Neuronal Ceroid Lipofuscinoses - Diagnosis, Treatment, and Prognosis

Introduction:

Neuronal ceroid lipofuscinoses are the most commonly occuring lysosomal storage disorder. Neuronal ceroid lipofuscinoses is an inherited disorder. It is a rare neurological disorder and shows both autosomal dominant and recessive types of inheritance. If the symptoms of this disease show up early in childhood, the outcome is more severe with more complications. The adult form of this disease is less fatal. The condition is characterized by seizures, memory loss, and vision problems.

How Is Neuronal Ceroid Lipofuscinosis Inherited?

Each cell consists of DNA (deoxyribonucleic acid). DNA is present in the nucleus of the cell. It is made of chromosomes. The DNA molecules are tightly packed or coiled in a thread-like pattern known as the chromosome. DNA consists of genetic information related to the growth and development of the individual. Genes are present on the chromosomes, carrying this information for every individual.

This disease can be passed on from parents to children in two ways -

1. Autosomal Dominant Pattern of Inheritance - In this pattern, one of the parents has the abnormal gene responsible for causing the disease in the children. One of the parents is also affected by this disorder. There is a 50 percent chance (two in four) of children being affected by this disease.

2. Autosomal Recessive Pattern of Inheritance - Both parents are carriers of the abnormal gene, but none have the disease. They have an abnormal gene present in their DNA that causes the disease. There is a 25 percent chance (one in four) that the children of the carrier parents may be affected.

What Is Lipofuscin?

Lipofuscin is a yellow-brown pigment granules made up of fats and proteins, and ceroids are autofluorescent pigmented lipids (fluorescence emission when specific cells are exposed to UV-ultraviolet light or radiation) found in the lysosomes of cells. Abnormal accumulation of these pigments in the lysosomes is seen in neurodegenerative disorders. Accumulating this intracellular autofluorescent material is a part of the normal aging process, which is why it is also known as the aging pigment. This material builds up in the neuronal cells and other organs such as the liver, kidney, and spleen.

What Are Lysosomal Storage Disorders?

A group of disorders known as lysosomal storage disorders result from an abnormal buildup of toxic materials in the cells. The abnormal buildup is due to a deficiency of enzymes that inhibits the ability of lysosomes to function correctly. Lysosomes are cells' macrophages; their job is to break down complex substances into simpler forms.

What Are the Common Symptoms of These Disorders?

1. Muscle spasms (involuntary contraction and painful tightening of the muscles).

2. Blindness or vision problems.

3. Dementia (memory loss and other cognitive deterioration).

4. Lack of muscle coordination.

5. Intellectual disability (problems with thinking capabilities, mental confusion, and forgetfulness).

6. Movement disorder (difficulty with balance and coordination leading to an unsteady walk).

7. Loss of speech.

8. Seizures (sudden uncontrolled movements accompanied by loss of consciousness).

What Diseases Come Under This Disorder?

This disease is classified into three types based on the age of occurrence -

A) Adult form of the disease known as Kuf's or Parry disease.

B) Juvenile disease called Batten disease.

C) Late infantile Jansky-Bielschowsky disease.

1. Kufs or Parry disease.

• It is the primary adult form of neuronal ceroid lipofuscinoses.

• Mutations in the CLN6 (ceroid-lipofuscinosis neuronal protein 6) gene cause this disease. The CLN6 gene is responsible for giving instructions to make the CLN6 protein.

• The function of the CLN6 protein is to regulate the transport of specific proteins and fats from the endoplasmic reticulum to the lysosomes (the endoplasmic reticulum is a cell organelle involved in protein processing and transportation).

• The lysosomes then break down this protein and fat into simpler substances. Neuronal ceroid lipofuscinosis affects the ability of the lysosomes to function correctly.

• Abnormal accumulation of lipoproteins (ceroid and lipofuscin) in the neuronal cells of the brain and other organs.

• This disease differs from other forms of neuronal ceroid lipofuscinoses as it does not involve the retina, so vision is not hampered in this disease.

What are The symptoms of Kuf disease?

