Do you know anyone with Batten disease? If you don’t, that is not surprising. It is fortunately relatively rare. Unfortunately, those who do have Batten disease suffer greatly from its effects. Their quality of life is greatly diminished and their life is cut tragically short. If you ever wondered what Batten disease is and what effects it has on a person, you can find all the information you need below.

What is batten disease?

Batten disease or neuronal ceroid lipofuscinoses (NCLs) are a group of fatal illnesses which primarily affect the nerve cells of the brain and the spinal cord. It is most prevalent in infants and is seen approximately once in every 100,000 births worldwide.¹ 

Batten disease is caused by changes (mutations) in certain genes. These gene mutations lead to the dysfunction of certain cell types and also to the accumulation of compounds in the nerve cells of the brain and spinal cord. All of these processes result in the destruction of nerve cells.

Losing this many brain and spinal cord nerve cells has catastrophic effects on the affected individual. It leads to often severely impaired mental abilities, lack of movement control and ultimately death at an early age.¹

Subtypes of Batten disease

There are 13 types of  Batten disease or neuronal ceroid lipofuscinoses (NCLs). These subtypes are numbered from CLN1 to CLN8 and then from CLN10 to CLN14.¹ 

Batten disease is caused by certain mutations in certain genes. Each Batten disease subtype has its own characteristic gene that is affected by mutations, resulting in Batten disease of the corresponding subtype. For example, CLN1 Batten disease is caused by mutations of the PPT1 gene while CLN5 Batten disease is the result of mutations in a gene of the same name ( the CLN5 gene). Since there are 13 subtypes of Batten disease, there are 13 different genes whose mutated forms cause Batten disease.¹

Absence of a CLN9 subtype

CLN9 was removed as a subtype in 2012 because it e was found to be caused by mutations in the CLN5 gene, just like the former CLN5 Batten disease. As a result, the former CLN5 and CLN9 subtypes were categorised together to form the new CLN5 subtype, whilst the CLN9 subtype was removed.^1,2 

Origin of batten disease

The gene mutations causing Batten disease are not acquired over one’s lifetime. Instead, they are inherited from the biological parents, so are present from the moment of conception.¹

Illnesses, where two defective versions of a gene need to be inherited for them to occur, are called recessive. Additionally, the affected genes of Batten disease are found on the non-sex chromosomes ( autosomal). Therefore, all subtypes of Batten disease are classified as autosomal recessive with the exception of CLN4 and CLN6.^1,2 

This means that both biological parents are unaffected, but are able to pass it on to their offspring. We have two versions of each gene, called alleles. One allele is inherited from each biological parent. For almost all of the Batten disease subtypes, both inherited alleles of the corresponding gene need to have the mutations for an infant to develop Batten disease. If an infant inherits both alleles, there is a 1 in 4 chance they will develop the disease. For example, CLN2 Batten disease only occurs if the affected person receives mutated versions of the TPP1 gene from both biological parents.

CLN4 Batten disease only requires one of the two inherited versions of the DNAJC5 gene to be dysfunctional for the disease to manifest. This is referred to as dominant. Since the DNAJC5 gene is also located on the non-sex chromosomes  (autosomal), CLN4 Batten disease is referred to as an autosomal dominant illness.² In contrast, CLN6 Batten disease can be either autosomal recessive or autosomal dominant.¹

Consequences of batten disease gene mutations

The 13 different genes give rise to 13 different proteins; each with a different function. Despite their different functions, all of these proteins affect the same part of the human cell,  the lysosome. That is why all 13 different gene mutations can cause illnesses with similar characteristics. This family of similar illnesses is collectively known as neuronal ceroid lipofuscinoses (NCLs) or Batten disease.³

The lysosome is considered the garbage disposal of the cell, digesting and degrading waste products from the cell, but it also has other important functions. Lysosome impairment due to faulty proteins will alter the behaviour of more resilient cell types and impair more vulnerable cell types (e.g. nerve cells). It also leads to the accumulation of a compound known as ceroid in the lysosomes of the nerve cells of the brain and spinal cord. Ceroid, also called autofluorescent storage material (AFSM or ASM), is a mix of different proteins and fats.³ 

This causes the continuous loss of brain and spinal cord nerve cells and disruption of synapses (the connection between different nerve cells or between a nerve cell and a different type of cell). This results in the severe signs and symptoms of Batten disease, which unfortunately will lead to death at an early age.^1,3

Signs and symptoms of batten disease?

While all the subtypes of Batten disease share a lot of similar signs and symptoms, there are also differences For example, some signs and symptoms are seen in all of the batten disease subtypes, whilst other signs and symptoms are only found in certain subtypes.¹

The most common signs and symptoms of Batten disease across all subtypes includes:¹

• Substantial loss of brain nerve cells and the connection between them (cerebral atrophy)
• Unusual behaviour
• Progressive visual disturbances 
• Seizures
• Trouble controlling voluntary movement (ataxia)
• Unintentional, sudden movements like jerking and twitching
• Developmental delay
• Cognitive decline and memory impairment (dementia)

Diagnosis of batten disease

The diagnosis usually involves checking for the signs and symptoms of Batten disease (see above). 

This is done by a variety of methods including examination of the eyes, EEG and a brain MRI. An EEG (electroencephalogram) is used to measure electrical brain activity. A brain MRI (magnetic resonance imaging) allows the examination of the overall appearance of the brain by producing detailed images of it.

A diagnosis of Batten disease is generally confirmed via both genetic and biochemical tests. Genetic testing can detect the characteristic genetic mutations of Batten disease. The biochemical tests can determine the presence of the dysfunctional proteins those mutated genes give rise to.¹

Treatment of batten disease

 There is currently only one treatment option available for Batten disease, called cerliponase alfa (also known as Brineura).  It was approved by the FDA in 2017. T The treatment only works in one Batten disease subtype; CLN2 Batten disease.¹

CLN2 Batten disease occurs due to mutations of the TPP1 gene. This TPP1 gene normally allows the production of a protein called tripeptidyl peptidase, which can be found in the lysosome. This particular protein is an enzyme. The function of enzymes is to increase the speed of certain biochemical reactions. Mutations in the TPP1 gene give rise to a faulty enzyme which therefore can not fulfil its function, thereby causing CLN2 Batten disease.¹

The treatment for CLN2 Batten disease, cerliponase alfa (Brineura),  is classified as an enzyme replacement therapy (ERT). ERT is designed to artificially provide the body with the enzyme it lacks. This is done by producing the enzyme in large quantities, and then administering it directly into the brain of CLN2 patients. his long-term, direct delivery into the brain requires surgery.¹ Cerliponase alfa (Brineura) has been shown to postpone the progression of CLN2 Batten disease. This means this treatment can prolong the life of the individuals with this disease.¹

Prognosis of batten disease

All subtypes of Batten disease significantly affect life expectancy. However, there is a certain variation among the Batten disease subtypes.¹ 

For example, babies born with    CLN10 Batten disease typically only live for a few hours after birth. Whereas people with CLN3 Batten disease usually live until their 20s and 30s.¹ 

Summary

Batten disease or neuronal ceroid lipofuscinoses (NCLs) are a family of 13 relatively rare illnesses, or subtypes, which occur due to mutations in certain genes. These mutations are inherited from the biological parents and therefore present at conception. Most Batten disease subtypes are autosomal recessive disorders. These gene mutations impair an important part of the human cell and thereby lead to the malfunction of nerve cells in the brain and the spinal cord. This eventually results in the ongoing and widespread death of nerve cells, causing severe symptoms and premature death.