What is Batten Disease (Juvenile Neuronal Ceroid Lipofuscinosis)?
Neuronal ceroid lipofuscinoses (NCLs) are a collection of severe and deadly brain diseases that often affect children. These diseases are each caused by a unique gene mutation, forming 14 different types. While each of these conditions is quite rare on its own, combined, they are the most common neurodegenerative disorder, a condition that causes nerve cells in the brain and spinal cord to die, in children. These disorders disrupt the cellular cleaning process that usually gets rid of a waste product named ceroid lipofuscin. If ceroid lipofuscin builds up in the cells, it suggests a problem with this cleaning process known as lysosomal function.
Batten disease is a term that has historically been used to describe the juvenile form of NCL, but some doctors use “Batten disease” to refer to all forms of NCL. The disease is named after Frederick Eustace Batten, an English doctor who played a large role in the development of pediatric neurology.
Every form of this disease is classified as ceroid lipofuscinosis neuronal (CLN) with a different number assigned based on the subtype (for example, CLN1 and CLN2). Each form, which differs based on the related gene variant, has different degrees of severity, average ages when symptoms begin and different speeds in progression.
Issues with the lysosomes in cells lead to nerve cell death over a period. Patients with NCLs usually grow and develop normally and meet developmental milestones at appropriate times early in life. However, once the disease starts, this progress halts, and the skills they’ve learned start to decline. Depending on when the symptoms first appear, the disease could be present from birth, or it could start during infancy (typically within the first year or around 6 to 18 months of life), late-infancy (usually starting when the child is 2 to 4 years old), childhood (starting from 4 to 10 years of age, typically 4 to 7), late childhood (typically begins at 8 to 16 years) or even early adulthood (beginning from late teens to mid-adulthood).
Doctors use methods such as genetic tests, tests to measure enzyme activity, examination of tissue disease, electron microscope studies, electrical tests, and brain scans to diagnose the condition. Treatment mainly focuses on managing symptoms, though specific therapies for the disease also exist.
What Causes Batten Disease (Juvenile Neuronal Ceroid Lipofuscinosis)?
Batten disease is mainly caused by gene mutations, although there’s some evidence that it could also be related to autoimmune issues.
Gene-related: What we know is that over a dozen genes (see Table 1) have more than 430 different mutations that lead to Batten disease. These genes are responsible for controlling a variety of proteins in our body, including those related to our lysosomes, which are little sacs in our cells that help to break stuff down.
However, for most cases of Batten disease, the exact way the messed-up gene causes problems hasn’t been fully figured out yet. Most of the time, we can see a typical progression of the disease based on the gene that’s mutated, but sometimes the onset, severity, and progression of the disease can vary. For instance, type CLN3 Batten disease is caused by a mutation in the CLN3 gene, which is believed to control a protein found in the lysosome. Without the right version of this protein, certain substances build up in all body cells, mainly affecting the retina and the brain.
Table 1: Genes Known to Cause Batten Disease
Here’s a simple rundown of diseases, chromosomes, affected genes, and proteins:
– Congenital Batten disease: chromosome 11p15.5, CTSD gene, Cathepsin D protein
– Infantile Batten disease: chromosome 1p32, CLN1 gene, Palmitoyl protein
– Late Infantile Batten disease: chromosome 11p15, CLN2 gene, Tripeptidyl peptidase protein
– Juvenile Batten disease: chromosome 16p12, CLN3 gene, Unknown protein
– Adult Batten disease: chromosome Unknown, CLN4 (DNAJC5), Unknown protein
Autoimmune connection: Studies on mice with Batten disease found that they had certain antibodies that were launching an attack on a protein (GAD65) that’s important for brain function. These antibodies were not present in healthy mice. When these antibodies attacked GAD65, it caused an increase in the brain’s levels of glutamate, a chemical that can cause nerve damage and symptoms like seizures when there’s too much of it. This same antibody was also found in people with Batten disease, leading researchers to think that this autoimmune response could contribute to the disease. The link between Batten disease and these anti-GAD antibodies is currently being examined.
There’s some evidence to suggest that the autoimmune response in Batten disease may also target other parts of the neuron, the cells in our brain. Changes to certain cells involved in the immune response have been noted in people with the disease, which might make the brain more prone to inflammation. An antibody that responds to a protein called alpha fetoprotein has been found in some patients with Batten disease. Again, the way this antibody relates to Batten disease is not fully clear.
