NORD gratefully acknowledges Sara E. Mole, PhD, MRC Laboratory for Molecular Cell Biology, University College London, for assistance in the preparation of this report.
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. 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 ANCLs are caused by changes (mutations) in different genes and can have different signs and symptoms.
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.
ANCL or Kufs disease was generally broken down into Type A and Type B. The signs and symptoms of these two subtypes often overlap and the distinction between the two is not always clear. Symptoms typically become worse over time. Generally, Type A is associated with progressive myoclonic epilepsy (PME). PME is a condition characterized by both muscle contractions (myoclonus) and seizures (epilepsy). Some individuals experience difficulties in coordinating voluntary movements (ataxia) or difficulty speaking (dysarthria).
Type B often has similar symptoms to Type A. However, individuals may also experience abnormalities of movement and coordination including ataxia and involuntary movements such as tics or tremors, including those affecting the face (facial dyskinesia). Some individuals develop a decline in intellectual and cognitive ability (dementia) and changes in behavior and other psychiatric abnormalities. Seizures are rare in Type B, but can occur.
Adult neuronal ceroid lipofuscinosis is caused by changes (mutations) in one several different genes, including CLN6 gene or the PPT1 gene for Type A and the DNAJC5 gene or the CTSF gene for type B. There are also people with adult onset of neuronal ceroid lipofuscinosis due to changes in the CTSD, the GRN, the CLN3, and the CLN5 genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.
ANCL caused by alterations in the CLN6, CTSF or PPT1 genes is inherited in an autosomal recessive manner. 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 for 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.
ANCL caused by alterations in the DNAJC5 gene is inherited in an autosomal dominant manner. 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 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. Because of the missing protein, people with ANCL cannot break down certain fatty, granular substances called pigmented lipids (lipopigments) 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.
Adult neuronal ceroid lipofuscinoses are extremely rare disorders. The prevalence is estimated to be about 1.5 people per 9,000,000 in the general population. Prevalence is the total numbers of individuals with a disease at a given time. Studies into the incidence of ANCL have varied based on the country conducting the study. Estimates range from 1.5-7 infants per 100,000 live births. Incidence is the number of new people born with a disorder in a given year.
A diagnosis of adult neuronal ceroid lipofuscinosis is based upon 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.
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 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 can confirm a diagnosis of ANCL. Molecular genetic testing can detect mutations in specific genes known to cause the various subtypes, but is available only as a diagnostic service at specialized laboratories.
The treatment of adult neuronal ceroid lipofuscinosis is directed toward the specific symptoms that are apparent in each individual. 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.
There are no disease-specific treatments for ANCL yet. Treatments are palliative and are based on the specific symptoms that are present. Psychosocial support for the entire family is essential as well. Genetic counseling may be of benefit for affected individuals and their families.
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