What is Neuronal Ceroid Lipofuscinosis?

Neuronal Ceroid Lipofuscinosis (NCL) belongs to a group of neurodegenerative disorders where accumulation of lipopigments is seen which is thought to be the main cause of this disorder. Sometimes, due to many reasons, death of neurons or loss of structure and function of neurons take place.1 These conditions are referred to as neurodegenerative disorders which are usually progressive in nature. Let us understand the causes, symptoms, diagnosis and treatment of Neuronal Ceroid Lipofuscinosis.

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Neurons are the basic structural and functional unit of nervous system of humans. It is the longest cell in the human body. It is found that in the first trimester of gestation, the differentiation of neuroepithelial cells takes place and complete neurons are formed. Some stem cells including glial cells form new neurons till 3 – 5 years of age. The other parts of the brain say ventricles, glial tissue; blood vessels continue to grow even after puberty.

What is Neuronal Ceroid Lipofuscinosis?

This would help to form the new neuronal connections. The research is going on whether the stem cells are capable of producing new neurons at all ages particularly in case of any damage caused to the neurons. Well this is a controversial topic at present. One thing is proved from researches that except afferent and efferent neurons, the other neurons usually do not differentiate or regenerate. Usually division or differentiation is done through a process called mitosis which is not possible in case of neurons. Actually, neurons lack centrioles which take a major role in mitosis. Hence there is a need of protecting the already produced neurons. Let us check out the causes, symptoms, and treatment of Neuronal Ceroid Lipofuscinosis.

Causes for Neuronal Ceroid Lipofuscinosis

During lysosomal digestion, some residues are left over sometimes which are rich in lipid and oxidized proteins. These are greenish yellow or yellowish brown pigments which also contain sugars, minerals like mercury, aluminum, iron, copper and zinc. These entities are called lipofuscins. Lipofuscins are produced as a result of oxidation of unsaturated fatty acids. The presence of these lipopigments is known to cause membrane damage which is a typical signal of aging or ‘wear and tear’ process. Lipofuscins are deposited in neurons, ganglia, liver, kidneys, and muscles of heart, adrenals and retina.

The main causes of Neuronal Ceroid Lipofuscinosis (NCL) revolve around the accumulation of lipofuscins in neurons. It is a genetic disorder which is caused mainly because of mutation of eight genes namely CLN1, CLN2, CLN3, CLN5, CLN6, CLN7 CLN8 and CLN10. NCL can be classified into 4 main categories based on the clinical onset of symptoms. They are, INCL (Infantile NCL – also called CLN1 disease), LINCL (Late infantile NCL – also called CLN2 disease), JNCL (juvenile NCL – also called CLN3 disease) and ANCL (Adult NCL).

Symptoms of Neuronal Ceroid Lipofuscinosis

Symptoms of Neuronal Ceroid Lipofuscinosis (NCL) depend upon the extent of accumulation of lipofuscins in the neurons, different forms of lipofuscins, onset of symptoms, duration. Severe intracellular accumulation of lipofuscin causes permanent loss of motor and psychological ability. Eventual death of patients is observed from the records. The following are the different stages with signs and symptoms of NCL depending on the above factors and also the age at which these symptoms appear.

Infantile Neuronal Ceroid Lipofuscunosis. Normal at birth, loss of vision starts and suffers from retinal blindness before reaching 2 years of age, a vegetative stage is reached before 3 years of age, and brain dies by the age of 4 years which can be confirmed by isoelectric encephalograms.

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Late Infantile Neuronal Ceroid Lipofuscunosis. Manifestations such as seizures, deterioration of vision starts between the age of 2 and 4 years, individuals die before reaching the age of 12 years.

Juvenile Neuronal Ceroid Lipofuscunosis. Also called Batten disease or Spielmeyer – Vogt usually starts at the age of 4 to 10 years, manifestations include loss of vision caused by retinal dystrophy, seizures, psychological degenerations, and individuals die between 20 to 30 years of age.

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Adult Neuronal Ceroid Lipofuscunosis. It is also called Kufs disease, symptoms might be mild and start by the age of 30 years and the individuals die before reaching the age of 40 years.

How is Neuronal Ceroid Lipofuscinosis Inherited?

Inheritance of Neuronal Ceroid Lipofuscinosis (NCL) is observed in two ways. It depends upon whether the type is infantile or adult.

In childhood NCLs, it might be autosomal recessive disorders. The sufferers must have two copies of the defective gene from both of their parents. Single copy of defective gene will fail to express the disorder in the child. The individual who is normal but has one defective gene is called just a ‘carrier’ and they can pass onto the next generation.

On the other hand, adult NCL is inherited in two ways. One would be as in case of infantile type, that is autosomal recessive disorders what is seen in case of Kufs syndrome. Here, the inheritance follows the same pattern as explained above. In autosomal dominant disorders, since the defective gene is dominant, only a single copy of it is enough to express the disorder.