Risk Factors and Frequency for Batten Disease (Juvenile Neuronal Ceroid Lipofuscinosis)
Batten disease is the most frequently seen neurodegenerative disorder in children. This disease can occur from changes in different genes and is seen in about 1 in 100,000 live births worldwide. The country where this disease is mostly seen is in Scandinavian countries like Finland.
JNCL (CLN3) is the most common form of this disease around the world. Other common forms include adult NCL (also known as CLN4, Kufs, or Parry disease) and late infantile NCL (CLN2, Jansky-Bielschowsky disease). In Finland, Santavuori-Haltia disease or CLN1 is common, occurring in 1 in 20,000 individuals, and 1 in 70 are carriers of it. In the United States, about 20% of Batten disease cases are due to CLN1.
JNCL Batten disease is brought on by a mutation in the CLN3 gene that’s inherited and usually occurs in White populations. The incidence of this mutation varies between 0.02 to 4.8 per 100,000 people worldwide. Thanks to advancements in genetic analyses and databases, estimates have been made for the carrier frequencies of the most common mutation. In Finnish and non-Finnish Europeans, it’s estimated to be 1/558 and 1/380 individuals respectively, while in Latinos and Americans, it’s estimated to be 1/1169 and 1/506 individuals respectively.
Signs and Symptoms of Batten Disease (Juvenile Neuronal Ceroid Lipofuscinosis)
Neuronal Ceroid Lipofuscinoses (NCLs) come in various types, presenting different symptoms and features. Let’s break down the different types:
- CLN1 (classic infantile-onset form): This affects infants. Symptoms include small head size, seizures, muscle weakness, speech deterioration, and specific changes in the back of the eye.
- CLN2 (classic late infantile-onset form): Symptoms usually start when the child is around 4 to 5 years old with language delay, epilepsy, unsteady walking, and overall developmental delay.
- CLN3 (classic juvenile-onset form): This usually starts with vision-related symptoms, followed by mental and behavioral issues. Different eye changes may also be observed in an examination.
- CLN4 (Kufs disease): This disease is either characterized by seizures and worsening muscle coordination (Type A) or symptoms that affect mental health with no vision loss (Type B). This is the only variant of NCL that is inherited directly from one parent.
- CLN5 (Finnish variant late infantile NCL): Symptoms typically starts with unsteady walking between 2 to 6 years old, followed by regression in mental and physical abilities. Vision loss and retinal degeneration occur between 6 and 10 years of age.
- CLN6 (Costa Rican variant LINCL): The disease may start from as early as 18 months to as late as 8 years, with symptoms including seizures and multiple signs of motor dysfunction.
- CLN7 (Turkish variant LINCL): Symptoms include tremors, lower limb weakness, vision impairment and sluggish movements in later stages of the disease.
- CLN8 (Northern Epilepsy Syndrome): This variant comes in two forms characterized by either the onset of seizures and cognitive decline but no vision loss or severe motor decline and vision loss along with severe seizures.
- CLN9: This rare form also presents with motor dysfunction and seizures. However, its genetic causes are yet unclear, meaning that it is not yet confirmed as a distinct type.
- CLN10 (Congenital Neuronal Ceroid Lipofuscinoses): This severe variant presents right after birth with symptoms like difficulty breathing and severe seizures. Affected newborns have small heads and severe brain atrophy.
- CLN11: Symptoms appear between the ages of 13 and 25 and include unsteady walking, seizures, and cognitive impairments alongside eye disorders.
- CLN12: The onset happens in childhood with learning difficulties, signs similar to Parkinson’s disease, and specific eye movement. However, the retina is typically unaffected in this form.
- CLN13: This form usually presents between the ages of 12 and 16, characterized by issues with coordination, muscle strength, and early death.
- CLN14: Characterized by rapid degradation of nerve cells and uncontrollable seizures before the age of 2. Vision loss progresses rapidly as well.
Testing for Batten Disease (Juvenile Neuronal Ceroid Lipofuscinosis)
Batten disease is a serious and complicated disease of the nervous system. There are at least 14 different types of Batten disease, but the most commonly seen ones are NCL1, NCL2, and NCL3. There are different ways to diagnose these forms and understand their symptoms.
Some signs and symptoms of Batten disease are: troubles with sight, either failing to reach normal development stages or going backwards in development, behavioral issues, the brain shrinking over time, seizures, decline in thinking capability, and memory loss. However, these symptoms can show up in a different order or frequency depending on the type and variation of Batten disease.