1. Myoclonic Seizures: A severe form of epilepsy that includes involuntary jerking of muscles or a group of muscles.

2. Ataxia: It is a group of disorders affecting voluntary actions like walking, balancing, and coordination.

3. Dysarthria: The patient also experiences difficulty in speech.

How to Diagnose Kuf Disease?

1. Brain biopsy (removal of affected tissue for examination) is a complex and invasive procedure because the lipid pigments are mainly accumulated in the neurons of the brain, which require a brain biopsy to be examined and obtain a final diagnosis.

2. Molecular genetic testing is another way to diagnose this condition, as this helps in identifying mutations in the genes causing this disease.

How Is Kuf's Disease Treated?

Supportive care is essential in managing this disease, and the primary focus of the healthcare provider is to relieve the patient from the symptoms.

Batten Disease:

• This disease commonly occurs in infants, children, and teenagers. It is caused by an abnormal accumulation of toxic substances inside the cell.

• Failure of lysosomal activity is the main reason for this abnormal buildup of lipids in the cells.

• Children with batten disease grow and develop normally in the initial years of life. But as they grow older, they show a significant cognitive decline.

What Are the Symptoms of Batten Disease?

1. Vision loss.

2. Seizures.

3. Speech delay, problems in speaking like stuttering or stammering, and repeating phrases.

4. Patients experience difficulties with coordination, balance, and movement.

How Is Batten Disease Diagnosed?

• DNA (deoxyribonucleic acid) Testing - It is the only reliable option for confirming the diagnosis of batten disease. DNA testing helps identify the mutations in the genes (changes in structure).

• Tissue Biopsy - A sample of tissue is taken from the skin. The biopsy will show large amounts of the pigment lipofuscin (yellow or brown deposits of fat) accumulated in the skin and other body tissues.

• Electroretinography - This test measures how the retina responds to light. The retina is a layer of cells on the back wall inside the eye. This layer is sensitive to light. It receives information and sends signals to the brain.

How Is Batten's Disease Treated?

• There is no cure for this disease. The treatment is mainly symptomatic.

• Physical therapy is indicated to minimize muscle rigidity and spasms.

• Anti-epileptic medication is required to control seizures.

• Support for patients with a physical disability.

Jansky-Bielschowsky Disease

A late infantile neuronal ceroid lipofuscinosis appears around two to four. The disease is characterized by -

• Loss of all motor and mental capacities before the kid starts school.

• Seizures.

• Progressive encephalopathy.

• Failure of vision.

• Motor abnormalities.

How Is Jansky-Bielschowsky Disease Diagnosed?

The diagnosis of this disease is similar to other neuronal ceroid lipofuscinosis disorders, and the following tests are carried out to diagnose this disease-

• Enzymatic Testing - This is done to test if there is a deficiency of enzymes that cause this disease in patients with mutations in their genes. The enzymes are palmitoyl-protein thioesterase 1 (PPT1), tripeptidyl-peptidase 1 (TPP1), and cathepsin D (CTSD).

• Skin Biopsy - Affected tissues are examined under an electron microscope, and an abnormal accumulation of lip pigments can be seen.

• Molecular Genetic Testing helps identify rare mutations in the genes that cause this disease. This test confirms the diagnosis.

What Are the Treatment Options for Jansky-Bielchowsky's Disease?

Management of this disease involves-

• Treatment of symptoms, such as administering anti-epileptic medications to control seizures.

• Physical therapy for relieving muscle spasms and rigidity.

• Support from family and healthcare providers.

What Is the Prognosis of This Disease?

The prognosis of these disorders is very poor. Children may become disabled by the age of 10 to 15. Most children do not survive until adulthood. There are promising treatment options that may be available in the future, like improved medications, stem cell therapy, and gene-replacement therapy. But until then, symptomatic care remains the only option to treat these disorders.

Conclusion:

The diagnosis of these disorders is challenging as it requires invasive procedures to be carried out. Patient history and symptoms need to be recorded carefully to diagnose this disease. The treatment is palliative care and support from healthcare providers. Treating symptoms is the only way the patient can lead daily life. Patient education is essential regarding adopting methods to improve daily life. Genetic counseling is recommended for affected individuals and their families.