NORD gratefully acknowledges Sandra Hofmann, MD, PhD, Professor, Internal Medicine, Molecular Genetics, University of Texas Southwestern Medical Center, for assistance in the preparation of this report.
Classic infantile CLN1 disease is a rare genetic disorder with an onset of symptoms between 6 and 24 months of age. CLN1 disease is characterized by delays in reaching developmental milestones (developmental delays), twitching or jerking of muscles (myoclonic jerks), seizures, and mild to moderate intellectual disability. As children age, the psychomotor abilities (abilities that require coordination of muscular and mental activity) will deteriorate. Progressive vision loss leading to blindness can also occur. The severe form of CLN1 disease is often fatal during childhood. However, some children do not become ill until later because their genetic defect does not completely abolish the function of the gene and their disease can appear very much like juvenile CLN3 disease.
Classic infantile CLN1 disease belongs 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. Classic infantile CLN1 disease was previously called infantile neuronal ceroid lipofuscinosis or Santavuori disease. The NCLs 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 that may result in progressive deterioration (atrophy) of certain areas of the brain, neurological impairment, and other characteristic symptoms and physical findings.
The neuronal ceroid lipofuscinoses are further classified as lysosomal storage diseases. Lysosomal storage diseases are inherited metabolic diseases that are characterized by an abnormal build-up of various toxic materials in the body’s cells because of enzyme deficiencies. There are more than 50 of these disorders altogether, and they may affect different parts of the body, including the skeleton, brain, skin, heart, and central nervous system. New lysosomal storage disorders continue to be identified. While clinical trials are in progress on possible treatments for some of these diseases, there is currently no approved treatment for many lysosomal storage diseases.
The signs and symptoms of classic infantile CLN1 disease usually become apparent between 2 and 24 months of age. Infants will develop normally initially, but then become to regress. Their mental and motor development levels off and then begins to decline. Many infants are never able to speak or walk. However, some children do not become ill until later because they still have residual enzyme activity.
Initial symptoms can include signs of intellectual and motor decline including delays in reaching developmental milestones (developmental delays), twitching or jerking of muscles (myoclonic jerks), and seizures. Infants may fail to gain weight and grow as the expected rate (failure to thrive) and may have diminished muscle tone (hypotonia). They may be restless, irritable and have difficulty sleeping through the night. Some infants exhibit microcephaly, a condition that indicates that a child’s head circumference is smaller than would otherwise be expected based on age and gender. Affected infants and children may also exhibit rhythmic, repetitive, predictable movements of their hands called hand stereotypies.
As children age, the psychomotor abilities (abilities that require coordination of muscular and mental activity) will deteriorate. Infants and children may lose interest in playing. Mild to moderate intellectual disability may be present. Some children will develop spasticity, where the muscles become tight and stiff and difficult to move and sometimes painful. Progressive vision loss leading to blindness can also occur.
In infants and children with the severe form, the disorder is often fatal anywhere between the ages of 2 to 9.
Classic infantile CLN1 disease is caused by an alteration in the PPT1 gene (designated CLN1). 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.
The PPT1 gene contains instructions for creating the enzyme palmitoyl-protein thioesterase 1. This enzyme is essential for the proper function of lysosomes. Lysosomes are the primary digestive units within cells. Enzymes within lysosomes break down or “digest” nutrients, such as fats and carbohydrates. In the lysosomal storage disorders, deficiency or improper functioning of particular lysosomal enzymes may lead to an abnormal accumulation of certain complex compounds consisting of fatty materials and/or carbohydrates within the cells of particular tissues of the body. Researchers suspect that classic infantile CLN1 disease is caused by alterations within the cell so that the body is unable to break down and recycle substances such as fats, and their associated sugars and proteins in the normal way in lysosomes. Some of these fats, sugars, and proteins then appear to form the lipopigments that accumulate in nerve and other tissue alongside the symptoms associated with this disorder. Although these substances accumulate in most cells, brain cells are affected first.
The gene alterations that cause classic infantile CLN1 disease are 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.
Classic infantile CLN1 disease affects males and females in equal numbers. In the United States, classic infantile CLN1 disease along with other forms of neuronal ceroid lipofuscinosis occurs in approximately three in 100,000 live births. Classic infantile CLN1 disease occurs with greater frequency in Finland where its prevalence is estimated to be 1 in 190,000.
A diagnosis of classic infantile CLN1 disease may be based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic physical findings, and a variety of specialized tests including enzyme assays and molecular genetic testing.