The genes causing Batten disease can be different in each case. This is why the same gene can have different outcomes among different individuals. And to make it more complex, scientists found that different genes could lead to the same outcome.
There are several techniques that your doctor can use to diagnose Batten disease:
– Genetic testing: This identifies the changes in your DNA that may be causing Batten disease.
– Biochemical testing: This method is used for checking enzyme activity. For instance, they look at PPT levels for CLN1 and TTP1 levels for CLN2.
– Neuroimaging: Scans like MRI, MR Spectroscopy, and PET scans give images of the brain to check for abnormalities.
– Other diagnostic measures: These include microscope checks of muscle, skin, and eye tissues. Blood film exams may show some abnormalities as well. Special staining approaches reveal lipid pigments.
– Eye assessments: Examination of the back of your eye may reveal signs of disease. OCT imaging may be used to evaluate in detail the back of the eye.
– Electrophysiology: This consists of an EEG which records the electrical activity of your brain, visually evoked potentials (VEP), and electroretinogram (ERG) which tests the response of your eyes to light.
Overall, diagnosing Batten disease involves a combination of different tests and methods. This is necessary due to the complex nature of the disease.
Treatment Options for Batten Disease (Juvenile Neuronal Ceroid Lipofuscinosis)
Neuronal Ceroid Lipofuscinoses (NCL), also known as Batten disease, is complex and currently there’s no cure for some types of it, like CLN4, CLN9, CLN12, CLN13, and CLN14. There are treatments being developed which could potentially slow down or even pause the disease’s progress. However, even though some treatments might be able to reverse some of the effects of the disease, completely reversing it is likely not possible. That’s why it’s important to diagnose and start treatment as early as possible.
One of the biggest challenges in treating Batten disease is making sure the treatment can reach the brain. Treatments usually focus on fixing problems in certain proteins found in cells. This can be done through things like replacing missing enzymes, gene therapy, stem cell therapy, or medication.
There are several ways that Batten disease is treated today, including handling symptoms, targeted treatments and supportive care, and all are aimed at improving patients’ lives and slowing the disease’s progress.
Treating the symptoms usually involves using medication to help manage things like seizures, muscle stiffness, and improving nerve health. This includes anticonvulsant medications like carbamazepine, oxcarbazepine, and others; antiepileptic medication like isradipine; and antispasmodic medication like baclofen.
Targeted treatments are designed to directly impact the root causes of Batten disease. For example, one of the main types of Batten disease, CLN2, can be treated using an enzyme replacement therapy with a product called cerliponase alfa. The treatment is given through the fluid around the brain. It’s shown to slow the decline in patients’ movement and language abilities, although it does have some serious side effects like device failure and infections. It also does not seem to improve or slow vision loss.
Supporting patients with Batten disease involves using a range of strategies to ensure an overall good quality of life. This includes maintaining a balanced diet and calorie intake; managing sleep using melatonin, a hormone that helps regulate sleep cycles; maintaining physical strength and managing pain with physical rehabilitation; and offering mental and emotional support, like cognitive behavioral therapy.
Although the research is ongoing for gene therapy, a study showed positive results in a mouse model of a type of Batten disease called CLN7. However, it is still unclear whether this will have the same benefits when used in humans.
What else can Batten Disease (Juvenile Neuronal Ceroid Lipofuscinosis) be?
When trying to diagnose Batten disease, doctors consider a number of other conditions that have similar symptoms. These include:
- Inherited metabolic disorders: Conditions like Niemann Pick type C, which can lead to eye movement defects, developmental regression, and spleen enlargement in babies. Mitochondrial disorders may also be considered, as they can cause retinitis pigmentosa—an eye disease leading to the loss of vision.
- Retinitis pigmentosa: This is an eye disease characterized by changes in the retinal pigment, narrowed small arteries in the eye, and a pale optic disc—the part where the optic nerve enters the eye. These changes often occur in the mid-peripheral area of the back of the eye, mostly affecting the rods, which are cells that allow us to see in low light. These eye changes are often very similar in both eyes.
- Stargardt disease: This involves a young person’s fovea—the area of the eye responsible for sharp vision—taking on a bronze appearance. This disease is also characterized by yellow flecks surrounding the fovea. This condition is usually caused by mutations in the ABCA4 gene and is typically inherited.
- Cone rod dystrophies: These are inherited eye disorders that lead to pigment deposits in the eye. They belong to the group of pigmentary retinopathies and are mostly found in the macular region—the part of the eye responsible for straight-ahead vision.
