Clinical Picture
The late infantile neuronal ceroid lipofuscinosis (LINCL) usually starts around the age of three years. The children are completely healthy until this age. Then a delay in psychomotor development may be diagnosed and the children start having seizures. These epileptic seizures typically are very difficult to treat. Since the disease affects the retina of the eye, the patients become visually impaired over time. Most patients are bedridden by the age of 10 years and only few live longer than the age of 15 years.
Disease Mechanism
Late Infantile neuronal ceroid lipofuscinosis (LINCL) is an inherited disease. The mode of inheritance is autosomal recessive. This means that both parents are only carriers of the defective NCL gene. They have a functional NCL gene in addition which keeps them healthy. If a child inherits two defective NCL genes, one from each parent, there will be no functional NCL gene to prevent the disease. This child will develop NCL.
Late infantile NCL occurs worldwide and has an incidence of around 0.46 per 100,000 live births. The most common form of LINCL is caused by a defect or mutation of the CLN2 gene. The CLN2 gene is responsible for the enzyme TPP1 or tripeptidyl peptidase 1. This enzyme works in cell lysosomes. Lysosomes are recycling machines of the cells through which waste is disposed of and cleaned up. If this enzyme does not work properly the waste will accumulate as storage material in all cells of the body. The reason why only neuronal cells are affected by this storage material and die is still unknown. This neuronal death causes the clinical picture of NCL.
Rare cases of late infantile NCL are caused by mutations in other genes. Some of these genes have been identified already; they are called CLN5, CLN6 and CLN8. The function of these genes and why a defect in them causes LINCL remains unknown.
Diagnostics
There are different ways to diagnose late infantile NCL. A specialized physician should decide which diagnostics are necessary in an individual patient. Specialists from the NCL-Clinic at the University Medical Center, Hamburg, Germany, will be happy to discuss which diagnostic methods should be applied (see Contact). They also provide complete facilities for the diagnosis of all forms of NCL.
Measurement of TPP1 Enzyme Activity
TPP1 enzyme activity can be measured, exactly like PPT1, in dry blood spots (blood drops dried on special filter paper), in leucocytes (white blood cells isolated from a blood sample), and in skin fibroblasts (cultured from a skin biopsy). Low or missing enzyme activity verifies the diagnosis of late infantile NCL. But normal enzyme activity does NOT exclude the diagnosis of late infantile NCL since this disease can also be caused by other rare genetic defects as well. .
Mutation Analysis
Identification of the exact defect within a gene is called mutation analysis. A blood sample from the patient and, if possible, from the parents as well, is needed for this.
If TPP1 enzyme activity is low mutation analysis should be performed in the CLN2 gene. If TPP1 enzyme activity is normal the patient might have one of the rare NCL types like CLN6 or CLN8. These genes then have to be analyzed.
Once the defect or so-called mutation within the NCL gene is identified genetic counselling is possible for the affected family, including genetic testing of relatives and the possibility of prenatal diagnostics.
Electronmicroscopy
The NCL-characteristic intracellular storage material can be visualized by electron microscopy. Electron microscopy should be performed either on lymphocytes (blood cells) or on a skin biopsy. The presence of the typical storage material confirms the diagnosis of NCL. The ultrastructure of the storage material helps to identify the NCL type.
Treatment
To date no cure has been developed for late infantile NCL. But it is important to know that symptoms such as epileptic seizures and spasticity, for example, can be relieved by proper medication, thus reducing patient suffering as effectively as possible.Tube feeding might become necessary for advanced cases in patients who have difficulties in swallowing food and liquids.
In experimental gene transfer studies an artificially constructed CLN2 gene virus is injected into the patient's brain. Another experimental therapy study is being planned in which late infantile NCL patients receive a neuronal stem cell transplantion. Other planned studies intend to test the effect of medications that should prevent cell death in the brain.
