipids [lipopigments] ceroid and lipofuscin) within nerve cells (neurons) of the brain as well as other tissues of the body. This is accompanied by progressive deterioration (atrophy) of certain areas of the brain, neurological impairment, and other characteristic symptoms and physical findings. ANCL is sometimes called Kufs disease. Historically, Kufs disease was broken down into type A or type B. The ACLs are caused by changes (mutations) in different genes and can have different signs and symptoms.
Adult-onset neuronal ceroid lipofuscinoses (ANCL, Kufs disease) are rare hereditary neuropsychiatric disorders characterized by intralysosomal accumulation of ceroids in tissues. The ceroid accumulation primarily affects the brain, leading to neuronal loss and progressive neurodegeneration.
Before the identification of the underlying genes, the neuronal ceroid lipofuscinoses or NCLs were broken down by age of onset. Kufs disease was the name for the adult-onset form. However, many researchers now feel that it is more appropriate to classify these disorders based upon the gene that is affected rather than by age of onset. Several genes that are known to cause neuronal ceroid lipofuscinoses can have the onset of symptoms in adulthood.
Types
Type A and Type B Kufs disease are caused by mutations in two sets of different genes. Both gene sets are responsible for producing proteins and enzymes that are heavily involved in protein degradation and excretion in the cell – specifically, the nerve cell.
Type A
Mutations to the CLN6 and PPT1 genes result in Kufs disease Type-A.[rx] CLN6 produces proteins that facilitate fat transport throughout a cell, as well as excretion out of the cell. The PPT1 gene codes for the enzyme palmitoyl-protein thioesterase-1. This enzyme is responsible for removing the fatty-acid side chains off of proteins that have been translocated into the lysozyme. By removing the surrounding fats, palmitoyl-protein thioesterase-1 creates easier access for other enzymes to break down the rest of the protein. Fatty substance builds up in the brain is a consequence of the mutated genes. The fats and proteins that build up are called lip pigments. Eventually, the buildup of lip pigments results in the death of the neuron cells, giving way to the phenotypic symptoms. Type A is an autosomal recessive disease, indicating that it is inherited from the parents. Each parent must carry one copy of the mutation; however, the recessive designation indicates that with only one copy, the parents are not affected, and do not show any symptoms.
Type B
Kufs disease Type B is caused by mutations to the DNAJC5 and CTSF genes.[rx] This form of Kufs is autosomal dominant, meaning that only one copy of each mutated gene is enough for the disease to manifest. When there is a mutation in the DNAJC5 gene, it affects the production of a cysteine string protein (CSP) that is coded within DNAJC5.[rx] CSP aids in transmitting signals through the nerves found in the brain. When the CTSF gene is mutated, it cannot produce Cathepsin F an enzyme that cuts proteins in the lysozyme.[rx] By cutting proteins, Cathepsin F can modify the function of the proteins, as well as help, break them down. Similar to Type A, when both DNAJC5 and CTSF are non-functional, it results in the incomplete breakdown of proteins. Once again, lip pigments build-up and brain function is decreased as the neuron cells die
Causes
Changes (mutations) in several different genes can cause adult neuronal ceroid lipofuscinosis. These include the CLN6 gene for type A and the CTSF gene for type B. There are also people with adult-onset of neuronal ceroid lipofuscinosis due to changes in the PPT1 gene, the CLN5 gene, the CTSD gene, and the GRN gene. Adult-onset disease that affects vision or the heart is caused by changes in the CLN3 gene and the MFSD8 gene. Some very specific changes in the DNAJC5 gene can also cause adult-onset neuronal ceroid lipofuscinoses.
Most types of ANCL are inherited in an autosomal recessive manner. These types of diseases appear in adults whose parents were not affected by the same disease. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier of the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
One type of ANCL caused by specific alterations in the DNAJC5 gene is inherited in an autosomal dominant manner (Parry disease). This type of disease is passed down from an affected adult to their children, who have a 1 in 2 chance of being affected. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
The genes that cause ANCL to produce proteins. These proteins have specific roles in the body, including breaking down proteins and other substances in the body. When a gene is altered, the protein it produces is deficient, absent, or ineffective. The missing or abnormal protein can interfere with the breakdown of certain fatty, granular substances called pigmented lipids (lip pigments: ceroid and lipofuscin). These materials accumulate within nerve cells (neurons) of the brain as well as other tissues of the body and their presence can be used to help obtain a diagnosis. The faulty protein can result in progressive deterioration (atrophy) of certain areas of the brain, neurological impairment, and other characteristic symptoms and physical findings.
Diagnosis
A diagnosis of adult neuronal ceroid lipofuscinosis is based upon the identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. The tests used may be different based on the specific subtype of ANCL. These tests can include enzyme assays, the study of affected tissue under an electron microscope, and molecular genetic testing to identify changes in genes that can cause disease.
Clinical Testing and Workup
Enzymes assays are tests that measure the activity of specific enzymes. In some types of ANCL, reduced enzyme activity can be demonstrated on an assay. For example, ANCL caused by the CTSF gene will show the reduced activity of cathepsin F, the enzyme produced by the CTSF gene, on an enzyme assay.
Some types of ANCL require that affected tissue is surgically removed and studied under an electron microscope. This can show the buildup of storage material within the affected tissue.
Molecular genetic testing or gene sequencing can confirm a diagnosis of ANCL. The aim is to detect mutations in specific genes known to cause the various subtypes.
These tests are available only at specialized laboratories.
Treatment
The treatment of adult neuronal ceroid lipofuscinosis is directed toward the specific symptoms that are apparent in each individual. There are no disease-specific treatments for ANCL yet. Treatment may require the coordinated efforts of a team of specialists. General internists, metabolic geneticists, neurologists, psychiatrists, and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support for the entire family is essential.
Genetic counseling is recommended for affected individuals and their families.
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