Recognising these conditions helps doctors perform appropriate tests and arrive at the correct diagnosis.
What to expect with Batten Disease (Juvenile Neuronal Ceroid Lipofuscinosis)
The only treatment currently approved by the U.S. Food and Drug Administration (FDA) for Batten disease is a drug called cerliponase alfa. This is a type of enzyme replacement therapy, which is intended to slow down the loss of walking ability in children who have a later-onset form of the disease (known as late-infantile NCL, CLN2). Although there’s no cure right now for Batten disease, other interventions like antiseizure medications can help manage the disease’s symptoms. Physical and occupational therapies can also support children in carrying out day-to-day activities. These treatments can’t cure the disease, but they can help children maintain their abilities for as long as possible.
Batten disease typically results in vision loss, seizures, developmental delays, behavioral problems, and mental and physical learning difficulties. Some children with early-onset Batten disease also have a condition called microcephaly, where their head is smaller than expected. The vision loss is often the first symptom to show up and can worsen quickly. In older children, parents might notice clumsiness or stumbling due to a loss of motor control. In time, kids with Batten disease might become blind, lose their ability to walk, talk or swallow, and could become dependent on a wheelchair or bed. Research is still ongoing to find other potential treatments for Batten disease, such as gene therapy, other types of enzyme replacement therapies, small molecule carriers, stem cell therapy, and RNA and lysosomal modifiers.
The age when symptoms of Batten disease first appear tends to strongly influence the severity of the disease and the person’s prognosis. The earlier the disease onset, the more severe it usually is, and there is a higher risk of disability and premature death. Batten disease often results in a decreased life span in spite of treatment options, with many people living only until their teens or early 30s. Most patients become fully blind by the time they are 10 to 14 years old. However, adult variants of Batten disease (such as Kufs disease) often have milder symptoms and people diagnosed with these forms of the disease may have a normal life expectancy.
Possible Complications When Diagnosed with Batten Disease (Juvenile Neuronal Ceroid Lipofuscinosis)
Living with Batten disease can be taxing for both the patients and their caregivers. It requires adjustments in treatment, diet, and lifestyle, in addition to the support from loved ones and relevant groups to help ensure the best possible quality of life.
The severity and speed of vision loss differ from patient to patient. For instance, those who have the disease since childhood may experience partial or total vision loss. On the other hand, adults with Batten disease usually retain their sight. Unfortunately, no effective treatment is currently available to prevent vision loss. Nevertheless, early detection of this condition can pave the way for interventions that help children maximize their development.
Furthermore, Batten disease may cause changes in balance, coordination, and even walking or standing posture in children. It can also affect fine motor skills needed for daily activities like writing, getting dressed, taking a bath, and eating.
Emotional changes, such as anxiety and depression, may also surface and worsen as the disease progresses. This can be linked to the patient’s growing concern and frustration over their condition. Moreover, Batten disease may lead to a gradual loss in speech ability. As vision impairment, seizures, and issues with learning and communication make it harder for children, they might become more dependent on their hearing sense. Therefore, it’s crucial to adapt teaching resources and methods accordingly.
Main Issues:
- Vision loss
- Changes in balance and coordination
- Impairment of fine motor skills
- Emotional changes
- Deterioration in speech ability
- Increased reliance on hearing
Preventing Batten Disease (Juvenile Neuronal Ceroid Lipofuscinosis)
Batten disease is a genetic disorder, which means that it’s passed down through families. Unfortunately, there’s currently no way to prevent it from happening. But early detection and genetic counseling can help. Genetic counseling is a service that can help you understand what the disease means for your family.
Education is a key part of managing this disease. It’s important for patients and families to understand exactly what Batten disease is, how it’s likely to progress, and what choices they have for care. Detailed education should include how often the patient needs to be monitored, what treatments might be available, and where to find additional resources.
Education can also help families to handle the emotional and psychological challenges associated with Batten disease. Knowledge can give families the power to manage the challenges of the illness and improve life quality.
Support groups and organizations dedicated to Batten disease can be very helpful. The Beyond Batten Disease Foundation was created to eliminate juvenile Batten disease by raising awareness and money to boost research for a treatment or cure. The Batten Disease Support and Research Association (BDSRA) is an international organization which supports and conducts research for families of children and young adults with the disorder. In the UK, there are also organizations like the Batten Disease Family Association (BDFA) and Metabolic Support UK, which used to be called Climb. They provide information to families, healthcare professionals, and others.
