Information for Parents and Patients


 

Neuronal Ceroid Lipofuscinoses

The neuronal ceroid lipofuscinoses (NCL) are the most common neurodegenerative diseases in childhood and adolescence. They have an incidence of about 1:30,000 live births. NCL consists of a group of diseases with similar symptoms: Most patients have dementia. Most patients have epileptic seizures that are difficult to treat. Over a period of time most patients become blind.

The different types of NCL can be distinguished according to the age of the patient at onset: Infantile NCL starts in the first year of life, children with late infantile NCL show the first symptoms around the age of three, and juvenile NCL begins at the age of 5-7 years. All NCL-forms have a "wax-like" storage material (Ceroid Lipofuscin) in common that accumulates in all tissues of the body. But only the neuronal cells get clogged and even die because of this storage material. The reason for this process is unknown so far.

The NCL diseases are inherited in an autosomal recessive mode. This means that both parents have both a functional and a defective NCL gene. The parents are so-called "carriers". The healthy gene secures that the parents do not have the NCL disease. If both parents are carriers of the same defective NCL gene, their children have a 25% risk of being affected by NCL. NCL patients inherit two defective NCL genes, one from each of their parents. They do not have a functional NCL gene to keep them healthy, so they develop the disease.

Different NCL types are caused by defects (mutations) in different NCL genes. Why and how these genetic defects cause the disease is still being researched. NCL research is a necessary precondition to develop treatment options. To date there is no cure for NCL. Some experimental therapies are now being tested (to date only on animals). You will find further information about experimental therapies in the following sections about the different forms of NCL.


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Infantile NCL (INCL / CLN1)

Clinical Picture

The age at onset of infantile neuronal ceroid lipofuscinosis (INCL) is usually around the end of the first year of life. The children are completely healthy during the earlier months of life. When NCL first sets in a delay in psychomotor development can be diagnosed. At the age of about two years the psychomotor development stops completely or even regresses. Children tend to forget the skills they previously mastered. They become microcephalic (the head stays small) and they develop seizures. The visual function often begins to fail. Children can no longer establish eye contact once the retina is affected by the disease. They first develop muscular hypotonia and later on muscular spasticity. Most patients become bedridden within two to three years and may die by the age of 5-10 years.

 

Disease Mechanism

Infantile neuronal ceroid-lipofuscinosis (INCL) 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.

Infantile NCL (INCL) is observed worldwide but is distinctly more prevalent in Finland.

The most common form of INCL is caused by a defect or mutation in the CLN1 gene. Sometimes mutations in the CLN1 gene can cause a late infantile, juvenile or even adult onset of disease.. The CLN1 gene codes for the enzyme palmitoyl protein thioesterase 1 (PPT1). This enzyme works in cell lysosomes. Lysosomes are the cells' recycling machines where 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 INCL.

 

Diagnostics

There are different ways to diagnose infantile NCL. A specialized physician should decide which diagnostics are necessary in an individual patient. Specialists from the NCL Clinic at the University Medical Centre Hamburg, Germany, will be happy to discuss which diagnostic method should be applied for an individual patient (see Contact). They also provide complete facilities for the diagnosis of all forms of NCL.

 

Measurement of PPT1 Enzyme Activity

PPT1 enzyme activity can be measured 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 (cultures from a skin biopsy). Low or missing enzyme activity confirms the diagnosis of infantile NCL.

 

Mutation Analysis

Identification of the exact defect within the CLN1 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 CLN1 gene is identified genetic counselling is possible for the affected family, including genetic testing of relatives and the possibility of prenatal diagnostics.

 

Electronmicroscopy

The 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 the typical storage material confirms the diagnosis of NCL. The ultrastructure of the storage material helps to identify the NCL type. In infantile NCL, for example, inclusion bodies typically have a granular structure.

 

Treatment

To date no cure has been developed for rapidly progressing infantile NCL. But it is important to know that symptoms such as epileptic seizures and spasticity can be relieved through proper medication, thus effectively reducing patient suffering.

Tube feeding might become necessary for advanced cases in patients who have difficulties in swallowing food and liquids.

In experimental therapy studies substances with effects similar to the enzyme PPT1 are administered. Another experimental therapy study is being planned in which neuronal stem cells will be transplanted in infantile NCL patients.


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Late Infantile NCL (LINCL / CLN2)

 

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.


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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.


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NCL-Literature for Patients and Parents

To be published soon

 

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