Clinical Testing and Workup
An enzyme assay is a test that measures the activity of a specific enzyme. For infantile CLN1 disease, doctors will look for the activity of the enzyme palmitoyl-protein thioesterase 1 in white blood cells (leukocytes), a dried blood sample, or cultured fibroblasts. Cultured fibroblasts are connective tissue cells obtained from a skin sample and grown in a laboratory.
Molecular genetic testing can confirm a diagnosis of classic infantile CLN1 disease. Molecular genetic testing looks for alterations (mutations) in the PPT1 gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories.
In some instances, diagnosis may require the microscopic examination (i.e., electron microscopy) and study of the chemical components (histochemical examination) of samples of tissue (biopsy), usually from the skin. The study of such tissue samples reveals abnormal accumulations of deposits (i.e., pigmented lipids [lipopigments] ceroid and lipofuscin) in membrane-bound cavities within the body (cytoplasm) of cells (inclusion bodies).
The treatment of classic infantile CLN1 disease is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, specialists who diagnose and treat eye disorders (ophthalmologists), specialists who diagnose and treat disorders of the central nervous system (neurologists), speech pathologists, a medical geneticist, a psychiatrist and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Psychosocial support for the entire family is essential as well. Genetic counseling is of benefit for affected individuals and their families.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with neuronal ceroid lipofuscinosis.
Specific therapies for affected infants includes anti-seizure medications called anti-convulsants and medications that relax the muscles to treat spasticity. Specific medications may be used to treat anxiety and sleep disorders. Myoclonus can be treated by medications called diazepines or valproate. Pain medications including opioids and transdermal fentanyl patches have been recommended. Affected children may benefit from occupational, physical, and speech therapy. Additional medical, social, and/or vocation services including special remedial education may be necessary.
Some affected infants may require the insertion of a tube through a small opening in the stomach (gastronomy tube) to ensure they receive sufficient food and nutrition.
There are several different therapies under investigation for the treatment of neuronal ceroid lipofuscinosis including classic infantile CLN1 disease. These therapies include gene therapy, enzyme replacement therapy, hematopoietic stem cell transplantation, and several medications.
Gene therapy is also being studied as another approach to therapy for individuals with classic infantile CLN1 disease. In gene therapy, the defective gene present in a patient is replaced with a normal gene to enable the produce of the active enzyme and prevent the development and progression of the disease in question. Given the permanent transfer of the normal gene, which is able to produce active enzyme at all sites of disease, this form of therapy is theoretically most likely to lead to a “cure.” However, at this time, there remain some technical difficulties to resolve before gene therapy can be advocated as a viable alternative approach.
Researchers have been studying enzyme replacement therapy for lysosomal storage diseases such as classic infantile CLN1 disease. Enzyme replacement therapy involves replacing a missing enzyme in individuals who are deficient or lack a specific enzyme. Synthetic versions of missing enzymes have been developed and used to treat individuals with certain lysosomal diseases including Hurler syndrome, Fabry syndrome and Gaucher disease.
Hematopoietic stem cell transplantation (HSCT) has been used to treat lysosomal storage disorders like classic infantile CLN1 disease. Hematopoietic stem cells are specialized cells found in the bone marrow (the soft spongy material found in long bones). These blood stem cells grow and eventually develop into one of the three main types of blood cells– red blood cells, white blood cells or platelets. A transplant is done to replace the bone marrow (and consequently the whole blood system) of an affected individual with marrow from a person who does not have a particular disorder. The healthy cells produced by the new marrow contain sufficient levels of lysosomal acid lipase required to breakdown cholesterol and triglycerides. Hematopoietic stem cell transplantation has not been effective in treating classic infantile CLN1 diseases and the procedure is not without drawbacks. The procedure is expensive and carries the risk of serious complications including graft-versus-host disease and other long-term and late effects.
Neural (or neuronal) stem cell transplantation is also being explored for the treatment of classic infantile CLN1 disease. In this procedure, stem cells are obtained from the central nervous system and then cultured, purified and saved. A phase one clinical was conducted to test this treatment. Further studies are required to determine the long-term safety and effectiveness of this new treatment option.
Several medications have been tried to treat children with classic infantile CLN1 disease including cysteamine, and various anti-inflammatory medications. More research is necessary to determine the long-term safety and effectiveness of these medications as treatments for classic infantile CLN1 disease.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
For information about clinical trials sponsored by private sources, in the main, contact:www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., seizures, visual impairment, etc.].)
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