Diagnosis of Neuronal Ceroid Lipofuscinosis

Diagnosis of Neuronal Ceroid Lipofuscinosis (NCL) is done by a neurologist depending on several aspects such as medical history, clinical examinations and laboratory tests.

Eye Examination for Diagnosing Neuronal Ceroid Lipofuscunosis. An ophthalmologist identifies the abnormalities in the eye during an eye examination. In most of the patients suffering from Neuronal Ceroid Lipofuscinosis (NCL), there is vision problem which would be the primary sign of the disease. Any abnormalities like degeneration otherwise known as loss of cells is detected during this test. However, loss of cells is observed in other eye diseases also. When ophthalmologists find degeneration in the eye, they direct the patients to a neurologist to confirm whether it is related to any neurological disorder. In case a neurologist confirms any neurological degenerative disease, the ophthalmologist uses a different technique using electrical studies of the eyes. The abnormalities of the eyes can be detected using VER (Visual Evoked Responses) and ERG (Electroretinograms).

Tissue Sampling to Diagnose Neuronal Ceroid Lipofuscunosis. Deposition of lipofuscins can be viewed under a powerful electronic microscope. Tissues from different parts like skin, muscle, conjunctiva, rectum, blood, etc., are taken out for observation. Even the type of NCL could be guessed based on the shape and place where the deposition occurs.

EEG (Electroencephalogram). From this test, doctors are able to detect the seizures based on the patterns of electrical activity of brain. This gives an understating of the nature of seizures, which helps in confirming the diagnosis of Neuronal Ceroid Lipofuscinosis (NCL).

Imaging of Brain for Diagnosing Neuronal Ceroid Lipofuscunosis. Any structural abnormalities of brain can be detected using X-rays and CT – scan (Computed Tomography). Sometimes, for more specification another imaging technique called MRI (Magnetic Resonance Imaging) is also used to take the picture of the brain.

Enzyme Assay to Diagnose Neuronal Ceroid Lipofuscunosis. This is a new technique used to detect the missing lysosomal enzyme. One disadvantage of this technique is that, it can be used only for INCL and LINCL.

Treatment for Neuronal Ceroid Lipofuscinosis

At present, there is no specific treatment for Neuronal Ceroid Lipofuscinosis (NCL) which cures it completely. There are some ways to reduce the symptoms of Neuronal Ceroid Lipofuscinosis (NCL).

Some of the methods used as treatment of Neuronal Ceroid Lipofuscinosis (NCL) include the following,

Antiepileptic drugs are prescribed to control seizures.

Rehabilitation therapies like physical therapy, speech therapy and occupational therapy are also found to be helpful.

Cystagon is suggested for INCL. Cystinosis a rare genetic disease is treated using a drug namely cystagon. From recent researches, it is found that, the same drug is also helpful in treating INCL. Reports say that the stored lipofuscins are completely cleared from white blood cells and/or slowed down the rate of neurodegeneration of INCL.

Some reports give us information about the gene therapies are helpful for LINCL patients.

  • Flupirtine is a painkiller which is found to slow down the neurogeneration in JNCL and LINCL.
  • Stem cell transplantation from fetus is also a new research found out to treat JNCL.
  • Bone marrow transplantation is considered as a promising treatment for Neuronal Ceroid Lipofuscinosis (NCL), which helps to slow down the neurodegeneration in some INCL.
  • In some JNCL patients, progression of neurodegeneration is slowed down by immunosuppressants generally used in bone marrow transplants.

In some LINCL type 2 patients enzyme replacement therapy is found to be helpful.2 The enzyme cerlliponase alfa used in replacement therapies are prepared from recombinant DNA technology.

Conclusion

Neuronal Ceroid Lipofuscinosis is a lysosomal storage disorder. Since this is an autosomal recessive or autosomal dominant disorder, either the individuals are carriers or sufferers. One of the ways either to reduce the prevalence or to reduce the symptoms of Neuronal Ceroid Lipofuscinosis (NCL) is genetic counseling. Genetic counseling can help the individuals to make some important medical and personal decisions. This may involve the parents, patients, siblings and medical professionals. Prenatal testing before pregnancy and family planning are the major topics for discussion during genetic counseling. Also, timely diagnosis and early treatment of symptoms can help in managing the condition to a great extent.

References

  1. https.//www.ncbi.nlm.nih.gov/pubmed/20301601
  2. https.//www.ncbi.nlm.nih.gov/pmc/articles/PMC3983784/
Pramod Kerkar

Written, Edited or Reviewed By:

, MD,FFARCSI

Pain Assist Inc.

Last Modified On: April 16, 2019

This article does not provide medical advice. See disclaimer

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