Juvenile NCL (JNCL / CLN3)
Clinical Picture
Juvenile neuronal ceroid lipofuscinosis (JNCL) usually sets in at around the age of five to seven years. The children are completely healthy until this age. Then they develop visual problems. These visual problems aggravate until the children are blind at about the age of ten years. In addition, their ability to concentrate and their intellectual level decreases, which is reflected by learning problems in school. The children start having seizures and motoric problems. Later on, psychic symptoms such as depression or panic attacks may occur, sometimes with hallucinations. Despite these multiple problems most patients reach the age of 30 years and older.
Disease Mechanism
Juvenile neuronal ceroid lipofuscinosis (JNCL) is an inherited disease. The mode of inheritance is autosomal-recessive. This means that both parents are only carriers of the defective NCL gene. They have a functional NCL gene in addition which keeps them healthy. If a child inherits two defective NCL genes, one from each parent, there will be no functional NCL gene to prevent the disease. This child will develop NCL.
Juvenile NCL occurs worldwide and is the second most common form of NCL after late infantile NCL. The highest incidence of 7 per 100,000 live births was reported in Iceland.
JNCL is mostly caused by a defect or mutation in the CLN3-gene. The CLN3-gene leads to a membrane protein of unknown function. The genetic defect leads to accumulation of storage material in all cells of the body. Why only neuronal cells are affected by this storage material and die is still unknown. This neuronal death causes the clinical picture of NCL.
Diagnostics
There are different ways to diagnose juvenile NCL. A specialized physician should decide which diagnostics are necessary.Specialists from the NCL Clinic at the University Medical Center, Hamburg, Germany, will be happy to discuss which diagnostic procedures should be carried out (see Contact). They also provide complete facilities for the diagnosis of all forms of NCL.
Vacuolized Lymphocytes in a Blood Smear
Juvenile NCL can be simply diagnosed by examining a patient's blood smear under light microscopy. Presence of vacuolized lymphocytes in a blood smear confirms the diagnosis of JNCL. Lymphocyte vacuoles are caused by the NCL storage material in the cell.
Mutation Analysis
Juvenile NCL can be caused by defects in different genes. Most frequently the CLN3 gene is effected, other genes are CLN1, CLN8. CLN9 and CLN10.
Identification of the exact defect within a gene is called mutation analysis. A blood sample from the patient and, if possible, from the parents as well is needed for this.
Once the defect or so-called mutation within the NCL-gene is identified genetic counselling is possible for the affected family including genetic testing of relatives and the possibility of prenatal diagnostics.
Electronmicroscopy
Intracellular storage material that is characteristic for NCL can be visualized by electron microscopy. Electron microscopy should be performed either on lymphocytes (blood cells) or on a skin biopsy. The presence of typical storage material confirms the diagnosis of NCL. The ultrastructure of the storage material helps to identify the NCL type. Storage material in JNCL patients usually has the structure of fingerprint profiles or curvilinear bodies.
Treatment
To date no cure has been developed for juvenile NCL. But it is important to know that typical symptoms such as epileptic seizures and spasticity, can be treated by proper medication in order to relieve patient suffering. Patients with JNCL live longer than most other NCL patients, meaning that long term special care and education is very important for them. These children and adolescents are very conscious of their condition and they bereave loss of their once obtained skills. This frequently results in depression that should be psychiatrically evaluated and treated, if necessary. Children who suffer panic attacks and hallucinations also need special psychiatric help. Activities such as horse riding, swimming or a tandem bicycle riding have proven to be greatly beneficial for these patients. For advanced cases tube feeding might become necessary when swallowing foods and liquids becomes difficult.
Experimental therapy studies are planned that should test the effect of medications in order to prevent cell death in the brain. Other experimental therapies are being tested in animals. Since the function of the involved genes is still unknown there is a great amount of research to be done until new therapeutic approaches can be developed.
NCL-Literature for Patients and Parents
To be published soon
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